Title of Invention	"A PROCESS FOR THE PREPARATION OF A COMPUND OF FORMULA (I)"
Abstract	A process for the preparation of a compound of formula (I): wherein R1 is ethyl; R2 and R3 are methyl; and R4 is benzyl optionally substituted by C14 alkyl; the process comprising reacting a compound of formula (II): wherein R2, R3 and R4 are as defined above, with a base which is an alkali metal C1-6 alkoxide; and reacting the product so formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo; wherein the process is carried out in a solvent selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, benzene, toluene and xylene or a mixture of two or more of said solvents, at a temperature in the range -25°C to -15°C; wherein the molar ratio of base: R1O2CCH2X: compound of formula (II) is (1 to 1.3):(1 to 1.3): 1; and wherein at least 0.2 moles of the compound of formula (II) are used in the process.

Title of Invention

"A PROCESS FOR THE PREPARATION OF A COMPUND OF FORMULA (I)"

Abstract

A process for the preparation of a compound of formula (I): wherein R1 is ethyl; R2 and R3 are methyl; and R4 is benzyl optionally substituted by C14 alkyl; the process comprising reacting a compound of formula (II): wherein R2, R3 and R4 are as defined above, with a base which is an alkali metal C1-6 alkoxide; and reacting the product so formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo; wherein the process is carried out in a solvent selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, benzene, toluene and xylene or a mixture of two or more of said solvents, at a temperature in the range -25°C to -15°C; wherein the molar ratio of base: R1O2CCH2X: compound of formula (II) is (1 to 1.3):(1 to 1.3): 1; and wherein at least 0.2 moles of the compound of formula (II) are used in the process.

Full Text	CHEMICAL PROCESS The present invention concerns a process for the preparation of alkoxycarbonylmethoxy cyclopentanes which are useful intermediates in the preparation of pharmaceutically active triazolo[4,5-rf]pyrimidine cyclopentanes. The compound [1S-(lα, 2α, 3 ,5β)]-3-[7-[2-(3,4-difluorophenyl)- cyclopropyl]ainino]-5-(propylthio)-3//-l,2,3-triazolo[4,5-(fIpyrimidin-3-yl)-5-(2- hydroxyethoxy)-cyclopentane-l,2-diol (Compound A), and similar such compounds, are disclosed in WO 00/34283 and WO 99/05143. These compounds are disclosed as P2T (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as, infer alia, inhibitors of platelet activation, aggregation or degranulation. Compounds of formula (I) (see below) are useful in the preparation of Compound A (see example 1 of WO 01/92263). The preparation of a compound of formula (I) is disclosed in example 1 of WO 01/92263 and in that example the process was conducted at 0°C. It has been found that when scaling up the process of example 1 of WO 01/92263 (say to more than 0.2 mole scale) and keeping the temperature at 0°C, competing side-reactions lead to a significant increase in the level of impurities, an increase in the reagent requirement, and a resulting reduction in the percentage yield of compound of fomula (I). This is clearly a problem as it makes the process more costly and less efficient. We have now unexpectedly found that when the process is operated on a 0.2 mole scale or more, the use of a lower temperature allows the compound of formula (I) to be produced in good yield and minimizes the products of the unwanted side reactions. The present invention provides a process for the preparation of a compound of formula wherein R1 is C1-6 alkyl; R2 and R3 are, independently, C1-6 alKyl; and R4 is Ci-6 allcyl (such as tert-butyl) or benzyl (wherein the phenyl ring of benzyl is optionally substituted by nitro, S(0)2(C1-6 alkyl), cyano, C1-4 alkyl, C1-4 alkoxy, C(O)(C1-4 allcyl), N(C1-6alkyl)2, CF3 or the process comprising reacting a compound of formula (II): wherein R2, R3 and R4 are as defined above, with a suitable base; and reacting the product so formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo; wherein the process is carried out in a suitable solvent at a temperature in the range -40°C to -5°C; and wherein at least 0.2 moles of the compound of formula (II) are used in the process. Alkyl groups and moieties are straight or branched chain and comprise, for example, 1 to 6 (such as 1 to 4) carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl or tert-butvl. In one particular aspect the present invention provides a process wherein R is CM alkyl (for example ethyl). In another aspect the present invention provides a process wherein R and R are, independently, CM alkyl; for example R2 and R3 are both methyl. In a further aspect of the invention R4 is benzyl (wherein the phenyl ring of benzyl is optionally substituted by CM alkyl); for example R4 is unsubstituted benzyl. In a still further aspect the present invention provides a process wherein X is bromo. Suitable bases include an alkali metal Cue alkoxide (for example potassium tertbutoxide). In another aspect of the invention the molar ratio of suitable base: R^CCHiX : compound of formula (II) is (1 to 1.3):(1 to 1.3):1, for example (1.1 to 1.3):(1.1 to 1.3):1, such as about 1.2:1.2:1. Suitable solvents include cyclic and aliphatic ethers (such as tetrahydrofuran, diethyl ether, diisopropyl ether or methyl tort-butyl ether) and aromatic solvents (such as benzene, toluene or a xylene). The solvent can be a mixture of two or more solvents (for example a mixture of an ether and an aromatic solvent, as exemplified above). In another aspect the invention provides a process wherein an ether, as exemplified above, is used as solvent. In yet another aspect of the invention the temperature is in the range -30°C to -10°C, for example -25°C to -15°C. In a further aspect the process of the present invention comprises adding a solution of suitable base to a solution of a compound of formula (II) at -15 to -25°C, and then adding to this mixture a solution of R'OC(O)CH2X at -15 to -25°C, a suitable ether being used as solvent. A compound of formula (II) can be prepared by a method, or a method analogous to a method, disclosed in the literature (for example WO 01/92263). The following Example illustrates the invention. EXAMPLE 1 This Example illustrates a process for the preparation of [3aS-(3aa34a,6a,6aa)]-[2,2- dimethyl-6-((ethoxycarbonyl)methoxy)-tetrahydro-4H-cyclopenta-l,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester. A solution (Solution A) of [3aS-(3aa,4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2- dimethyl-4H-cyclopenta-l,3-dioxol-4-yl]-cai-baniic acid, phenylmethyl ester (80g, 260 ramol) in THF (160ml), under a nitrogen atmosphere, was cooled to -22°C. A solution of potassium tert-butoxide (36.lg, 312 mmol) in THF was prepared and added to the cooled Solution A over a period of 30 minutes, while maintaing the reaction temperature at about-2O°C. This provided a reaction mixture. A pre-made solution of ethyl bromoacetate (53.2g, 312 mmol) in THF was then added to the reaction mixture over a period of 30 minutes while maintaining the reaction temperature at about -20°C. The resulting mixture was stirred for approximately an'hour at - 22°C. HPLC analysis showed that there was a 98% conversion to the desired product. Table below shows variations on this process.(Table Removed) We claim: 1. A process for the preparation of a compound of formula (I): (Formula Removed) wherein R1 is ethyl; R2 and R3 are methyl; and R4 is benzyl optionally substituted by C1-4 alkyl; the process comprising reacting a compound of formula (II): (Formula Removed) wherein R2, R3 and R4 are as defined above, with a base which is an alkali metal C1-6 alkoxide; and reacting the product so formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo; wherein the process is carried out in a solvent selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, benzene, toluene and xylene or a mixture of two or more of said solvents, at a temperature in the range -25°C to -15°C; wherein the molar ratio of base: R1O2CCH2X: compound of formula (II) is (1 to 1.3):(1 to 1.3):1; and wherein at least 0.2 moles of the compound of formula (II) are used in the process. 2. A process as claimed in claim 1 wherein X is bromo. 3. A process as claimed in claim 1 or 2 wherein the base is potassium tert-butoxide. 4. A process as claimed in any one of claims 1 to 3 wherein the molar ratio of suitable base : R1O2CCH2X: compound of formula (II) is 1.2: 1.2:1.

Full Text

CHEMICAL PROCESS
The present invention concerns a process for the preparation of
alkoxycarbonylmethoxy cyclopentanes which are useful intermediates in the preparation of
pharmaceutically active triazolo[4,5-rf]pyrimidine cyclopentanes.
The compound [1S-(lα, 2α, 3 ,5β)]-3-[7-[2-(3,4-difluorophenyl)-
cyclopropyl]ainino]-5-(propylthio)-3//-l,2,3-triazolo[4,5-(fIpyrimidin-3-yl)-5-(2-
hydroxyethoxy)-cyclopentane-l,2-diol (Compound A), and similar such compounds, are
disclosed in WO 00/34283 and WO 99/05143. These compounds are disclosed as P2T (which
is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as,
infer alia, inhibitors of platelet activation, aggregation or degranulation.
Compounds of formula (I) (see below) are useful in the preparation of Compound A
(see example 1 of WO 01/92263). The preparation of a compound of formula (I) is disclosed
in example 1 of WO 01/92263 and in that example the process was conducted at 0°C. It has
been found that when scaling up the process of example 1 of WO 01/92263 (say to more than
0.2 mole scale) and keeping the temperature at 0°C, competing side-reactions lead to a
significant increase in the level of impurities, an increase in the reagent requirement, and a
resulting reduction in the percentage yield of compound of fomula (I). This is clearly a
problem as it makes the process more costly and less efficient. We have now unexpectedly
found that when the process is operated on a 0.2 mole scale or more, the use of a lower
temperature allows the compound of formula (I) to be produced in good yield and minimizes
the products of the unwanted side reactions.
The present invention provides a process for the preparation of a compound of formula
wherein R1 is C1-6 alkyl; R2 and R3 are, independently, C1-6 alKyl; and R4 is Ci-6 allcyl (such as
tert-butyl) or benzyl (wherein the phenyl ring of benzyl is optionally substituted by nitro,
S(0)2(C1-6 alkyl), cyano, C1-4 alkyl, C1-4 alkoxy, C(O)(C1-4 allcyl), N(C1-6alkyl)2, CF3 or
the process comprising reacting a compound of formula (II):
wherein R2, R3 and R4 are as defined above, with a suitable base; and reacting the product so
formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo;
wherein the process is carried out in a suitable solvent at a temperature in the range
-40°C to -5°C; and wherein at least 0.2 moles of the compound of formula (II) are used in the
process.
Alkyl groups and moieties are straight or branched chain and comprise, for example, 1
to 6 (such as 1 to 4) carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl
or tert-butvl.
In one particular aspect the present invention provides a process wherein R is CM
alkyl (for example ethyl).
In another aspect the present invention provides a process wherein R and R are,
independently, CM alkyl; for example R2 and R3 are both methyl.
In a further aspect of the invention R4 is benzyl (wherein the phenyl ring of benzyl is
optionally substituted by CM alkyl); for example R4 is unsubstituted benzyl.
In a still further aspect the present invention provides a process wherein X is bromo.
Suitable bases include an alkali metal Cue alkoxide (for example potassium tertbutoxide).
In another aspect of the invention the molar ratio of suitable base: R^CCHiX :
compound of formula (II) is (1 to 1.3):(1 to 1.3):1, for example (1.1 to 1.3):(1.1 to 1.3):1, such
as about 1.2:1.2:1.
Suitable solvents include cyclic and aliphatic ethers (such as tetrahydrofuran, diethyl
ether, diisopropyl ether or methyl tort-butyl ether) and aromatic solvents (such as benzene,
toluene or a xylene). The solvent can be a mixture of two or more solvents (for example a
mixture of an ether and an aromatic solvent, as exemplified above). In another aspect the
invention provides a process wherein an ether, as exemplified above, is used as solvent.
In yet another aspect of the invention the temperature is in the range -30°C to
-10°C, for example -25°C to -15°C.
In a further aspect the process of the present invention comprises adding a solution of
suitable base to a solution of a compound of formula (II) at -15 to -25°C, and then adding to
this mixture a solution of R'OC(O)CH2X at -15 to -25°C, a suitable ether being used as
solvent.
A compound of formula (II) can be prepared by a method, or a method analogous to a
method, disclosed in the literature (for example WO 01/92263).
The following Example illustrates the invention.
EXAMPLE 1
This Example illustrates a process for the preparation of [3aS-(3aa34a,6a,6aa)]-[2,2-
dimethyl-6-((ethoxycarbonyl)methoxy)-tetrahydro-4H-cyclopenta-l,3-dioxol-4-yl]-carbamic
acid, phenylmethyl ester.
A solution (Solution A) of [3aS-(3aa,4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-
dimethyl-4H-cyclopenta-l,3-dioxol-4-yl]-cai-baniic acid, phenylmethyl ester (80g, 260 ramol)
in THF (160ml), under a nitrogen atmosphere, was cooled to -22°C. A solution of potassium
tert-butoxide (36.lg, 312 mmol) in THF was prepared and added to the cooled Solution A
over a period of 30 minutes, while maintaing the reaction temperature at about-2O°C. This
provided a reaction mixture.
A pre-made solution of ethyl bromoacetate (53.2g, 312 mmol) in THF was then added
to the reaction mixture over a period of 30 minutes while maintaining the reaction
temperature at about -20°C. The resulting mixture was stirred for approximately an'hour at -
22°C. HPLC analysis showed that there was a 98% conversion to the desired product.
Table below shows variations on this process.(Table Removed)

We claim:
1. A process for the preparation of a compound of formula (I):
(Formula Removed)
wherein R1 is ethyl; R2 and R3 are methyl; and R4 is benzyl optionally substituted by C1-4 alkyl; the process comprising reacting a compound of formula (II):
(Formula Removed)
wherein R2, R3 and R4 are as defined above, with a base which is an alkali metal C1-6 alkoxide; and reacting the product so formed with R1OC(O)CH2X, wherein R1 is as defined above and X is chloro, bromo or iodo; wherein the process is carried out in a solvent selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, benzene, toluene and xylene or a mixture of two or more of said solvents, at a temperature in the range -25°C to -15°C; wherein the molar ratio of base: R1O2CCH2X: compound of formula (II) is (1 to 1.3):(1 to 1.3):1; and wherein at least 0.2 moles of the compound of formula (II) are used in the process.
2. A process as claimed in claim 1 wherein X is bromo.
3. A process as claimed in claim 1 or 2 wherein the base is potassium tert-butoxide.
4. A process as claimed in any one of claims 1 to 3 wherein the molar ratio of suitable base : R1O2CCH2X: compound of formula (II) is 1.2: 1.2:1.

Documents:

5343-delnp-2006-pct-402.pdf

5343-delnp-2006-pct-409.pdf

5343-delnp-2006-pct-416.pdf

5353-DELNP-2006-Abstract-(02-01-2012).pdf

5353-delnp-2006-abstract.pdf

5353-DELNP-2006-Claims-(02-01-2012).pdf

5353-delnp-2006-claims.pdf

5353-DELNP-2006-Correspondence Others-(02-01-2012).pdf

5353-delnp-2006-correspondence-others.pdf

5353-delnp-2006-description (complete).pdf

5353-DELNP-2006-Form-1-(02-01-2012).pdf

5353-delnp-2006-form-1.pdf

5353-DELNP-2006-Form-2-(02-01-2012).pdf

5353-delnp-2006-form-2.pdf

5353-DELNP-2006-Form-3-(02-01-2012).pdf

5353-delnp-2006-form-3.pdf

5353-delnp-2006-form-5.pdf

5353-DELNP-2006-GPA-(02-01-2012).pdf

5353-delnp-2006-gpa.pdf

5353-delnp-2006-pct-210.pdf

5353-delnp-2006-pct-304.pdf

5353-DELNP-2006-Petition-137-(02-01-2012).pdf

« Previous Patent

Next Patent »

Patent Number

252484

Indian Patent Application Number

5353/DELNP/2006

PG Journal Number

21/2012

Publication Date

25-May-2012

Grant Date

17-May-2012

Date of Filing

15-Sep-2006

Name of Patentee

ASTRAZENECA AB

Applicant Address

S-151 85 SODERTALJE, SWEDEN

Inventors:

#	Inventor's Name	Inventor's Address
1	VAHAK ABEDI	ASTRAZENECA R & D SODERTALJE, S-151 85 SODERTALJE, SWEDEN

PCT International Classification Number

C07D 317/44

PCT International Application Number

PCT/GB2005/001200

PCT International Filing date

2005-03-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0400873-6	2004-03-31	Sweden