FIELD OF THE INVENTION
The present invention relates to a process for the preparation of xylene linked
cyclam compounds, more particularly, it relates to an improved process for
preparing 1,1'-[1,4-phenylenebis (methylene)]-bis [1,4,8,11-tetraazacyclotetra
decane] and its intermediates. In another aspect, the present invention relates to
intermediates used in the above processes.
BACKGROUND OF THE INVENTION
The compound 1,1'-[1,4-phenylenebis (methylene)]-bis [1,4,8,11-tetraazacyclo
tetradecane], also known as plerixafor is represented by the Formula (I):
fl fl NH HN cN)USNJ
NH HN v v
Formula (I)
Plerixafor (marketed under the trade name Mozobil, Genzyme Corporation) is a
hematopoietic stem cell mobilizer and is inhibitor of the CXCR4 chemokine
receptors. It was approved by the U.S. Food and Drug Administration (FDA) on
15 December 2008 to mobilize hematopoietic stem cells (HSCs) to the peripheral
blood for collection and subsequent autologous transplantation in patients with
non-Hodgkin's lymphoma and multiple myeloma.
Plerixafor, as represented by Formula (I) was first reported by Ciampolini et al. in
Inorg. Chern, 1987,26 (21), pp 3527-3533.
Various processes for the preparation of plerixafor have been described in
literature. Conventionally, the compound of formula (I) is prepared by selective
functionalization of the cyclam ring, followed by reaction with a, a' -dihalo-p-
2
xylene and dimerization. The product is deprotected to obtain the compound of
formula (I) which is further purified by recrystallization in various solvents.
WO 93/12096 describes the synthesis of different xylene linked polyamine
macrocyclic compounds as explained above, wherein the cyclam ring is tosyl
protected and reacted with an activated xylene diol intermediate to obtain an
intermediate which is purified by column chromatography and deprotected to
obtain the final product.
A similar process for the synthesis of compound of formula (I) is described in the
WO 00/28987. The synthetic scheme is depicted below as scheme-1:
Chlorofonn
AcOH, Aq_ HBr
(l
(l NH HN c :JOS.) NH HN u u
aq. NaOH, cone. HCI
(1
(1 NH HN cN)OiN)
t) u
BHCI. 2H 20
Scheme-l
3
Cyclam is reacted with p-toluene sulfonyl chloride m the presence of
triethylamine to obtain tris-(p-toluenesulfonyl) 1, 4, 8, 11-
tetraazacyclotetradecane in 33% yield. This tosyl protected cyclam ring is reacted
with a,a' -dibromo-p-xylene in the presence of base in solvent at reflux
temperature to give 1,1 '-[1 ,4- phenylenebis(methylene )]-bis[ 4,8, 11-tris-(p-toluene
sulfonyl)- 1 ,4,8, 11 tetraazacyclotetradecane which 1s purified by
chromatography. Finally this intermediate is subjected to hydrolysis in a mixture
of acetic acid and hydrobromic acid to afford the final compound as
octahydrobromide salt, the purity of which is not mentioned.
Further, WO 2014/125499 also describes a similar process for the preparation of
plerixafor. Cyclam is protected with tosyl groups in the presence of triethylamine
in dichloromethane. The yield is 36.4%. The resulting compound was reacted with
a,a'-dibromo-p-xylene m the presence of potassium carbonate m
dimethylformamide. The yield is 40%. Deprotection of this intermediate in the
presence of acetic acid and hydrobromic acid gives plerixafor octahydrobromide
dihydrate in 90.3% yield.
The above mentioned synthetic processes do not afford the intermediate
compounds in good yield or purity. Column chromatography is required to purify
the intermediates and therefore a significant amount of yield is lost.
In WO 02/26721A1, the authors disclose a process for the preparation of
plerixafor base using ethyl trifluoroacetate as protecting reagent instead of ptoluene
sulfonyl chloride. The reaction scheme is summarized below in scheme-2.
(1
CNH HN)
NH H v MeOH
4
MeOH, ~co3
(l
(l NH HN
c·~J t) v
Scheme-2
Cyclam is reacted with ethyl trifluoroacetate in the presence of triethylamine in
methanol to give tris trifluoroacetyl cyclam. The resulting compound is isolated
by column chromatography technique. The yield is 92.5%. The purity of the
compound is not mentioned. The compound is coupled with a,a' -dichloro-pxylene
in the presence of potassium carbonate and potassium iodide in acetonitrile
at reflux temperature to get the product in 85% yield. Here also compound purity
is not mentioned. Deprotection of trifluoro acetyl group of the product is carried
out by treatment with potassium carbonate in methanol to afford plerixafor base in
86% yield. The compound is isolated from toluene but the purity is not
mentioned.
This process gives better yield but the purity of the intermediates or of plerixafor
base is not mentioned. Also, column chromatography is required for the isolation
of the tris trifluoroacetyl cyclam intermediate. Column chromatography, needless
to say, is a tedious process which makes this route unfit for commercial purposes.
Indian patent application IN2011CH2459 describes a process for the preparation
of plerixafor using tert-butoxycarbonyl as the protecting group. The reaction
scheme is summarized below in scheme 3:
Bee anhydride
Boc..,_~ Soc ()
eoe'lJ
Dichloromethane
5
HCI
(']
('] NH HN
CN~N)
NuH H N. V
Scheme-3
wherein, "Boc" means tert-butoxycarbonyl. Cyclam is reacted with di-tert-butyl
dicarbonate in methylene chloride to give tris-Boc protected cyclam. The
compound is reacted with a,a'-dibromoxylene in the presence of potassium
carbonate in acetonitrile to yield 1,1 '-xylyl-bis [ 4,8, 1 1-tris(tert- butoxycarbonyl) -
1,4,8, 11-tetraazacyclotetradecane]. The resulting compound is subjected to
treatment with 1N hydrochloric acid and later with sodium hydroxide to obtain
plerixafor, which is crystallized from acetone. The purity of final compound or
intermediates is not mentioned and the overall yield is extremely low.
The inventors of the present invention have found that in all the above mentioned
processes the purity of intermediate compounds is very low leading to significant
yield losses during purification. A possible reason for such high amount of
impurity formation appears to be the presence of four secondary nitrogen atoms in
cyclam, out of which only three need to be protected. But during the reaction of
cyclam with p-toluene sulfonyl chloride, Boc anhydride or ethyltrifluoroacetate,
mono, di, tri and tetraprotected cyclam is formed. The structures of these are as
shown below:
PG ('I PG~ rl PG'-..._ ('I /PG PG"'-.('1 /PG
c:H :) ( "") () ( ")
N HN N N""-
u
PG/ u PG/ u PG/u PG
monoprotected diprotected triprotected tetraprotected
cyclam cyclam cyclam cyclam
6
wherein PG represents a protecting group like Tosyl or Boc etc.
Such mono- or di-protected cyclam rings will give side reactions leading to
further impurities while the tetra protected cyclam will remain unreacted as an
impurity in the subsequent steps. These impurities are difficult to remove and
result in low yield and purity of further steps as well.
New J. Chern. 2001, 25, 1168-1174, describes an alternative process for the
preparation of plerixafor. The cyclam ring is protected with the help of glyoxal,
the protected cyclam ring is then reacted with dibromo-p-xylene to yield an
intermediate which is deprotected with the help of hydroxylamine hydrochloride
and sodium ethoxide to yield the final compound. The overall synthesis is shown
in scheme-4:
NH20H, HCI
NaOEt, EtOH, N 2
Aq. NaOH
Scheme-4
ACN,RT
('!
('! NH HN c ·)OS. J
NuH H N u
The glyoxal protection of the cyclam ring prevents the formation of mono, di or
tetra-protected impurities and therefore it is expected that the yield and purity of
the final compound be better than those of the other processes.
However, it was found that the purity of plerixafor obtained via this process is
very low. It was further found by the inventors that the glyoxal protected cyclam
is a low melting and hygroscopic solid which is impossible to isolate or purify.
7
Any process generated impurities are carried forward to the next stages leading to
an impure final compound.
Also, the final deprotection reaction involves the use of the hazardous, difficult to
handle and hygroscopic reagent, sodium ethoxide. The use of strong reagents like
sodium ethoxide leads to large amounts of impurity formation. Thus the final
compound obtained by this process has very low purity.
Various inorganic bases have been described in literature for the removal of hisaminal
bridge from the cyclam moiety. J. Org. Chern., 2005, 70, 7042-7053
describes the use of sodium hydroxide for the deprotection of cyclam rings from
plerixafor. But no information about the quality or purity of the product is
mentioned.
(l
(l NH HN
NaOH, reflux c·~.J
t) v
From the foregoing, it is apparent that the reported methods for the preparation of
plerixafor suffer from one or more of the following drawbacks:
(a) extensive column chromatography needed to purify the intermediates used
in the process,
(b) low yields obtained due to the formation of impurities, and
(c) use of hazardous and moisture sensitive reagents.
Thus, there still remains the need to formulate an efficient, simple and industrially
viable synthetic process which can overcome the drawbacks of the prior art and
which provides plerixafor and its intermediates free of impurities.
OBJECT OF THE INVENTION
8
It is an objective of the present invention to overcome the above-mentioned drawbacks
of the prior art.
It is another objective of the present invention to provide an improved and
commercially viable process for the synthesis of plerixafor without the use of
expensive and hazardous reagents.
It is a further objective of the present invention to provide useful intermediates for
the synthesis of plerixafor.
SUMMARY OF THE INVENTION
The present invention provides an improved, commercially viable process for the
preparation of plerixafor. The process of the present invention is easy and cost
effective when implemented on industrial scale.
In first aspect, the present invention relates to a process for the preparation of a
compound of formula (I),
(l
(l NH HN
(HN~J
NuH HN u
Formula (I)
comprising, the reaction of the compound of formula (VII),
Formula (VII)
wherein x- is ion of a leaving group
with hydroxylamine or hydroxylamine hydrochloride in the presence of tertiary
amine or tertiary alkoxide.
9
In another aspect, the present invention provides a process for the preparation of a
compound of formula (1),
(l
(l NH HN
(" N~N H)
NuH H N u
Formula (I)
comprising the steps of:
a) reacting a compound of formula (II),
(l
(" HN)
NH HN u
Formula (II)
with a compound of formula (III),
0~0
Formula (III)
to obtain a compound of formula (IV) or its salts,
10
Formula (IV)
b) reacting the compound of formula (IV) with a compound of formula
(V),
0('x
X~
Formula (V)
wherein X is a leaving group
to obtain a compound of formula (VII),
Formula (VII)
wherein x- is ion of the leaving group, and
c) reacting the compound of formula (VII) with hydroxylamine or
hydroxylamine hydrochloride in the presence of tertiary amine or tertiary
alkoxide.
Another aspect of the present invention is to provide a process for the preparation
of compound of formula (I) using the compound of formula (VI).
Another aspect of the invention is to provide a compound of formula (VI),
Formula (VI)
wherein n=1,2 and R1, R2 may be independently selected from hydrogen,
optionally substituted alkyl, aryl, acyl, alkylaryl or aralkyl group.
11
In another aspect, the present invention provides a process for the preparation of
the compound of formula (VI).
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, a process for the preparation of a compound of formula (1),
fJ fJ NH HN (" N)OSN J
NH HN v v
Formula (I)
comprising, the reaction of the compound of formula (VII),
Formula (VII)
wherein x- is ion of a leaving group
with hydroxylamine or hydroxylamine hydrochloride in the presence of tertiary
amine or tertiary alkoxide is provided.
The reaction may optionally be carried out in the presence of a solvent.
The solvent used in this reaction may be selected from the group comprising of
water, alcohols like methanol, ethanol, isopropyl alcohol or halogenated
hydrocarbons like dichloromethane, chloroform or esters like methyl acetate, ethyl
acetate or ketones like methyl ethyl ketone, acetone, isobutyl ketone or
hydrocarbons like hexane, heptanes, toluene or polar apotic solvents, polar protic
solvents, ethers or mixtures thereof. Preferably the reaction is carried out in the
presence of, methanol, ethanol or isopropyl alcohol. Most preferably the reaction
is carried out in the presence of isopropyl alcohol.
12
The tertiary amine may be selected from triethylamine or diisopropylethylamine.
Tertiary alkoxides may be selected from sodium tertiary butoxide or potassium
tertiary butoxide.
The methods for the preparation of plerixafor reported in prior art involve the use
of tedious purification techniques or the use of hazardous chemicals and the
product obtained has low yield and purity.
The inventors have found that the above mentioned process, which comprises of
deprotection reaction with hydroxylamine or hydroxylamine hydrochloride in the
presence of tertiary amine or tertiary alkoxide, provides plerixafor in high yield
and purity.
Another aspect of the present invention is to provide a process for the preparation
of a compound of formula (I),
(I
(I NH HN
(" NsmN H)
NvH H N v
Formula (I)
comprising the steps of:
a) reacting a compound of formula (II),
(l
(" "")
NH HN v
Formula (II)
with a compound of formula (III),
13
0~0
Formula (III)
to obtain· a compound of formula (IV) or its salts,
Formula (IV)
b) reacting the compound of formula (IV) with a compound of formula
(V),
~X
X~
Formula (V)
wherein X is a leaving group
to obtain a compound of formula (VII),
Formula (VII)
wherein x- is ion of the leaving group, and
14
c) reacting the compound of formula (VII) with hydroxylamine or
hydroxylamine hydrochloride in the presence of tertiary amine or tertiary
alkoxide.
The product obtained by this process has higher yield and purity and there is no
need for the use of column chromatography or expensive and hazardous
chemicals.
In one embodiment, the reaction of compound of formula (II) with the compound
of formula (III) in step a) is carried out in the presence of a solvent.
In a preferred embodiment, the solvent used in step a) may be selected from the
group comprising of water, alcohols like methanol, ethanol, isopropyl alcohol or
halogenated hydrocarbons like dichloromethane, chloroform or esters like methyl
acetate, ethyl acetate or ketones like methyl ethyl ketone, acetone, isobutyl ketone
or hydrocarbons like hexane, heptanes, toluene or polar apotic solvents, polar
protic solvents, ethers or mixtures thereof. Preferably, the reaction is carried out in
the presence of methanol, ethanol or isopropyl alcohol. Most preferably the
reaction is carried out in the presence of methanol.
As discussed above, the reaction of compound of formula (IV) with a compound
of formula (V) is carried out to produce a compound of formula (VII) in step b).
In the compound of formula (V), X is a leaving group, preferably, a halogen or
mesyl or tosyl, more preferably the leaving group is a halogen and most
preferably the leaving group is bromine.
The reaction may be carried out in the presence of solvents selected from the
group comprising of halogenated hydrocarbons like dichloromethane,
dichloroethane or chloroform, polar aprotic solvents like dimethylformamide,
dimethylacetamide or dimethylsulfoxide, nitriles like acetonitrile or propionitrile.
Preferably, the reaction is carried out in the presence acetonitrile, propionitrile,
dimethylformamide or dimethylsulfoxide. Most preferably, the reaction is carried
out in the presence of acetonitrile.
15
In step c) of the first embodiment, the compound of formula (VII) is reacted with
hydroxylamine or hydroxylamine hydrochloride in the presence of tertiary amine
or tertiary alkoxide.
The tertiary amine may be selected from triethylamine or diisopropylethylamine.
Tertiary alkoxides may be selected from sodium tertiary butoxide or potassium
tertiary butoxide.
It was found that the purity and yield of the product are much improved when
hydroxylamine or hydroxylamine hydrochloride is used in the presence of tertiary
amines or tertiary alkoxides, unlike the methods reported in literature which lead
to the formation of impure product.
Data on purity of the product obtained usmg hydroxylamine hydrochloride
reagent in the presence ofvarious bases is given in table-I.
Table-1
s. Base used Reagent used HPLC Purity of
No crude product (%)
1 Triethylamine Hydroxylamine 91.31
hydrochloride
2 Diisopropylethylamine Hydroxylamine 92.56
hydrochloride
3 Potassium tert. Hydroxylamine 84.93
butoxide hydrochloride
4 Sodium ethoxide Hydroxylamine 62.78
hydrochloride
5 Without base Hydroxylamine No product formed
hydrochloride
The solvent used in this reaction may be selected from the group comprising of
water, alcohols like methanol, ethanol, isopropyl alcohol or halogenated
16
hydrocarbons like dichloromethane, chloroform or esters like methyl acetate, ethyl
acetate or ketones like methyl ethyl ketone, acetone, isobutyl ketone or
hydrocarbons like hexane, heptanes, toluene or polar apotic solvents, polar protic
solvents, ethers or mixtures thereof. Preferably the reaction is carried out in the
presence of, methanol, ethanol or isopropyl alcohol. Most preferably the reaction
is carried out in the presence of isopropyl alcohol.
In another embodiment, the reaction of a salt of compound of formula (IV) with a
compound of formula (V) to obtain a compound of formula (VII) is provided. The
salt of compound of formula (IV) is a compound of formula (VI),
Formula (VI)
wherein n is 1 or 2; and R1, R2 may be independently selected from hydrogen,
optionally substituted alkyl, aryl, acyl, alkylaryl or aralkyl group.
The present invention also relates to a compound of formula (VI).
Formula (VI)
wherein R 1 and R2 and n are as defined above.
The compound of formula (VI) is a salt of compound of formula (IV) which is a
hygroscopic, low melting compound that cannot be purified except by column
chromatography. But the substituted tartaric acid salts can be isolated and
purified.
17
In a preferred embodiment, the compound of formula (VI) is a compound of
formula (X),
Formula (X)
wherein Bz is benzoyl group.
The compound of formula (X) is the Dibenzoyl-L-tartaric acid salt of compound
of formula (IV). The compound of formula (IV), glyoxal protected cyclam, is a
low melting, hygroscopic solid which is difficult to isolate or purify. Further
various salts of this compound are also difficult to isolate as either these salts do
not precipitate and if they precipitate, they are highly soluble in most organic
solvents and water and therefore cannot be purified.
However, the substituted tartaric acid salts, especially dibenzoyl-L-tartaric acid
salt is unique as this salt can be isolated, purified and also shows greater stability
compared to the free base or other salts of this compound. Various acids, organic
and inorganic, were used to isolate the stable salt of compound of formula (IV).
For example: hydrochloric acid, tartaric acid, p-toluenesulfonic acid, acetic acid,
benzoic acid etc. But only the substituted tartaric acids, represented by formula
(VIII), were found to give stable, non-hygroscopic salts of compound of formula
(IV).
Another aspect of the present invention is to provide a process for the preparation
of compound of formula (I) using the compound of formula (VI).
Yet another aspect of the present invention is to provide a process for the
preparation of the compound of formula (VI), comprising the reaction of a
compound of formula (IV),
18
Formula (IV)
with a compound of formula (VIII),
Formula (VIII)
wherein R1 and R2 may be independently selected from hydrogen, optionally
substituted alkyl, aryl, acyl, alkylaryl or aralkyl group
to obtain the compound of formula (VI).
The reaction may be carried out in the presence of suitable solvent. Suitable
solvent may be selected from a group comprising of water, alcohols like
methanol, ethanol, isopropyl alcohol or halogenated hydrocarbons like
dichloromethane, chloroform or esters like methyl acetate, ethyl acetate or ketones
like methyl ethyl ketone, acetone, isobutyl ketone or hydrocarbons like hexane,
heptanes, toluene or polar apotic solvents, polar protic solvents, ethers or mixtures
thereof. Preferably the reaction is carried out in the presence of acetone or methyl
acetate or ethyl acetate. Most preferably the reaction is carried out in the presence
of ethyl acetate.
Preferably, the compound of formula (VIII) is a compound of formula (IX),
HOOCXOBz
BzO COOH
Formula (IX)
wherein Bz is benzoyl.
In a further aspect, a compound of formula (VI) is provided,
19
Formula (VI)
wherein n=l,2 and R1, R2 may be independently selected from hydrogen,
optionally substituted alkyl, aryl, acyl, alkylaryl or aralkyl group.
Preferably, the compound of formula (VI) is a compound of formula (X),
Formula (X)
wherein Bz is benzoyl group.
EXPERIMENTAL
Detailed experimental parameters suitable for the preparation of plerixafor
according to the present invention are provided by the following examples, which
are intended to be illustrative and not limiting of all possible embodiments of the
invention.
Example-1
Preparation of (2R, 3R)-2,3-bis(benzoyloxy)butanedioic acid-decahydro-1H,6H-
3a,5a,8a,10a-tetraazapyrene (Compound of formula VI)
To a stirred solution of 1,4,8,11-tetraazacyclotetradecane (50.0g, 0.249 mole) in
methanol (1625 ml) at -5°C was added a solution of glyoxal (44.2 g, 0.304 mole)
20
in methanol (250 ml) dropwise. After complete addition the reaction temperature
was raised to 30°C and stirred for 4 hrs. Methanol was distilled off and the residue
was stirred with ethyl acetate (750 ml) and filtered through celite bed. The filtrate
was added dropwise to a stirred solution of dibenzoyl-L-tartaric acid (205.7g,
0.574 mole) in ethyl acetate (1500 ml) and the reaction mixture was stirred for 3
hrs at 30°C. The reaction mixture was filtered and solid obtained was washed with
ethyl acetate. The crude product was dried under vacuum at 55°C for 20 hrs. The
crude product was again slurry washed with water and dried to give the title
compound.
Yield: 78.9% (185g)
GC Purity: 99.87%
Example-2
Preparation of 3a,3a' -(benzene-1 ,4-diyldimethanediyl)bisdecahydro-1 H,6H-
5a,8a,10a-triaza-3a-azoniapyrene dibromide (Compound offormula VII)
To a stirred solution of (2R, 3R)-2, 3-bis(benzoyloxy)butanedioic acid-decahydro-
1H,6H-3a,5a,8a,10a-tetraazapyrene (lOOOg, 1.065 mole) in dichloromethane
(10000 ml) was added a solution of potassium carbonate (588.8g, 4.260 mole) in
water at room temperature. The reaction mixture was stirred for 15 minutes and
the layers were separated. The solvent was distilled off and acetonitrile ( 4500ml)
and a, a'-dibromo-p-xylene (115.3g, 0.436 mole) were added. The reaction
mixture was stirred at room temperature for 30 hrs. The solid obtained was
filtered and dried under vacuum and finally recrystallized from a mixture of
methanol and IP A to obtain the title compound.
Yield: 72.3% (273.0g)
HPLC Purity: 98.65%
Example-3
Preparation of Plerixafor
21
To a stirred solution of hydroxylamine hydrochloride (760g, 10.937 mole) in
isopropyl alcohol (5000 ml) was added triethylamine (1071g, 10.584 mole) at
room temperature and the reaction mixture was stirred for 1.5 hrs. To this was
added the product of example-2 (250g, 0.353 mole) and the reaction mixture was
heated to 90°C and stirred at same temperature for 24 hrs. The solvent was
distilled off and water (2500 ml) was added. An aqueous solution of sodium
hydroxide was added and reaction mass was stirred. The layers were allowed to
separate and dichloromethane was added to the organic layer. The organic layer
was then washed with water. The organic solvent was distilled off and product
was crystallized from toluene.
Yield: 52% (92.4g)
HPLC Purity: 99.25%
Example-4
Purification of Plerixafor
To a stirred mixture of acetone (2250 ml) and water (250 ml) was added crude
plerixafor (250g) and reaction mixture was heated to 60°C and stirred for 15
minutes. The solution obtained was filtered through 5 micron filter paper and the
filtrate was stirred at 20°C for 2.5 hrs. The solution was further cooled to 0°C and
stirred for 2 hrs. The solid obtained was filtered and dried under vacuum.
Yield: 91.6% (229g)
HPLC Purity: 99.80%
1HNMR (400MHz, CDC13) 8: 1.646-1.656 (m, 4H), 1.842-1.852 (m, 4H), 2.446-
2.456 (m, 4H), 2.517-2.531 (m, 4H), 2.545-2.560 (m, 4H), 2.602-2.615 (m, 4H),
2.627-2.652 (m, 4H), 2.663-2.710 (m, 4H), 2.720-2.736 (m, 4H), 2.750-2.804 (m,
4H), 2.966 (s, 4H), 3.352 (s, 2H), 3.511 (s, 4H), 7.276 (s, 4H).

WE CLAIM:
1. A process for the preparation of a compound of formula (I),
(l
(l NH HN (" N)m J
NuH H N u
Formula (I)
comprising the reaction of the compound of formula (VII),
Formula (VII)
wherein x· is ion of a leaving group
with hydroxylamine or hydroxylamine hydrochloride m the presence of
tertiary amine or tertiary alkoxide.
2. A process according to claim 1, for the preparation of a compound of formula
(1),
rl rl NH HN
(" N~N H)
NH HN u u
Formula (I)
further comprising the steps of:
d) reacting a compound of formula (II),
23
Formula (II)
with a compound of formula (III),
0~0
Formula (III)
to obtain a compound of formula (IV) or its salts,
Formula (IV)
e) reacting the compound of formula (IV) with a compound of formula
(V),
X
X
Formula (V)
24
wherein X is a leaving group
to obtain a compound of formula (VII),
Formula (VII)
wherein x- is ion of the leaving group.
3. The process according to claim 1 or 2, wherein the leaving group is halogen,
preferably bromine.
4. The process according to any of claims 1-3, wherein the tertiary amine is
selected from triethylamine, diisopropylethylamine and the tertiary alkoxide
is potassium tertiary butoxide.
5. The process according to claims 2-4, wherein step a) is carried out in the
presence of a solvent selected from a group of methanol, ethanol or isopropyl
alcohol, preferably methanol.
6. The process according to claims 2-5, wherein step b) is carried out in the
presence of a solvent selected from a group of acetonitrile, propionitrile,
dimethylformamide or dimethylsulfoxide, preferably acetonitrile.
7. The process according to claim 1, wherein the reaction is carried out in the
presence of a solvent selected from a group of methanol, ethanol or isopropyl
alcohol, preferably isopropyl alcohol.
8. The process according to claims 2-6, wherein the salt of compound of
formula (IV) is a compound of formula (VI),
25
Formula (VI)
wherein n is 1 or 2; and R1, R2 may be independently selected from hydrogen,
optionally substituted alkyl, aryl, acyl, alkylaryl or aralkyl group.
9. A process for the preparation of the compound of formula (VI), comprising
the reaction of a compound of formula (IV),
Formula (IV)
with a compound of formula (VIII),
R,oocXoR,
R10 COOR2
Formula (VIII)
wherein R1 and R2 may be independently selected from hydrogen, optionally
substituted alkyl, aryl, acyl, alkylaryl or aralkyl group
to obtain the compound of formula (VI).
26
10. The process according to claim 9, wherein the compound of formula (VIII) is
a compound of formula (IX),
HOOCXOBz
BzO COOH
Formula (IX)
wherein Bz is benzoyl.
11. The process according to claim 8, wherein the compound of formula (VI) is a
compound of formula (X),
Formula (X)
wherein, Bz is benzoyl group.
12. A process for the preparation of compound of formula (I) using the compound of
formula (VI).
13. A compound of formula (VI),
Formula (VI)
27
wherein n=1,2 and R1, R2 may be independently selected from hydrogen,
optionally substituted alkyl, aryl, acyl, alkylaryl or aralkyl group.
14. A compound according to claim 13, wherein the compound of formula (VI) is
a compound of formula (X),
Formula (X)
wherein Bz is benzoyl group.