Technical Field
[00015 ]
The present invention relates to a deprotection method of
a tetrazole compound useful as an intermediate for angiotensin
II receptor blockers.
Background Art
10 [0002]
Losartan potassium, valsartan, olmesartan medoxomil,
candesartan cilexetil, telmisartan, irbesartan and the like are
useful as angiotensin II receptor blockers.
As a production method of these compounds, for example,
15 the production method described in J. Org. Chem., 1994, vol. 59,
pages 6391 - 6394 (non-patent document 1) is known as a
synthesis method of losartan, the production method described
in Org. Process Res. Dev., 2007, vol. 11, pages 892 - 898 (nonpatent
document 2) is known as a synthesis method of valsartan,
20 and the production method described in J. Med. Chem., 1993, vol.
36, pages 3371 - 3380 (non-patent document 3) is known as a
synthesis method of irbesartan.
As a production method of olmesartan, the production
methods described in JP-B-7-121918 (patent document 1), JP-A-
25 2010-505926 (patent document 2), WO 2004/085428 (patent
document 3) and the like are known.
Also, as a conventional method of biphenylation reaction,
for example, the method described in Chem. Lett., 2008, vol. 37,
NO. 9, pages 994 - 995 (non-patent document 4), and the methods
30 described in Tetrahedron, 2008, vol. 64, pages 6051 - 6059
(non-patent document 5), Angewandte Chemie International
Edition, 2009, vol. 48, pages 9792 - 9827 (non-patent document
6), and WO 2011/061996 (patent document 4) are known.
[Document List]
35 [patent document]
2
[0003]
patent document 1: JP-B-7-121918
patent document 2: JP-A-2010-505926
patent document 3: WO 2004/085428
patent document 4: WO 2011/061995 6
[non-patent document]
[0004]
non-patent document 1: J. Org. Chem., 1994, vol. 59, pages 6391
- 6394
10 non-patent document 2: Org. Process Res. Dev., 2007, vol. 11,
pages 892 - 898
non-patent document 3: J. Med. Chem., 1993, vol. 36, pages 3371
- 3380
non-patent document 4: Chem. Lett., 2008, vol. 37, No. 9, pages
15 994 - 995
non-patent document 5: Tetrahedron, 2008, vol. 64, pages 6051 -
6059
non-patent document 6: Angewandte Chemie International Edition,
2009, vol. 48, pages 9792 - 9827
20 SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0005]
Since the aforementioned production methods of the Prior
Art require expensive metal compounds and include plural
25 reaction steps, the development of a more economical production
method has been desired.
The present invention relates to a method of deprotecting
a tetrazole compound, useful as an intermediate for angiotensin
II receptor blockers, under conditions that are economical and
30 suitable for industrial production, and aims to provide a novel
production method of angiotensin II receptor blockers.
Means of Solving the Problems
[0006]
The present inventors have conducted intensive studies in
35 an attempt to solve the aforementioned problems and found that
3
a tetrazole compound, useful as an intermediate for angiotensin
II receptor blockers, can be deprotected and an angiotensin II
receptor blocker can be produced, under conditions that are
economical and suitable for industrial production, by using a
metal catalyst and an alkaline earth metal salt, or by reactin5 g
with a particular amount of Brønsted acid, which resulted in
the completion of the present invention.
Accordingly, the present invention relates to;
[1] a method of producing a compound represented by the formula
10 [3]:
[0011]
[0012]
wherein R1 is an alkyl group, an aralkyl group or an aryl group,
15 each of which is optionally substituted,
or a salt thereof (to be also referred to as compound [3]), or
the formula [4]:
[0013]
20 [0014]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [4]),
comprising (i) reducing a compound represented by the formula
[1]:
25 [0007]
4
[0008]
wherein R1 is as defined above, each R2 is an alkyl group, an
alkoxy group or a nitro group, or two alkoxy groups are
optionally bonded to form an alkylenedioxy group, and p is an
integer of 0 to 55 ,
or a salt thereof (to be also referred to as compound [1]), or
a compound represented by the formula [2]:
[0009]
10 [0010]
wherein each symbol is as defined above,
or a salt thereof (to be also referred to as compound [2]), in
the presence of a metal catalyst and an alkaline earth metal
salt, or (ii) reacting compound [1] or compound [2] with 0.1
15 equivalents - 50 equivalents of Brønsted acid relative to
compound [1] or compound [2]
(hereinafter to be also referred to as “production method 1”);
[2] the method of the above-mentioned [1], wherein the metal
catalyst is supported by an alkaline earth metal salt;
20 [3] a method of producing a compound represented by the formula
[23]:
[0031]
5
[0032]
or a salt thereof (that is, olmesartan medoxomil or a salt
thereof, hereinafter to be also referred to as compound [23]),
comprisin5 g
1) reacting, in the presence of a base, a compound represented
by the formula [11]:
[0015]
10 [0016]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
15 or a salt thereof (to be also referred to as compound [11]),
with a compound represented by the formula [15]:
[0017]
6
[0018]
wherein R9 is a carboxy-protecting group,
or a salt thereof (to be also referred to as compound [15]) to
give a compound represented by the formula [16]:
[00195 ]
[0020]
wherein the symbols are as defined above,
10 or a salt thereof (to be also referred to as compound [16]);
2) (i) reducing compound [16] in the presence of a metal
catalyst and an alkaline earth metal salt, or (ii) reacting
compound [16] with 0.1 equivalents - 50 equivalents of Brønsted
acid relative to compound [16], to give a compound represented
15 by the formula [17]:
[0021]
[0022]
20 wherein the symbol is as defined above,
7
or a salt thereof (to be also referred to as compound [17]);
3) reacting compound [17] with a compound represented by the
formula [18]: Tr-X wherein Tr is a trityl group and X is a
halogen atom (to be also referred to as compound [18]) in the
presence of a base to give a compound represented by th5 e
formula [19]:
[0023]
10 [0024]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [19]);
4) removing R9 of compound [19] to give a compound represented
by the formula [20]:
15 [0025]
[0026]
wherein the symbol is as defined above,
8
or a salt thereof (to be also referred to as compound [20]);
5) reacting compound [20] with a compound represented by the
formula [21]:
[0027]
5
[0028]
(to be also referred to as compound [21]) to give a compound
represented by the formula [22]:
[0029]
10
[0030]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [22]);
15 and
6) removing a trityl group of compound [22]
(hereinafter to be also referred to as “production method 3”);
[4] a method of producing a compound represented by the formula
[28]:
20 [0043]
9
[0044]
or a salt thereof (that is, losartan or a salt thereof,
hereinafter to be also referred to as compound [28]),
comprisin5 g
1) reacting a compound represented by the formula [11]:
[0033]
[0034]
10 wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
or a salt thereof (to be also referred to as compound [11])
15 with a compound represented by the formula [24]:
[0035]
[0036]
10
or a salt thereof (to be also referred to as compound [24]) to
give a compound represented by the formula [25]:
[0037]
[00385 ]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [25]);
and
2-A) reducing compound [25] with a reducing agent to give a
10 compound represented by the formula [26]:
[0039]
[0040]
wherein the symbol is as defined above,
15 or a salt thereof (to be also referred to as compound [26]),
and (i) further reducing compound [26] in the presence of a
metal catalyst and an alkaline earth metal salt, or (ii)
11
reacting compound [26] with 0.1 equivalents - 50 equivalents of
Brønsted acid relative to compound [26],
or
2-B) (i) reducing compound [25] in the presence of a metal
catalyst and an alkaline earth metal salt, or (ii) reactin5 g
compound [25] with 0.1 equivalents - 50 equivalents of Brønsted
acid relative to compound [25], to give a compound represented
by the formula [27]:
[0041]
10
[0042]
or a salt thereof (to be also referred to as compound [27]),
and further reducing compound [27] with a reducing agent
15 (hereinafter to be also referred to as “production method 4”);
[5] a method of producing a compound represented by the formula
[35]:
[0057]
20 [0058]
or a salt thereof (that is, valsartan or a salt thereof,
12
hereinafter to be also referred to as compound [35]),
comprising
1) reacting a compound represented by the formula [11]:
[0045]
5
[0046]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
10 halogen atom,
or a salt thereof (to be also referred to as compound [11])
with a compound represented by the formula [29]:
[0047]
15
[0048]
wherein R10 is a carboxy-protecting group,
or a salt thereof (to be also referred to as compound [29]) to
give a compound represented by the formula [30]:
20 [0049]
13
[0050]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [30]);
2-A) (i) reducing compound [30] in the presence of a meta5 l
catalyst and an alkaline earth metal salt, or (ii) reacting
compound [30] with 0.1 equivalents - 50 equivalents of Brønsted
acid relative to compound [30], to give a compound represented
by the formula [31]:
10 [0051]
[0052]
wherein the symbol is as defined above,
15 or a salt thereof (to be also referred to as compound [31]);
3-A) reacting compound [31] with a compound represented by the
formula [32]: CH3CH2CH2CH2CO-X3 wherein X3 is a leaving group (to
be also referred to as compound [32]) to give a compound
represented by the formula [33]:
14
[0053]
[0054]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [33])5 ;
4-A) removing R10 of compound [33]; or
2-B) reacting compound [30] with compound [32] to give a
compound represented by the formula [34]:
[0055]
10
[0056]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [34]);
and
15 3-B) (i) reducing compound [34] in the presence of a metal
catalyst and an alkaline earth metal salt to remove R10
(preferably, reducing in the presence of a metal catalyst and
an alkaline earth metal salt while removing R10), or (ii)
reacting compound [34] with 0.1 equivalents - 50 equivalents of
15
Brønsted acid relative to compound [34] to remove R10
(preferably, reacting with 0.1 equivalents - 50 equivalents of
Brønsted acid relative to compound [34] while removing R10)
(hereinafter to be also referred to as “production method 5”);
[6] a method of producing a compound represented by the formul5 a
[38]:
[0065]
[0066]
10 or a salt thereof (that is, irbesartan or a salt thereof,
hereinafter to be also referred to as compound [38]),
comprising
1) reacting a compound represented by the formula [11]:
[0059]
15
[0060]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
20 halogen atom,
16
or a salt thereof (to be also referred to as compound [11])
with a compound represented by the formula [36]:
[0061]
[00625 ]
or a salt thereof (to be also referred to as compound [36]) to
give a compound represented by the formula [37]:
[0063]
10 [0064]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [37]),
and
2) (i) further reducing compound [37] in the presence of a
15 metal catalyst and an alkaline earth metal salt, or (ii)
reacting compound [37] with 0.1 equivalents - 50 equivalents of
Brønsted acid relative to compound [37]
(hereinafter to be also referred to as “production method 6”);
[7] a method of producing a compound represented by the formula
20 [47]:
[0089]
17
[0090]
or a salt thereof (that is, candesartan cilexetil or a salt
thereof, hereinafter to be also referred to as compound [47]),
comprisin5 g
1-A-i) reacting a compound represented by the formula [11]:
[0067]
[0068]
10 wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
or a salt thereof (to be also referred to as compound [11]),
15 with a compound represented by the formula [39]:
[0069]
[0070]
18
wherein R11 is a carboxy-protecting group, and R12 is an aminoprotecting
group,
or a salt thereof (to be also referred to as compound [39]) to
give a compound represented by the formula [40]:
[00715 ]
[0072]
wherein the symbols are as defined above,
10 or a salt thereof (to be also referred to as compound [40]);
1-A-ii) removing R12 of compound [40] to give a compound
represented by the formula [41]:
[0073]
15
[0074]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [41]);
20 1-A-iii) reducing compound [41] to give a compound represented
by the formula [42]:
[0075]
19
[0076]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [42])5 ;
1-A-iv) reacting compound [42] with tetraethoxymethane; or
1-B) reacting a compound represented by the formula [11]:
[0077]
10 [0078]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
15 or a salt thereof, with a compound represented by the formula
[49]:
[0079]
[0080]
20 wherein the symbol is as defined above, to give a compound
20
represented by the formula [43]:
[0081]
[0082]
wherein the symbols are as defined above5 ,
or a salt thereof (to be also referred to as compound [43]);
2) removing R11 of compound [43] to give a compound represented
by the formula [44]:
[0083]
10
[0084]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [44]);
3) reacting compound [44] with a compound represented by the
15 formula [45]:
[0085]
21
[0086]
wherein X4 is a leaving group or a hydroxyl group,
or a salt thereof (to be also referred to as compound [45]) to
give a compound represented by the formula [46]:
[00875 ]
[0088]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [46]);
10 and
4) (i) reducing compound [46] in the presence of a metal
catalyst and an alkaline earth metal salt, or (ii) reacting
compound [46] with 0.1 equivalents - 50 equivalents of Brønsted
acid relative to compound [46]
15 (hereinafter to be also referred to as “production method 7”);
[8] a compound represented by the formula [48]:
[0091]
[0092]
20 wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
22
alkylenedioxy group, p is an integer of 0 to 5, and R13 is
[0093]
,
[0094]
or a salt thereof5 ;
[9] a method of producing a compound represented by the formula
[3]:
[0099]
10 [0100]
wherein R1 is an alkyl group, an aralkyl group or an aryl group,
each of which is optionally substituted,
or a salt thereof (to be also referred to as compound [3]), or
a compound represented by the formula [4]:
15 [0101]
[0102]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [4]),
20 comprising reducing a compound represented by the formula [1]:
[0095]
[0096]
or
23
wherein R1 is as defined above, each R2 is an alkyl group, an
alkoxy group or a nitro group, or two alkoxy groups are
optionally bonded to form an alkylenedioxy group, and p is an
integer of 0 to 5,
or a salt thereof (to be also referred to as compound [1]), o5 r
a compound represented by the formula [2]:
[0097]
[0098]
10 wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [2]), in
the presence of a metal catalyst and an alkaline earth metal
salt
(hereinafter to be also referred to as “production method 1A”);
15 [10] the method of the above-mentioned [9], wherein the metal
catalyst is supported by the alkaline earth metal salt;
[11] a method of producing a compound represented by the
formula [23]:
[0119]
20
[0120]
24
or a salt thereof (that is, olmesartan medoxomil or a salt
thereof, hereinafter to be also referred to as compound [23]),
comprising
1) reacting a compound represented by the formula [11]:
[01035 ]
[0104]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
10 alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
or a salt thereof (to be also referred to as compound [11]), in
the presence of a base, with a compound represented by the
formula [15]:
15 [0105]
[0106]
wherein R9 is a carboxy-protecting group,
or a salt thereof (to be also referred to as compound [15]) to
20 give a compound represented by the formula [16]:
[0107]
25
[0108]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [16]);
2) reducing compound [16] in the presence of a metal catalys5 t
and an alkaline earth metal salt to give a compound represented
by the formula [17]:
[0109]
10 [0110]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [17]);
3) reacting compound [17] with a compound represented by the
formula [18]: Tr-X wherein Tr is a trityl group, and X is a
15 halogen atom (to be also referred to as compound [18]) in the
presence of a base to give a compound represented by the
formula [19]:
[0111]
26
[0112]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [19]);
4) removing R9 of compound [19] to give a compound represente5 d
by the formula [20]:
[0113]
[0114]
10 wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [20]);
5) reacting compound [20] with a compound represented by the
formula [21]:
[0115]
15
[0116]
(to be also referred to as compound [21]) to give a compound
represented by the formula [22]:
27
[0117]
[0118]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [22])5 ;
and
6) removing a trityl group of compound [22]
(hereinafter to be also referred to as “production method 3A”);
[12] a method of producing a compound represented by the
10 formula [28]:
[0131]
[0132]
or a salt thereof (that is, losartan or a salt thereof,
15 hereinafter to be also referred to as compound [28]),
comprising
1) reacting a compound represented by the formula [11]:
[0121]
28
[0122]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is 5 a
halogen atom,
or a salt thereof (to be also referred to as compound [11])
with a compound represented by the formula [24]:
[0123]
10
[0124]
or a salt thereof (to be also referred to as compound [24]) to
give a compound represented by the formula [25]:
[0125]
15
[0126]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [25]);
29
2-A) reducing compound [25] with a reducing agent to give a
compound represented by the formula [26]:
[0127]
[01285 ]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [26]),
further reducing compound [26] in the presence of a metal
catalyst and an alkaline earth metal salt, or
10 2-B) reducing compound [25] in the presence of a metal catalyst
and an alkaline earth metal salt to give a compound represented
by the formula [27]:
[0129]
15 [0130]
or a salt thereof (to be also referred to as compound [27]),
and further reducing compound [27] with a reducing agent
(hereinafter to be also referred to as “production method 4A”);
[13] a method of producing a compound represented by the
20 formula [35]:
30
[0145]
[0146]
or a salt thereof (that is, valsartan or a salt thereof,
hereinafter to be also referred to as compound [35])5 ,
comprising
1) reacting a compound represented by the formula [11]:
[0133]
10 [0134]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
15 or a salt thereof (to be also referred to as compound [11])
with a compound represented by the formula [29]:
[0135]
[0136]
20 wherein R10 is a carboxy-protecting group,
or a salt thereof (to be also referred to as compound [29]) to
31
give a compound represented by the formula [30]:
[0137]
[0138]
wherein the symbols are as defined above5 ,
or a salt thereof (to be also referred to as compound [30]);
2-A) reducing compound [30] in the presence of a metal catalyst
and an alkaline earth metal salt to give a compound represented
by the formula [31]:
10 [0139]
[0140]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [31]);
15 3-A) reacting compound [31] with a compound represented by the
formula [32]: CH3CH2CH2CH2CO-X3 wherein X3 is a leaving group (to
be also referred to as compound [32]) to give a compound
represented by the formula [33]:
[0141]
32
[0142]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [33]);
4-A) removing R10 of compound [33]; o5 r
2-B) reacting compound [30] with compound [32] to give a
compound represented by the formula [34]:
[0143]
10 [0144]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [34]);
3-B) reducing compound [34] in the presence of a metal catalyst
and an alkaline earth metal salt while removing R10
15 (hereinafter to be also referred to as “production method 5A”);
[14] a method of producing a compound represented by the
formula [38]:
[0153]
33
[0154]
or a salt thereof (that is, irbesartan or a salt thereof,
hereinafter to be also referred to as compound [38]),
comprisin5 g
1) reacting a compound represented by the formula [11]:
[0147]
[0148]
10 wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
or a salt thereof (to be also referred to as compound [11])
15 with a compound represented by the formula [36]:
[0149]
[0150]
or a salt thereof (to be also referred to as compound [36]) to
34
give a compound represented by the formula [37]:
[0151]
[0152]
wherein the symbol is as defined above5 ,
or a salt thereof (to be also referred to as compound [37]),
and further reducing compound [37] in the presence of a metal
catalyst and an alkaline earth metal salt
(hereinafter to be also referred to as “production method 6A”);
10 [15] a method of producing a compound represented by the
formula [47]:
[0173]
[0174]
15 or a salt thereof (that is, candesartan cilexetil or a salt
thereof, hereinafter to be also referred to as compound [47]),
comprising
1) reacting a compound represented by the formula [11]:
[0155]
35
[0156]
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is 5 a
halogen atom,
or a salt thereof (to be also referred to as compound [11])
with a compound represented by the formula [39]:
[0157]
10
[0158]
wherein R11 is a carboxy-protecting group, and R12 is an aminoprotecting
group,
or a salt thereof (to be also referred to as compound [39]) to
15 give a compound represented by the formula [40]:
[0159]
[0160]
wherein the symbols are as defined above,
20 or a salt thereof (to be also referred to as compound [40]);
36
2) removing R12 of compound [40] to give a compound represented
by the formula [41]:
[0161]
5
[0162]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [41]);
3) reducing compound [41] to give a compound represented by the
10 formula [42]:
[0163]
[0164]
wherein the symbols are as defined above,
15 or a salt thereof (to be also referred to as compound [42]);
4) reacting compound [42] with tetraethoxymethane to give a
compound represented by the formula [43]:
[0165]
37
[0166]
wherein the symbols are as defined above,
or a salt thereof (to be also referred to as compound [43]);
5) removing R11 of compound [43] to give a compound represente5 d
by the formula [44]:
[0167]
[0168]
10 wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [44]);
6) reacting compound [44] with a compound represented by the
formula [45]:
[0169]
15
[0170]
wherein X4 is a leaving group or a hydroxyl group,
or a salt thereof (to be also referred to as compound [45]) to
give a compound represented by the formula [46]:
20 [0171]
38
[0172]
wherein the symbol is as defined above,
or a salt thereof (to be also referred to as compound [46]);
an5 d
7) reducing compound [46] in the presence of a metal catalyst
and an alkaline earth metal salt
(hereinafter to be also referred to as “production method 7A”).
Effect of the Invention 10
[0175]
According to the present invention, a tetrazole compound,
useful as an intermediate for angiotensin II receptor blockers,
can be deprotected and an angiotensin II receptor blocker can
15 be produced, under conditions that are economical and suitable
for industrial production, by (i) reducing in the presence of a
metal catalyst and an alkaline earth metal salt, or (ii)
reacting with 0.1 equivalents - 50 equivalents of Brønsted acid.
Description of Embodiments 20
[0176]
The definitions of the symbols and terms used in the
present invention are described in detail in the following.
[0177]
25 In the present specification, the “tetrazolyl-protecting
group” is not particularly limited as long as it can stably
protect a tetrazolyl group during reactions. Specifically,
those described in Protective Groups in Organic Synthesis 3rd
39
Ed., T.W. Greene, P.G.M. Wuts, John Wiley and Sons, Inc., 1999
can be mentioned.
Examples of the tetrazolyl-protecting group include
C7-19 aralkyl group (e.g., benzyl, diphenylmethyl, trityl etc.);
substituted C7-19 aralkyl groups such as substituted benzyl5 ,
substituted diphenylmethyl and the like (preferably, C7-19
aralkyl substituted by 1 to 3 substituents selected from the
group consisting of C1-6 alkyl, nitro, C1-6 alkylenedioxy and C1-6
alkoxy (when two or more substituents are present, they may be
10 the same or different and the substituents may be bonded to
each other to form a ring), for example, p-methylbenzyl, pnitrobenzyl,
2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,4-
(methylenedioxy)benzyl, p-methoxybenzyl, o-methoxybenzyl,
3,4,5-trimethoxybenzyl etc.);
15 substituted C1-6 alkyl group (preferably, C1-6 alkyl substituted
by 1 to 3 substituents selected from the group consisting of
hydroxy, alkoxy (e.g., C1-6 alkoxy), aryloxy (e.g., C6-10
aryloxy) and dialkylamino (e.g., di(C1-6 alkyl)amino), for
example, hydroxymethyl, alkoxymethyl, aryloxymethyl,
20 dialkylaminomethyl etc.);
trialkylsilyl group (preferably, tri(C1-6 alkyl)silyl);
C1-6 alkyl group (e.g., t-butyl etc.)
and the like.
[0178]
25 In the present specification, the “carboxy-protecting
group” is not particularly limited as long as it can stably
protect a carboxy group during reaction, and specific examples
thereof include those described in Protective Groups in Organic
Synthesis 3rd Ed., T.W. Greene, P.G.M. Wuts, John Wiley and
30 Sons, Inc., 1999.
Examples of the carboxy-protecting group include
alkyl group (preferably, C1-6 alkyl, for example, methyl, ethyl,
propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl),
C3-8 cycloalkyl group (e.g., cyclohexyl),
35 C7-19 aralkyl group (e.g., benzyl, diphenylmethyl, trityl),
40
C2-6 alkenyl group (e.g., allyl)
and the like.
Examples of the protecting group not deprotected by
reduction (e.g., formic acid reduction, catalytic reduction)
include an alkyl group, a C3-8 cycloalkyl group and the like5 .
Examples of the protecting group deprotected by reduction (e.g.,
formic acid reduction, catalytic reduction) include benzyl.
[0179]
In the present specification, the “amino-protecting group”
10 is not particularly limited as long as it can stably protect an
amino group during reaction, and specific examples thereof
include those described in Protective Groups in Organic
Synthesis 3rd Ed., T.W. Greene, P.G.M. Wuts, John Wiley and
Sons, Inc., 1999.
15 Examples of the amino-protecting group include acyl group
(preferably, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C6-10
aryl-carbonyl, for example, acetyl, propionyl, butyryl,
isobutyryl, pivaloyl, cyclohexylcarbonyl, benzoyl etc.), lower
alkoxycarbonyl group and the like.
20 In the present specification, examples of the “lower
alkoxycarbonyl group” include linear or branched chain C1-12
alkoxy-carbonyl group, with preference given to methoxycarbonyl,
ethoxycarbonyl, butoxycarbonyl (e.g., tert-butoxycarbonyl) and
the like.
25 [0180]
Examples of the “leaving group” for X1 include
halogen atom,
C6-10 arylsulfonyloxy group optionally substituted by 1 to 3 C1-6
alkyl group (e.g., toluenesulfonyloxy etc.),
30 C1-6 alkylsulfonyloxy group optionally substituted by 1 to 3
halogen atoms (e.g., methanesulfonyloxy,
trifluoromethanesulfonyloxy etc.)
and the like.
Examples of the “leaving group” for X3 and X4 include
35 halogen atom,
41
C6-10 arylsulfonyloxy group optionally substituted by 1 to 3 C1-6
alkyl groups (e.g., toluenesulfonyloxy etc.),
C1-6 alkylsulfonyloxy group optionally substituted by 1 to 3
halogen atoms (e.g., methanesulfonyloxy etc.),
alkanoyloxy group (preferably, C1-6 alkyl-carbonyloxy)5 ,
aroyloxy group (preferably, C6-10 aryl-carbonyloxy),
dialkoxyphosphoryloxy group (preferably, di(C1-6
alkoxy)phosphoryloxy),
diaryloxyphosphoryloxy group (preferably, di(C6-10
10 aryloxy)phosphoryloxy)
and the like.
[0181]
Examples of the “halogen atom” in the present
specification include fluorine, chlorine, bromine and iodine.
15 Examples of the “alkyl group” in the present
specification include, unless otherwise specified, linear or
branched chain alkyl groups having 1 – 12 carbon atoms, such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,
20 nonyl, decyl and the like.
Examples of the “aralkyl group” in the present
specification include, unless otherwise specified, aralkyl
groups having 7 - 14 carbon atoms, such as benzyl, phenethyl,
1-methyl-2-phenylethyl, diphenylmethyl, 1-naphthylmethyl, 2-
25 naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-
phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-
biphenylylmethyl, 4-biphenylylmethyl and the like.
Examples of the “alkoxy group” in the present
specification include, unless otherwise specified, linear or
30 branched chain alkoxy groups having 1 - 12 carbon atoms, such
as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy,
hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like.
Examples of the “alkylenedioxy group” in the present
35 specification include, unless otherwise specified,
42
alkylenedioxy groups having 1 - 6 carbon atoms, such as
methylenedioxy, ethylenedioxy, trimethylenedioxy,
tetramethylenedioxy, pentamethylenedioxy, hexamethylenedioxy
and the like.
[01825 ]
Examples of the “aryl group” in the present specification
include, unless otherwise specified, aryl groups having 6 – 14
carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 2-
biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like.
10 The aryl group may be fused with “C3-8 cycloalkane” or “C3-8
cycloalkene” described below and, for example,
tetrahydronaphthyl and the like can be mentioned.
Examples of the “heterocyclic group” in the present
specification include, unless otherwise specified, a 3- to 14-
15 membered (monocyclic, bicyclic or tricyclic)heterocyclic group
containing, as a ring-constituting atom besides carbon atom,
one or two kinds of 1 to 4 heteroatoms selected from a nitrogen
atom, a sulfur atom and an oxygen atom, which is optionally
fused with carbocycle. Preferred are (i) 5- to 14-membered
20 (preferably, 5- to 10-membered) aromatic heterocyclic group,
(ii) 3- to 14-membered non-aromatic heterocyclic group and the
like. Of these, a 5- or 6-membered aromatic heterocyclic group
or a 5- to 10-membered non-aromatic heterocyclic group is
preferable.
25 Specific examples thereof include aromatic heterocyclic
groups such as thienyl (e.g., 2-thienyl, 3-thienyl), furyl
(e.g., 2-furyl, 3-furyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,
4-pyridyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-
thiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
30 pyrazinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl),
pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl
(e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl
(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g.,
1-triazolyl, 2-triazolyl), tetrazolyl, pyridazinyl (e.g., 3-
35 pyridazinyl, 4-pyridazinyl), isothiazolyl (e.g., 3-isothiazolyl,
43
4-isothiazolyl, 5-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl,
4-isoxazolyl, 5-isoxazolyl), indolyl (e.g., 1-indolyl, 2-
indolyl, 3-indolyl), 2-benzothiazolyl, 2-benzoxazolyl,
benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl),
benzo[b]thienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl)5 ,
benzo[b]furyl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl),
quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,
8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl), pyrazolopyridinyl (e.g.,
10 pyrazolo[1,5-a]pyridin-3-yl) and the like;
non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-
pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl
(e.g., 2-oxazolidinyl), imidazolinyl (e.g., 1-imidazolinyl, 2-
imidazolinyl, 4-imidazolinyl), piperidinyl (e.g., piperidino,
15 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g.,
1-piperazinyl, 2-piperazinyl), morpholinyl (e.g., 2-morpholinyl,
3-morpholinyl, morpholino), thiomorpholinyl (e.g., 2-
thiomorpholinyl, 3-thiomorpholinyl, thiomorpholino),
tetrahydrofuryl, tetrahydropyranyl, 1,3-azaspiro[4.4]nonenyl
20 and the like, and the like.
Examples of the “cycloalkyl group” in the present
specification include, unless otherwise specified, cycloalkyl
groups having 3 - 8 carbon atoms, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl
25 and the like.
Examples of the “C3-8 cycloalkane” in the present
specification include cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane and the like.
Examples of the “C3-8 cycloalkene” in the present
30 specification include cyclopropene, cyclobutene, cyclopentene,
cyclohexene and the like.
[0183]
Examples of “an alkyl group, an aralkyl group or an aryl
group, each of which is optionally substituted” in the present
35 specification include
44
[0184]
“alkyl group”, “aralkyl group” and “aryl group”, each
optionally having, at substitutable position(s), 1 to 5
substituents selected from
(1) a halogen atom5 ;
(2) hydroxy;
(3) amino;
(4) nitro;
(5) cyano;
10 (6) a heterocyclic group optionally substituted by 1 to 3
substituents selected from halogen atom, hydroxy, amino, nitro,
cyano, C1-6 alkyl optionally substituted by 1 to 3 halogen atoms
or hydroxy, mono- or di-C1-6 alkyl-amino, C6-14 aryl, mono- or
di-C6-14 aryl-amino, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6
15 alkoxy, C1-6 alkoxy-carbonyl, C7-14 aralkyloxy-carbonyl, C1-6
alkylsulfanyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, optionally
esterified carboxy, carbamoyl, thiocarbamoyl, mono- or di-C1-6
alkyl-carbamoyl, mono- or di-C6-14 aryl-carbamoyl, sulfamoyl,
mono- or di-C1-6 alkyl-sulfamoyl, mono- or di-C6-14 aryl20
sulfamoyl, oxo and C3-8 cycloalkyloxycarbonyloxy-C1-6 alkoxycarbonyl;
(7) mono- or di-C1-6 alkyl-amino;
(8) mono- or di-C6-14 aryl-amino;
(9) mono- or di-C7-14 aralkyl-amino;
25 (10) N-C1-6 alkyl-N-C6-14 aryl-amino;
(11) N-C1-6 alkyl-N-C7-14 aralkyl-amino;
(12) C3-8 cycloalkyl;
(13) optionally halogenated C1-6 alkoxy;
(14) C1-6 alkylsulfanyl;
30 (15) C1-6 alkylsulfinyl;
(16) C1-6 alkylsulfonyl;
(17) optionally esterified carboxyl;
(18) C1-6 alkyl-carbonyl;
(19) C3-8 cycloalkyl-carbonyl;
35 (20) C6-14 aryl-carbonyl;
45
(21) carbamoyl;
(22) thiocarbamoyl;
(23) mono- or di-C1-6 alkyl-carbamoyl;
(24) mono- or di-C6-14 aryl-carbamoyl;
(25) N-C1-6 alkyl-N-C6-14 aryl-carbamoyl5 ;
(26) mono- or di-5- to 7-membered heterocyclyl-carbamoyl;
(27) C1-6 alkyl-carbonylamino optionally substituted by
carboxyl;
(28) C6-14 aryloxy optionally substituted by 1 to 3 substituents
10 selected from halogen atom, hydroxy, amino, nitro, cyano,
optionally halogenated C1-6 alkyl, mono- or di-C1-6 alkyl-amino,
C6-14 aryl, mono- or di-C6-14 aryl-amino, C3-8 cycloalkyl, C1-6
alkoxy, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkylsulfanyl, C1-6
alkylsulfinyl, C1-6 alkylsulfonyl, optionally esterified
15 carboxyl, carbamoyl, thiocarbamoyl, mono- or di-C1-6 alkylcarbamoyl,
mono- or di-C6-14 aryl-carbamoyl, sulfamoyl, mono- or
di-C1-6 alkyl-sulfamoyl and mono- or di-C6-14 aryl-sulfamoyl;
(29) C6-14 aryl optionally substituted by 1 to 3 substituents
selected from halogen atom, hydroxy, amino, nitro, cyano,
20 optionally halogenated C1-6 alkyl, mono- or di-C1-6 alkyl-amino,
C6-14 aryl, mono- or di-C6-14 aryl-amino, C3-8 cycloalkyl, C1-6
alkoxy, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkylsulfanyl, C1-6
alkylsulfinyl, C1-6 alkylsulfonyl, optionally esterified
carboxyl, carbamoyl, thiocarbamoyl, mono- or di-C1-6 alkyl25
carbamoyl, mono- or di-C6-14 aryl-carbamoyl, sulfamoyl, mono- or
di-C1-6 alkyl-sulfamoyl and mono- or di-C6-14 aryl-sulfamoyl;
(30) heterocyclyl-oxy;
(31) sulfamoyl;
(32) mono- or di-C1-6 alkyl-sulfamoyl;
30 (33) mono- or di-C6-14 aryl-sulfamoyl;
(34) C7-14 aralkyloxy optionally substituted by 1 to 3
substituents selected from halogen atom, hydroxy, amino, nitro,
cyano, optionally halogenated C1-6 alkyl, mono- or di-C1-6 alkylamino,
C6-14 aryl, mono- or di-C6-14 aryl-amino, C3-8 cycloalkyl,
35 C1-6 alkoxy, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkylsulfanyl, C1-6
46
alkylsulfinyl, C1-6 alkylsulfonyl, optionally esterified
carboxyl, carbamoyl, thiocarbamoyl, mono- or di-C1-6 alkylcarbamoyl,
mono- or di-C6-14 aryl-carbamoyl, sulfamoyl, mono- or
di-C1-6 alkyl-sulfamoyl and mono- or di-C6-14 aryl-sulfamoyl;
(35) C1-6 alkyl-carbonyloxy5 ;
(36) C7-14 aralkyloxy-carbonyl;
(37) tri-C1-6 alkylsilyloxy;
(38) C1-6 alkyl;
(39) C2-6 alkenyl;
10 (40) C2-6 alkynyl;
(41) C1-6 alkoxy-carbonyl;
(42) N-C1-6 alkyl (said C1-6 alkyl is optionally substituted by
C7-14 aralkyloxy-carbonyl)-N-C1-6 alkyl-carbonylamino; and the
like. When a plurality of substituents exist, the respective
15 substituents may be the same or different. The substituents
are optionally further substituted by 1 to 5 substituents
selected from the above-mentioned (1) - (42). When a plurality
of substituents exist, the respective substituents may be the
same or different.
20 [0185]
Examples of the “linear or branched chain alkyl group
having 1 – 20 carbon atoms, aralkyl group having 7 - 14 carbon
atoms, aryl group having 6 - 18 carbon atoms and cycloalkyl
group having 3 - 7 carbon atoms, each optionally having a
25 nitrogen atom, an oxygen atom or a sulfur atom” in the present
specification include dimethylaminomethyl, methoxymethyl,
methylthiomethyl, anilinomethyl, phenoxymethyl, pyridyl,
pyrimidyl, piperidinyl, morpholinyl and the like.
[0186]
30 The deprotection method in the present invention is
explained below.
[0187]
[Production method 1] and [Production method 1A] (deprotection
method)
35 (i) Deprotection method by reducing in the presence of metal
47
catalyst and alkaline earth metal salt
[0188]
5
[0189]
wherein R1 is an alkyl group, an aralkyl group or an aryl group,
each of which is optionally substituted, each R2 is an alkyl
group, an alkoxy group or a nitro group, or two alkoxy groups
10 are optionally bonded to form an alkylenedioxy group, and p is
an integer of 0 to 5.
Compound [3] or [4] can be produced by reduction (e.g.,
formic acid reduction, catalytic reduction etc.) of compound
[1] or [2] in the presence of a metal catalyst and an alkaline
15 earth metal salt, followed by deprotection (elimination of the
following substituent).
[0190]
[0191]
20 Compounds [3] and [4] form an equilibrium mixture.
Examples of the metal catalyst include palladium catalyst,
rhodium catalyst, platinum catalyst and the like. Preferred is
palladium catalyst.
The amount of the metal catalyst to be used is generally
25 0.00001 equivalents - 1 equivalent, preferably, 0.001
equivalents - 0.5 equivalents, more preferably, 0.01
equivalents - 0.1 equivalents, relative to compound [1] or [2].
While the alkaline earth metal salt is not particularly
or or
48
limited, for example, an alkaline earth metal salt of inorganic
acid can be mentioned. Preferred is barium sulfate or calcium
carbonate.
The amount of the alkaline earth metal salt to be used is
generally 0.00001 equivalents - 1 equivalent, preferably, 0.005 1
equivalents - 0.5 equivalents, more preferably, 0.01
equivalents - 0.1 equivalents, relative to compound [1] or [2].
The metal catalyst can also be used by being supported by
an alkaline earth metal salt. It is preferably a supported
10 type palladium catalyst, particularly preferably palladium
barium sulfate (Rosenmund catalyst) or palladium calcium
carbonate (Lindlar catalyst).
In the case of formic acid reduction, formic acid or
formic acid salt (ammonium formate, sodium formate, potassium
15 formate, lithium formate, magnesium formate etc.) is added as
an additive.
In the case of catalytic reduction, the hydrogen pressure
is 1 atm - 100 atm, preferably 1 atm – 10 atm.
Reduction (deprotection) can also be performed in the
20 presence of a solvent. While the solvent is not particularly
limited as long as the reaction proceeds, isopropyl alcohol, npropyl
alcohol, methanol, ethanol, tetrahydrofuran, methylene
chloride, ethyl acetate and the like, or a mixed solvent of the
above-mentioned solvent and water can be mentioned. The amount
25 of the solvent to be used is generally 0.1 mL - 100 mL,
preferably 0.5 mL - 10 mL, per 1 mmol of compound [1] or [2].
The reaction temperature is generally 0C - 150C,
preferably, 10C - 80C.
The reaction time is generally 0.1 hr - 72 hr, preferably,
30 0.5 hr - 24 hr.
[0192]
The above-mentioned compound [1] or [2] can be produced
by the method described in WO 2011/061996, or a method
analogous thereto. For example, a biphenyltetrazole derivative
35 can be produced by the following method.
49
(ii) Deprotection method by reaction with Brønsted acid
Compound [3] or [4] can be produced by reacting compound
[1] or [2] with 0.1 equivalents - 50 equivalents of Brønsted
acid relative to compound [1] or [2]. It is industrially
preferable since a catalyst is not necessary for the reactio5 n
with Brønsted acid.
In the case of deprotection by this method, R1 in
compounds [1], [2], [3] and [4] is preferably a benzyl group
substituted by an alkoxy group, particularly preferably a
10 benzyl group wherein the 2-position and the 4-position are
substituted by the same alkoxy group. As the alkoxy group, an
alkoxy group having 1 - 6 carbon atoms is preferable, an alkoxy
group having 1 - 3 carbon atoms is further preferable.
Particularly preferred is a methoxy group.
15 As Brønsted acid, trifluoroacetic acid, methanesulfonic
acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid,
phosphoric acid, phosphate and the like can be mentioned.
Preferred is trifluoroacetic acid. The amount of the Brønsted
acid to be used is generally 0.1 - 50 equivalents, preferably
20 0.5 equivalents - 10 equivalents, relative to compound [1] or
[2].
While the solvent is not particularly limited as long as
the reaction proceeds, halogenated solvents such as methylene
chloride, chloroform, chlorobenzene and the like, polar
25 solvents such as N-methyl-2-pyrrolidone, N,N-dimethylformamide,
N,N-dimethylacetamide, dimethyl sulfoxide, water and the like,
and non-polar solvents such as toluene, xylene and the like are
preferable. These halogenated solvents, polar solvents and/or
non-polar solvents may be used as a mixture. The amount of the
30 solvent to be used is generally 0 mL - 100 mL, preferably 0.1
mL - 10 mL, per 1 mmol of compound [1] or [2].
This method can be performed in the presence of a
scavenger as necessary. While the scavenger is not
particularly limited as long as the reaction proceeds,
35 mercaptans such as anisole, mesitylene, 1-octanethiol and the
50
like, and the like can be mentioned. The amount of the
scavenger to be used is generally 0.001 mL - 10 mL, preferably
0.1 mL - 5mL, per 1 mmol of compound [1] or [2].
The reaction temperature is generally 0C - 100C,
preferably 5C - 50C, particularly preferably 10C - 40C5 .
The reaction time is generally 0.01 - 200 hr, preferably
0.5 - 12 hr.
[0193]
[Production method 2]
10 2-Phenyltetrazole derivative [5] and benzene derivative
[6] may be commercially available products, and 2-
phenyltetrazole derivative [5] may be produced by the method
described in WO 2009/49305, or a method analogous thereto.
[0194]
15
[0195]
wherein R3 is a tetrazolyl-protecting group, R4 to R7 are each
independently a hydrogen atom or an alkyl group, an aralkyl
group or an aryl group, each optionally having substituent(s),
20 R8 is an alkyl group, an aralkyl group or an aryl group, each
optionally having substituent(s), m is an integer of 0 to 5,
and X1 is a leaving group.
Biphenyltetrazole derivative [7] can be produced by
reacting 2-phenyltetrazole derivative [5] with benzene
25 derivative [6] in the presence of a metal catalyst, a base and
one or more kinds of compounds selected from the group
consisting of the aforementioned (a) - (d). This reaction can
51
also be performed in a solvent.
As the metal catalyst, ruthenium catalyst, iridium
catalyst, rhodium catalyst or palladium catalyst can be used.
Examples of the ruthenium catalyst include
dichlorotris(triphenylphosphine)ruthenium (II) (RuCl2(PPh3)3)5 ,
dichloro(1,5-cyclooctadiene)ruthenium (II) polymer (sometimes
indicated as [RuCl2(η4-COD)]n or poly[(η2,η2-cycloocta-1,5-
diene)ruthenium-di-μ-chloro]), [RuCl2(η6-C6H6)]2, dichloro(pcymene)
ruthenium (II) dimer ([Ru(p-cymene)Cl2]2),
10 dichloro(mesitylene)ruthenium (II) dimer ([Ru(mesitylene)Cl2]2),
ruthenium chloride (III) (RuCl3), ruthenium chloride (III)
hydrate (RuCl3･xH2O), ruthenium carbon, and dipivaloyloxy(pcymene)
ruthenium (II). Preferred are ruthenium catalysts (e.g.,
dichloro(p-cymene)ruthenium (II) dimer ([Ru(p-cymene)Cl2]2),
15 ruthenium chloride (III) hydrate(RuCl3･xH2O), dipivaloyloxy(pcymene)
ruthenium (II)).
The amount of the metal catalyst to be used is generally
0.00001 - 10 equivalents, preferably, 0.001 equivalents - 0.3
equivalents, more preferably, 0.003 equivalents - 0.015
20 equivalents, relative to 2-phenyltetrazole derivative [5].
Examples of the base include potassium carbonate (K2CO3),
sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3),
potassium hydrogen carbonate (KHCO3), potassium phosphate
(K3PO4), cesium carbonate (Cs2CO3), rubidium carbonate (Rb2CO3)
25 and the like. Preferred is potassium carbonate.
The amount of the base to be used is generally 0.1
equivalents - 10 equivalents, preferably, 0.1 equivalents - 3
equivalents, more preferably, 0.3 equivalents - 2 equivalents,
relative to 2-phenyltetrazole derivative [5].
30 [0196]
While (a) monocarboxylic acid metal salt of the present
invention is not particularly limited, for example, a
carboxylic acid metal salt represented by RCO2M and the like
can be mentioned.
35 R is a hydrogen atom, or a straight chain or branched
52
chain alkyl group having 1 - 20 carbon atoms, an aralkyl group
having 7 - 14 carbon atoms, an aryl group having 6 - 18 carbon
atoms or a cycloalkyl group having 3 - 7 carbon atoms, each of
which optionally contains a nitrogen atom, an oxygen atom or a
sulfur atom, and the alkyl group, aralkyl group, cycloalky5 l
group and aryl group optionally have substituent(s). R is
preferably a straight chain or branched chain alkyl group
having 1 - 12 carbon atoms (e.g., methyl, tert-butyl, 2-ethylhexyl,
n-dodecyl), an aralkyl group having 7 - 10 carbon atoms,
10 an aryl group having 6 - 12 carbon atoms optionally substituted
by an alkyl group having 1 - 6 carbon atoms (e.g., mesityl), or
a cycloalkyl group having 3 - 7 carbon atoms (e.g., cyclohexyl),
particularly preferably, a methyl group or a tert-butyl group.
M is a metal atom, which is preferably Li (lithium), Na
15 (sodium), K (potassium), Rb (rubidium), Cs (cesium), Mg
(magnesium) or Zn (zinc), more preferably an alkali metal atom,
particularly preferably K.
Preferable examples of the monocarboxylic acid metal salt
include a potassium salt of carboxylic acid wherein R is a
20 straight chain or branched chain alkyl group having 1 - 12
carbon atoms (e.g., methyl, tert-butyl, 2-ethyl-hexyl, ndodecyl),
a cycloalkyl group having a having 3 - 7 carbon atoms
(e.g., cyclohexyl), or an aryl group having 6 - 12 carbon atoms
(e.g., mesityl) optionally substituted by an alkyl group having
25 1 - 6 carbon atoms, and a potassium salt of acetic acid or a
potassium salt of pivalic acid is particularly preferable.
While (b) dicarboxylic acid metal salt of the present
invention is not particularly limited, for example, a metal
salt of dicarboxylic acid represented by
30 [0197]
or
53
[0198]
and the like can be mentioned.
R’ is a hydrogen atom, or a straight chain or branched
chain alkyl group having 1 – 10 carbon atoms, an aralkyl group
having 7 - 14 carbon atoms or an aryl group having 6 - 15 8
carbon atoms, each of which optionally contains a nitrogen atom,
an oxygen atom or a sulfur atom. The alkyl group, aralkyl
group and aryl group optionally have substituent(s). R’ is
preferably a hydrogen atom, or a straight chain or branched
10 chain alkyl group having 1 - 6 carbon atoms, an aralkyl group
having 7 - 10 carbon atoms, or an aryl group having 6 - 12
carbon atoms, and particularly preferable a hydrogen atom.
n is an integer of 0 - 10, preferably, an integer of 0 –
5, particularly preferably, 0 or 3.
15 Ring Z is cycloalkylene having 3 - 8 carbon atoms,
cycloalkenylene having 3 - 8 carbon atoms, arylene, or
heterocyclylene, preferably, phenylene, naphthylene, anthrylene,
phenanthrylene or the like.
M is a metal atom, preferably, Li (lithium), Na (sodium),
20 K (potassium), Rb (rubidium), Cs (cesium), Mg (magnesium) or Zn
(zinc), more preferably, an alkali metal atom, particularly
preferably, K.
A preferable example of a dicarboxylic acid metal salt is
a potassium salt of dicarboxylic acid wherein R’ is a hydrogen
25 atom and n is an integer of 0 - 5, and a potassium salt of
oxalic acid and a potassium salt of glutaric acid are
particularly preferable.
While (c) sulfonic acid metal salt of the present
invention is not particularly limited, for example, a sulfonic
30 acid metal salt represented by R”SO3M and the like can be
mentioned.
R” is a hydrogen atom, or a straight chain or branched
chain alkyl group having 1 – 10 carbon atoms, an aralkyl group
having 7 - 14 carbon atoms or an aryl group having 6 - 18
35 carbon atoms, each of which optionally contains a nitrogen atom,
54
an oxygen atom or a sulfur atom. The alkyl group, aralkyl
group and aryl group optionally have substituent(s). Preferred
are a straight chain or branched chain alkyl group having 1 - 6
carbon atoms, an aralkyl group having 7 - 10 carbon atoms, and
an aryl group having 6 - 12 carbon atoms (e.g., 2,4,65 -
trimethylphenyl or 4-dodecylphenyl) which is optionally
substituted by an alkyl group having 1 - 12 carbon atoms, and
particularly preferred is a 4-dodecylphenyl group.
M is a metal atom, preferably, Li (lithium), Na (sodium),
10 K (potassium), Rb (rubidium), Cs (cesium), Mg (magnesium) or Zn
(zinc), more preferably, an alkali metal atom, particularly
preferably, K. A preferable example of (c) a sulfonic acid
metal salt of the present invention is a potassium salt of
sulfonic acid wherein R” is a phenyl group optionally
15 substituted by an alkyl group having 1 - 12 carbon atoms, and
potassium 4-dodecylbenzenesulfonate is particularly preferable.
R”’ of (d) phosphate metal salt represented by
(R”’O)xP(O)(OM)y of the present invention is a hydrogen atom,
or a straight chain or branched chain alkyl group having 1 - 20
20 carbon atoms, an aralkyl group having 7 - 14 carbon atoms or an
aryl group having 6 - 18 carbon atoms, each of which optionally
contains a nitrogen atom, an oxygen atom or a sulfur atom. The
alkyl group, aralkyl group and aryl group optionally have
substituent(s). Two R”’ may form a ring in a molecule.
25 Preferred are a straight chain or branched chain alkyl group
having 1 - 12 carbon atoms (e.g., ethyl, n-butyl, t-butyl,
dodecyl, 2-ethyl-n-hexyl), an aralkyl group having 7 - 10
carbon atoms and an aryl group having 6 - 12 carbon atoms (e.g.,
2-naphthyl), and particularly preferred is a 2-ethyl-n-hexyl
30 group.
x and y are each independently an integer of 1 or 2, and
x+y is 3.
M is a metal atom, preferably, Li (lithium), Na (sodium),
K (potassium), Rb (rubidium), Cs (cesium), Mg (magnesium) or Zn
35 (zinc), more preferably, an alkali metal atom, particularly
55
preferably, K.
A preferable example of (d) phosphate metal salt
represented by (R”’O)xP(O)(OM)y of the present invention is a
potassium salt of phosphate wherein R”’ is a straight chain or
branched chain alkyl group having 1 - 12 carbon atoms (e.g.5 ,
ethyl, n-butyl, t-butyl, dodecyl, 2-ethyl-n-hexyl) or an aryl
group having 6 - 12 carbon atoms (e.g., 2-naphthyl), and
potassium bis(2―ethyl-n-hexyl)phosphate is particularly
preferable.
10 The amount of one or more kinds of compounds selected
from the group consisting of (a) - (d) to be used is generally
0.00001 equivalents - 10 equivalents, preferably, 0.001
equivalents - 8.0 equivalents, more preferably, 0.005
equivalents - 5.0 equivalents, relative to 2-phenyltetrazole
15 derivative [5].
A method of adding a metal catalyst, a base and one or
more kinds of compounds selected from the group consisting of
(a) - (d) is not particularly limited, and a method including
adding a base and one or more kinds of compounds selected from
20 the group consisting of (a) - (d), and then adding a metal
catalyst, a method including adding a base, and then adding a
ruthenium catalyst prepared from a metal catalyst and one or
more kinds of compounds selected from the group consisting of
(a) - (d) and the like can be mentioned.
25 [0199]
For preferable progress of the reaction, the reaction may
be performed in the further presence of a phosphine compound.
Examples of the phosphine compound include triphenylphosphine
(sometimes referred to as triphenylphosphane), tri(t30
butyl)phosphine, triethylphosphine, tricyclohexylphosphine,
tri(o-tolyl)phosphine, tri(p-tolyl)phosphane, tri(pmethoxyphenyl)
phosphane, cyclohexyldiphenylphosphane and the
like, with preference given to triphenylphosphine.
The amount of the phosphine compound to be used is
35 generally 0.00001 equivalents - 10 equivalents, preferably,
56
0.001 equivalents - 1 equivalent, relative to 2-phenyltetrazole
derivative [5].
In addition, the reaction may be performed in the
presence of a conjugate acid of a metal salt described in the
above-mentioned (a) - (d)5 .
The amount of the conjugate acid to be used is generally
0.00001 equivalents - 3 equivalents, preferably, 0.05
equivalents - 1.0 equivalent, more preferably, 0.1 equivalents
- 0.5 equivalents, relative to 2-phenyltetrazole derivative [5].
10 While the solvent is not particularly limited as long as
the reaction proceeds, polar solvents such as N-methyl-2-
pyrrolidone (sometimes to be abbreviated as NMP), N,Ndimethylformamide
(sometimes to be abbreviated as DMF), N,Ndimethylacetamide
(sometimes to be abbreviated as DMA),
15 dimethyl sulfoxide (sometimes to be abbreviated as DMSO) and
the like, non-polar solvents such as toluene, xylene and the
like, and a mixture of the polar solvent and the non-polar
solvent are preferable.
The amount of the solvent to be used is generally 0 mL -
20 100 mL, preferably, 0.1 mL - 10 mL, per 1 mmol of 2-
phenyltetrazole derivative [5].
The reaction temperature is generally 20C - 300C,
preferably, 100C - 200C.
The reaction time is generally 0.01 hr - 200 hr,
25 preferably, 0.5 hr - 24 hr.
[0200]
[Production method 2-1]
Compound [11] which is compound [1] wherein R1 is 4’-
halomethylbiphenyl-2-yl can be produced by the following method.
30 [0201]
57
[0202]
wherein the symbols are as defined above.
(step 1)
A biphenyltetrazole derivative or a salt thereof [10] ca5 n
be produced by processing a phenyltetrazole derivative or a
salt thereof [8] and a benzene derivative [9] in the same
manner as in the method described in the above-mentioned
Production method 2.
10 [0203]
(step 2)
[0204]
15 [0205]
wherein R2 is as defined above, and X2 is a halogen atom.
Compound [11] can be produced by reacting a
biphenyltetrazole derivative or a salt thereof [10] with a
halogenating agent.
20 As the halogenating agent, a halogenating agent known per
se can be used. Preferably, 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH), sodium bromate (NaBrO3) and the like can be mentioned.
The amount of the halogenating agent to be used is generally
0.1 equivalents - 10 equivalents, preferably 0.5 equivalents -
25 1.1 equivalents, relative to the biphenyltetrazole derivative
58
or a salt thereof [10].
The reaction can also be performed in the presence of a
reaction initiator. As the reaction initiator, 2,2’-
azobisisobutyronitrile (AIBN), benzoyl peroxide (BPO) and the
like can be mentioned. The amount of the reaction initiator t5 o
be used is generally 0.0001 equivalents - 10 equivalents,
preferably 0.005 equivalents - 0.1 equivalents, relative to the
biphenyltetrazole derivative or a salt thereof [10].
To accelerate the reaction rate, the reaction can also be
10 performed in the presence of an acid. As the acid, aromatic
acid is preferable, for example, p-toluenesulfonic acid,
benzenesulfonic acid, 2,4,6-trimethylbenzoic acid, 1-
adamantylcarboxylic acid and the like can be mentioned, and ptoluenesulfonic
acid is particularly preferable. The amount of
15 the acid to be used is generally 0.00001 equivalents - 10
equivalents, preferably 0.01 equivalents - 5 equivalents,
relative to the biphenyltetrazole derivative or a salt thereof
[10].
The reaction can also be performed using a solvent.
20 While the solvent is not particularly limited as long as the
reaction proceeds, ester solvents such as ethyl acetate, methyl
acetate and the like, non-polar solvents such as cyclohexane,
n-hexane, n-heptane and the like, halogen solvents such as
methylene chloride, chloroform, carbon tetrachloride and the
25 like, ether solvents such as tert-butyl methyl ether, THF and
the like, polar solvents such as N-methyl-2-pyrrolidone, N,Ndimethylformamide,
N,N-dimethylacetamide, dimethyl sulfoxide,
water and the like, and a mixture of these polar solvents and
non-polar solvents are preferable. The amount of the solvent
30 to be used is generally 0 mL - 100 mL, preferably 0.1 mL - 10
mL, per 1 mmol of the biphenyltetrazole derivative or a salt
thereof [10].
The reaction temperature is generally 0C - 200C,
preferably 20C - 110C.
35 The reaction time is generally 0.01 hr - 200 hr,
59
preferably 0.5 hr - 24 hr.
[0206]
[Production method 2-2]
A compound which is compound [7] wherein R4 to R7 are
hydrogen, R8 is 4-bromomethyl, and m is 1 can be produced b5 y
the following method.
[0207]
10 [0208]
wherein the symbols are as defined above.
(step 1)
A biaryltetrazole derivative or a salt thereof [13] can
be produced by processing a phenyltetrazole derivative or a
15 salt thereof [12] and a benzene derivative [9] in the same
manner as in the method described in the above-mentioned
Production method 2.
Of the biaryltetrazole derivatives or a salt thereof [13]
obtained in this step, one wherein R3 is benzyl is superior in
20 crystallinity and can be purified by a mere crystallization
step.
[0209]
(step 2)
A biaryltetrazole derivative or a salt thereof [14] can
25 be produced by reacting a biaryltetrazole derivative or a salt
thereof [13] with a brominating agent by a method similar to
that in the above-mentioned Production method 2-1, step 2.
As the brominating agent, 1,3-dibromo-5,5-
dimethylhydantoin (DBDMH) or sodium bromate (NaBrO3) is
30 preferably used.
60
[0210]
[Production method 3] and [Production method 3A] (olmesartan
medoxomil production method)
[0211]
5
(olmesartan medoxomil)
[0212]
Olmesartan medoxomil or a salt thereof can be produced
from compound [11] by a known method described in JP-B-7-121918,
10 JP-A-2010-505926 and the like. It can also be produced by the
following method.
[0213]
(step 1)
[0214]
15
[0215]
wherein R9 is a carboxy-protecting group, and other symbols are
as defined above.
20 Compound [16] can be produced by reacting compound [11]
61
with compound [15] in the presence of a base. This reaction
can also be performed in a solvent.
R9 in compound [15] is a carboxy-protecting group, and is
a protecting group not deprotected by reduction (e.g., formic
acid reduction, catalytic reduction). Preferred is an alky5 l
group.
The base is not particularly limited, and a base known
per se can be applied. For example, potassium carbonate,
cesium carbonate, sodium hydroxide, potassium hydroxide,
10 triethylamine, diisopropylethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and the like can be
mentioned. The amount of the base to be used is generally 1
equivalent - 10 equivalents, preferably 1 equivalent - 3
equivalents, relative to compound [11].
15 The solvent is not particularly limited as long as the
reaction proceeds, and DMA, DMF, DMSO, NMP, acetonitrile,
toluene, THF, dioxane, acetone and the like can be mentioned.
The amount of the solvent to be used is generally 0.001 mL -
100 mL, preferably 0.1 mL - 10 mL, per 1 mmol of compound [11].
20 The reaction temperature is generally -50C - 150C,
preferably 20C - 50C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 5 hr.
[0216]
25 (step 2)
[0217]
62
[0218]
wherein the symbols are as defined above.
Compound [17] can be produced using compound [16] in the
same manner as in the method described in the above-mentione5 d
Production method 1.
[0219]
(step 3)
[0220]
10
[0221]
wherein Tr is a trityl group, X is a halogen atom, R9 is as
defined above.
Compound [19] can be produced by reacting compound [17]
15 with compound [18] in the presence of a base. This reaction
can also be performed in a solvent.
The base is not particularly limited, and a base known
per se can be applied. For example, triethylamine, N,N63
diisopropylethylamine, pyridine, lutidine, sodium carbonate,
potassium carbonate, cesium carbonate and the like can be
mentioned. The amount of the base to be used is generally 0.1
equivalents - 10 equivalents, preferably 1 equivalent - 5
equivalents, relative to compound [17]5 .
The solvent is not particularly limited as long as the
reaction proceeds, and methylene chloride, chloroform, toluene,
acetone, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide
and the like can be mentioned. The amount of the solvent to be
10 used is generally 0.01 mL - 50 mL, preferably 0.5 mL – 5 mL,
per 1 mmol of compound [17].
The reaction temperature is generally -10C - 50C,
preferably -5C - 30C.
The reaction time is generally 0.1 hr - 24 hr, preferably
15 1 hr - 5 hr.
[0222]
(step 4)
[0223]
20 [0224]
wherein the symbols are as defined above.
Compound [20] can be produced by hydrolysis of compound
[19] in the presence a base and a water-soluble organic solvent.
While the base is not particularly limited, a base known
25 per se can be applied. For example, potassium hydroxide,
potassium carbonate, sodium hydroxide, sodium hydride and the
like can be mentioned. The amount of the base to be used is
64
generally 1 equivalent - 10 equivalents, preferably 1
equivalent - 3 equivalents, relative to compound [19].
As the water-soluble organic solvent, methanol, ethanol,
acetone and the like can be mentioned. The amount of the
solvent to be used is generally 0.001 mL - 100 mL, preferabl5 y
0.1 mL - 10 mL, per 1 mmol of compound [19].
The reaction temperature is generally 0C - 120C,
preferably 50C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
10 0.5 hr - 5 hr.
[0225]
(step 5)
[0226]
15 [0227]
wherein Tr is as defined above.
Compound [22] can be produced by reacting compound [20]
with compound [21] in the presence of a base.
The base is not particularly limited, and a base known
20 per se can be applied. For example, potassium carbonate,
cesium carbonate, sodium hydroxide, potassium hydroxide,
triethylamine, diisopropylethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and the like can be
mentioned. The amount of the base to be used is generally 1
25 equivalent - 10 equivalents, preferably 1 equivalent - 3
equivalents, relative to compound [20].
65
The solvent is not particularly limited as long as the
reaction proceeds, and DMA, DMF, DMSO, NMP, acetonitrile,
toluene, THF, dioxane, acetone and the like can be mentioned.
The amount of the solvent to be used is generally 0.001 mL -
100 mL, preferably 0.1 mL - 10 mL, per 1 mmol of compound [20]5 .
The reaction temperature is generally 0C - 150C,
preferably 30C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 5 hr.
10 [0228]
(step 6)
[0229]
[0230]
15 wherein Tr is as defined above.
Compound [23] (olmesartan medoxomil or a salt thereof)
can be produced by removing a trityl group of compound [22].
This reaction can also be performed in a solvent.
To remove R6, an acid can be used. The acid is not
20 particularly limited, and acids known per se can be applied.
For example, trifluoroacetic acid, trichloroacetic acid,
trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric
acid, hydrochloric acid, acetic acid and the like can be
mentioned. The amount of the acid to be used is generally 0.1
25 equivalents - 1000 equivalents, preferably 1 equivalent - 500
equivalents, relative to compound [22].
66
Removal of a trityl group by an acid can be preferably
performed in the presence of a scavenger. While the scavenger
is not particularly limited as long as the reaction proceeds,
mercaptans such as anisole, mesitylene, 1-octanethiol and the
like, and the like can be mentioned. The amount of th5 e
scavenger to be used is generally 0.001 mL - 10 mL, preferably
0.1 mL – 5 mL, per 1 mmol of compound [22].
The above-mentioned acid or scavenger may act as a
solvent in this step.
10 The reaction temperature is generally -50C - 150C,
preferably 10C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 20 hr.
[0231]
15 [Production method 4] and [Production method 4A] (losartan
production method)
[0232]
(step 1)
[0233]
20
[0234]
wherein the symbols are as defined above.
Compound [25] can be produced by reacting compound [11]
with compound [24] in the same manner as in the method
25 described in Production method 3, step 1.
[0235]
67
(step 2-A(2))
[0236]
[0237]
wherein the symbol is as defined above5 .
Compound [26] can be produced by reducing compound [25]
by using a reducing agent. This reaction can also be performed
in a solvent.
The reducing agent is not particularly limited, and
10 reducing agents known per se can be applied. For example,
sodium borohydride, lithium borohydride, zinc borohydride,
sodium triacetoxyborohydride and the like can be mentioned.
The amount of the reducing agent to be used is generally 1
equivalent - 10 equivalents, preferably 1 equivalent - 5
15 equivalents, relative to compound [25].
While the solvent is not particularly limited as long as
the reaction proceeds, methanol, ethanol, isopropyl alcohol,
dimethoxyethane, water and the like can be mentioned. The
amount of the solvent to be used is generally 0.01 mL - 100 mL,
20 preferably 0.1 mL - 10 mL, per 1 mmol of compound [25].
In this reaction, a base can also be used as necessary.
Examples of the base include sodium hydroxide and the like.
The amount of the base to be used is generally 0 equivalents -
10 equivalents, preferably 1 equivalent - 2 equivalents,
25 relative to compound [25].
The reaction temperature is generally -50C - 100C,
preferably 20C - 50C.
68
The reaction time is generally 0.01 hr - 48 hr,
preferably 0.1 hr - 5 hr.
[0238]
(step 2-A(3))
[02395 ]
[0240]
wherein the symbol is as defined above.
Compound [28] can be produced using compound [26] by the
10 method described in the above-mentioned Production method 1.
[0241]
(step 2-B(1))
[0242]
15
[0243]
wherein the symbol is as defined above.
Compound [27] can be produced using compound [25] by the
69
method described in the above-mentioned Production method 1.
[0244]
(step 2-B(2))
[0245]
5
[0246]
Compound [28] can be produced by reducing compound [27]
in the same manner as in the method described in the abovementioned
step 2-A(1).
10 [0247]
[Production method 5] and [Production method 5A] (valsartan
production method)
[0248]
(step 1)
15 [0249]
[0250]
70
wherein R10 is a carboxy-protecting group, and other each
symbol is as defined above.
Compound [30] can be produced by reacting compound [11]
with compound [29] (e.g., p-toluenesulfonate, hydrochloride
etc.) in the presence of a base. This reaction can also b5 e
performed in a solvent.
R10 of compound [29] is a carboxy-protecting group, and
R10 in step 2-A and 2-B is a protecting group not deprotected
by reduction (e.g., formic acid reduction, catalytic reduction),
10 which is preferably an alkyl group. R10 in step 2-B is a
protecting group optionally deprotected by reduction (e.g.,
formic acid reduction, catalytic reduction), which is
preferably a benzyl group.
The base is not particularly limited, and a base known
15 per se can be applied. For example, diisopropylethylamine,
triethylamine, pyridine, sodium hydride, potassium t-butoxide
and the like can be mentioned. The amount of the base to be
used is generally 1 equivalent - 10 equivalents, preferably 1
equivalent - 5 equivalents, relative to compound [11].
20 The solvent is not particularly limited as long as the
reaction proceeds, and acetonitrile, toluene, THF, dioxane,
chloroform, methylene chloride and the like can be mentioned.
The amount of the solvent to be used is generally 0.1
equivalents - 100 mL, preferably 0.5 equivalents – 5 mL, per 1
25 mmol of compound [11].
The reaction temperature is generally -50C - 150C,
preferably 5C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 5 hr.
30 [0251]
(step 2-A)
[0252]
71
[0253]
wherein the symbols are as defined above.
Compound [31] can be produced using compound [30] and in
the same manner as in the method described in the above5 -
mentioned Production method 1.
[0254]
(step 3-A)
[0255]
10
[0256]
wherein X3 is a leaving group, and other symbols are as defined
above.
Compound [33] can be produced by reacting compound [31]
15 with compound [32] in the presence of a base. This reaction
can also be performed in a solvent.
While the base is not particularly limited, for example,
triethylamine, diisopropylethylamine, DBU, sodium hydroxide,
sodium carbonate, sodium hydrogen carbonate, potassium
20 hydroxide, potassium carbonate, potassium hydrogen carbonate,
72
potassium phosphate, 4-dimethylaminopyridine (DMAP), lutidine,
pyridine and the like can be mentioned. The amount of the base
to be used is generally 1 equivalent - 10 equivalents,
preferably 1 equivalent - 3 equivalents, relative to compound
[31]5 .
While the solvent is not particularly limited as long as
the reaction proceeds, toluene, xylene, methylene chloride,
chloroform, acetonitrile, NMP, DMF, DMSO, THF, dimethoxyethane,
t-butyl methyl ether (hereinafter to be also referred to as t-
10 BME), 1,4-dioxane and the like can be mentioned. The amount of
the solvent to be used is generally 0.001 mL - 100 mL,
preferably 0.1 mL - 10 mL, per 1 mmol of compound [31].
The reaction temperature is generally -20C - 150C,
preferably 0C - 100C.
15 The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 5 hr.
[0257]
(step 4-A)
[0258]
20
[0259]
wherein the symbol is as defined above.
Compound [35] can be produced by removing R10 of compound
[33] in the presence of an acid. This reaction can also be
25 performed in a solvent.
The acid is not particularly limited, and an acid known
per se can be applied. For example, trifluoroacetic acid,
73
trichloroacetic acid, trifluoromethanesulfonic acid,
methanesulfonic acid, sulfuric acid, hydrochloric acid and the
like can be mentioned. The amount of the acid to be used is
generally 0.1 equivalents - 1000 equivalents, preferably 1
equivalent - 500 equivalents, relative to compound [33]5 .
Deprotection by an acid can be preferably performed in
the presence of a scavenger. While the scavenger is not
particularly limited as long as the reaction proceeds,
mercaptans such as anisole, mesitylene, 1-octanethiol and the
10 like, and the like can be mentioned. The amount of the
scavenger to be used is generally 0.001 mL - 10 mL, preferably
0.1 mL – 5 mL, per 1 mmol of compound [33].
The above-mentioned acid or scavenger may act as a
solvent in this step.
15 The reaction temperature is generally -50C - 150C,
preferably 10C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 5 hr.
[0260]
20 Alternatively, compound [35] can also be produced by
removing R10 of compound [33] in the presence of a base. This
reaction can also be performed in a solvent.
As the base, sodium methoxide, sodium ethoxide,
dimethylamine, methylamine, ammonia, potassium carbonate,
25 sodium carbonate and the like can be mentioned. The amount of
the base to be used is generally 0.001 equivalents - 10
equivalents, preferably 0.01 equivalents - 1 equivalent,
relative to compound [34].
The solvent is not particularly limited as long as the
30 reaction proceeds, and methanol, ethanol, propanol and the like
can be mentioned. The amount of the solvent to be used is
generally 0.01 mL - 100 mL, preferably 0.1 mL - 10 mL, per 1
mmol of compound [34].
The reaction temperature is generally -50C - 100C,
35 preferably 0C - 20C.
74
The reaction time is generally 0.001 hr - 10 hr,
preferably 0.1 hr - 5 hr.
[0261]
(step 2-B)
[02625 ]
[0263]
wherein the symbols are as defined above.
Compound [34] can be produced using compound [30] and
10 compound [32] in the same manner as in the method described in
the above-mentioned step 3-A.
[0264]
(step 3-B)
[0265]
15
[0266]
wherein the symbols are as defined above.
When R10 is a protecting group deprotected by reduction,
compound [35] can be produced using compound [34] in the same
20 manner as in the method described in the above-mentioned
75
Production method 1.
When R10 is a protecting group not deprotected by
reduction, compound [35] can be produced by deprotecting
compound [34] in the same manner as in the method described in
the above-mentioned Production method 1, removing R10 in th5 e
same manner as in the method described in the above-mentioned
step 4-A, or removing R10 in the same manner as in the method
described in the above-mentioned step 4-A and deprotecting in
the same manner as in the method described in the above10
mentioned Production method 1.
[0267]
[Production method 6] and [Production method 6A] (irbesartan
production method)
[0268]
15 (step 1)
[0269]
[0270]
wherein the symbol is as defined above.
20 Compound [37] can be produced by reacting compound [11]
with compound [36] (e.g., hydrochloride etc.) in the presence
of a base or a base and an additive. This reaction can also be
performed in a solvent.
While the base is not particularly limited, for example,
25 triethylamine, ethyldiisopropylamine, DBU, sodium hydroxide,
76
sodium carbonate, sodium hydrogen carbonate, potassium
hydroxide, potassium carbonate, potassium hydrogen carbonate,
potassium phosphate, 4-dimethylaminopyridine (DMAP) and
lutidine can be mentioned. The amount of the base to be used
is generally 1 equivalent - 10 equivalents, preferably 5 1
equivalent - 3 equivalents, relative to compound [11].
As the additive, tetraalkylammonium halide (e.g.,
tetrabutylammonium bromide), tetraalkylphosphonium halide and
the like can be mentioned. The amount of the additive to be
10 used is generally 0.01 equivalents - 10 equivalents, preferably
0.05 equivalents - 1 equivalent, relative to compound [11].
While the solvent is not particularly limited as long as
the reaction proceeds, toluene, xylene, methylene chloride,
chloroform, acetonitrile, DMF, DMSO, THF, dimethoxyethane, t-
15 BME, 1,4-dioxane and the like and a mixture of the abovementioned
solvent and water can be mentioned. The amount of
the solvent to be used is generally 0.001 mL - 100 mL,
preferably 0.1 mL - 10 mL, per 1 mmol of compound [11].
The reaction temperature is generally -20C - 150C,
20 preferably 0C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 10 hr.
[0271]
(step 2)
25 [0272]
77
[0273]
wherein the symbol is as defined above.
Compound [38] can be produced using compound [37] and in
the same manner as in the methods described in the abovementioned
Production method 15 .
[0274]
[Production method 7] and [Production method 7A] (candesartan
cilexetil production method)
[0275]
10 (step 1-A-i)
[0276]
[0277]
wherein R11 is a carboxy-protecting group, R12 is an amino15
protecting group, and other each symbol is as defined above.
Compound [40] can be produced by reacting compound [11]
with compound [39] in the presence or absence of a base. This
reaction can also be performed in a solvent.
This reaction is preferably performed in the presence of
20 a base. As such base, metal hydrides such as sodium hydride
and the like, metal alkoxides such as sodium t-butoxide,
potassium t-butoxide and the like, carbonates such as potassium
carbonate, potassium hydrogen carbonate, sodium carbonate,
sodium hydrogen carbonate and the like, and the like can be
25 mentioned. Of these, carbonate, particularly, potassium
carbonate, is preferably used. The amount of the base to be
used is generally 1 equivalent - 5 equivalents relative to
compound [11].
78
As the solvent, aprotic polar solvents such as
dimethylformamide, dimethyl sulfoxide, dimethylacetamide and
the like, ketones such as acetone, ethylmethylketone and the
like, ethers such as tetrahydrofuran, dioxane and the like,
esters such as ethyl acetate and the like, aromati5 c
hydrocarbons such as benzene, toluene, xylene and the like,
hydrocarbon halides such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane and the like, acetonitrile and
the like can be mentioned. Of these, acetonitrile is
10 preferably used. The amount of the solvent to be used is
generally 0.1 mL - 10 mL per 1 mmol of compound [11].
The reaction temperature is generally 70C - 90C, and
the reaction time is 3 hr - 10 hr.
[0278]
15 (step 1-A-ii)
[0279]
[0280]
wherein the symbols are as defined above.
20 Compound [41] can be produced by removing R12 of compound
[40] in the presence of an acid.
While the acid is not particularly limited, an acid known
per se can be applied. For example, Brønsted acid (e.g.,
trifluoromethanesulfonic acid, methanesulfonic acid, phosphoric
25 acid, sulfuric acid, hydrochloric acid etc.) or Lewis acid
(e.g., aluminum chloride, tin chloride, boron fluoride diethyl
ether etc.) can be mentioned. The amount of the acid to be
used is generally 0.1 equivalents - 1000 equivalents,
preferably 1 equivalent - 500 equivalents, relative to compound
79
[40].
While the solvent is not particularly limited as long as
the reaction proceeds, water, methanol, ethanol, isopropyl
alcohol, tetrahydrofuran, dimethoxyethane, methyl t-butyl ether
and the like can be mentioned. The amount of the solvent to b5 e
used is generally 0.01 mL - 100 mL, preferably 0.1 mL - 10 mL,
per 1 mmol of compound [40].
The reaction temperature is generally -50C - 150C,
preferably 10C - 100C.
10 The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 20 hr.
[0281]
(step 1-A-iii)
[0282]
15
[0283]
wherein the symbols are as defined above.
Compound [42] can be produced by reducing compound [41]
20 with a reducing agent. This reaction can also be performed in
a solvent.
While the reducing agent is not particularly limited, a
reducing agent known per se can be applied. For example, tin
chloride, sodium borohydride, lithium borohydride, boron zinc
25 borohydride, sodium triacetoxyborohydride and the like can be
mentioned. The amount of the reducing agent to be used is
generally 1 equivalent - 10 equivalents, preferably 1
equivalent - 5 equivalents, relative to compound [41].
While the solvent is not particularly limited as long as
80
the reaction proceeds, water, methanol, ethanol, isopropyl
alcohol, dimethoxyethane, methyl t-butyl ether and the like can
be mentioned. The amount of the solvent to be used is
generally 0.01 mL - 100 mL, preferably 0.1 mL - 10 mL, per 1
mmol of compound [41]5 .
The reaction temperature is generally -50C - 100C,
preferably 20C - 50C.
The reaction time is generally 0.01 hr - 48 hr,
preferably 0.1 hr - 5 hr.
10 [0284]
(step 1-A-iv)
[0285]
[0286]
15 wherein the symbols are as defined above.
Compound [43] can be produced by reacting compound [42]
with tetraethoxymethane in the presence or absence of a solvent.
While the solvent is not particularly limited as long as
the reaction proceeds, ethanol, tetrahydrofuran, toluene, ethyl
20 acetate, acetic acid, dimethoxyethane, t-butyl methyl ether and
the like can be mentioned.
The reaction temperature is generally 0C - 120C,
preferably 50C - 100C.
The reaction time is generally 0.01 hr - 48 hr,
25 preferably 0.1 hr - 5 hr.
[0287]
(step 1-B)
[0288]
81
[0289]
wherein the symbols are as defined above.
Compound [43] can be produced by reacting compound [11]
with compound [49] in the presence of a base. This reactio5 n
can also be performed in a solvent.
The base is not particularly limited and, for example,
potassium carbonate, potassium hydrogen carbonate, potassium
phosphate, sodium hydroxide, sodium carbonate, sodium hydrogen
10 carbonate, potassium hydroxide, triethylamine,
diisopropylethylamine, DBU, 4-dimethylaminopyridine (DMAP),
lutidine, alkali metal salts of carboxylic acid such as sodium
acetate, potassium acetate and the like, zinc salts or
magnesium salts of carboxylic acid such as zinc acetate,
15 magnesium acetate and the like, alkali metal salts, magnesium
salts or zinc salts of phosphate such as potassium salt of
bis(2-ethylhexyl)phosphoric acid and the like, alkali metal
salts, magnesium salts or zinc salts of sulfonic acid such as
potassium n-dodecylsulfonate and the like, and the like can be
20 mentioned. The amount of the base to be used is generally 1
equivalent - 10 equivalents, preferably 1 equivalent - 3
equivalents, relative to compound [11].
The solvent is not particularly limited as long as the
reaction proceeds, and DMA, methanol, ethanol, propanol,
25 toluene, xylene, methylene chloride, chloroform, acetonitrile,
DMF, DMSO, NMP, THF, dimethoxyethane, t-butyl methyl ether,
1,4-dioxane, water and the like, and a mixed solvent of two or
more kinds selected therefrom can be mentioned. The amount of
82
the solvent to be used is generally 0.001 mL - 100 mL,
preferably 0.1 mL - 10 mL, per 1 mmol of compound [11].
The reaction temperature is generally -20C - 150C,
preferably 10C - 40C.
The reaction time is generally 0.1 hr - 48 hr, preferabl5 y
0.5 hr - 36 hr.
[0290]
(step 2)
[0291]
10
[0292]
wherein the symbols are as defined above.
Compound [44] can be produced using compound [43] and in
the same manner as in the method described in the above15
mentioned Production method 5, step 4-A. Furthermore, compound
[44] may be purified by crystallization as alkylamine salt such
as dicyclohexylamine and the like.
[0293]
(step 3)
20 [0294]
[0295]
83
wherein X4 is a leaving group or a hydroxyl group, and other
each symbol is as defined above.
Compound [46] can be produced by reacting compound [44]
or an amine salt thereof with compound [45] in the presence or
absence of a base. This reaction can also be performed in 5 a
solvent.
The base is not particularly limited, and a base known
per se can be applied. For example, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate,
10 sodium hydrogen carbonate, potassium hydrogen carbonate,
triethylamine, tributylamine, methylamine, dimethylamine can be
mentioned. The amount of the base to be used is generally 0.1
equivalents - 10 equivalents relative to compound [44].
The solvent is not particularly limited as long as the
15 reaction proceeds, and methanol, ethanol, isopropyl alcohol,
dimethylformamide and the like can be mentioned. The amount of
the solvent to be used is generally 0.01 mL - 100 mL,
preferably 0.1 mL - 10 mL, per 1 mmol of compound [44].
The reaction temperature is generally -50C - 150C,
20 preferably 10C - 100C.
The reaction time is generally 0.1 hr - 48 hr, preferably
0.5 hr - 20 hr.
[0296]
(step 4)
25 [0297]
[0298]
wherein the symbol is as defined above.
Compound [47] can be produced using compound [46] in the
30 same manner as in the method described in the above-mentioned
84
Production method 1.
[0299]
The salt of compound [11] is not particularly limited and,
for example, salts with hydrochloric acid, sulfuric acid and
the like can be mentioned5 .
The salt of compound [23], compound [28], compound [35],
compound [38] or compound [47] is not particularly limited as
long as it is pharmacologically acceptable and, for example,
salts with mineral acids such as hydrochloric acid, sulfuric
10 acid, hydrobromic acid, phosphoric acid and the like;
salts with organic acids such as methanesulfonic acid, ptoluenesulfonic
acid, acetic acid, oxalic acid, citric acid,
malic acid, fumaric acid and the like;
salts with alkali metals such as sodium, potassium and the
15 like;
salts with alkaline earth metals such as magnesium and the
like;
salts with amines such as ammonia, ethanolamine, 2-amino-2-
methyl-1-propanol and the like can be mentioned.
20 [0300]
Compound [23], compound [28], compound [35], compound
[38], compound [47], and salts thereof include solvates.
Examples of the solvate include hydrate and alcohol solvates
(e.g., methanol solvate, ethanol solvate).
25
Examples
[0301]
The present invention is specifically explained in the
following by referring to Reference Examples and Examples,
30 which are not to be construed as limitative.
In the following Reference Example and Examples, “room
temperature” means 15C - 30C.
In the following Reference Examples and Examples, “%” of
the concentrations and contents means “wt%” unless particularly
35 indicated.
85
In the following Reference Examples and Examples, “vol”
used for solvents means the amount (volume) per 1 g of
substrate.
[0302]
Abbreviations in the Examples show the followin5 g
compounds.
HBT: 1-benzyl-5-phenyltetrazole
BAC: [2’-(1-benzyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylacetate
BBA: p-bromobenzylacetate
10 BAL: [2’-(1-benzyl-1H-tetrazol-5-yl)biphenyl-4-yl]methanol
BBR: 1-benzyl-5-[4’-(bromomethyl)biphenyl-2-yl]-1H-tetrazole
VB: benzyl N-({2’-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-
yl}methyl)-L-valinate
VBV: benzyl N-({2’-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-
15 yl}methyl)-N-pentanoyl-L-valinate
CPI: 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one hydrochloride
IAL: 2-butyl-4-chloroimidazole-5-carbaldehyde
BIR: 3-[2’-(1-benzyl-1H-tetrazol-5-yl)biphenyl-4-yl]-2-butyl-
1,3-diazaspiro[4.4]non-1-en-4-one
20 LALD: 2-butyl-4-chloro-1-({2’-[1-benzyl-1H-tetrazol-5-
yl]biphenyl-4-yl}methyl)imidazole-5-carbaldehyde
LAL: 2-butyl-4-chloro-1-{[2’-(1-benzyl-1H-tetrazol-5-
yl)biphenyl-4-yl]methyl}imidazole-5-methanol
BCAN: 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2’-(1H25
tetrazol-5-yl)biphenyl-4-yl]methyl]benzoimidazole-7-carboxylate
IME: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-
carboxylate
BIA: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2’-[1-
benzyl-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-
30 carboxylate
BIH: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2’-[1Htetrazol-
5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate
BIT: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2’-[1-
(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-
35 yl]methyl]imidazole-5-carboxylate
86
BIC: potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2’-[1-
(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-
yl]methyl]imidazole-5-carboxylate
OXC: 4-(chloromethyl)-5-methyl-2-oxo-1,3-dioxol
TOLM: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-5 1-
methylethyl)-2-propyl-1-[[2’-[1-(triphenylmethyl)-1H-tetrazol-
5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate
BME: 1-benzyl-5-(4’-methylbiphenyl-2-yl)-1H-tetrazole
BBB: p-bromobenzylbenzoate
10 BBZ: 1-benzyl-5-[4’-(benzoyloxymethyl)biphenyl-2-yl]-1Htetrazole
OLM: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2’-(1H-tetrazol-
5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid
OLM MDX: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-
15 methylethyl)-2-propyl-1-[[2’-(2H-tetrazol-5-yl)biphenyl-4-
yl]methyl]imidazole-5-carboxylate
BVAL: benzyl N-{4-[2-(1-benzyl-1H-tetrazole―5-
yl)phenyl]benzyl}-N-valeryl-L-valinate
VAL: N-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-N-valeryl-L20
valine
VM: methyl N-[[2’-benzyl-1H-tetrazol-5-yl][1,1’-biphenyl]-4-
yl]methyl]-L-valinate
BMVAL: methyl N-{4-[2-(1-benzyl-1H-tetrazol-5-
yl)phenyl]benzyl}-N-valeryl-L-valinate
25 MVAL: methyl N-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-Nvaleryl-
L-valinate
IR: 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-
diazaspiro[4.4]non-1-en-4-one
LOS: 2-butyl-4-chloro-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-
30 yl]methyl}imidazole-5-methanol
CAN: (1RS)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2’-
(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-
carboxylate
BIM: methyl 2-ethoxy-1H-benzimidazole-7-carboxylate
35 CBCA: 2-ethoxy-1-[2’-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl]-
87
1H-benzimidazole-7-carboxylic acid
CV: 2-ethoxy-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1Hbenzo[
d]imidazole-7-carboxylic acid
CBME: methyl 2-ethoxy-1-[2’-[1-benzyl-1H-tetrazol-5-
yl]biphenyl-4-yl]-1H-benzimidazole-7-carboxylat5 e
DPOLM: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-
methylethyl)-2-propyl-1-[[2’-[2-(2,4-dimethoxybenzyl)-2Htetrazol-
5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate
[0303]
10 Reference Example 1 (synthesis of BBR)
1. BME
[0304]
[0305]
15 A mixture of triphenylphosphine (0.355 g, 1.35 mmol), 1-
benzyl-5-phenyl-1H-tetrazole (HBT, 10 g, 42.3 mmol), potassium
carbonate (5.85 g, 42.3 mmol), potassium bis(2-
ethylhexyl)phosphate NMP solution (2.5 wt%, 19.46 mL, 1.35
mmol), p-bromotoluene (BTL, 7.96 g, 46.6 mmol) and N-methyl-2-
20 pyrrolidone (50 mL) was heated under a nitrogen atmosphere to
138C, dichloro(p-cymene)ruthenium (II) dimer (0.207 g, 0.338
mmol as monomer) was added and the mixture was stirred at the
same temperature for 12 hr. The reaction mixture was cooled,
and mixed with water (20 mL) and t-butyl methyl ether (40 mL).
25 The aqueous layer was extracted with t-butyl methyl ether (40
mLx2), and the organic layers were combined and washed with
water (40 mL×2) and brine (20 mL), dried over sodium sulfate,
88
and concentrated under reduced pressure to give a crude product
of BME (14.0 g, 101.4% of theoretical yield) as a dark brown
oil. t-Butyl methyl ether (6 mL) was added to 2 g of this
product to allow for crystallization, and the obtained solid
was filtered to give 1-benzyl-5-(4’-methylbiphenyl-2-yl)-5 1Htetrazole
(BME, 1.5 g, yield 76%).
melting point: 140C;
IR (KBr): νmax = 1455, 1093 cm-1;
1H NMR (CDCl3): δ= 7.61 (dt, J = 8.0, 1.6 Hz, 1H), 7.56 (dd, J
10 = 7.8, 0.8 Hz, 1H), 7.39 (dt, J = 7.8, 1.2 Hz, 1H), 7.33 (dd, J
= 7.8, 1.2 Hz, 1H), 7.22 - 7.08 (m, 5H), 7.03 (d, J = 8.4 Hz,
2H), 6.75 (d, J = 7.2 Hz, 2H), 4.76 (s, 2H), 2.34 (s, 3H);
13C NMR (CDCl3): δ = 154.5, 141.4, 137.7, 135.6, 132.9, 131.3,
130.9, 129.9, 129.4, 128.4, 128.2, 127.6, 127.3, 122.3, 50.5,
15 20.8;
HRMS: [M+Na]+ calcd for C21H18N4Na 349.1429, found 349.1425;
Mass (M+H): 327.0 amu;
HPLC Purity (Area %): 99.3.
[0306]
20 2. BBR
[0307]
[0308]
1-Benzyl-5-(4’-methylbiphenyl-2-yl)-1H-tetrazole (BME,
25 1.0 g, 3.06 mmol) was dissolved in ethyl acetate (4 mL), 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH, 0.86 g, 3 mmol) and 2,2’-
azobisisobutyronitrile (AIBN, 15 mg, 0.091 mmol) were added,
and the mixture was heated under reflux for 6 hr. Crude 1-
benzyl-5-(4’-bromomethylbiphenyl-2-yl)-1H-tetrazole (BBR) was
30 produced at a conversion ratio of about 40%. Purification by
89
silica gel column chromatography gave BBR.
melting point: 70.9C;
IR (neat): 1603 cm-1;
1H NMR (CDCl3): δ = 7.65 (td, J = 7.5, 1.5 Hz, 1H), 7.57 (dd, J
= 7.5, 1.5 Hz, 1H), 7.45 (td, J = 7.9, 1.4 Hz, 1H), 7.35 (dd, 5 J
= 7.9, 1.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.22 (t, J = 8.2
Hz, 1H), 7.17 (t, J = 8.2 Hz, 2H), 7.10 (2H, J = 8.2 Hz, 2H),
6.77 (d, J = 8.2 Hz, 2H), 4.82 (s, 2H), 4.46 (s, 2H).
13C NMR (CDCl3): δ = 154.0, 140.3, 139.2, 137.9, 133.0, 131.9,
10 131.0, 130.2, 129.0, 128.7, 128.6, 128.4, 128.3, 122.4, 50.9,
31.7.
MS: 405 [M + H]+.
HRMS: Calcd for C21H17BrN4, 427.0534 [M + Na]+. Found 427.0536 [M
+ Na]+.
15 [0309]
Example 1-1
[0310]
[0311]
20 A mixture of IME (5 g, 21.0 mmol), BBR (9.05 g, 22.3
mmol), potassium carbonate (5.1 g, 37.4 mmol) and acetonitrile
(50 mL, 10 vol) was stirred at 84C for 18 hr. The conversion
yield of this reaction was 92.68%. The reaction mixture was
filtered through celite, and ethyl acetate was added. The
25 mixture was washed with 2% hydrochloric acid and saturated
brine, dried over sodium sulfate, and concentrated under
90
reduced pressure to give BIA (9.78 g, yield 83.2%).
melting point: 88C - 91C;
IR (KBr): νmax = 3416, 2967, 1702, 1466, 1218, 1172 cm-1;
1H NMR (CDCl3): δ = 7.64 (dt, J = 15.3, 7.6, 1.2 Hz, 1H), 7.50
(dd, J = 7.6, 1.2 Hz, 1H), 7.43 (dt, J = 15.3, 7.6, 1.2 Hz, 1H)5 ,
7.31 (dd, J = 7.6, 1.2 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.08 (d, J
= 8.2 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.0 Hz,
2H), 5.42 (s, 2H), 4.82 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.63
(t, J = 7.6 Hz, 2H), 1.75 - 1.64 (m, 2H), 1.61 (s, 6H), 1.15 (t,
10 J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).
[0312]
Example 1-2(a): deprotection
[0313]
15
[0314]
A mixture of BIA (0.3 g, 0.53 mmol), ammonium formate
(0.16 g, 2.58 mmol), 5% Pd-BaSO4 (0.057 g, 5 mol%), isopropyl
alcohol (3 mL, 10 vol) and water (1.8 mL, 6 vol) was stirred at
20 55C for 11 hr. The conversion yield of this reaction was
93.1%. The reaction mixture was filtered, the filtrate was
concentrated, and the concentrated residue was purified by
silica gel column chromatography (2 - 3% methanol/methylene
chloride) to give the object compound (211 mg, yield 84.3%).
25 IR (KBr): νmax = 1706, 1604, 1273 cm-1;
1H NMR (CDCl3): δ = 7.91 (d, J = 7.6 Hz, 1H), 7.60 - 7.52 (m,
91
2H), 7.42 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.75 Hz, 2H), 6.81
(d, J = 8 Hz, 2H), 5.40 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.38
(t, J = 7.2 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.45 (s, 6H), 1.25 (s,
1H), 1.13 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.6 Hz, 3H)
13C NMR (CDCl3): δ = 161.6, 158.5, 155.5, 151.6, 140.8, 138.95 ,
136.4, 131.2, 130.8, 130.5, 129.6, 128.1, 125.3, 123.5, 117.1,
70.5, 61.7, 48.9, 29.0, 28.7, 21.7, 13.8;
Mass: 475 [M + H]+.
[0315]
10 Example 1-2(b): deprotection
[0316]
[0317] 15
A mixture of BIA (0.1 g, 0.17 mmol), sodium formate
(0.092 g, 0.86 mmol), 5% Pd-BaSO4 (0.019 g, 5 mol%), isopropyl
alcohol (1 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred at
55C for 4 hr. The conversion yield of this reaction was
20 91.16%.
[0318]
Example 1-2(c): deprotection
[0319]
92
[0320]
A mixture of BIA (0.1 g, 0.17 mmol), ammonium formate
(0.055 g, 0.86 mmol), 5% Pd-CaCO3 (0.019 g, 5 mol%), isopropy5 l
alcohol (1 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred at
55C for 9 hr. The conversion yield of this reaction was
90.44%.
[0321]
10 Example 1-3
[0322]
[0323] 15
To a mixture of BIH (0.656 g, 1.38 mmol), triethylamine
(0.22 mL, 1.52 mmol) and methylene chloride (7.8 mL, 12 vol)
93
was added a solution of trityl chloride (0.416 g, 1.49 mmol) in
methylene chloride (1.5 mL) at 0 - 5C, and the mixture was
stirred at the same temperature for 1 hr and at 25C for 3.5 hr.
The reaction mixture was concentrated under reduced pressure,
and the concentrated residue was purified by silica gel colum5 n
chromatography (17 - 18% ethyl acetate/hexane) to give BIT (746
mg, yield 75.4%).
1H NMR (CDCl3): δ = 7.88 (d, J = 1.6 Hz, 1H), 7.50 - 7.44 (m,
2H), 7.37 - 7.24 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 6.96 - 6.94
10 (m, 6H), 6.72 (d, J = 8.4 Hz, 2H), 5.81 (s, 1H), 5.35 (s, 2H),
4.13 (q, J = 7.2 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.64 (s,
6H), 1.69 - 1.61 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H), 0.88 (t, J
= 7.2 Hz, 3H);
Mass: 717.6 [M+ H]+.
15 [0324]
Example 1-4
[0325]
[0326] 20
To a mixture of BIT (0.7 g, 0.98 mmol) and isopropyl
alcohol (10.5 mL, 15 vol) was added a solution of potassium
hydroxide in isopropyl alcohol (0.224 g in 5.0 mL), and the
mixture was stirred at 40C for 4 hr. The reaction mixture was
25 concentrated under reduced pressure, and to the concentrated
residue were added water (5 mL), sodium chloride (0.5 g) and
ethyl acetate (7 mL). The aqueous layer was extracted with
94
ethyl acetate (3×3.5 mL, 5 vol). The organic layers were
combined, washed with aqueous sodium hydrogen carbonate
solution (2×3.5 mL, 5 vol), and concentrated under reduced
pressure to give BIC (730 mg, quant.).
Mass: 711 [M+ Na]+5 .
[0327]
Example 1-5
[0328]
10
[0329]
A mixture of BIC (0.6 g, 0.83 mmol), potassium iodide
(0.069 g, 0.41 mmol), OXC (0.245 g, 1.65 mmol) and methyl ethyl
ketone (9.0 mL, 15 vol) was stirred at 50C for 20 hr. The
15 reaction mixture was filtered, the filtrate was concentrated
under reduced pressure, and the obtained concentrated residue
was purified by silica gel column chromatography (20 - 22%
ethyl acetate/hexane) to give TOLM (650 mg, yield 84.4%).
Mass: 801 [M + H]+, 824 [M+ Na]+.
20 [0330]
Example 1-6
[0331]
95
[0332]
A mixture of TOLM (0.6 g, 0.75 mmol), sulfuric acid (0.08
g, 0.82 mmol) and 1:1 water-containing acetic acid (2.6 mL, 4.5 3
vol) was stirred at 25C for 1 hr. The reaction mixture was
filtered, and the obtained solid was washed with 1:1 watercontaining
acetic acid (6.0 mL, 10 vol). The filtrates were
combined and adjusted to pH 4 - 5 by adding 25% aqueous sodium
10 carbonate solution. The mixture was partitioned by adding
methylene chloride (6.0 mL, 10 vol). The aqueous layer was
extracted with methylene chloride (3×5 mL). The organic layer
was washed with water (2×5 mL) and saturated brine (5 mL), and
concentrated under reduced pressure. The concentrated residue
15 was purified by silica gel column chromatography (5 - 6%
methanol/methylene chloride) and recrystallized from
acetonitrile to give OLM (0.45 g, yield 100%).
melting point: 174.5C - 175.2C;
IR (KBr): νmax = 2969, 1831, 1706, 1475, 1226, 1134, 760 cm-1;
20 1H NMR (DMSO-d6): δ = 7.70 - 7.63 (m, 2H), 7.59 - 7.52 (m, 2H).
7.04 (d, J = 8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.42 (s, 2H),
5.21 (s, 1H), 5.05 (s, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.07 (s,
3H), 1.60 - 1.55 (m, 2H), 1.47 (s, 6H), 0.87 (t, J = 7.2 Hz,
3H);
25 Mass: 559 [M + H]+.
[0333]
96
Example 2-1
[0334]
[0335]
A mixture of L-valine benzyl ester p-toluenesulfonate (5 2
g, 5.27 mmol), BBR (2.35 g, 5.8 mmol), diisopropylethylamine
(2.18 mL, 13.8 mmol) and acetonitrile (20 mL, 10 vol) was
stirred at 78C for 8 hr. The reaction mixture was
concentrated under reduced pressure, and ethyl acetate was
10 added to the concentrated residue. The mixture was washed with
water and saturated brine, and concentrated under reduced
pressure. The concentrated residue was purified by neutral
alumina column chromatography (25 - 30% ethyl acetate/hexane)
to give VB (2.4 g, yield 85.7%).
15 1H NMR (CDCl3): δ = 7.64 - 7.62 (m, 1H), 7.61 (dd, J = 14.0,
1.6 Hz, 1H), 7.57 - 7.06 (m, 14H), 6.75 (d, J = 1.6 Hz, 1H),
5.19 (d, J = 1.2 Hz, 2H), 4.76 (s, 2H), 3.81 (d, J = 13.6 Hz,
1H), 3.55 (d, J = 13.6 Hz, 1H), 3.01 (d, J = 6.0 Hz, 1H), 1.98
- 1.93 (m, 1H), 0.95 - 0.92 (m, 6H);
20 13C NMR (CDCl3): δ = 174.8, 154.5, 141.3, 140.0, 137.3, 135.6,
132.9, 131.4, 131.1, 130.1, 128.5, 128.4, 128.4, 128.3, 127.7,
127.5, 122.5, 66.5, 66.2, 51.7, 50.6, 31.5, 19.2, 18.4;
Mass: 532 [M + H]+.
[0336]
25 Example 2-2
[0337]
97
[0338]
To a mixture of VB (0.4 g, 0.75 mmol),
diisopropylethylamine (0.44 mL, 2.65 mmol) and toluene (4 mL,
10 vol) was added dropwise valeryl chloride (0.18 g, 1.5 mmol5 )
at 0 - 5C. The reaction mixture was stirred at room
temperature for 2 hr, and water (2 mL, 5 vol) was added. The
organic layer was washed successively with water (2×10 mL),
0.2N aqueous sodium hydroxide solution (2×10 mL), water (2×10
10 mL) and saturated brine (10 mL), and concentrated under reduced
pressure. The concentrated residue was purified by silica gel
column chromatography (20 - 22% ethyl acetate/hexane) to give
BVAL (0.38 g, yield 82.6%).
IR(KBr) νmax = 2961, 1739, 1652, 1467, 1407, 1262, 1188, 1003,
15 759, 665 cm-1;
1H NMR (DMSO-d6): δ= 8.318 (s, 0.4H), 7.73 (dt, J = 1.5, 8.0,
15.0 Hz, 0.8H), 7.56 - 7.51 (m, 2H), 7.37 - 7.33 (m, 2H), 7.27
- 7.21 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8Hz, 0.5
H), 6.86 (d, J = 8.0 HZ, 1H), 6.81 (dd, J = 2.0, 7.6 Hz, 1H),
20 5.11 (d, J = 7.6 Hz, 0.4 H), 5.03 (s, 1H), 4.84 (q, J = 13.2 Hz,
1.6H), 4.64 (d, J = 7.0 Hz, 0.8H), 4.45 (d, J = 9.8 Hz, 0.7H),
4.27 (d, J = 10.5 Hz, 0.7H), 2.60 - 2.55 (m, 1H), 2.30 - 2.08
(m, 2H), 1.54 - 1.39 (m, 2H), 1.28 - 1.11 (m, 3H), 0.92 (d, J =
6.5 Hz, 2H), 0.87 - 0.83 (m, 5H);
25 Mass: 638 [M + H]+.
[0339]
Example 2-3: deprotection
[0340]
98
[0341]
A mixture of BVAL (0.1 g, 0.16 mmol), ammonium formate
(0.1 g, 1.58 mmol), 5% Pd-BaSO4 (0.035 g, 10 mol%), isopropyl
alcohol (1 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred a5 t
65C for 8 hr, the reaction mixture was cooled to 25C, and 5%
Pd-BaSO4 (7.0 mg, 2.0 mol%) was further added. The reaction
mixture was stirred at 65C for 3 hr. The conversion yield of
this reaction was 98.9%. The reaction mixture was filtered
10 through celite, the filtrate was concentrated under reduced
pressure, and the obtained concentrated residue was purified by
silica gel column chromatography (5% methanol/methylene
chloride) to give valsartan (VAL) (0.1 g, yield 70.7%).
melting point: 70C - 95C;
15 IR (KBr): νmax = 1730, 1619 cm-1;
1H NMR (DMSO-d6): (CM: major rotamer; Cm: minor rotamer): δ =
16.3 (brs, 1H), 12.6 (brs, 1H), 7.70 - 7.63 (m, 2H, CM, Cm),
7.58 - 7.53 (m, 2H, CM, Cm), 7.20 (d, J = 8.2 Hz, 1H, CM), 7.08
(d, J = 8.2 Hz, 1H, Cm), 7.07 (d, J = 8.2 Hz, 1H, CM), 6.97 (d,
20 J = 8.2 Hz, 1H, Cm), 4.62 (s, 2H, CM), 4.48 (d, J = 15.2 Hz, 1H,
Cm), 4.46 (d, J = 10.3 Hz, 1H, CM), 4.43 (d, J = 15.2 Hz, 1H,
Cm), 4.08 (d, J = 10.5 Hz, 1H, Cm), 2.53 - 2.45 (m, 2H, Cm),
2.22 - 2.12 (m, 1H, CM, Cm), 2.21 (dt, J = 15.8, 7.9 Hz, 1H, CM),
2.03 (dt, J = 15.8, 7.9 Hz, 1H, CM), 1.54 (quint, J = 6.9 Hz,
25 2H, Cm), 1.41 (dquint, J = 14.1, 7.9 Hz, 1H, CM), 1.37 (dquint,
J = 14.1, 7.9 Hz, 1H, CM), 1.31 (sext, J = 6.9 Hz, 2H, Cm),
1.15 (sext, J = 7.9 Hz, 2H, CM), 0.93 (d, J = 6.9 Hz, 3H, Cm),
99
0.93 (d, J = 7.9 Hz, 3H, CM), 0.88 (t, J = 6.9 Hz, 3H, Cm),
0.76 (t, J = 7.9 Hz, 3H, CM), 0.75 (d, J = 7.9 Hz, 3H, CM),
0.70 (d, J = 6.9 Hz, 3H, Cm);
HRMS: Calcd for C24H29N5O3, 435.2270 [M]+. Found 435.2267 [M]+.
[03425 ]
Example 3-1
[0343]
[0344]
10 L-valine methyl ester hydrochloride (5 g, 1 equivalent)
and acetonitrile (100 mL, 20 vol) were charged in a flask, and
potassium carbonate (20.6 g, 5 equivalents) was added. The
reaction mixture was stirred for 5 min, and BBR (12 g, 1
equivalent) was added. The mixture was stirred at 40C - 45C
15 for 12 hr. The degree of progression of the reaction was
checked by TLC: thin layer chromatography (TLC eluent: 30%
ethanol/hexane, detection method: UV), and complete consumption
of BBR was confirmed. The reaction mixture was filtered, and
the obtained solid was washed with acetonitrile (10 mL, 2 vol).
20 The filtrate and washing were combined, and concentrated under
reduced pressure at 40C - 45C to give a crude product. To
this crude product was added toluene (12.5 mL, 10 vol). The
mixture was adjusted to pH 1 - 2 with concentrated hydrochloric
acid, and stirred at 25C - 30C for 2 hr. The precipitated
25 solid was collected by filtration, and dried with suction for
30 min to give hydrochloride of VM as a crude product. The
100
solid was suspended in 10% ethyl acetate/hexane (25 mL, 5 vol),
and the suspension was stirred for 30 min. This suspension was
filtered, and washed with hexane (25 mL, 5 vol). The obtained
solid was dried with suction for 30 min to give hydrochloride
of VM (10.4 g, yield 71%)5 .
[0345]
Example 3-2
[0346]
10 [0347]
Hydrochloride of VM (4.5 g, 1 equivalent) and toluene (45
mL, 10 vol), and diisopropylethylamine (5.7 mL, 3.5
equivalents) were charged in a flask. The mixture was stirred
for 5 min, and cooled to 0C - 5C. To this mixture was added
15 dropwise valeryl chloride (2.35 mL, 2 equivalents) over 10 min.
After completion of the dropwise addition, the mixture was
stirred at 25C - 30C for 2 hr. The degree of progression of
the reaction was checked by TLC (TLC eluent: 30% ethyl
acetate/hexane, detection method: UV), and complete consumption
20 of VM was confirmed. The reaction mixture was cooled to 0C -
5C, and water (22.5 mL, 5 vol) was added. A mixture of these
two layers was stirred at 25C - 30C for 1 hr, left standing,
and partitioned. The organic layer was washed with deionized
water (2×10 mL, 2×2.2 vol) and further washed successively with
25 0.2N aqueous sodium hydroxide solution (2×10 mL, 2×2.2 vol) and
saturated brine (2×10 mL), and dried over sodium sulfate. The
101
mixture was filtered, and the filtrate was concentrated under
reduced pressure at 40C - 45C to give BMVAL (5.44 g, yield
91%).
[0348]
Example 3-3: deprotectio5 n
[0349]
[0350]
BMVAL (5 g, 1 equivalent), isopropanol (50 mL, 10 vol)
10 and water (30 mL, 6 vol) were charged in a flask. To this
mixture were added ammonium formate (5.72 g, 9.8 equivalents)
and 5% Pd/BaSO4-Type29a (0.098 g, 10 mol%), and the mixture was
stirred at 60C - 65C for 4 hr. The degree of progression of
the reaction was checked by TLC (TLC eluent: 30% ethyl
15 acetate/hexane, detection method: UV), and complete consumption
of BMVAL was confirmed. The reaction mixture was cooled to
25C - 30C, and filtered with a filter lined with celite. The
celite was washed with isopropanol (25 mL, 5 vol). The
filtrate and washing were combined, and the mixture was
20 concentrated under reduced pressure at 40C - 45C to give a
syrup. To this syrup were added t-butyl methyl ether (25 mL, 5
vol) and deionized water (10 mL, 2 vol), and the mixture was
stirred for 5 min, left standing for 5 min, and partitioned.
The aqueous layer was extracted with t-butyl methyl ether (10
25 mL, 2 vol). The organic layers were combined, washed with
deionized water (15 mL, 3 vol), and dried over sodium sulfate.
The mixture was dried under reduced pressure at 40C - 45C to
give crude MVAL (2.0 g, yield 48%). The crude product was used
102
without purification for the next step.
[0351]
Example 3-4
[0352]
5
[0353]
MVAL (2 g, 1 equivalent) was dissolved in methanol (5 mL,
2.5 vol). The solution was cooled to 0C - 5C, aqueous sodium
hydroxide solution (0.53 g sodium hydroxide/2.5 mL deionized
10 water) was added, and the mixture was stirred at 0C - 5C for
5 min. The mixture was stirred at 60C - 65C for 4 hr. The
degree of progression of the reaction was checked by TLC (TLC
eluent: 5% methanol/methylene chloride, detection method: UV),
and complete consumption of MVAL was confirmed. The reaction
15 mixture was concentrated under reduced pressure at 40C - 45C.
To the concentrated residue were added deionized water (10 mL,
5 vol) and methylene chloride (10 mL, 5 vol), and the mixture
was stirred for 5 min and partitioned. Concentrated
hydrochloric acid was added at 0 - 5C, and the aqueous layer
20 was adjusted from pH 10 - 12 to 1 - 2. The obtained mixture
was extracted with methylene chloride (2×10 mL, 2×5 vol). To
the organic layer was added sodium sulfate, and the mixture was
dried. The mixture was filtered, and the filtrate was
concentrated under reduced pressure to give crude VAL (2.1 g,
25 yield 108%). The crude product was recrystallized from ethyl
acetate to give the object compound (HPLC purity: 99.72 area%).
[0354]
Example 4-1
103
[0355]
[0356]
A mixture of CPI (0.2 g, 0.87 mmol), BBR (0.39 g, 0.95
mmol), potassium carbonate (0.2 g, 1.47 mmol) and acetonitril5 e
(5.0 mL, 25.0 vol) was stirred at 80 - 85C for 20 hr. The
reaction mixture was filtered, the filtrate was concentrated
under reduced pressure, and the concentrated residue was
purified by silica gel column chromatography (1%
10 methanol/methylene chloride) to give BIR (0.43 g, yield 47.7%).
IR(KBr): νmax= 1723(COO), 1632(CON), 1604 cm-1;
1H NMR(CDCl3): δ = 7.64 (td, J = 7.7, 1.5 Hz, 1H), 7.54(dd, J =
7.7, 1.5 Hz, 1H), 7.44(td, J = 7.7, 1.5 Hz, 1H), 7.38(dd, J =
7.7, 1.5 Hz, 1H), 7.22(t, J = 7.7 Hz, 1H), 7.16(t, J = 7.7 Hz,
15 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.08(d, J = 7.7 Hz, 2H), 7.07(d,
J = 7.7 Hz, 1H), 6.77(d, J = 7.7 Hz, 2H), 4.81(s, 2H), 4.65(s,
2H, CH2N), 2.28(t, J = 7.7 Hz, 2H), 2.03 - 1.94(m, 6H), 1.83 -
1.81(m, 2H), 1.58(quint, J = 7.7 Hz, 2H), 1.33(sext, J = 7.7 Hz,
2H), 1.87(t, J = 7.7 Hz, 2H);
20 13C NMR(CDCl3): δ = 187, 161, 154, 141, 141, 138, 137, 133, 132,
131, 131, 130, 129, 129, 129, 129, 128, 128, 128, 127, 127, 123,
51, 43, 37, 29, 28, 26, 22, 14; Mass: 519 [M + H]+.
[0357]
Example 4-2(a): deprotection
25 [0358]
104
[0359]
A mixture of BIR (0.1 g, 0.19 mmol), ammonium formate
(0.059 g, 0.94 mmol), 5% Pd-BaSO4 (0.021 g, 5.0 mol%)5 ,
isopropyl alcohol (1.0 mL, 10 vol) and water (0.6 mL, 6 vol)
was stirred at 55C for 3.5 hr. The conversion yield of this
reaction was 87.42%. The reaction mixture was filtered through
celite, the filtrate was concentrated under reduced pressure,
10 and the concentrated residue was purified by silica gel column
chromatography to give irbesartan (IR) (0.091 g).
IR (KBr): νmax = 1725, 1630cm-1;
1H NMR (DMSO-d6): δ = 7.68 (t, J = 7.8 Hz, 1H), 7.64 (d, J =
7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H),
15 7.08 (s, 4H), 4.68 (s, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.86-1.60
(m, 8H), 1.47 (quint, J = 7.5 Hz, 2H), 1.26 (sext, J = 7.5 Hz,
2H), 0.80 (t, J = 7.5 Hz, 2H);
Mass: 429 [M + H]+.
[0360]
20 Example 4-2(b): deprotection
[0361]
105
[0362]
A mixture of BIR (0.1 g, 0.19 mmol), ammonium formate
(0.059 g, 0.94 mmol), 5% Pd-BaSO4 (0.021 g, 5.0 mol%),
isopropyl alcohol (1.0 mL, 10 vol) and water (0.6 mL, 6 vol5 )
was stirred at 55C for 4 hr. The conversion yield of this
reaction was 87.42%. The reaction mixture was filtered through
celite, and the filtrate was concentrated under reduced
pressure. To the concentrated residue were added ethyl acetate
10 and water, and the mixture was partitioned. The aqueous layer
was extracted with chloroform, and the organic layers were
combined and concentrated under reduced pressure. To the
concentrated residue was added 95% ethanol, and the mixture was
dissolved by heating, and cooled to 10C to allow for
15 crystallization. The precipitated crystals were filtered,
washed with cold ethanol, and dried under reduced pressure to
give irbesartan (IR) (0.056 g, yield 68.3%).
[0363]
Example 5-(1)(a)
20 [0364]
106
[0365]
A mixture of IAL (0.2 g, 0.11 mmol), BBR (0.48 g, 1.18
mmol), potassium carbonate (0.25 g, 1.82 mmol) and acetonitrile
(5 mL, 25 vol) was stirred at 80 - 85C for 20 hr. Th5 e
reaction mixture was filtered, the filtrate was concentrated
under reduced pressure, and the concentrated residue was
purified by silica gel column chromatography (18 - 20% ethyl
acetate/hexane) to give LALD (0.4 g, yield 76.9%).
10 IR (KBr): νmax = 1665, 1517, 1459, 1275cm-1;
1H NMR (CDCl3): δ = 9.76 (s, 1H), 7.65 - 7.61 (m, 1H), 7.53 (dd,
J = 8.0, 1.2 Hz, 1H), 7.44 (dt, J = 7.6, 1.2 Hz, 1H), 7.33 (dd,
J = 7.6, 1.2 Hz, 1H), 7.24 - 7.14 (m, 3 H) 7.08 (d, J = 8.0 Hz,
2H), 6.99 (d, J = 8 Hz, 2H), 6.78 (d, J = 7.6 Hz, 2H), 5.52 (s,
15 2H), 4.80 (s, 2H), 2.61 (t, J = 7.6 Hz, 2H), 1.72 - 1.64 (m,
2H), 1.40 - 1.31 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H);
Mass: 511 [M]+.
[0366]
Example 5-(1)(b)
20 [0367]
107
[0368]
A mixture of IAL (2 g, 10.7 mmol), BBR (4.8 g, 11.8 mmol),
potassium carbonate (2.5 g, 18.2 mmol) and acetonitrile (20 mL,
10 vol) was stirred at 25C for 20 hr. Furthermore, BBR (0.25 2
g) was added at 25C, and the mixture was stirred at the same
temperature for 5 hr. The reaction mixture was filtered, the
filtrate was concentrated under reduced pressure, and the
concentrated residue was purified by silica gel column
10 chromatography (17 - 18% ethyl acetate/hexane) to give LALD
(3.5 g, yield 64.3%).
[0369]
Example 5-(2)(a)
[0370]
15
[0371]
To a mixture of LALD (0.38 g, 0.74 mmol), methanol (1.8
mL, 4.7 vol) and toluene (0.76 mL, 2 vol) was added sodium
108
borohydride (0.028 g, 0.73 mmol) at 0 - 5C, and the mixture
was stirred at 0 - 5C for 5 min and at 25C for 30 min. To
the reaction mixture was added water (1 mL) at 10C, then ethyl
acetate was added, and the mixture was partitioned. The
aqueous layer was extracted with ethyl acetate, and the organi5 c
layers were combined, washed with water and saturated brine,
and concentrated under reduced pressure. The concentrated
residue was purified by silica gel column chromatography (30%
ethyl acetate/hexane) to give LAL (0.3 g, yield 78.7%).
10 IR (KBr): νmax= 2935, 1725, 1577, 1256 cm-1;
1H NMR (CDCl3): δ= 7.51 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 6.8
Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1 H),
7.10-7.00 (m, 3H), 6.95 (d, J = 8 Hz, 2H), 6.79 (d, J = 8.0 Hz,
2H), 6.66 (d, J = 8.0 Hz, 2H), 5.05 (s, 2H), 4.71 (s, 2H), 4.36
15 (s, 2 H), 2.42 (t, J = 8.0 Hz, 2H), 1.57-1.50 (m, 2H), 1.25 -
1.15 (m, 2H), 0.92 - 0.83 (m, 3H);
13C NMR (CDCl3): δ= 154.3, 148.4, 141.0, 138.4, 136.1, 132.9,
131.6, 131.1, 130.2, 129.2, 128.7, 128.7, 128.0, 127.8, 127.2,
126.5, 124.9, 122.5, 52.9, 50.9, 47.1, 29.6, 26.7, 22.3, 13.7.
20 [0372]
Example 5-(2)(b)
[0373]
[0374]
25 To a mixture of LALD (2 g, 3.9 mmol), methanol (9.5 mL,
4.75 vol) and toluene (4 mL, 2 vol) was added sodium
borohydride (0.145 g, 3.8 mmol) at 0 - 5C, and the mixture was
109
stirred at 0 - 5C for 5 min and at 25C for 30 min. To the
reaction mixture was added water (4 mL) at 10C, then ethyl
acetate was added, and the mixture was partitioned. The
aqueous layer was extracted with ethyl acetate, and the organic
layers were combined, washed with water and saturated brine5 ,
and concentrated under reduced pressure. To the concentrated
residue was added a mixture of ethyl acetate/hexane=3/97 to
allow for crystallization, and the obtained crystals were
washed with hexane and dried under reduced pressure to give LAL
10 (1.9 g, yield 94.6%).
[0375]
Example 5-3(a): deprotection
[0376]
15
[0377]
A mixture of LAL (0.1 g, 0.195 mmol), ammonium formate
(0.06 g, 0.95 mmol), 5% Pd-BaSO4 (0.033 g, 8.0 mol%), isopropyl
alcohol (1.0 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred
20 at 60C for 8 hr. The conversion yield of this reaction was
96.98%. The reaction mixture was filtered through celite, and
the filtrate was concentrated under reduced pressure. To the
concentrated residue was added ethyl acetate, and the mixture
was extracted. The aqueous layer was extracted with ethyl
25 acetate, and the organic layers were combined and concentrated
under reduced pressure. The concentrated residue was purified
by silica gel column chromatography (6% methanol/methylene
110
chloride) to give losartan (LOS) (0.57 g, yield 70.7%).
melting point: 161C - 164C;
IR (KBr): νmax = 1469, 1256, 1021, 756 cm-1;
1H NMR (DMSO-d6): δ = 7.70 - 7.50 (m, 4H), 7.12 - 7.00 (m, 4H),
5.23 (s, 2H), 4.32 (s, 2H), 2.45 (t, J = 7.6 Hz, 2H), 1.46 5 -
1.42 (m, 2H), 1.25 - 1.20 (m, 2H), 0.79 (t, J = 8 Hz, 3H);
13C NMR (DMSO-d6): δ =147.0, 140.5, 138.0 136.2, 135.4, 130.6,
130.1, 128.6, 127.3, 125.8, 125.5, 50.8, 46.1, 28.4, 25.1, 21.1,
13.1;
10 MS: 423 [M + H]+.
[0378]
Example 5-3(b): deprotection
[0379]
15
[0380]
A mixture of LAL (0.1 g, 0.195 mmol), ammonium formate
(0.06 g, 0.95 mmol), 5% Pd-BaSO4 (0.021 g, 5.0 mol%), isopropyl
alcohol (1.0 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred
20 at 30C for 20 hr. The conversion yield of this reaction was
93.77%.
[0381]
Example 6-1
[0382]
111
[0383]
A mixture of BBR (9.82 g, 24 mmol), 2-(tertbutoxycarbonylamino)-
3-nitrobenzoic acid methyl ester (7.32 g,
24.7 mmol), potassium carbonate (3.68 g, 26.7 mmol) an5 d
acetonitrile (100 mL) was heated under reflux under an argon
stream for 6 hr. To the reaction mixture was added potassium
carbonate (1.34 g), and the mixture was heated under reflux for
3 hr. The reaction mixture was cooled and filtered, and the
10 insoluble material was washed with chloroform. The filtrate
and washing were combined and concentrated under reduced
pressure. The concentrated residue was purified by silica gel
column chromatography (hexane→hexane:ethyl
acetate=5:1→4:1→3:1→2:1→3:2) to give a Boc compound of the
15 object compound as a yellow amorphous product (12.17 g, yield
81%).
IR: 1710 cm-1.
1H NMR (CDCl3): δ = 8.05 - 8.11 and 7.88 - 7.90 (m, 2H), 7.60 -
7.61 (m, 1H), 7.50 - 7.52 (m, 1H), 7.05 - 7.26 (m, 10H), 6.78 -
20 6.80 (m, 2H), 4.85 - 4.94 and 4.72 - 4.75 (m, 4H), 3.79 (s, 3H),
1.34 (s, 9H).
MS: m/z = 621 (NH+)
[0384]
Example 6-2
25 [0385]
112
[0386]
To a mixture of the Boc compound (11.93 g, 19.2 mmol) in
methanol (15 mL) was added 2N hydrogen chloride/methanol
solution (30 mL) under ice-cooling, and the mixture was stirre5 d
at the same temperature for 2 hr and at room temperature
overnight. The reaction mixture was concentrated under reduced
pressure, methanol and diisopropyl ether were added to the
concentrated residue to allow for crystallization, and the
10 crystals were collected by filtration. The obtained crystals
were washed with diisopropyl ether and hexane, and dried under
reduced pressure to give a nitro compound of the object
compound as yellow crystals (8.64 g, yield 86%).
melting point: 115C - 117C.
15 IR: 1696, 1530, 1451, 1256 cm-1.
1H NMR (CDCl3): δ = 8.59 - 8.62 (m, 1H), 8.05 - 8.08 (m, 2H),
7.94 - 7.96 (m, 2H), 7.73 - 7.75 (m, 1H), 7.52 - 7.62 (m, 3H),
7.17 - 7.26 (m, 4H), 6.94 - 6.96 (m, 2H), 6.80 - 6.83 (m, 3H).
MS: m/z = 521 (NH+)
20 Anal: Calcd for C29H24N6O4: C: 6691; H: 9.65; N: 16.14%. Found:
C: 66.75; H: 4.66; N: 16.19%.
[0387]
Example 6-3
[0388]
25
[0389]
A mixture of the nitro compound (8.396 g), tin(II)
113
chloride dihydrate (13.56 g) and methanol (155 mL) was heated
under reflux for 2 hr. The reaction mixture was concentrated
under reduced pressure, to the concentrated residue were added
saturated aqueous sodium hydrogen carbonate solution and ethyl
acetate, and the mixture was stirred for 1 hr. The mixture wa5 s
filtered, and the insoluble material was washed with ethyl
acetate. The filtrate and washing were combined and
concentrated under reduced pressure, and the concentrated
solution was extracted with ethyl acetate. A solution of the
10 resultant product in ethyl acetate was dried over magnesium
sulfate and filtered. The filtrate was concentrated under
reduced pressure, and the concentrated residue was purified by
silica gel column chromatography (hexane→hexane:ethyl
acetate=5:1→4:1→3:1→2:1→3:2) to give a diamino compound of the
15 object compound as a brown amorphous product (6.68 g, yield
84%).
IR: 1692, 1468 cm-1.
1H NMR (CDCl3): δ = 7.56 - 7.64 (m, 2H), 7.05 - 7.43 (m, 10H),
6.86 - 6.90 (m, 2H), 6.74 - 6.76 (m, 2H), 4.68 (s, 2H), 4.16 (s,
20 2H), 3.80 (s, 3H).
MS: m/z = 491 (NH+)
[0390]
Example 6-4
[0391]
25
[0392]
A mixture of the diamino compound (6.46 g, 13 mmol),
tetraethoxymethane (3.6 mL, 17 mmol) and acetic acid (8 mL) was
stirred at 90C for 1 hr. The reaction mixture was cooled, ice
30 and saturated aqueous sodium hydrogen carbonate solution were
added, and the mixture was extracted with chloroform. The
114
extract was dried over magnesium sulfate and filtrated, and the
filtrate was concentrated under reduced pressure. The
concentrated residue was purified by silica gel column
chromatography (hexane→hexane:ethyl
acetate=5:1→4:1→3:1→2:1→1:1) to give a methyl ester compound o5 f
the object product as a brown amorphous product (5.61 g, yield
78%).
IR: 1715, 1548 cm-1
1H NMR (CDCl3): δ = 7.72 - 7.74 (m, 1H), 7.10 - 7.62 (m, 9H),
10 6.99 (d, J = 8Hz, 2H), 6.90 (d, J = 8Hz, 2H), 6.70 - 6.72 (m,
2H), 5.59 (s, 2H), 4.70 (q, J = 4Hz, 2H), 4.65 (s, 2H), 3.76 (s,
3H), 1.50 (t, J = 4Hz, 3H).
MS: m/z = 545 (NH+)
[0393]
15 Example 6-5
[0394]
[0395]
A mixture of the methyl ester compound (5.4 g, 9.9 mmol),
20 1N aqueous sodium hydroxide solution (30 mL) and methanol (15
mL) was stirred at 90C for 2 hr. Methanol was concentrated
under reduced pressure, 10% hydrochloric acid was added, and
the resultant product was extracted with a mixture of
chloroform and THF. The extract was dried over magnesium
25 sulfate and filtrated, and the filtrate was concentrated under
reduced pressure. The concentrated residue was purified by
silica gel column chromatography (2%→4% methanol/chloroform).
A fraction of the object compound was collected and
concentrated under reduced pressure. To the concentrated
30 residue was added a mixture of chloroform and diisopropyl ether
115
to allow for crystallization, and the obtained crystals were
washed with diisopropyl ether and dried to give a carboxylic
acid compound of the object compound as a colorless solid (3.96
g, yield 75%).
melting point: 171C - 1735 C
IR: 1696, 1530, 1451, 1256 cm-1
1H NMR (DMSO-d6): δ = 7.65 - 7.72 (m, 2H), 7.49 - 7.56 (m, 4H),
7.15 - 7.23 (m, 4H), 6.86 - 6.90 (m, 4H), 6.75 - 6.77 (m, 2H),
5.59 (s, 2H), 4.97 (s, 2H), 4.59 (q, J = 8Hz, 2H), 1.37 (t, J =
10 8Hz, 3H).
MS: m/z = 531 (NH+)
Anal: Calcd for C31H26N6O3･0.1H2O: C: 69.94; H: 4.96; N: 15.79%.
Found: C: 69.83; H: 4.96; N: 15.73%.
[0396]
15 Example 6-6
[0397]
[0398]
20 A mixture of the carboxylic acid compound (3.71 g, 6.99
mmol), 1-chloroethylcyclohexyl carbonate (1.73 g), potassium
carbonate (1.54 g) and DMF (20 mL) was stirred at 65C for 4 hr.
To the reaction mixture was added water, and the resultant
product was extracted with ethyl acetate. The extract was
25 washed with water, dried over magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure, and the
concentrated residue was purified by silica gel column
chromatography (hexane→hexane:ethyl acetate=4:1→2:1→3:2→1:1) to
give BCAN of the object compound as a yellow amorphous product
30 (4.9 g, quant.).
IR: 1751, 1549, 1458 cm-1
116
1H NMR (CDCl3): δ = 7.74 - 7.76 (m, 1H), 7.57 - 7.61 (m, 2H),
7.48 - 7.50 (m, 1H), 7.30 - 7.40 (m, 2H), 7.13 - 7.18 (m, 3H),
6.87 - 7.02 (m, 5H), 6.70 - 6.72 (m, 2H), 5.56 - 5.67 (m, 2H),
4.61 - 4.71 (m, 6H), 1.85 - 1.93 (m, 2H), 1.65 - 1.80 (m, 2H),
1.20 - 1.62 (m, 13H)5 .
MS: m/z = 701 (NH+)
[0399]
Example 6-7: deprotection
[0400]
10
[0401]
A mixture of BCAN (0.1 g, 0.14 mmol), ammonium formate
(0.044 g, 0.69 mmol), 5% Pd-BaSO4 (0.0152 g, 5 mol%), isopropyl
15 alcohol (1 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred at
25C for 14 hr. The conversion yield of this reaction was
92.10%.
[0402]
Example 6-8: deprotection
20 [0403]
[0404]
A mixture of 2-ethoxy-1-[2’-[1-benzyl-1H-tetrazol-5-
25 yl]biphenyl-4-yl]-1H-benzimidazole-7-carboxylic acid (CBCA)
117
(0.05 g, 0.094 mmol), ammonium formate (0.029 g, 0.46 mmol),
10% Pd/BaSO4-Type29a (0.005 g, 5 mol%), isopropyl alcohol (0.5
mL, 10 vol) and water (0.3 mL, 6 vol) was stirred at 45 - 48C
for 7 hr. After completion of the reaction, the reaction
mixture was cooled to 25C and filtered through celite. Th5 e
filtrate was concentrated under reduced pressure, to the
concentrated residue were added water (2.0 mL) and methylene
chloride (5.0 mL), and the mixture was adjusted to pH 2 with
10% hydrochloric acid (0.3 mL). The precipitated solid was
10 filtered, washed with methylene chloride (2.0 mL), and dried
under reduced pressure at 45C to give 2-ethoxy-1-{[2’-(2Htetrazol-
5-yl)-1,1’-biphenyl]-4-yl]methyl}-1H-benzimidazole-7-
carboxylic acid (CV) (0.03 g, yield 73.2%).
IR (KBr): νmax = 3436, 2986, 2756, 1704, 1550, 1479, 1428, 1283,
15 1241, 1036, 746 cm-1;
1H NMR (DMSO-d6): δ = 16.29 (s, 1H), 13.19 (s, 1H), 7.67 - 1.63
(m, 3H), 7.57 - 7.48 (m, 3H), 7.19 - 7.16 (m, 1H), 7.01 (d, J =
7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 5.62 (s, 2H), 4.57 (t, J
= 6.8 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H)
20 [0405]
Example 7-1
[0406]
[0407]
25 A mixture of 1-benzyl-5-phenyl-1H-tetrazole (HBT, 100 g,
1 eq), p-bromobenzyl benzoate (BBB, 135.5 g, 1.1 eq), potassium
carbonate (58.5 g, 1 eq), triphenylphosphine (2.23 g, 2 eq
118
relative to Ru) and N-methyl-2-pyrrolidone (380 mL, 3.8 vol)
was stirred for 5 min. A solution (122 mL, 2 eq relative to
Ru) of 2.5% potassium bis(2-ethylhexyl)phosphate in N-methyl-2-
pyrrolidone was added thereto, and the mixture was stirred for
5 min. Argon gas was blown into the mixture for 10 min t5 o
remove oxygen from the mixture. The reaction mixture was
heated to 138C - 140C, and dichloro(p-cymene)ruthenium (II)
dimer (1.3 g, 0.005 eq) was added at 138C - 140C.
Furthermore, argon gas was blown into the mixture for 10 min to
10 remove oxygen from the reaction mixture. Then, the reaction
mixture was stirred at 138C - 140C for 8 hr. The reaction
was checked by TLC (TLC eluent: 30% ethyl acetate/hexane,
detection method: UV) and HBT contained therein was confirmed
to be in a trace amount.
15 The reaction mixture was cooled to 25C - 30C, t-butyl
methyl ether (500 mL, 5 vol) was added thereto, and the mixture
was stirred for 5 min and filtered through a filter lined with
celite. The celite layer was washed with t-butyl methyl ether
(500 mL, 5 vol). The filtrate and washing were combined,
20 deionized water (500 mL, 5 vol) was added thereto, and the
mixture was stirred for 10 min and left standing for 5 min.
After partitioning, the aqueous layer was extracted with tbutyl
methyl ether (2x500 mL, 2x5 vol). The extracts were
combined with the organic layer, deionized water (500 mL, 5
25 vol) was added, and the mixture was stirred for 10 min. The
mixture was left standing for 5 min and partitioned. To the tbutyl
methyl ether layer was added saturated brine (500 mL, 5
vol), and the mixture was stirred for 10 min. After standing,
the mixture was partitioned, and the t-butyl methyl ether layer
30 was dried over sodium sulfate (50 g, 0.5 w/w). The residue was
filtered and the filtrate was concentrated under reduced
pressure at 40C - 45C to give a crude product of BBZ (220 g)
as a green syrup.
To the obtained crude product was added t-butyl methyl
35 ether (400 mL, 4 vol), and the mixture was stirred at 25C -
119
30C for 24 hr to allow for precipitation of a solid. The
obtained solid was collected by filtration and dried with
suction to give BBZ as a green solid (140 g, yield 68.5%).
[0408]
Example 7-5 2
[0409]
[0410]
To BBZ (135 g, 1 eq) cooled to 0C - 5C was added 33%
10 hydrogen bromide/acetic acid solution (405 mL, 3 vol) at 0C -
5C over 15 min. The reaction mixture was stirred at 25C -
30C for 18 hr. The degree of progression of the reaction was
checked by TLC (TLC eluent: 30% ethyl acetate/hexane, detection
method: UV), and complete disappearance of BBZ was confirmed.
15 The reaction mixture was filtered, precipitated BBR was
collected by filtration, and the obtained solid was dried with
suction for 1 hr and further blast-dried for 8 hr. To the
obtained solid was added 50% ethyl acetate/hexane (270 mL, 2
vol), and the obtained suspension was stirred at 25C - 30C
20 for 1 hr. The suspension was filtered to give BBR as a paleyellow
solid (113 g, yield 92%).
[0411]
Example 7-3
[0412]
120
[0413]
Dimethylacetamide (1 mL, 1 vol), methanol (4 mL, 4 vol),
BIM (1 g, 1 equivalent) and potassium carbonate (1.56 g, 2.5
equivalents) were charged in a two-neck flask at 25C - 30C5 .
The reaction mixture was stirred at 25C - 30C for 15 min, and
BBR (1.93 g, 1.05 equivalents) was gradually added. The
reaction mixture was stirred at 25C - 30C for 24 hr. The
degree of progression of the reaction was checked by TLC (TLC
10 eluent: 40% ethyl acetate/hexane, detection method: UV). After
BBR was completely consumed, water (10 mL, 10 vol) was added to
the reaction mixture, and the mixture was stirred for 1 hr.
The precipitated solid was filtered, washed with water (3 mL, 3
vol), and dried with suction for 15 min. The obtained solid
15 was blast-dried at 50C - 55C for 4 hr to give crude CBME (2.3
g, yield 93.1%, HPLC purity: 74.80 area%) as a pink solid.
To the above-mentioned pink solid was added MTBE (8.0 mL,
8 vol), and the mixture was stirred at 25C - 30C for 1 hr.
The precipitated solid was filtered, washed with t-butyl methyl
20 ether (4.0 mL, 4 vol), and dried with suction for 15 min. The
obtained solid was blast-dried at 50C - 55C for 4 hr to give
CBME as a pink solid (1.7 g, yield 68.8%, HPLC purity: 88.47
area%).
To this pink solid was added acetone (10 mL, 10 vol), and
25 the obtained solution was heated to 50C - 55C. Water (5.0 mL,
5 vol) was added, and the mixture was stirred at 50C - 55C
for 30 min and at 0C - 5C for 45 min. The precipitated solid
was collected by filtration and washed with water (2.0 mL, 2
121
vol). The obtained solid was dried with suction and blastdried
at 50C - 55C for 4 hr to give CBME (1.5 g, yield 60.7%,
HPLC purity: 95.66 area%).
The steps after acetone addition were performed once
again to obtain CBME (1.1 g, yield 44.5%, HPLC purity: 97.65 4
area%).
[0414]
Example 7-4
[0415]
10
[0416]
Methanol (14 mL, 4 vol), CBME (3.5 g, 1 equivalent) and
aqueous sodium hydroxide solution (0.771 g as sodium hydroxide,
3 equivalents) (14 mL, 4 vol) were charged in a two-neck flask.
15 The reaction mixture was stirred at 75C - 80C for 3 hr. The
degree of progression of the reaction was checked by TLC (TLC
eluent: 5% methanol/methylene chloride, detection method: UV).
The reaction mixture was cooled, and the solvent was evaporated
under reduced pressure at 45C - 50C. To the concentrated
20 residue was added water (35 mL, 10 vol), and the mixture was
cooled to 10C - 15C. The mixture was adjusted from pH 10 -
11 to pH 5 - 6 with acetic acid (1.0 mL, 0.3 vol), and stirred
at 25C - 30C for 1 hr. The precipitated solid was collected
by filtration and washed with deionized water (3.5 mL, 1 vol).
25 The obtained solid was dried with suction for 15 min, and
blast-dried at 50C - 55C for 4 hr to give CBCA (3.2 g, yield
93.8%, HPLC purity: 98.34 area%).
[0417]
Example 7-5
30 [0418]
122
[0419]
Acetonitrile (5 mL, 5 vol), CBCA (1 g, 1 equivalent) and
potassium carbonate (0.521 g, 2.0 equivalents) were added into
a two-neck flask, and 1-chloroethylcyclohexyl carbonate (0.585 4
g, 1.5 equivalents) was added at 25C - 30C. The reaction
mixture was heated to 60C - 65C and stirred for 8 hr. The
degree of progression of the reaction was confirmed by TLC (TLC
eluent: 5% methanol/DCM, detection method: UV). The solvent
10 was evaporated under reduced pressure at 45C - 50C, water (5
mL, 5 vol) was added to the concentrated residue, and the
resultant product was extracted with ethyl acetate. The
organic layer was washed successively with water and saturated
brine. The organic layer was concentrated under reduced
15 pressure at 45C - 50C to give a crude resultant product. To
this crude resultant product was added cyclohexane (5.0 mL, 5
vol), and the mixture was stirred at 75C - 85C for 1 hr. The
mixture was gradually cooled to 5C - 10C and stirred at 5C -
10C for 2 hr. The precipitated solid was filtered, washed
20 with cold cyclohexane (1.0 mL, 1 vol), and dried with suction.
The obtained solid was further dried at 50C - 55C for 4 hr to
give BCAN (1.1 g, yield 83.3%, HPLC purity: 98.59 area%).
[0420]
Example 7-6: deprotection
25 [0421]
123
[0422]
BCAN (0.1 g, 1 equivalent), ammonium formate (0.045 g,
4.84 equivalents), 5% Pd/BaSO4-Type29a (0.015 g, 5 mol%),
isopropanol (1 mL, 10 vol) and water (0.6 mL, 6 vol) were mixe5 d
by stirring in a flask at 25C - 30C. The reaction mixture
was stirred at 40C - 45C for 16 hr. The degree of
progression of the reaction was confirmed by TLC (TLC eluent:
5% methanol/methylene chloride, detection method: UV). The
10 reaction mixture was filtered with a filter lined with celite,
and the celite was washed with isopropanol (0.5 mL, 5 vol).
The filtrate and washing were combined and concentrated under
reduced pressure at 45C - 50C. To the concentrated residue
was added water (1 mL, 10 vol), whereby precipitation of a
15 solid was observed. The mixture was further stirred for 1 hr,
and the precipitated solid was collected by filtration and
washed with deionized water (1 mL, 10 vol). The obtained solid
was dried with suction, and further dried at 50C - 55C for 5
hr to give CAN (0.07 g, yield 80.45%, HPLC purity 92.20 area%).
20 [0423]
Example 7-7: deprotection
[0424]
[0425]
25 Isopropanol (10 mL, 10 vol), water (6.0 mL, 6 vol), CBCA
(1 g, 1 equivalent) and ammonium formate (0.58 g, 4.90
124
equivalents) were charged in a flask at 25 - 30C. 10%
Pd/BaSO4-Type29a (0.1 g, 5 mol%) was added, and the mixture was
stirred at 45C - 50C for 6 hr. The degree of progression of
the reaction was confirmed by TLC (TLC eluent: 5%
methanol/methylene chloride, detection method: UV). Th5 e
catalyst was filtered off with a filter lined with celite, and
the celite was washed with isopropanol (5 mL, 5 vol). The
filtrate and washing were combined and concentrated under
reduced pressure at 45C - 50C. To the concentrated residue
10 were added water (10 mL, 10 vol) and methylene chloride (20 mL,
20 vol), and the mixture was adjusted to pH 5 - 6 with acetic
acid. Precipitation of the solid was observed and the mixture
was further stirred for 1 hr. The obtained solid was collected
by filtration, washed with methylene chloride (5 mL, 5 vol),
15 and dried with suction. The solid was further blast-dried at
50C - 55C for 5 hr to give CV (0.6 g, yield 72.28%, HPLC
purity: 97.15 area%).
[0426]
Reference Example 2
20 [0427]
[0428]
Chloroform (10.0 mL), OLM MDX (5.0 g, 8.95 mmol),
potassium iodide (0.074 g, 0.44 mmol) and diisopropylethylamine
25 (4.7 mL, 26.8 mmol) were charged in a flask at 25C under a
nitrogen stream, and the mixture was cooled to -10C to -5C.
125
Chloroform (5.0 mL), 2,4-dimethoxybenzyl alcohol (2.5 g, 14.86
mmol) and 30% hydrochloric acid (20.0 mL) were added into
another flask, and the mixture was stirred for 5 min. The
chloroform layer was separated and added to the earlier mixture
at -10C to -5C. To the aqueous layer was added chlorofor5 m
(5.0 mL), and the mixture was partitioned. The chloroform
layer was further added to the earlier mixture at -10C to -5C,
and the mixture was stirred for 6 hr. After completion of the
reaction, water (10.0 mL) was added, and the mixture was
10 stirred for 1 hr and partitioned. The organic layer was washed
with water (20.0 mL), and concentrated under reduced pressure.
The resultant product was purified by silica gel column
chromatography (0.4% - 0.5% methanol/methylene chloride) to
give the object product.
15 [0429]
Example 8: reaction with Brønsted acid
[0430]
[0431]
20 (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-
methylethyl)-2-propyl-1-[[2’-[2-(2,4-dimethoxybenzyl)-2Htetrazol-
5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate
(DPOLM) (0.2 g, 0.28 mmol) was dissolved in methylene chloride
(1.0 mL, 5.0 vol), trifluoroacetic acid (0.14 mL) was added at
25 25C, and the mixture was stirred for 6 hr. After completion
of the reaction, the reaction mixture was concentrated under
126
reduced pressure, to the concentrated residue was added
methylene chloride (5 mL), and the mixture was concentrated
under reduced pressure. To the concentrated residue was added
methylene chloride (5 mL), and the mixture was concentrated
under reduced pressure. To the concentrated residue was adde5 d
methylene chloride (5 mL), and the mixture was filtered through
celite. To the filtrate was added 0.5 mol/L aqueous potassium
dihydrogen phosphate solution (4 mL), and the mixture was
stirred for 30 min. The reaction mixture was adjusted to pH 4
10 - 5 with 5% aqueous sodium carbonate solution. The organic
layer was partitioned and washed with water (5 mL). The
organic layer was dried over sodium sulfate and concentrated
under reduced pressure, and the obtained solid was dried under
reduced pressure at 45C for 1 hr to give olmesartan medoxomil
15 (OLM MDX) (yield 0.154 g, yield 97.5%, HPLC purity: 98.06
area%).
column: Unisol C18 (4.6×150 mm, 3 μm),
buffer: 2.76 g NaH2PO4･H2O in 1.0 L H2O+1.0 mL (C2H5)3N (adjusted
to pH 3.3 with H3PO4),
20 mobile phase A (SOLUTION A): buffer/CH3CN (80/20),
mobile phase B (SOLUTION B): CH3CN,
gradient program: 0 min (SOLUTION A/SOLUTION B = 50/50), 2 min
(SOLUTION A/SOLUTION B = 5/95), 20 min (SOLUTION A/SOLUTION B =
5/95), 22 min (SOLUTION A/SOLUTION B = 50/50), 25 min (SOLUTION
25 A/SOLUTION B = 50/50),
flow: 1.0 mL/min,
injection volume: 10 μL,
column temperature: 30C,
dilution solvent: CH3CN:H2O (90:10)
30
Industrial Applicability
[0432]
According to the present invention, a tetrazole compound,
useful as an intermediate for angiotensin II receptor blockers,
35 can be deprotected and an angiotensin II receptor blocker can
127
be produced, under conditions that are economical and suitable
for industrial production, by (i) reducing in the presence of a
metal catalyst and an alkaline earth metal salt, or (ii)
reacting with a specific amount of Brønsted acid.
[04335 ]
This application is based on a patent application No.
2012-213212 filed in Japan, the contents of which are
incorporated in full herein.

WE CLAIMS:-
1. A method of producing a compound represented by the formula
[3]:
5
wherein R1 is an alkyl group, an aralkyl group or an aryl group,
each of which is optionally substituted,
10 or a salt thereof, or the formula [4]:
wherein the symbol is as defined above,
15 or a salt thereof, comprising (i) reducing a compound
represented by the formula [1]:
wherein R1 is as defined above, each R2 is an alkyl group, an 20
alkoxy group or a nitro group, or two alkoxy groups are
optionally bonded to form an alkylenedioxy group, and p is an
integer of 0 to 5,
or a salt thereof, or a compound represented by the formula
25 [2]:
129
wherein each symbol is as defined above,
or a salt thereof, in the presence of a metal catalyst and an
alkaline earth metal salt, or (ii) reacting a compoun5 d
represented by the formula [1] or a salt thereof or a compound
represented by the formula [2] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to
compound [1] or compound [2].
10
2. The method according to claim 1, wherein the metal catalyst
is supported by an alkaline earth metal salt.
3. A method of producing a compound represented by the formula
15 [23]:
or a salt thereof,
20 comprising
1) reacting, in the presence of a base, a compound represented
130
by the formula [11]:
wherein each R2 is an alkyl group, an alkoxy group or a nitr5 o
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
or a salt thereof, with a compound represented by the formula
10 [15]:
wherein R9 is a carboxy-protecting group,
15 or a salt thereof to give a compound represented by the formula
[16]:
131
wherein the symbols are as defined above,
or a salt thereof;
2) (i) reducing a compound represented by the formula [16] or a
salt thereof in the presence of a metal catalyst and a5 n
alkaline earth metal salt, or (ii) reacting a compound
represented by the formula [16] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to
compound [16], to give a compound represented by the formula
10 [17]:
wherein the symbol is as defined above,
15 or a salt thereof;
3) reacting a compound represented by the formula [17] or a
salt thereof with a compound represented by the formula [18]:
Tr-X wherein Tr is a trityl group and X is a halogen atom in
the presence of a base to give a compound represented by the
20 formula [19]:
132
wherein the symbol is as defined above,
or a salt thereof;
4) removing R9 of a compound represented by the formula [19] o5 r
a salt thereof to give a compound represented by the formula
[20]:
10
wherein the symbol is as defined above,
or a salt thereof;
5) reacting a compound represented by the formula [20] or a
salt thereof with a compound represented by the formula [21]:
15
133
to give a compound represented by the formula [22]:
5
wherein the symbol is as defined above,
or a salt thereof; and
6) removing a trityl group of a compound represented by the
formula [22] or a salt thereof.
10
4. A method of producing a compound represented by the formula
[28]:
15
or a salt thereof, comprising
1) reacting a compound represented by the formula [11]:
134
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is 5 a
halogen atom,
or a salt thereof with a compound represented by the formula
[24]:
10
or a salt thereof to give a compound represented by the formula
[25]:
15
135
wherein the symbol is as defined above,
or a salt thereof; and
2-A) reducing a compound represented by the formula [25] or a
salt thereof with a reducing agent to give a compound
represented by the formula [26]5 :
wherein the symbol is as defined above,
10 or a salt thereof, and (i) further reducing a compound
represented by the formula [26] or a salt thereof in the
presence of a metal catalyst and an alkaline earth metal salt,
or (ii) reacting a compound represented by the formula [26] or
a salt thereof with 0.1 equivalents - 50 equivalents of
15 Brønsted acid relative to a compound represented by the formula
[26] or a salt thereof,
or
2-B) (i) reducing a compound represented by the formula [25] or
a salt thereof in the presence of a metal catalyst and an
20 alkaline earth metal salt, or (ii) reacting a compound
represented by the formula [25] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to a
compound represented by the formula [25] or a salt thereof, to
give a compound represented by the formula [27]:
25
136
or a salt thereof, and further reducing a compound represented
by the formula [27] or a salt thereof with a reducing agent.
5
5. A method of producing a compound represented by the formula
[35]:
10
or a salt thereof, comprising
1) reacting a compound represented by the formula [11]:
137
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom5 ,
or a salt thereof with a compound represented by the formula
[29]:
10
wherein R10 is a carboxy-protecting group,
or a salt thereof to give a compound represented by the formula
[30]:
15
wherein the symbols are as defined above,
or a salt thereof;
2-A) (i) reducing a compound represented by the formula [30] or
20 a salt thereof in the presence of a metal catalyst and an
alkaline earth metal salt, or (ii) reacting a compound
represented by the formula [30] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to a
compound represented by the formula [30] or a salt thereof, to
138
give a compound represented by the formula [31]:
wherein the symbol is as defined above5 ,
or a salt thereof;
3-A) reacting a compound represented by the formula [31] or a
salt thereof with a compound represented by the formula [32]:
CH3CH2CH2CH2CO-X3 wherein X3 is a leaving group to give a
10 compound represented by the formula [33]:
wherein the symbol is as defined above,
15 or a salt thereof;
4-A) removing R10 of a compound represented by the formula [33]
or a salt thereof; or
2-B) reacting a compound represented by the formula [30] or a
salt thereof with a compound represented by the formula [32] or
20 a salt thereof to give a compound represented by the formula
[34]:
139
wherein the symbols are as defined above,
or a salt thereof; and
3-B) (i) reducing a compound represented by the formula [34] o5 r
a salt thereof in the presence of a metal catalyst and an
alkaline earth metal salt to remove R10, or (ii) reacting a
compound represented by the formula [34] or a salt thereof with
0.1 equivalents - 50 equivalents of Brønsted acid relative to a
10 compound represented by the formula [34] or a salt thereof to
remove R10.
6. A method of producing a compound represented by the formula
[38]:
15
140
or a salt thereof, comprising
1) reacting a compound represented by the formula [11]:
5
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is a
halogen atom,
10 or a salt thereof with a compound represented by the formula
[36]:
or a salt thereof to give a compound represented by the formula 15
[37]:
141
wherein the symbol is as defined above,
or a salt thereof, and
2) (i) further reducing a compound represented by the formul5 a
[37] or a salt thereof in the presence of a metal catalyst and
an alkaline earth metal salt, or (ii) reacting a compound
represented by the formula [37] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to a
10 compound represented by the formula [37] or a salt thereof.
7. A method of producing a compound represented by the formula
[47]:
15
or a salt thereof, comprising
1-A-i) reacting a compound represented by the formula [11]:
142
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is 5 a
halogen atom,
or a salt thereof, with a compound represented by the formula
[39]:
10
wherein R11 is a carboxy-protecting group, and R12 is an aminoprotecting
group,
or a salt thereof to give a compound represented by the formula
15 [40]:
143
wherein the symbols are as defined above,
or a salt thereof;
1-A-ii) removing R12 of a compound represented by the formula
[40] or a salt thereof to give a compound represented by the
formula [41]5 :
wherein the symbols are as defined above,
10 or a salt thereof;
1-A-iii) reducing a compound represented by the formula [41] or
a salt thereof to give a compound represented by the formula
[42]:
15
wherein the symbols are as defined above,
or a salt thereof;
1-A-iv) reacting a compound represented by the formula [42] or
20 a salt thereof with tetraethoxymethane; or
1-B) reacting a compound represented by the formula [11]:
144
wherein each R2 is an alkyl group, an alkoxy group or a nitro
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and X2 is 5 a
halogen atom,
or a salt thereof, with a compound represented by the formula
[49]:
10
wherein the symbol is as defined above, to give a compound
represented by the formula [43]:
15
wherein the symbols are as defined above,
or a salt thereof;
145
2) removing R11 of a compound represented by the formula [43]
or a salt thereof to give a compound represented by the formula
[44]:
5
wherein the symbol is as defined above,
or a salt thereof;
3) reacting a compound represented by the formula [44] or a
salt thereof with a compound represented by the formula [45]10 :
wherein X4 is a leaving group or a hydroxyl group,
15 or a salt thereof to give a compound represented by the formula
[46]:
146
wherein the symbol is as defined above,
or a salt thereof; and
4) (i) reducing a compound represented by the formula [46] or a
salt thereof in the presence of a metal catalyst and a5 n
alkaline earth metal salt, or (ii) reacting a compound
represented by the formula [46] or a salt thereof with 0.1
equivalents - 50 equivalents of Brønsted acid relative to a
compound represented by the formula [46] or a salt thereof.
10
8. A compound represented by the formula [48]:
wherein each R2 is an alkyl group, an alkoxy group or a nitro 15
group, or two alkoxy groups are optionally bonded to form an
alkylenedioxy group, p is an integer of 0 to 5, and R13 is
,
20
or a salt thereof.
Dated this 19th day of March, 2015
AMRISH TIWARI
25 Of K & S PARTNERS
ATTORNEY FOR THE APPLICANT(S)
or
ABSTRACT
Title: “DEPROTECTION METHOD FOR TETRAZOLE COMPOUND”
The present invention relates to a method of deprotecting a tetrazole compound,
useful as an intermediate for angiotensin II receptor blockers, and provides a novel
production method of angiotensin II receptor blockers.
Provided is a production method of a compound represented by the formula [3] or
[4] or a salt thereof, including (i) reducing a compound represented by the formula [1] or
[2] or a salt thereof in the presence of a metal catalyst and an alkaline earth metal salt, or (ii)
reacting the compound with a particular amount of Brønsted acid:
wherein each symbol is as defined in the present specification.