Specification
DESCRIPTION
AROMATIC COMPOUND CONTAINING SPECIFIC BRANCH
Technical Field
[0001]
5 The present invention relates to an aromatic compound
containing a particular branched chain. The present invention
further relates to a protecting reagent containing the
compound or an adduct thereof. The present invention also
relates to a production method of peptide by using the
10 compound, and further relates to an organic synthesis method
including the production method of the peptide.
Background Art
[0002]
The production methods of peptide are generally divided
15 into solid phase methods and liquid phase methods. The solid
phase methods are advantageous since isolation and
purification after reaction can be performed by only washing
resin. However, they are associated with problems in that the
reaction is essentially that of heterogeneous phases, reaction
20 agents and reagents need to be used in excess to compensate
for the low reactivity, and tracing of reaction and analysis
of reaction product supported by carrier are difficult. On the
other hand, the liquid phase method is advantage since it
shows good reactivity, and intermediate peptide can be
25 purified by extraction and washing, isolation and the like
after condensation reaction. However, the method is associated
with problems since the production step is complicated due to
an extraction and washing step with a nonpolar organic solvent
and an acidic or basic aqueous solution to remove residual
30 reagents and/or byproducts in each step of coupling reaction
and deprotection, and/or an isolation and purification step
such as crystallization and the like, and the like.
[0003]
In recent years, approaches to improve the problems of
35 the aforementioned two methods have been ongoing.
1
Patent document 1 and non-patent document 1 each disclose
a method using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol type
compound as a protecting reagent of carboxyl group and the
like. Patent documents 2 - 4 each disclose a 3,5-
5 di(docosyloxy)benzyl alcohol type compound, a 2,4-
di(docosyloxy)benzyl alcohol type compound, a trityl type
compound and the like as protecting reagents. Using these
protecting reagents, the reaction can be performed in a
homogeneous liquid phase, a precipitate can be produced by
10 changing the solvent composition after the reaction, which can
be isolated and purified by filtration and washing alone.
However, use of these protecting reagents is associated with
problems in that a reaction solvent evaporation step for
precipitation is required, a long time is necessary for a
15 precipitate filtration step, and these protecting reagents are
insoluble or slightly-soluble in acetate ester or toluene.
Therefore, the methods disclosed in the above-mentioned
documents are not entirely industrially universal methods.
[0004]
20 Patent document 5 introduces an example of a peptide
synthesis reaction using a 3,4,5-tris(n-octadecyloxy)benzyl
alcohol type compound as a protecting reagent. However, the
document only discloses an example of a specific layerseparating
separation of organic solvents under dilute
25 conditions, and this example is not entirely an industrially
universal method.
[Document List]
[patent documents]
[0005]
30 patent document 1: JP-A-2000-44493
patent document 2: WO2006/104166
patent document 3: WO2007/034812
patent document 4: WO2007/122847
patent document 5: WO2003/018188
35 [non-patent document]
2
[0006]
non-patent document 1: Bull. Chem. Soc. Jpn 74, 733-738(2001)
[SUMMARY OF THE INVENTION]
Problems to be Solved by the Invention
5 [0007]
The problem of the present invention is to provide a
novel compound which is easily-soluble in isopropyl acetate
superior in liquid-separating operability, and usable for a
production method of peptide and the like which leads to a
10 final product simply by extraction separation without
crystallization and isolation of each intermediate in each
step (one-pot synthesis method).
Means of Solving the Problems
[0008]
15 The present inventors have conducted intensive studies
and found that the aforementioned problems can be solved by a
particular branched chain-containing aromatic compound, which
resulted in the completion of the present invention. The
present invention includes the following embodiments.
20 [0009]
[1] A branched chain-containing aromatic compound represented
by the formula (I):
[0010]
25 [0011]
wherein
Q in the number of k are each a single bond, or -0-, -S-, -
C(=0)0-, -C(=0)NH- or -NH-;
Ra in the number of k are each independently an organic group
30 having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
3
not less than 3 and a total carbon number of not less than 14
and not more than 300;
k is an integer of 1 - 4;
Ri is a hydrogen atom or, when Z is a group represented by the
5 following formula (a), it optionally shows a single bond
together with R2 to form a fluorene ring together with ring B;
ring A optionally further has, in addition to Ri, QRa in the
number of k, and C(X)(Y)Z, substituent(s) selected from the
group consisting of a halogen atom, a Ci-g alkyl group
10 optionally substituted by one or more halogen atoms, and a Ci-g
alkoxy group optionally substituted by one or more halogen
atoms;
X is a hydrogen atom or a phenyl group;
Y is a hydroxyl group or an -NHR group (R is a hydrogen atom,
15 an alkyl group or an aralkyl group); and
Z is a hydrogen atom or a group represented by the formula
(a):
[0012]
* r ^ (a)
20 [0013]
wherein * shows a bonding position;
m is an integer of 0 - 4;
Q in the number of m are as defined above;
Rb in the number of m are each independently an organic group
25 having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
R2 is a hydrogen atom, or optionally shows a single bond
30 together with Ri to form a fluorene ring together with ring A;
and
ring B optionally further has, in addition to QRb in the number
of m, and R2, substituent(s) selected from the group consisting
4
of a halogen atom, a Ci-s alkyl group optionally substituted by
one or more halogen atoms, and a Ci-e alkoxy group optionally
substituted by one or more halogen atoms);
the organic group having at least one aliphatic hydrocarbon
5 group having one or more branched chains, a total number of
the branched chain of not less than 3 and a total carbon
number of not less than 14 and not more than 300 for the
aforementioned Ra and Rb is a group having 3 or more the same
or different divalent groups, which is represented by the
10 formula (b):
[0014]
R3
R4 (b)
[0015]
wherein * shows a bonding position with the adjacent atom;
15 R3 and R4 are each independently a hydrogen atom or a C1-4 alkyl
group;
Xi is a single bond, a C1-4 alkylene group or an oxygen atom,
provided that R3 and R4 are not hydrogen atoms at the same time.
[2] The branched chain-containing aromatic compound of the
20 aforementioned [1], wherein the organic group having at least
one aliphatic hydrocarbon group having one or more branched
chains, a total number of the branched chain of not less than
3 and a total carbon number of not less than 14 and not more
than 300 for the aforementioned Ra and Rb is a group
25 represented by the formula (c):
[0016]
R7 1'
R5—C-^ "~ ^^^^^-"""^Rio (c)
RB RB
[0017]
wherein * shows a bonding position to Q;
30 R5 and Re are both hydrogen atoms, or taken together to show
=0;
5
no is an integer of 2 - 40;
R7 and Rg in the number of no are each independently a hydrogen
atom or a Ci_4 alkyl group;
X2 in the number of no are each independently a single bond or
. 5 a Ci-4 alkylene group; and
R9 is a hydrogen atom or a C1-4 alkyl group;
Rio is a Ci-4 alkyl group or the formula (I'):
[0018]
A' ^
^ ik (I')
^^/^ Q*
10 [0019]
wherein * shows a bonding position;
other symbols are as defined above, and ring A' optionally has,
in addition to Ri, Q, and C(X) (Y)Z, substituent (s) selected
from the group consisting of a halogen atom, a Ci-e alkyl group
15 optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
atoms,
provided that R7 and Re are not hydrogen atoms at the same time,
and when no is 2, Rg is a C1-4 alkyl group.
20 [3] The branched chain-containing aromatic compound of the
aforementioned [2], wherein, in the aforementioned formula (c),
R5 and Re are both hydrogen atoms;
R7 and Rs in the number of no are each independently a hydrogen
atom, a methyl group or an ethyl group;
25 X2 in the number of no are each independently a single bond, a
methylene group or an ethylene group; and
R9 is a hydrogen atom, a methyl group or an ethyl group.
[4] The branched chain-containing aromatic compound of the
aforementioned [1], wherein the organic group having at least
30 one aliphatic hydrocarbon group having one or more branched
chains, a total number of the branched chain of not less than
6
3 and a total carbon number of not less than 14 and not more
than 300 for the aforementioned Ra and Rb is a group
represented by the formula (d):
[0020]
5 \^^~(QRll)m1
[0021]
wherein * shows a bonding position to Q;
ORii in the number of mi is a hydroxyl group substituted by a
group represented by the formula (c'):
10 [0022]
r R 1 ^^
R5—,0^"^^^"^ ^^~~^^ R10 (C)
Re Rs
[0023]
wherein * shows a bonding position to 0;
R5 and Rg are both hydrogen atoms, or taken together show =0;
15 no is an integer of 2 - 40;
R7 and Rs in the number of no are each independently a hydrogen
atom or a C1-4 alkyl group;
X2 in the number of no are each independently a single bond or
a Ci-4 alkylene group; and
20 R9 is a hydrogen atom or a C1-4 alkyl group;
Rio is a Ci-4 alkyl group or a group represented by the formula
(I'):
[0024]
X
A' \l
^^/''"^ Q
25 [0025]
wherein * shows a bonding position;
other symbols are as defined above, and ring A' optionally has,
in addition to Ri, Q, and C(X) (Y)Z, substituent (s) selected
from the group consisting of a halogen atom, a Ci-6 alkyl group
7
optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
atoms,
provided that R7 and Rs are not hydrogen atoms at the same time,
5 and when no is 2, R9 is a C1-4 alkyl group; and
mi is an integer of 1 - 3.
[5] The branched chain-containing aromatic compound of the
aforementioned [1], wherein the organic group having at least
one aliphatic hydrocarbon group having one or more branched
10 chains, a total number of the branched chain of not less than
3 and a total carbon number of not less than 14 and not more
than 300 for the aforementioned Ra and Rb is a group
represented by the formula (e):
[0026]
R r '^isn r p -, Ri9
K12 Kl7
[0027]
wherein * shows a bonding position to Q;
ni is an integer of 1 - 10;
n2 is an integer of 1 - 10;
20 Ri5 and Rie in the number of ni are each independently a
hydrogen atom or a C1-4 alkyl group;
X3 in the number of ni is a single bond or a C1-4 alkylene
group;
Ri7 and Ris in the number of n2 are each independently a
25 hydrogen atom or a C1-4 alkyl group;
X5 in the number of n2 is a single bond or a C1-4 alkylene
group;
X4 is a single bond or a C1-4 alkylene group; and
RI2A Ri3f Ri4f Ri9, R20 and R21 are each independently a hydrogen
30 atom or a C1-4 alkyl group,
provided when R15 and Rie, and/or R17 and Ris are not hydrogen
atoms at the same time, and when ni+n2 is 2, then two or more
of R12, Ri3 and R14 are each independently a C1-4 alkyl group, or
8
two or more of Rig, R20 and R21 are each independently a C1-4
alkyl group.
[6] The branched chain-containing aromatic compound of the
aforementioned [5], wherein, in the aforementioned formula (e),
5 ni is an integer of 1 - 5;
n2 is an integer of 1 - 5;
Ri5 and Rie in the number of ni are each independently a
hydrogen atom, a methyl group or an ethyl group;
X3 in the number of ni is a single bond, a methylene group or
10 an ethylene group;
Ri7 and Ris in the number of na are each independently a
hydrogen atom, a methyl group or an ethyl group;
X5 in the number of n2 is a single bond, a methylene group or
an ethylene group; and
15 X4 is a single bond, a methylene group or an ethylene group.
[7] The branched chain-containing aromatic compound of the
aforementioned [6], wherein, in the aforementioned formula (e),
Ri5 and Rig in the number of ni are each independently a
hydrogen atom or a methyl group;
20 X3 in the number of ni is a single bond or a methylene group;
Ri7 and Ris in the number of n2 are each independently a
hydrogen atom or a methyl group;
X5 in the number of n2 is a single bond or a methylene group;
X4 is a single bond or a methylene group; and
25 RI2A RI3/ Ri4f RI9A R20 and R21 are each a methyl group.
[8] The branched chain-containing aromatic compound of the
aforementioned [1], wherein Ra and Rb are each independently a
3,7,11,15-tetramethylhexadecyl group, a 3,7,11-
trimethyldodecyl group, a 2,2,4,8,10,lO-hexamethyl-5-
30 dodecanoyl group, a 3,4,5-tri(3',7',11',15'-
tetramethylhexadecyloxy)benzyl group, a 3,5-di(3',7',11',15'-
tetramethylhexadecyloxy)benzyl group, a group represented by
the formula (f):
[0028]
9
* [ L Rio (f^
[0029]
wherein * shows a bonding position to Q, nio is 23 - 34, Rio is
a group represented by the formula (I'):
5 [0030]
X
[0031]
wherein * shows a bonding position; and other symbols are as
defined above, wherein ring A' optionally has, in addition to
10 Ri, Q, and C(X)(Y)Z, substituent(s) selected from the group
consisting of a halogen atom, a Ci-g alkyl group optionally
substituted by one or more halogen atoms, and a Ci-e alkoxy
group optionally substituted by one or more halogen atoms,
a group represented by the formula (g):
15 [0032]
L J "11
[0033]
wherein * shows a bonding position to Q, and nn is 1 - 10,
a group represented by the formula (h):
20 [0034]
U Jni2 (h)
[0035]
10
wherein * shows a bonding position to Q, and ni2 is 2 - 10,
a group represented by the formula (i):
[0036]
* k ^ o ^ ^ / ^ 0 J X ^ J ^ * (i)
"13 "14'
5 [0037]
wherein * shows a bonding position to Q, and ni3 and ni4 are
each independently 1 - 10, or
a group represented by the formula (j):
[0038]
JLJ L J "15 (j)
•J.Q CgHig
[0039]
wherein * shows a bonding position to Q, and nis is 2 - 20.
[9] The branched chain-containing aromatic compound of any one
of the aforementioned [1] - [8], wherein X and Z are both
15 hydrogen atoms, and Ri is a hydrogen atom.
[10] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [8], wherein X is a hydrogen
atom, Ri is a hydrogen atom, k is 1, and Z is a group
represented by the formula (a) {R2 is a hydrogen atom, and m is
20 0) .
[11] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [8], wherein X is a phenyl
group, k is 1, Z is a group represented by the formula (a) (m
is 0) , and R2 is a single bond together with Ri to form a
25 fluorene ring with ring A.
[12] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [11], wherein Q is -0-.
[13] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [12], wherein Y is a hydroxyl
30 group.
11
[14] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [12], wherein Y is an -NHR
group.
[15] The branched chain-containing aromatic compound of the
5 aforementioned [1], which is selected from the group
consisting of 2,4-di(2',3'-dihydrophytyloxy)benzyl alcohol;
3,5-di(2',3'-dihydrophytyloxy)benzyl alcohol;
4-(2',3'-dihydrophytyloxy)benzyl alcohol;
1-[(2-chloro-5-(2',3'-dihydrophytyloxy)phenyl)]-1-
10 phenylmethanamine;
3,4,5-tri(2',3'-dihydrophytyloxy)benzyl alcohol;
3,4,5-tri(2',3'-dihydrophytyloxy)benzylamine;
4-(2',3'-dihydrophytyloxy)benzylamine;
2-[3',4',5'-tri(2",3"-dihydrophytyloxy)benzyloxy]-4-
15 methoxybenzyl alcohol;
4-(2',3'-dihydrophytyloxy)-2-methoxybenzyl alcohol;
4-(2',3'-dihydrophytyloxy)-2-methoxybenzylamine;
4-(2',3'-dihydrophytyloxy)-2-methylbenzyl alcohol;
4-(2',3'-dihydrophytyloxy)-2-methylbenzylamine;
20 2,2,4,8,10,lO-hexamethyl-5-dodecanoic acid (4-
hydroxymethyl)phenylamide;
4-(3,7,11-trimethyldodecyloxy)benzyl alcohol;
2-(3,7,11-trimethyldodecyloxy)-9-phenylfluoren-9-ol;
a compound represented by the formula:
25 [0040]
OMe
OMe
[0041]
wherein nie is 23 or 34;
a compound represented by the formula:
30 [0042]
12
[0043]
wherein ni7 is 23 or 34;
a compound represented by the formula:
5 [0044]
•J "18 1^
OH
[0045]
wherein nig is 5 - 7; and
a compound represented by the formula:
10 [0046]
O U J2
[0047]
[16] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [15], which shows a saturation
15 solubility in isopropyl acetate (100 g) at 20°C of 1 - 95 wt%.
[17] The branched chain-containing aromatic compound of any
one of the aforementioned [1] - [15], which shows a saturation
solubility in isopropyl acetate (100 g) at 20°C of 10 - 95 wt%.
[18] A protecting reagent for a carboxyl group or an amido
20 group of amino acid or peptide, comprising the branched chaincontaining
aromatic compound of any one of the aforementioned
[1] - [17].
[19] The protecting reagent of the aforementioned [18],
wherein the amino acid or peptide is protected at the C-
13
terminus.
[20] A branched chain-containing aromatic compound adduct
which is protected by the branched chain-containing aromatic
compound of any one of the aforementioned [1] - [17].
5 [21] A method of producing a peptide comprising steps (1) -
(4);
(1) a step of condensing the branched chain-containing
aromatic compound of any one of the aforementioned [1] - [17]
with a C-terminus of an N-protected amino acid or an N-
10 protected peptide in a solvent solubilizing the compound to
give an N-protected C-protected amino acid or N-protected Cprotected
peptide having a C-terminus protected with an anchor
which is a protecting group derived from the compound,
(2) a step of removing the N-terminal protecting group from
15 the obtained N-protected C-protected amino acid or N-protected
C-protected peptide to give a C-protected amino acid or Cprotected
peptide,
(3) a step of condensing an N-protected amino acid or Nprotected
peptide with the N-terminus of the obtained C-
20 protected amino acid or C-protected peptide to give an Nprotected
C-protected peptide, and
(4) a step of removing the N-terminal protecting group and the
C-terminal anchor from the obtained N-protected C-protected
peptide to give a peptide.
25 [22] The method of the aforementioned [21] , further comprising
one or more repetitions of steps (5) - (7);
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
peptide,
30 (6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7) a step of adding water to the reaction system after step
(6), and separating the impurity by extraction into an aqueous
35 layer.
14
[23] The method of the aforementioned [21], further comprising
one or more repetitions of steps (5) - [!')}
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
5 peptide,
(6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7') a step of adding a hydrophilic organic solvent to the
10 reaction system after step (6), and separating the impurity by
extraction into a hydrophilic organic solvent layer.
[24] An organic synthesis method comprising the peptide
production method of any one of the aforementioned [21] - [23].
[25] A branched chain-containing aromatic compound represented
15 by the formula (I):
[0048]
[0049]
wherein
20 Q in the number of k are each a single bond, or -0-, -S-, -
C(=0)0-, -C(=0)NH- or -NH-;
Ra in the number of k are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
25 not less than 3 and a total carbon number of not less than 14
and not more than 300;
k is an integer of 1 - 4;
Ri is a hydrogen atom or, when Z is a group represented by the
following formula (a), it optionally shows a single bond
30 together with R2 to form a fluorene ring together with ring B;
ring A optionally further has, in addition to Ri, QRa in the
number of k, and C(X)(Y)Z, substituent(s) selected from the
15
group consisting of a halogen atom, a Ci-e alkyl group
optionally substituted by one or more halogen atoms, and a Ci-g
alkoxy group optionally substituted by one or more halogen
atoms;
5 X is a hydrogen atom or a phenyl group;
Y is a hydroxyl group, an -NHR group (wherein R is a hydrogen
atom, an alkyl group, or an aralkyl group), or a halogen atom
(preferably halogen atom); and
Z is a hydrogen atom or a group represented by the formula
10 (a) :
[0050]
[0051]
wherein * shows a bonding position;
15 m is an integer of 0 - 4;
Q in the number of m are as defined above;
Rb in the number of m are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
20 not less than 3 and a total carbon number of not less than 14
and not more than 300;
R2 is a hydrogen atom, or optionally shows a single bond
together with Ri to form a fluorene ring together with ring A;
and
25 ring B optionally further has, in addition to QRb in the niomber
of m, and R2, substituent(s) selected from the group consisting
of a halogen atom, a Ci-e alkyl group optionally substituted by
one or more halogen atoms, and a Ci-e alkoxy group optionally
substituted by one or more halogen atoms);
30 the organic group having at least one aliphatic hydrocarbon
group having one or more branched chains, a total number of
the branched chain of not less than 3 and a total carbon
number of not less than 14 and not more than 300 for the
16
aforementioned Ra and Rb is a group having 3 or more the same
or different divalent groups, which is represented by the
formula (b):
[0052]
R3
5 R4 (b)
[0053]
wherein * shows a bonding position with the adjacent atom;
R3 and R4 are each independently a hydrogen atom or a C1-4 alkyl
group;
10 Xi is a single bond, a C1-4 alkylene group or an oxygen atom,
provided that R3 and R4 are not hydrogen atoms at the same time.
[26] A protecting reagent for a carboxyl group or an amido
group of amino acid or peptide, comprising the branched chaincontaining
aromatic compound of the aforementioned [25].
15 [27] A branched chain-containing aromatic compound adduct
which is protected by the branched chain-containing aromatic
compound of the aforementioned [25].
[28] A method of producing a peptide comprising steps (1) -
(4);
20 (1) a step of condensing the branched chain-containing
aromatic compound of the aforementioned [25] with a C-terminus
of an N-protected amino acid or an N-protected peptide in a
solvent solubilizing the compound to give an N-protected Cprotected
amino acid or N-protected C-protected peptide having
25 a C-terminus protected with an anchor which is a protecting
group derived from the compound,
(2) a step of removing the N-terminal protecting group from
the obtained N-protected C-protected amino acid or N-protected
C-protected peptide to give a C-protected amino acid or C-
30 protected peptide,
(3) a step of condensing an N-protected amino acid or Nprotected
peptide with the N-terminus of the obtained Cprotected
amino acid or C-protected peptide to give an N-
17
protected C-protected peptide, and
(4) a step of removing the N-terminal protecting group and the
C-terminal anchor from the obtained N-protected C-protected
peptide to give a peptide.
5 [29] The method of the aforementioned [28], further comprising
one or more repetitions of steps (5) - (7);
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
peptide,
10 (6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7) a step of adding water to the reaction system after step
(6), and separating the impurity by extraction into an agueous
15 layer.
[30] The method of the aforementioned [28], further comprising
one or more repetitions of steps (5) - [1')}
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
20 peptide,
(6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7') a step of adding a hydrophilic organic solvent to the
25 reaction system after step (6), and separating the impurity by
extraction into a hydrophilic organic solvent layer.
[31] An organic synthesis method comprising the peptide
production method of any one of the aforementioned [28] - [30].
30 Effect of the Invention
[0054]
The branched chain-containing aromatic compound of the
present invention is easily-soluble in isopropyl acetate
superior in liquid-separating operability. Using the branched
35 chain-containing aromatic compound of the present invention,
18
therefore, a production method of peptide and the like
comprising leading to a final product via extraction
separation alone, without crystallization and isolation of
each intermediate in each step, can be performed.
5 [Description of Embodiments]
[0055]
Unless otherwise specified in the sentences, any
technical terms and scientific terms used in the present
specification, have the same meaning as those generally
10 understood by those of ordinary skill in the art the present
invention belongs to. Any methods and materials similar or
equivalent to those described in the present specification can
be used for practicing or testing the present invention, and
preferable methods and materials are described in the
15 following. All publications and patents referred to in the
present specification are hereby incorporated by reference so as
to describe and disclose constructed products and methodology
described in, for example, publications usable in relation to
the described invention.
20 [0056]
[The compound of the present invention]
The branched chain-containing aromatic compound of the
present invention (hereinafter sometimes to be abbreviated as
the compound of the present invention) is represented by the
25 following formula (I). The compound of the present invention
encompasses a particular benzyl compound (in the formula (I),
X and Z are both hydrogen atoms, and Ri is a hydrogen atom); a
particular diphenylmethane compound (in the formula (I), X is
a hydrogen atom, Ri is a hydrogen atom, k is 1, and Z is a
30 group represented by the formula (a) wherein R2 is a hydrogen
atom and m is 0; and a particular fluorene compound (in the
formula (I), X is a phenyl group, k is 1, Z is a group
represented by the formula (a) wherein m is 0, and R2 is a
single bond together with Ri to form a fluorene ring with ring
35 A) .
19
The formula (I):
[0057]
X
[0058]
5 wherein
Q in the number of k are each a single bond, or -0-, -S-, -
C(=0)0-, -C(=0)NH- or -NH-;
Ra in the number of k are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
10 more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
k is an integer of 1 - 4;
Ri is a hydrogen atom or, when Z is a group represented by the
15 following formula (a), it optionally shows a single bond
together with R2 to form a fluorene ring together with ring B;
ring A optionally further has, in addition to Ri, QRa in the
number of k, and C(X)(Y)Z, substituent(s) selected from the
group consisting of a halogen atom, a Ci-e alkyl group
20 optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
atoms;
X is a hydrogen atom or a phenyl group;
Y is a hydroxyl group, an -NHR group (R is a hydrogen atom, an
25 alkyl group or an aralkyl group) or a halogen atom; and
Z is a hydrogen atom or a group represented by the formula
(a):
[0059]
30 [0060]
20
wherein * shows a bonding position;
m is an integer of 0 - 4;
Q in the number of m are as defined above;
Rb in the number of m are each independently an organic group
5 having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
R2 is a hydrogen atom, or optionally shows a single bond
10 together with Ri to form a fluorene ring together with ring A;
and
ring B optionally further has, in addition to QRb in the number
of m, and R2, substituent(s) selected from the group consisting
of a halogen atom, a Ci-g alkyl group optionally substituted by
15 one or more halogen atoms, and a Ci-e alkoxy group optionally
substituted by one or more halogen atoms).
[0061]
The compound represented by the formula (I) of the
present invention and compounds intended to protect are bonded
20 by a condensation reaction of a hydroxyl group, an NHR group
or a halogen atom for Y group with a carboxyl group of a
compound to be protected or the like.
[0062]
In the present specification, examples of the "alkyl
25 group" for R include a Ci-30 alkyl group, preferably a Ci-10
alkyl group, more preferably a Ci-e alkyl group. Preferable
examples include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, and the like, and
particularly preferred are methyl and ethyl.
30 [0063]
In the present specification, examples of the "aralkyl
group" for R include a C7-30 aralkyl group. Preferred is a C7-20
aralkyl group, more preferred is a C7-16 aralkyl group (a Ce-io
aryl-Ci-6 alkyl group). Preferable examples include benzyl, 1-
35 phenylethyl, 2-phenylethyl, 1-phenylpropyl, a-naphthylmethyl,
21
1-(a-naphthyl)ethyl, 2-(a-naphthyl)ethyl, 1-(a-naphthyl)propyl,
p-naphthylmethyl, 1-(p-naphthyl)ethyl, 2-(P-naphthyl)ethyl, 1-
(P-naphthyl)propyl and the like, and particularly preferred is
benzyl.
5 [0064]
As R, a hydrogen atom, a Ci-e alkyl group or a C7-16
aralkyl group is preferable, a hydrogen atom, methyl, ethyl or
benzyl is more preferable, and a hydrogen atom is particularly
preferable.
10 [0065]
In the present specification, the "halogen atom" is a
fluorine atom, a chlorine atom, a bromine atom or an iodine
atom. Preferred as the ''^halogen atom" for Y is a chlorine atom,
a bromine atom or an iodine atom, and more preferred is a
15 bromine atom.
[0066]
In the present specification, the "organic group having
at least one aliphatic hydrocarbon group having one or more
branched chains, a total number of the branched chain of not
20 less than 3 and a total carbon number of not less than 14 and
not more than 300" for Ra and Rb is an organic group having at
least one aliphatic hydrocarbon group having one or more
branched chains in a molecular structure thereof, a total
number of the branched chain of not less than 3 and a total
25 carbon number of not less than 14 and not more than 300.
The "branched chain" of the "aliphatic hydrocarbon group
having one or more branched chains" is a straight or branched
saturated aliphatic hydrocarbon group. Preferred is a Ci-g
alkyl group, more preferred is a C1-4 alkyl group, and still
30 more preferred is a methyl group or an ethyl group. In
addition, the "branched chain" is optionally substituted by
one or more halogen atoms.
The "aliphatic hydrocarbon group" of the "aliphatic
hydrocarbon group having one or more branched chains" is a
35 straight saturated or unsaturated aliphatic hydrocarbon group,
22
a C2-C300 alkyl group (preferably, a C3-C100 alkyl group, more
preferably, a C3-C60 alkyl group) , a C2-C300 alkenyl group
(preferably, a C3-C100 alkenyl group, more preferably, a C3-C60
alkenyl group) or a C2-C300 alkynyl group (preferably, a C3-C100
5 alkynyl group, more preferably, a C3-C60 alkynyl group).
The moiety of the "aliphatic hydrocarbon group having one
or more branched chains" of the "organic group having at least
one aliphatic hydrocarbon group having one or more branched
chains, a total number of the branched chain of not less than
10 3 and a total carbon nuinber of not less than 14 and not more
than 300" is not particularly limited, and it may be present
at the terminal (monovalent group), or other site (e.g.,
divalent group).
Specific examples of the "aliphatic hydrocarbon group
15 having one or more branched chains" include a monovalent group
having one or more branched chain(s) of a branched isomer of a
propyl group, a butyl group, a pentyl group, a hexyl group, a
heptyl group, an octyl group, a nonyl group, a decyl group, an
undecyl group, a dodecyl group (a lauryl group), a tridecyl
20 group, a myristyl group, a cetyl group, a stearyl group, an
arachyl group, a behenyl group, an oleyl group, a linolyl
group, a lignoceryl group and the like, and a divalent group
derived therefrom, preferably, a 3,7,11-trimethyldodecyl group,
a 3,7,11,15-tetramethylhexadecyl group (hereinafter sometimes
25 to be referred to as a 2,3-dihydrophytyl group), a
2,2,4,8,10,lO-hexamethylundecan-5-yl group, a group
represented by the formula:
[0067]
\. L ^- J n n=23-34
30 [0068]
wherein * shows a bonding position to Q, and the like.
[0069]
When plural "aliphatic hydrocarbon groups having one or
23
more branched chains" are in the "organic group having at
least one aliphatic hydrocarbon group having one or more
branched chains, a total number of the branched chain of not
less than 3 and a total carbon number of not less than 14 and
5 not more than 300", each may be same or different.
[0070]
The moiety other than the "aliphatic hydrocarbon group
having one or more branched chains" of the "organic group
having at least one aliphatic hydrocarbon group having one or
10 more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300" can be set freely. For example, the
group optionally has moieties such as -0-, -S-, -CO-, -NH-, -
C00-, -OCONH-, -CONH-, -NHCO-, hydrocarbon group (monovalent
15 group or divalent group) and the like. Examples of the
"hydrocarbon group" include an aliphatic hydrocarbon group, an
aromatic aliphatic hydrocarbon group, a monocyclic saturated
hydrocarbon group, an aromatic hydrocarbon group and the like.
Specifically, for example, monovalent groups such as an alkyl
20 group, an alkenyl group, an alkynyl group, a cycloalkyl group,
an aryl group, an aralkyl group and the like, and divalent
groups derived therefrom are used. As the "alkyl group", a Ci_6
alkyl group and the like are preferable and, for example,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
25 tert-butyl, pentyl, hexyl and the like can be mentioned. As
the "alkenyl group", a C2-6 alkenyl group and the like are
preferable and, for example, vinyl, 1-propenyl, allyl,
isopropenyl, butenyl, isobutenyl and the like can be mentioned.
As the "alkynyl group", a C2-6 alkynyl group and the like are
30 preferable and, for example, ethynyl, propargyl, 1-propynyl
and the like can be mentioned. As the "cycloalkyl group", a
C3-6 cycloalkyl group and the like are preferable and, for
example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
can be mentioned. As the "aryl group", for example, a C6-14
35 aryl group and the like are preferable and, for example,
24
phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the
like can be mentioned. Of these, a Ce-io aryl group is more
preferable, and phenyl is particularly preferable. As the
"aralkyl group", a C7-20 aralkyl group is preferable and, for
5 example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl,
naphthylmethyl, 1-naphthylethyl, 1-naphthylpropyl and the like
can be mentioned. Of these, a C7-16 aralkyl group (Cs-io aryl-Ci-s
alkyl group) is more preferable, and benzyl is particularly
preferable. The "hydrocarbon group" is optionally substituted
10 by a substituent selected from a halogen atom (a chlorine atom,
a bromine atom, a fluorine atom, an iodine atom), an 0x0 group
and the like.
[0071]
The compound of the present invention has a QRa group in
15 the number of k. Here, Q is a single bond, or -0-, -S-, -
C(=0)0-, -C(=0)NH- or -NH-, preferably 0. The QRa group in the
niomber of k may be the same or different.
[0072]
In the compound of the present invention, the "organic
20 group having at least one aliphatic hydrocarbon group having
one or more branched chains, a total number of the branched
chain of not less than 3 and a total carbon number of not less
than 14 and not more than 300" for Rg and Rb preferably has a
total carbon number of not less than 14, preferably not less
25 than 16, more preferably not less than 18. The "organic group
having at least one aliphatic hydrocarbon group having one or
more branched chains, and an aliphatic hydrocarbon group
having a total number of the branched chain of not less than
3" for Ra and Rb preferably has a total carbon number of not
30 more than 300, preferably not more than 200, more preferably
not more than 160. In addition, in the compound of in the
present invention, the "organic group having at least one
aliphatic hydrocarbon group having one or more branched chains,
and an aliphatic hydrocarbon group having a total number of
35 the branched chain of not less than 3" for Ra and Rb preferably
25
has a total number of the branched chain of not less than 3,
preferably not less than 4, more preferably not less than 8,
further preferably not less than 10. When the total number of
the branched chain is higher, a compound protected by the
5 compound of the present invention becomes an oil showing good
solubility in various organic solvents even when the peptide
chain becomes long.
[0073]
As the "organic group having at least one aliphatic
10 hydrocarbon group having one or more branched chains, a total
number of the branched chain of not less than 3 and a total
carbon number of not less than 14 and not more than 300" for Ra
and Rb, a group having 3 or more, the same or different
divalent groups represented by the formula (b):
15 [0074]
R3
R4 (b)
[0075]
wherein * shows a bonding position with the adjacent atom;
R3 and R4 are each independently a hydrogen atom or a Ci_4 alkyl
20 group;
Xi is a single bond, a C1-4 alkylene group or an oxygen atom,
provided that R3 and R4 are not hydrogen atoms at the same time,
is preferable and, for example, a group represented by any of
the following formulas (c) - (e) can be mentioned.
25 [0076]
The carbon number, repeat unit number (mi, no - ng) and
the like in the definition of each symbol in the formulas (c)
- (e) are shown for convenience, and can be changed as
appropriate within the range defined above, so that the total
30 number of the carbon will be not less than 14 (preferably not
less than 16, more preferably not less than 18) and not more
than 300 (preferably not more than 200, more preferably not
more than 160). In the following, the formulas (c) - (e) are
26
explained in this order.
[0077]
The formula (c) is as described below.
[0078]
Rr 1 i'
Rg—C'^'~~~ ^ ^ 2 ~ ^ — " " ^ R i o (c)
/ •- -'"0
5 Re Rs
[0079]
wherein* shows a bonding position to Q;
Rs and Rg are both hydrogen atoms, or show =0 in combination;
no is an integer of 2 - 4 0;
10 R? and Re in the number of no are each independently a hydrogen
atom or a C1-4 alkyl group;
X2 in the number of no are each independently a single bond or
a Ci-4 alkylene group; and
R9 is a hydrogen atom or a C1-4 alkyl group;
15 Rio is a Ci-4 alkyl group or the formula (I'):
[0080]
X
A' •\l
[0081]
wherein * shows a bonding position;
20 other symbols are as defined above, and ring A' optionally has,
in addition to Ri, Q, and C(X) {Y)Z, substituent (s) selected
from the group consisting of a halogen atom, a Ci-e alkyl group
optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
25 atoms,
provided that R7 and Re are not hydrogen atoms at the same time,
and when no is 2, Rg is a Ci_4 alkyl group.
[0082]
In the group of the formula (c), a group wherein
30 R5 and Re are both hydrogen atoms;
27
no is an integer of 2 - 40;
R7 and Rs in the number of no are each independently a hydrogen
atom, a methyl group or an ethyl group;
X2 in the number of no are each independently a single bond, a
5 methylene group or an ethylene group; and
Rg is a hydrogen atom, a methyl group or an ethyl group
is preferable, provided that R7 and Rs are not hydrogen atoms
at the same time, and when no is 2, Rg is methyl or an ethyl
group.
10 [0083]
More preferable group of the formula (c) is a group of a
branched isomer having a carbon number of 14 to 160, of a
myristyl group, a cetyl group, a stearyl group, an arachyl
group, a behenyl group and the like, wherein the total number
15 of the branched chain is not less than 3. Of these, a 2,3-
dihydrophytyl group, a 3,7,11-trimethyldodecyl group and a
2,2,4,8,10,lO-hexamethyl-5-dodecanoyl group are particularly
preferable.
[0084]
20 The formula (d) is as described below.
[0085]
\_J7^QRll)m1
[0086]
wherein * shows a bonding position to Q;
25 ORii in the number of mi is hydroxyl group substituted by a
group represented by the formula (c') or a hydroxyl group
substituted by a group having a polyalkyleneglycol group
wherein the total number of the branched chain is not less
than 3 (e.g., a polypropylene glycol group, a
30 polyneopentylglycol group); and
mi is an integer of 1 - 3.
The explanation of the group represented by the abovementioned
formula (c') is the same as the explanation of a
group represented by the above-mentioned formula (c) except
28
that * does not show a bonding position to Q but shows a
bonding position to 0.
[0087]
In the group of the formula (d), Rn is more preferably a
5 group of a branched isomer having a carbon number of 14 to 30
of a myristyl group, a cetyl group, a stearyl group, an
arachyl group, a behenyl group and the like, wherein the total
number of the branched chain is not less than 3. Of these, a
2,3-dihydrophytyl group and a 3,7,11-trimethyldodecyl group
10 are particularly preferable.
[0088]
The formula (e) is as described below.
[0089]
Ki2 r "l R,0 "^1
HQ (Q'=0, S, CO2, NH) step(d-2)y^^ (l-b)
step (a) / 1
r^ ^°^Ki / step(cl-5)
O N ^
^ : = = ^ \ ^ ^ \ step(d-1) ^ ; ; = ^ = \ ^ ^ ^ ,<:;^=^\^--^T ^c ^ I T Re \ \ ^3
RaQ („a) ""^ RaQ (,,3) Rad ^1
\ step(b) step(d^)/ (I'-c)
\ (R,=ORdOrH) /^
ri^^y^^Qy^ step (6-3) r^:==^^^\'-''''^YiStep(d-6) f^^^^^^Y^^^^^
»- »-
A-^^R S<^= ?\p
HO z l)step(d-3) H2N z
V 2)step(d-4) \/
step(c) r ^ ^ ^ R 3)step(d-5) or ^ \ ^ \ p ^
(Rc^ORdOrH) W A \ step(d-7) S ^ ^ ^ D
RaQ (,.d)^^ RaQ (,.e)^^
[0131]
wherein Q' i s - 0 - , - S - , -C(=0)0- or -NH-, Re i s a hydrogen atom,
10 an ORd group (Rd i s an alkyl group such as a Ci-e alkyl group
and the l i k e , an aralkyl group such as a benzyl group e t c . and
the like) or a group represented by the formula (a):
[0132]
38
• r ^ (a)
B -4^
R{
[0133]
wherein each symbol is as defined above, Yi is a leaving group
such as a halogen atom and the like, other symbols are as
5 defined above.
[0134]
step (a)
In this step, an Ra group is introduced into a Q'H group
wherein Q' is -0-, -S-, -C(=0)0- or -NH- of a compound
10 represented by the formula (II) (hereinafter to be abbreviated
as compound (II)) to give a compound represented by the
formula (Ila) (hereinafter to be abbreviated as compound
(Ila)).
When Q' is -0-, -S- or -NH-, the reaction is carried out
15 in a solvent that does not influence the reaction, in the
presence or absence of a base and using a halide corresponding
to an Ra group (chloride, bromide or iodide), a carboxylic acid
or an acid halide corresponding to an Ra group or
alkylsulfonyloxylation product (e.g., methanesulfonyloxylation
20 product etc.) or an arylsulfonyloxylation product (e.g., ptoluenesulfonyloxylation
product etc.) corresponding to an Ra
group. In addition, when Q' is -0-, the reaction can be
carried out by reacting compound (II) with hydroxide
corresponding to an Ra group in the presence of
25 triphenylphosphine and diisopropyl azodicarboxylate, under the
conditions of Mitsunobu reaction. Furthermore, when Q' is -
C(=0)0-, for example, compound (Ila) can be synthesized by
reacting compound (II) with amine or hydroxide corresponding
to an Ra group in the presence of the below-mentioned
30 condensing agent.
Examples of the base include alkali metal salt such as
sodium carbonate, sodium hydrogen carbonate, potassium
carbonate, sodium hydride, potassium hydride, potassium tert-
39
butoxide and the like; amines such as pyridine, triethylamine,
N,N-dimethylaniline, 1,8-diazabicyclo[5.4,0]undec-7-ene etc.,
and the like. Of these, sodium carbonate, potassium carbonate,
sodium hydride and the like are preferable.
5 Examples of the solvent include aromatic hydrocarbons
such as toluene, xylene and the like; ethers such as
tetrahydrofuran, dioxane and the like; amides such as
dimethylformamide, dimethylacetamide and the like; halogenated
hydrocarbons such as chloroform, dichloromethane and the like;
10 nitriles such as acetonitrile and the like, Nmethylpyrrolidone,
and a mixture thereof. Of these,
dimethylformamide, tetrahydrofuran, toluene, Nmethylpyrrolidone
and the like are preferable.
The reaction temperature is generally 50°C to 150°C,
15 preferably 60°C to 130°C. The reaction time is generally 2 -
30 hr, preferably 3-10 hr.
[0135]
Step (b)
In this step, compound (Ila) is reduced to give a
20 compound represented by the formula (I-a) (hereinafter to be
abbreviated as compound (I-a)). The reduction reaction can be
performed by a method using a reducing agent.
[0135]
Examples of the reducing agent to be used for the
25 reduction reaction include metal hydride (sodium borohydride,
lithium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, dibutylaluminum hydride, aluminum
hydride, lithium aluminum hydride, etc.) and the like. Of
these, sodium borohydride, dibutylaluminum hydride and the
30 like are preferable.
[0137]
The reaction is performed in a solvent that does not
influence the reaction. Examples of the solvent include
alcohols such as methanol, ethanol and the like; ethers such
35 as diethyl ether, tetrahydrofuran, dioxane and the like;
40
aromatic hydrocarbons such as toluene, xylene and the like;
and a mixture thereof. Of these, tetrahydrofuran, toluene and
the like are preferable.
The reaction temperature is generally 0°C to 100°C,
5 preferably 30°C to 70°C, and the reaction time is generally 1 -
24 hr, preferably 2 - 5 hr.
[0138]
step (c)
In this step, compound (Ila) (in the formula (Ila), Re is
10 not a hydrogen atom or an ORd group) is reduced in the same
manner as in the above-mentioned step (b) or a phenyl group
(corresponding to the above-mentioned Z group) is introduced
by a Grignard reaction.
[0139]
15 In the Grignard reaction, a commercially available
Grignard reagent (e.g., phenylmagnesium bromide,
phenylmagnesium chloride etc.) can be used, or a reagent
prepared by reacting magnesium with halobenzene (chlorobenzene,
bromobenzene, iodobenzene) in the presence of iodine or
20 dibromoethane can be used.
[0140]
The Grignard reaction is carried out in a solvent that
does not influence the reaction. Examples of the solvent
include ethers such as diethyl ether, tetrahydrofuran, 1,2-
25 dimethoxyethane and the like; aromatic hydrocarbons such as
toluene, xylene and the like; and a mixture thereof. Of these,
tetrahydrofuran, 1,2-dimethoxyethane and the like are
preferable.
The reaction temperature is generally -20 to 100°C,
30 preferably 0 to 70°C, and the reaction time is generally 1-24
hr, preferably 2 - 1 0 hr.
[0141]
step (d-1)
In this step, compound (Ila) (in the formula (Ila), Re is
35 a hydrogen atom) is oximated to give a compound represented by
41
the formula (I'-a) (hereinafter to be abbreviated as compound
(I'-a)).
[0142]
The oximation reaction includes reacting compound (Ila)
5 with hydroxylamine acid addition salt in a solvent that does
not influence the reaction in the presence of a base.
Examples of the hydroxylamine acid addition salt include
mineral acid salts such as hydrochloride, sulfate, nitrate and
the like, organic acid salts such as acetate, trifluoroacetate,
10 methanesulfonate, trifluoromethanesulfonate, ptoluenesulfonate
etc., and the like, and hydrochloride is
particularly preferable.
Examples of such base include alkali metal salts such as
potassium hydroxide, sodium hydroxide, sodium hydrogen
15 carbonate, potassium carbonate and the like; organic amines
such as pyridine, triethylamine, diisopropylethylamine, N,Ndimethylaniline,
1,8-diazabicyclo[5.4.0]undec-7-ene etc., and
the like. Of these, triethylamine, diisopropylethylamine and
the like are preferable.
20 Examples of the solvent include halogen solvents such as
chloroform, dichloromethane and the like; aromatic
hydrocarbons such as toluene, xylene and the like; ethers such
as tetrahydrofuran, dioxane and the like; and/or a mixture
thereof. Of these, dichloromethane, chloroform, toluene and
25 the like are preferable.
The reaction temperature is generally 10°C to 100°C,
preferably 20°C to 60°C, and the reaction time is generally 0.5
- 30 hr, preferably 2 - 2 0 hr.
[0143]
30 step (d-2)
In this step, compound (I'-a) is reduced by a catalytic
hydrogenation reaction in the presence of a metal catalyst
such as palladium-carbon, Raney-nickel and the like, or by a
reducing agent such as metal hydride and the like, which is
35 similar to those in the aforementioned step (b), to give a
42
compound represented by the formula (I-b) (hereinafter to be
abbreviated as compound (I-b)), which is the compound of the
present invention.
[0144]
5 Compound (I-b) can also be produced from step (d-3) via
step (d-4) and step (d-5).
[0145]
step (d-3)
In this step, compound (I-a) is halogenated with, for
10 example, a chlorinating agent such as acetyl chloride, thionyl
chloride and the like or, for example, a brominating agent
such as acetyl bromide, phosphorus tribromide,
diphenylphosphine/bromine and the like to give a compound
represented by the formula (I'-b) (hereinafter to be
15 abbreviated as compound (I'-b)).
Examples of the solvent include halogenated hydrocarbons
such as chloroform, dichloromethane, and the like; aromatic
hydrocarbons such as toluene, xylene, and the like; ethers
such as tetrahydrofuran, dioxane, and the like; and a mixture
20 thereof. Of these, chloroform, tetrahydrofuran, toluene, and
the like are preferable.
The reaction temperature is generally 10°C to 150°C,
preferably 30°C to 80°C, and the reaction time is generally 0.5
- 30 hr, preferably 2 - 20 hr.
25 [0146]
step (d-4)
In this step, compound (I'-b) is azidated with an
azidating agent such as sodium azide and the like to give a
compound represented by the formula (I'-c) (hereinafter to be
30 abbreviated as compound (I'-c)).
The reaction includes reacting compound (I'-b) with an
azidating agent in a solvent that does not influence the
reaction.
Examples of the solvent include halogenated hydrocarbons
35 such as chloroform, dichloromethane, and the like; aromatic
43
hydrocarbons such as toluene, xylene, and the like; ethers
such as tetrahydrofuran, dioxane, and the like; amides such as
N,N-dimethylformaniide and the like; and a mixture thereof. Of
these, chloroform, N,N-dimethylformamide, and the like are
5 preferable.
The reaction temperature is generally 10°C to 150°C,
preferably 20°C to 100°C, and the reaction time is generally
0.5 - 30 hr, preferably 2 - 20 hr.
[0147]
10 step (d-5)
In this step, compound (I'-c) is aminated to give
compound (I-b).
The reaction is carried out by reacting compound (I'-c)
with triphenylphosphine in a solvent that does not influence
15 the reaction in the presence of water or catalytic
hydrogenation.
The amount of triphenylphosphine to be used is preferably
1 - 1 0 mol, particularly preferably 1 - 5 mol, per 1 mol of
compound (I'-c).
20 The amount of water to be used is preferably 1 - 1 0 mol,
particularly preferably 1 - 5 mol, per 1 mol of compound (I'-
c) .
Examples of the solvent include aromatic hydrocarbons
such as toluene, xylene, and the like; ethers such as
25 tetrahydrofuran, dioxane, and the like; and a mixture thereof.
Of these, toluene, tetrahydrofuran, and the like are
preferable.
The reaction temperature is generally 10°C to 150°C,
preferably 20°C to 100°C, and the reaction time is generally
30 0.5-30 hr, preferably 2 - 20 hr.
[0148]
step (d-6)
In this step, compound (I'-b) is reacted with RNH2
(wherein R is as defined above) to give a compound represented
35 by the formula (I-c) (hereinafter to be abbreviated as
44
compound (I-c)), which is the compound of the present
invention wherein Y is an -NHR group.
The reaction includes reacting compound (I'-b) with amine
represented by R-NH2 in a solvent that does not influence the
5 reaction in the presence of, where necessary, for example, a
base such as tertiary amine (triethylamine,
diisopropylethylamine etc.) and the like.
Examples of the solvent include aromatic hydrocarbons
such as toluene, xylene, and the like; ethers such as
10 tetrahydrofuran, dioxane, and the like; and, halogen solvents
such as chloroform, dichloromethane, and the like and a
mixture thereof. Of these, toluene, tetrahydrofuran,
chloroform, and the like are preferable.
The reaction temperature is generally 10°C to 100°C,
15 preferably 20°C to 60°C, and the reaction time is generally 0.5
- 30 hr, preferably 2 - 20 hr.
[0149]
step (d-7)
In this step, compound (I-d) is reacted with a compound
20 having a -CONH2 group or a -OCONH2 group, and treated with a
base to give compound (I-e).
The reaction of compound (I-d) with a compound having a -
CONH2 group or a -OCONH2 group is carried out in a solvent that
does not influence the reaction and under an acid catalyst.
25 Examples of the acid catalyst include methanesulfonic
acid, trifluoromethanesulfonic acid, toluenesulfonic acid and
the like. Of these, methanesulfonic acid and toluenesulfonic
acid are preferable.
The amount of the acid catalyst to be used is preferably
30 0.05-0.5 mol, particularly preferably 0.1 - 0.3 mol, per 1
mol of compound (I-d).
Examples of the compound having a -CONH2 group or a -
OCONH2 group include Fmoc-NH2, HCONH2, CF3CONH2, ACNH2, EtOCONH2,
Cbz-NH2 and the like. Of these, Fmoc-NH2, EtOCONH2 and the like
35 are preferable.
45
Here, the "Fmoc-" means a 9-fluorenylii:iethoxycarbonyl
group (hereinafter to be also referred to as a Fmoc group),
and "Cbz-" means a benzyloxycarbonyl group (hereinafter to be
also referred to as a Cbz group).
5 [0150]
The Ra forming-reagent to be used as a starting compound
of step (a) [i.e., hydroxide, halide, an
alkylsulfonyloxylation product (e.g., methanesulfonyloxylation
product etc.) or an arylsulfonyloxylation product (e.g., p-
10 toluenesulfonyloxylation product etc.) corresponding to Ra
group] may be a commercially available product. In addition,
the Ra forming-reagent can be produced by, for example,
(1) halogenation, alkylsulfonyloxylation or
arylsulfonyloxylation of hydroxide corresponding to an Ra group,
15 or
(2) reduction reaction of unsaturated hydroxide corresponding
to an Ra group (e.g., catalytic hydrogenation reaction in the
presence of a metal catalyst such as platinum-carbon (Pt/C),
palladium-carbon (Pd/C), rhodium-carbon (Rh/C), Raney-nickel
20 etc. and the like), and subsequently halogenation,
alkylsulfonyloxylation or arylsulfonyloxylation.
[0151]
In the production of the Ra forming-reagent, examples of
the reagent to be used for conversion to a leaving group from
25 a hydroxyl group include, in addition to halogenating agent
such as chlorinating agent (thionyl chloride, Nchlorosuccinimide
(NCS) and the like) , brominating agent
(hydrobromic acid, acetyl bromide, N-bromosuccinimide (NBS),
phosphorus tribromide, diphenylphosphine/bromine and the like)
30 and the like, alkylsulfonylating agent such as methanesulfonyl
chloride, trifluoromethanesulfonyl chloride and the like,
arylsulfonylating agent such as benzenesulfonyl chloride, ptoluenesulfonyl
chloride etc. and the like. Of these, thionyl
chloride, hydrobromic acid and the like are preferable, which
35 are the halogenating agents.
46
[0152]
The reaction is performed in a solvent that does not
influence the reaction. Examples of the solvent include water,
halogenated hydrocarbons such as chloroform, dichloromethane
5 and the like; aromatic hydrocarbons such as benzene, toluene,
xylene and the like; nitriles such as acetonitrile,
propionitrile and the like; ethers such as tetrahydrofuran,
1,4-dioxane, diethyl ether and the like. Of these, water,
halogenated hydrocarbons such as chloroform and the like are
10 preferable.
The reaction temperature is generally 10 - 120°C,
preferably 50 - 100°C, and the reaction time is generally 1 -
72 hr, preferably 3 - 2 4 hr.
[0153]
15 The compound of the present invention (a compound
represented by the formula (I) wherein the aforementioned Q is
a single bond) can be also produced by, for example, the
following method. That is, introduction of an Ra group onto a
benzene ring can be carried out by
20 (1) Friedel-Crafts reaction using halide corresponding to an Ra
group (chloride, bromide, or iodide), carboxylic acid or acid
halide corresponding to an Ra group,
(2) a method comprising subjecting a compound corresponding to
the above-mentioned compound (II) (a compound wherein a Q'H
25 group is substituted by a -CHO group) to carbon homologation
by a Wittig reaction and, followed by catalytic hydrogenation
and the like, or
(3) conventional organic synthesis reaction such as cross
coupling using a metal catalyst and the like.
30 [0154]
In each scheme above, the carbon number of an organic
group for Ra, the kind of halogen atom, reaction reagents and
the like are shown for the sake of convenience, and can be
appropriately changed within the scope of the above-mentioned
35 definitions.
47
[0155]
[Organic synthesis reaction]
The compound of the present invention can be used as a
protecting reagent in an organic synthesis reaction of peptide,
5 oligonucleic acid, and other organic compounds. The compound
of the present invention is preferably used as a protecting
reagent of amino acid or peptide in the peptide synthesis and
the like. To be specific, the compound of the present
invention is preferably introduced into amino acid or peptide
10 as a protecting group of C-terminal carboxyl group,
carboxamido group (amido group), i.e., a -CONHR' group that an
amino acid forming a C-terminus has (R' is a hydrogen atom, an
alkyl group or an aralkyl group), a functional group such as -
SH group and the like, and a side chain functional group
15 (hereinafter C-terminus and the like). The explanations of the
alkyl group and aralkyl group for R' are the same as those of
the alkyl group and aralkyl group for R. R' is preferably a
hydrogen atom. When used as a protecting reagent, the compound
of the present invention may be activated or converted to an
20 equivalent before reaction with a substituent to be protected.
An "organic compound protected by a branched chain-containing
aromatic compound of the present invention" is referred to as
a "branched chain-containing aromatic compound adduct".
[0156]
25 The compound of the present invention can be used as a
protecting reagent for various organic synthesis reactions.
For example, organic synthesis reactions can be performed by
the following steps:
step (i) a step of dissolving the compound of the present
30 invention in a compound-solubilizing solvent (dissolving step),
step (ii) a step of bonding the compound of the present
invention dissolved in the solubilizing solvent as obtained in
the above-mentioned step to a reaction substrate (bonding
step),
35 step (iii): a step of washing the reaction solution containing
48
the bonded product obtained in the above-mentioned step with
water, separating the layers and removing the aqueous layer
(layer-separating step),
step (iv): a step of subjecting the solution after washing
5 with water, which contains the bonded product obtained in the
above-mentioned step to a reaction, washing the resultant
product after the reaction with water, separating the layers
and removing the aqueous layer (reacting and layer-separating
step),
10 step (v): a step of removing a protecting group derived from
the compound of the present invention and other protecting
groups from a resultant product in the solution after washing
with water (deprotection step).
In the present specification, the "protecting group
15 derived from the compound of the present invention" and "other
protecting group" may be distinguished by referring them as
"anchor" and "temporary protecting group", respectively.
[0157]
Each of the above-mentioned steps is explained in detail
20 in the following.
[0158]
step (i) (dissolving step)
In this step, the compound of the present invention is
dissolved in a compound-solubilizing solvent.
25 As such solubilizing solvent, general organic solvents
can be used for the reaction. Since the compound of the
present invention has a long branched chain aliphatic
hydrocarbon group, it shows high solubility in various organic
solvents and is expected to show a superior reactivity.
30 Specific examples of the solubilizing solvent include
ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane,
methyl-t-butylether, cyclopentylmethylether (CPME) and the
like; acetate esters such as ethyl acetate, isopropyl acetate
and the like; halogenated hydrocarbons such as chloroform,
35 dichloromethane and the like; aromatic hydrocarbons such as
49
toluene, xylene and the like; and hydrocarbons such as hexane,
heptane, cyclohexane and the like. Two or more kinds of these
solvents may be used in a mixture at appropriate proportions.
Since good extraction operation can be expected, and
5 industrial use is possible, ethyl acetate, isopropyl acetate,
dichloromethane, cyclopentylmethylether and toluene are
preferable, ethyl acetate, isopropyl acetate,
cyclopentylmethylether and toluene are more preferable, ethyl
acetate, isopropyl acetate and cyclopentylmethylether are more
10 preferable, and isopropyl acetate and cyclopentylmethylether
are further preferable.
[0159]
While "the solubility of the compound of the present
invention in an organic solvent" should be evaluated as
15 "solubility of a bonded product of a substrate such as each
starting material and each resultant product in each reaction
and the compound of the present invention in an organic
solvent", it is extremely difficult to assume and confirm
solubility of a bonded product of a substrate and the compound
20 of the present invention for various substrates. Therefore, it
was evaluated as "solubility of the compound of the present
invention itself in an organic solvent".
[0160]
In.the following, the characteristics of the compound of
25 the present invention are shown by referring to isopropyl
acetate as a representative example of the solubilizing
solvent.
While the lower limit of saturation solubility of the
compound of the present invention in isopropyl acetate (100 g)
30 at 20°C is not particularly limited as long as the bonding to a
reaction substrate and the reaction thereafter proceed, 1 wt%
is preferable, 2 wt% is more preferable, 5 wt% is further
preferable, 10 wt% is still more preferable, 25 wt% is
especially preferable and 50 wt% is particularly preferable,
35 since the reaction proceeds stably with any industrial
Claims
1. A branched chain-containing aromatic compound represented
by the formula (I):
wherein
Q in the number of k are each independently a single bond, or
-0-, -S-, -C(=0)0-, -C(=0)NH- or -NH-;
Ra in the number of k are each independently an organic group
10 having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
k is an integer of 1 - 4;
15 Ri is a hydrogen atom or, when Z is a group represented by the
following formula (a), it optionally shows a single bond
together with R2 to form a fluorene ring together with ring B;
ring A optionally further has, in addition to Ri, QRa in the
number of k, and C(X)(Y)Z, one or more substituents selected
20 from the group consisting of a halogen atom, a Ci-e alkyl group
optionally substituted by one or more halogen atoms, and a Ci-g
alkoxy group optionally substituted by one or more halogen
atoms;
X is a hydrogen atom or a phenyl group;
25 Y is a hydroxyl group or an -NHR group (R is a hydrogen atom,
an alkyl group or an aralkyl group); and
Z is a hydrogen atom or a group represented by the formula
(a):
30 wherein * shows a bonding position;
112
m is an integer of 0 - 4;
Q in the number of m are as defined above;
Rb in the number of m are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
5 more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
R2 is a hydrogen atom, or optionally shows a single bond
together with Ri to form a fluorene ring together with ring A;
10 and
ring B optionally further has, in addition to QRb in the number
of m, and R2, one or more substituents selected from the group
consisting of a halogen atom, a Ci-g alkyl group optionally
substituted by one or more halogen atoms, and a Ci-g alkoxy
15 group optionally substituted by one or more halogen atoms);
the organic group having at least one aliphatic hydrocarbon
group having one or more branched chains, a total number of
the branched chain of not less than 3 and a total carbon
number of not less than 14 and not more than 300 for the
20 aforementioned Ra and Rb is a group having 3 or more the same
or different divalent groups, which is represented by the
formula (b):
R4 (b)
wherein * shows a bonding position with the adjacent atom;
25 R3 and R4 are each independently a hydrogen atom or a Ci_4 alkyl
group;
Xi is a single bond, a C1-4 alkylene group or an oxygen atom,
provided that R3 and R4 are not hydrogen atoms at the same time.
30 2. The branched chain-containing aromatic compound according
to claim 1, wherein the organic group having at least one
aliphatic hydrocarbon group having one or more branched chains,
a total number of the branched chain of not less than 3 and a
113
total carbon number of not less than 14 and not more than 300
for the aforementioned Ra and Rb is a group represented by the
formula (c):
R7 I
R5—C-''~^~~-^ ^^—^ Rio (c)
Re Rs
5 wherein * shows a bonding position to Q;
R5 and Re are both hydrogen atoms, or taken together to show
=0;
no is an integer of 2 - 40;
R7 and Rs in the number of no are each independently a hydrogen
10 atom or a Ci_4 alkyl group;
X2 in the number of no are each independently a single bond or
a Ci-4 alkylene group; and
Rg is a hydrogen atom or a C1-4 alkyl group;
Rio is a Ci-4 alkyl group or the formula (I'):
X
wherein * shows a bonding position;
other symbols are as defined above, and ring A' optionally has,
in addition to Ri, Q, and C{X) (Y)Z, one or more substituents
selected from the group consisting of a halogen atom, a Ci-e
20 alkyl group optionally substituted by one or more halogen
atoms, and a Ci-e alkoxy group optionally substituted by one or
more halogen atoms,
provided that R7 and Re are not hydrogen atoms at the same time,
and when no is 2, Rg is a C1-4 alkyl group.
25
3. The branched chain-containing aromatic compound according
to claim 2, wherein, in the aforementioned formula (c),
R5 and Rg are both hydrogen atoms;
R7 and Rs in the number of no are each independently a hydrogen
30 atom, a methyl group or an ethyl group;
114
X2 in the number of no are each independently a single bond, a
methylene group or an ethylene group; and
Rg is a hydrogen atom, a methyl group or an ethyl group.
5 4. The branched chain-containing aromatic compound according
to claim 1, wherein the organic group having at least one
aliphatic hydrocarbon group having one or more branched chains,
a total number of the branched chain of not less than 3 and a
total carbon number of not less than 14 and not more than 300
10 for the aforementioned Ra and Rb is a group represented by the
formula (d):
\ /^(ORii),„i
wherein * shows a bonding position to Q;
ORii in the number of mi is a hydroxyl group substituted by a
15 group represented by the formula (c' ):
R9
r R7 1 1'
R 5 — C - ^ ~~-'^^^"~~-~'''''^RlO (<:')
/ '• -'no
Re Rs
wherein shows a bonding position to 0;
R5 and Re are both hydrogen atoms, or taken together show =0;
no is an integer of 2 - 40;
20 R? and Rs in the number of no are each independently a hydrogen
atom or a C1-4 alkyl group;
X2 in the number of no are each independently a single bond or
a Ci-4 alkylene group; and
R9 is a hydrogen atom or a Ci_4 alkyl group;
25 Rio is a Ci-4 alkyl group or a group represented by the formula
(I') :
X
^5s,/^ Q
wherein * shows a bonding position;
other symbols are as defined above, and ring A' optionally has,
115
in addition to Ri, Q, and C(X) (Y)Z, one or more substituents
selected from the group consisting of a halogen atom, a Ci_6
alkyl group optionally, substituted by one or more halogen
atoms, and a Ci-e alkoxy group optionally substituted by one or
5 more halogen atoms,
provided that R7 and Rs are not hydrogen atoms at the same time,
and when no is 2, Rg is a Ci_4 alkyl group; and
mi is an integer of 1 - 3.
10 5. The branched chain-containing aromatic compound according
to claim 1, wherein the organic group having at least one
aliphatic hydrocarbon group having one or more branched chains,
a total number of the branched chain of not less than 3 and a
total carbon number of not less than 14 and not more than 300
15 for the aforementioned Ra and Rb is a group represented by the
formula (e):
f? r "^isn r • -, Ri9
'^ ^ - ^ X3 ^HC ^-^ R21 (e)
wherein * shows a bonding position to Q;
ni is an integer of 1 - 10;
20 n2 is an integer of 1 - 10;
Ri5 and Rie in the number of ni are each independently a
hydrogen atom or a C1-4 alkyl group;
X3 in the number of ni are each independently a single bond or
a Ci-4 alkylene group;
25 Ri7 and Ris in the number of n2 are each independently a
hydrogen atom or a C1-4 alkyl group;
X5 in the number of n2 are each independently a single bond or
a Ci-4 alkylene group;
X4 is a single bond or a C1-4 alkylene group; and
30 Ri2r Ri3r Ri4/- Ri9r R20 s^d R21 are each independently a hydrogen
atom or a C1-4 alkyl group,
provided when R15 and Rie, and/or R17 and Ris are not hydrogen
atoms at the same time, and when ni+n2 is 2, then two or more
116
of Ri2/ Ri3 and R14 are each independently a C1-4 alkyl group, or
two or more of R19, R20 and R21 are each independently a C1-4
alkyl group.
5 5. The branched chain-containing aromatic compound according
to claim 5, wherein, in the aforementioned formula (e),
ni is an integer of 1 - 5;
n2 is an integer of 1 - 5;
Ri5 and Rie in the number of ni are each independently a
10 hydrogen atom, a methyl group or an ethyl group;
X3 in the number of ni are each independently a single bond, a
methylene group or an ethylene group;
Ri7 and Rig in the number of n2 are each independently a
hydrogen atom, a methyl group or an ethyl group;
15 X5 in the number of na are each independently a single bond, a
methylene group or an ethylene group; and
X4 is a single bond, a methylene group or an ethylene group.
7. The branched chain-containing aromatic compound according
20 to claim 6, wherein, in the aforementioned formula (e),
Ri5 and Rig in the number of ni are each independently a
hydrogen atom or a methyl group;
X3 in the number of ni are each independently a single bond or
a methylene group;
25 Ri7 and Rie in the number of n2 are each independently a
hydrogen atom or a methyl group;
X5 in the number of n2 are each independently a single bond or
a methylene group;
X4 is a single bond or a methylene group; and
30 Ri2r Ri3, Ri4f Ri9/ R20 and R21 are each a methyl group.
8. The branched chain-containing aromatic compound according
to claim 1, wherein Ra and Rb are each independently a
3,7,11,15-tetramethylhexadecyl group, a 3,7,11-
35 trimethyldodecyl group, a 2,2,4,8,10,lO-hexamethyl-5-
117
dodecanoyl group, a 3,4,5-tri(3',7',11',15'-
tetramethylhexadecyloxy)benzyl group, a 3,5-di(3',7',11',15'-
tetramethylhexadecyloxy)benzyl group, a group represented by
the formula (f):
* I I ^'° (f)
^ \ L ^ ^ J "10
5
wherein * shows a bonding position to Q, nio is 23 - 34, Rio is
a group represented by the formula (I'):
X
wherein * shows a bonding position; and other symbols are as
10 defined above, wherein ring A' optionally has, in addition to
Ri, Q, and C (X) (Y)Z, one or more substituents selected from the
group consisting of a halogen atom, a Ci-e alkyl group
optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
15 atoms,
a group represented by the formula (g):
wherein * shows a bonding position to Q, and nn is 1 - 10,
a group represented by the formula (h):
U Jni2 (h)
20
wherein * shows a bonding position to Q, and ni2 is 2 - 10,
a group represented by the formula (i):
118
"13 "14'
wherein * shows a bonding position to Q, and ni3 and ni4 are
each independently 1-10, or
a group represented by the formula (j):
.1 J L J "15 G)
^ C9H19
wherein * shows a bonding position to Q, and nis is 2 - 20.
9. The branched chain-containing aromatic compound according
to any one of claims 1 - 8 , wherein X and Z are both hydrogen
10 atoms, and Ri is a hydrogen atom.
10. The branched chain-containing aromatic compound according
to any one of claims 1 - 8 , wherein X is a hydrogen atom, Ri is
a hydrogen atom, k is 1, and Z is a group represented by the
15 formula (a) (R2 is a hydrogen atom, and m is 0).
11. The branched chain-containing aromatic compound according
to any one of claims 1 - 8 , wherein X is a phenyl group, k is
1, Z is a group represented by the formula (a) (m is 0), and R2
20 is a single bond together with Ri to form a fluorene ring with
ring A.
12. The branched chain-containing aromatic compound according
to any one of claims 1 - 11, wherein Q is -0-.
25
13. The branched chain-containing aromatic compound according
to any one of claims 1-12, wherein Y is a hydroxyl group.
14. The branched chain-containing aromatic compound according
30 to any one of claims 1-12, wherein Y is an -NHR group.
119
15. The branched chain-containing aromatic compound according
to claim 1, which is selected from the group consisting of
2,4-di(2',3'-dihydrophytyloxy)benzyl alcohol;
5 3,5-di(2',3'-dihydrophytyloxy)benzyl alcohol;
4-(2',3'-dihydrophytyloxy)benzyl alcohol;
1-[(2-chloro-5-(2',3'-dihydrophytyloxy)phenyl)]-1-
phenylmethanamine;
3,4, 5-tri{2',3'-dihydrophytyloxy)benzyl alcohol;
10 3,4,5-tri (2',3'-dihydrophytyloxy)benzylamine;
4-(2' ,3'-dihydrophytyloxy)benzylamine;
2-[3',4',5'-tri(2",3"-dihydrophytyloxy)benzyloxy]-4-
methoxybenzyl alcohol;
4-(2' ,3'-dihydrophytyloxy)-2-methoxybenzyl alcohol;
15 4-(2' ,3'-dihydrophytyloxy)-2-methoxybenzylamine;
4-(2' ,3'-dihydrophytyloxy)-2-methylbenzyl alcohol;
4- (2'' , 3' -dihydrophytyloxy) -2-methylbenzylamine;
2,2,4,8,10,lO-hexamethyl-5-dodecanoic acid (4-
hydroxymethyl)phenylamide;
20 4-(3,7,11-trimethyldodecyloxy)benzyl alcohol;
2-(3, 7,11-trimethyldodecyloxy)-9-phenylfluoren-9-ol;
a compound represented by the formula:
OMe
J ^< V
OMe
wherein nie is 23 or 34;
25 a compound represented by the formula:
^< y
120
wherein ni7 is 23 or 34;
a compound represented by the formula:
••nis 1^
OH
wherein nig is 5 - 7; and
5 a compound represented by the formula:
HO-^Y^ H I
O [\ \2
16. The branched chain-containing aromatic compound according
to any one of claims 1-15, which shows a saturation
10 solubility in isopropyl acetate (100 g) at 20°C of 1 - 95 wt%.
17. The branched chain-containing aromatic compound according
to any one of claims 1 - 15, which shows a saturation
solubility in isopropyl acetate (100 g) at 20°C of 10 - 95 wt%.
15
18. A protecting reagent for a carboxyl group or an amido
group of amino acid or peptide, comprising the branched chaincontaining
aromatic compound according to any one of claims 1
- 17.
20
19. The protecting reagent according to claim 18, wherein the
amino acid or peptide is protected at the C-terminus.
20. A branched chain-containing aromatic compound adduct which
25 is protected by the branched chain-containing aromatic
compound according to any one of claims 1-17.
21. A method of producing a peptide comprising steps (1) -
(4);
121
(1) a step of condensing the branched chain-containing
aromatic compound according to any one of claims 1 - 1 7 with a
C-terminus of an N-protected amino acid or an N-protected
peptide in a solvent solubilizing the compound to give an N-
5 protected C-protected amino acid or N-protected C-protected
peptide having a C-terminus protected with an anchor which is
a protecting group derived from the compound,
(2) a step of removing the N-terminal protecting group from
the obtained N-protected C-protected amino acid or N-protected
10 C-protected peptide to give a C-protected amino acid or Cprotected
peptide,
(3) a step of condensing an N-protected amino acid or Nprotected
peptide with the N-terminus of the obtained Cprotected
amino acid or C-protected peptide to give an N-
15 protected C-protected peptide, and
(4) a step of removing the N-terminal protecting group and the
C-terminal anchor from the obtained N-protected C-protected
peptide to give a peptide.
20 22. The method according to claim 21, further comprising one
or more repetitions of steps (5) - (7) ;
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
peptide,
25 (6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7) a step of adding water to the reaction system after step
(6), and separating the impurity by extraction into an aqueous
30 layer.
23. The method according to claim 21, further comprising one
or more repetitions of steps (5) - (7' ) ;
(5) a step of removing the N-terminal protecting group of the
35 obtained N-protected C-protected peptide to give a C-protected
122
peptide,
(6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
5 [!') a step of adding a hydrophilic organic solvent to the
reaction system after step (6), and separating the impurity by
extraction into a hydrophilic organic solvent layer.
24. An organic synthesis method comprising the peptide
10 production method according to any one of claims 21 - 23.
25. A branched chain-containing aromatic compound represented
by the formula (I):
15 wherein
Q in the number of k are each independently a single bond, or
-0-, -S-, -C(=0)0-, -C(=0)NH- or -NH-;
Ra in the number of k are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
20 more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
and not more than 300;
k is an integer of 1 - 4;
Ri is a hydrogen atom or, when Z is a group represented by the
25 following formula (a), it optionally shows a single bond
together with R2 to form a fluorene ring together with ring B;
ring A optionally further has, in addition to Ri, QRa in the
number of k, and C(X)(Y)Z, one or more substituents selected
from the group consisting of a halogen atom, a Ci-g alkyl group
30 optionally substituted by one or more halogen atoms, and a Ci-e
alkoxy group optionally substituted by one or more halogen
atoms;
123
X is a hydrogen atom or a phenyl group;
Y is a hydroxyl group, an -NHR group (wherein R is a hydrogen
atom, an alkyl group, or an aralkyl group), or a halogen atom
(preferably halogen atom); and
5 Z is a hydrogen atom or a group represented by the formula
(a):
R2
wherein * shows a bonding position;
m is an integer of 0 - 4;
10 Q in the number of m are as defined above;
Rb in the number of m are each independently an organic group
having at least one aliphatic hydrocarbon group having one or
more branched chains, a total number of the branched chain of
not less than 3 and a total carbon number of not less than 14
15 and not more than 300;
R2 is a hydrogen atom, or optionally shows a single bond
together with Ri to form a fluorene ring together with ring A;
and
ring B optionally further has, in addition to QRb in the number
20 of m, and R2, one or more substituents selected from the group
consisting of a halogen atom, a Ci-g alkyl group optionally
substituted by one or more halogen atoms, and a Ci-g alkoxy
group optionally substituted by one or more halogen atoms);
the organic group having at least one aliphatic hydrocarbon
25 group having one or more branched chains, a total number of
the branched chain of not less than 3 and a total carbon
number of not less than 14 and not more than 300 for the
aforementioned Ra and Rb is a group having 3 or more the same
or different divalent groups, which is represented by the
30 formula (b) :
R4 (b)
124
wherein * shows a bonding position with the adjacent atom;
R3 and R4 are each independently a hydrogen atom or a C1-4 alkyl
group;
Xi is a single bond, a C1-4 alkylene group or an oxygen atom,
5 provided that R3 and R4 are not hydrogen atoms at the same time.
26. A protecting reagent for a carboxyl group or an amido
group of amino acid or peptide, comprising the branched chaincontaining
aromatic compound according to claim 25.
10
27. A branched chain-containing aromatic compound adduct which
is protected by the branched chain-containing aromatic
compound according to claim 25.
15 28. A method of producing a peptide comprising steps (1) -
(4);
(1) a step of condensing the branched chain-containing
aromatic compound according to claim 25 with a C-terminus of
an N-protected amino acid or an N-protected peptide in a
20 solvent solubilizing the compound to give an N-protected Cprotected
amino acid or N-protected C-protected peptide having
a C-terminus protected with an anchor which is a protecting
group derived from the compound,
(2) a step of removing the N-terminal protecting group from
25 the obtained N-protected C-protected amino acid or N-protected
C-protected peptide to give a C-protected amino acid or Cprotected
peptide,
(3) a step of condensing an N-protected amino acid or Nprotected
peptide with the N-terminus of the obtained C-
30 protected amino acid or C-protected peptide to give an Nprotected
C-protected peptide, and
(4) a step of removing the N-terminal protecting group and the
C-terminal anchor from the obtained N-protected C-protected
peptide to give a peptide.
35
125
29. The method according to claim 28, further comprising one
or more repetitions of steps (5) - (7);
(5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
5 peptide,
(6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
peptide to give an N-protected C-protected peptide, and
(7) a step of adding water to the reaction system after step
10 (6), and separating the impurity by extraction into an aqueous
layer.
30. The method according to claim 28, further comprising one
or more repetitions of steps (5) - (7');
15 (5) a step of removing the N-terminal protecting group of the
obtained N-protected C-protected peptide to give a C-protected
peptide,
(6) a step of condensing N-protected amino acid or N-protected
peptide with the N-terminus of the obtained C-protected
20 peptide to give an N-protected C-protected peptide, and
(7') a step of adding a hydrophilic organic solvent to the
reaction system after step (6), and separating the impurity by
extraction into a hydrophilic organic solvent layer.
25 31. An organic synthesis method comprising the peptide
production method according to any one of claims 28 - 30.