Chemical process Number:7,393,962 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides a process for the preparation of a compound of formula (I): wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 and R.sup.3 are, independently, C.sub.1-6 alkyl; and R.sup.4 is C.sub.1-6 alkyl or benzyl (wherein the phenyl ring of benzyl is optionally substituted by nitro, S(O).sub.2(C.sub.1-4 alkyl), cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)(C.sub.1-4 alkyl), N(C.sub.1-6 alkyl).sub.2, CF.sub.3 or OCF.sub.3); the process comprising reacting a compound of formula (II): wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above, with a suitable base; and reacting the product so formed with R.sup.1OC(O)CH.sub.2X, wherein R.sup.1 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.degree. C. to -5.degree. C.; and wherein at least 0.2 moles of the compound of formula (II) are used in the process.<H Chemical, process, Chemical, proces, 7393962.html, Patent, pto, 7393962

Title: Chemical process

Abstract: The present invention provides a process for the preparation of a compound of formula (I): wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 and R.sup.3 are, independently, C.sub.1-6 alkyl; and R.sup.4 is C.sub.1-6 alkyl or benzyl (wherein the phenyl ring of benzyl is optionally substituted by nitro, S(O).sub.2(C.sub.1-4 alkyl), cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)(C.sub.1-4 alkyl), N(C.sub.1-6 alkyl).sub.2, CF.sub.3 or OCF.sub.3); the process comprising reacting a compound of formula (II): wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above, with a suitable base; and reacting the product so formed with R.sup.1OC(O)CH.sub.2X, wherein R.sup.1 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.degree. C. to -5.degree. C.; and wherein at least 0.2 moles of the compound of formula (II) are used in the process.

Patent Number: 7,393,962 Issued on 07/01/2008 to Abedi

Inventors: Abedi; Vahak (Sodertalje, SE)
Assignee: AstraZeneca AB (Sodertalje, SE)

Appl. No.: 10/599,463

Filed: March 29, 2005

PCT Filed: March 29, 2005

PCT No.: PCT/GB2005/001200

371(c)(1),(2),(4) Date: September 29, 2006

PCT Pub. No.: WO2005/095377

PCT Pub. Date: October 13, 2005

Foreign Application Priority Data


Mar 31, 2004 [SE]			0400873

Current U.S. Class: 549/438

Current International Class: C07D 317/44 (20060101)

Field of Search: 549/438

References Cited [Referenced By]

Foreign Patent Documents


00/34283	Jun., 2000	WO
01/92263	Dec., 2001	WO

Primary Examiner: Seaman; D. Margaret
Assistant Examiner: Chandrakumar; Nizal S
Attorney, Agent or Firm: Pepper Hamilton LLP

Claims

The invention claimed is:

1. A process for the preparation of a compound of formula (I): ##STR00004## wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 and R.sup.3 are, independently, C.sub.1-6 alkyl; and R.sup.4 is C.sub.1-6 alkyl or benzyl (wherein the phenyl ring of benzyl is optionally substituted by cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3 or OCF.sub.3); the process comprising reacting a compound of formula (II): ##STR00005## wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above, with an alkoxide base; and reacting the product so formed with R.sup.1OC(O)CH.sub.2X, wherein R.sup.1 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.degree. C. to -5.degree. C.; 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 R.sup.1, R.sup.2 and R.sup.3 are independently selected from C.sub.1-4 alkyl.

3. A process as claimed in claim 1 wherein R.sup.1 is ethyl.

4. A process as claimed in claim 1, wherein R.sup.2 and R.sup.3 are methyl.

5. A process as claimed in claim 1, wherein R.sup.4 is benzyl optionally substituted by C.sub.1-4 alkyl.

6. A process as claimed in claim 1, wherein R.sup.4 is unsubstituted benzyl.

7. A process as claimed in claim 1 wherein X is bromo.

8. A process as claimed in claim 1 wherein the base is an alkyl metal C.sub.1-6 alkoxide.

9. A process as claimed in claim 1 wherein the base is potassium tert-butoxide.

10. A process as claimed in claim 1 wherein the molar ratio of suitable base: R.sup.1O.sub.2CCH.sub.2X:compound of formula (II) is (1 to 1.3):(1 to 1.3):1.

11. A process as claimed in claim 1 wherein the molar ratio of suitable base: R.sup.1O.sub.2CCH.sub.2X:compound of formula (II) is (1.1 to 1.3):(1.1 to 1.3):1.

12. A process as claimed in claim 1 wherein the molar ratio of suitable base: R.sup.1O.sub.2CCH.sub.2X:compound of formula (II) is 1.2:1.2:1.

13. A process as claimed in claim 1 wherein the solvent is selected from a cyclic ether, an aliphatic ether and an aromatic solvent.

14. A process as claimed in claim 1 wherein the solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, benzene, toluene and xylene; and a mixture of two or more of said solvents.

15. A process as claimed in claim 1 wherein the solvent is tetrahydrofuran.

16. A process as claimed in claim 1 wherein the temperature is in the range -30.degree. C. to -10.degree. C.

17. A process as claimed in claim 1 wherein the temperature is in the range -25.degree. C. to -15.degree. C.

18. A process as claimed in claim 1 wherein: R.sup.1 is ethyl; R.sup.2 and R.sup.3 are methyl; R.sup.4 is unsubstituted benzyl; X is bromo; and the base is potassium tert-butoxide.

19. A process as claimed in claim 18 wherein the molar ratio of suitable base: R.sup.1O.sub.2CCH.sub.2X:compound of formula (II) is 1.2:1.2:1, and wherein the solvent is 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.

20. A process as claimed in claim 19 wherein the the temperature is in the range -25.degree. C. to -15.degree. C.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage filing of International Application Serial No. PCT/GB2005/001200 filed Mar. 29, 2005, which claims priority to Swedish Application Serial No. 0400873-6 filed Mar. 31, 2004, each of which is incorporated herein by reference in its entirety.

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-d]pyrimidine cyclopentanes.

The compound [1S-(1.alpha.,2.alpha.,3.beta.(1S*,2R*),5.beta.)]-3-[7-[2-(3,4-difluoroph- enyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3- -yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol (Compound A), and similar such compounds, are disclosed in WO 00/34283 and WO 99/05143. These compounds are disclosed as P.sub.2T (which is now usually referred to as P.sub.2Y.sub.12) receptor antagonists. Such antagonists can be used as, inter 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.degree. 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.degree. 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 formula (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 (I):

##STR00001## wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 and R.sup.3 are, independently, C.sub.1-6 alkyl; and R.sup.4 is C.sub.1-6 alkyl (such as tert-butyl) or benzyl (wherein the phenyl ring of benzyl is optionally substituted by nitro, S(O).sub.2(C.sub.1-4 alkyl), cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)(C.sub.1-4 alkyl), N(C.sub.1-6 alkyl).sub.2, CF.sub.3 or OCF.sub.3); the process comprising reacting a compound of formula (II):

##STR00002## wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above, with a suitable base; and reacting the product so formed with R.sup.1OC(O)CH.sub.2X, wherein R.sup.1 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.degree. C. to -5.degree. 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, iso propyl or tert-butyl.

In one particular aspect the present invention provides a process wherein R.sup.1 is C.sub.1-4 alkyl (for example ethyl).

In another aspect the present invention provides a process wherein R.sup.2 and R.sup.3 are, independently, C.sub.1-4 alkyl; for example R.sup.2 and R.sup.3 are both methyl.

In a further aspect of the invention R.sup.4 is benzyl (wherein the phenyl ring of benzyl is optionally substituted by C.sub.1-4 alkyl); for example R.sup.4 is unsubstituted benzyl.

In a still further aspect the present invention provides a process wherein X is bromo.

Suitable bases include an alkali metal C.sub.1-6 alkoxide (for example potassium tert-butoxide).

In another aspect of the invention the molar ratio of suitable base: R.sup.1O.sub.2CCH.sub.2X: 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 tert-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.degree. C. to -10.degree. C., for example -25.degree. C. to -15.degree. 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.degree. C., and then adding to this mixture a solution of R.sup.1OC(O)CH.sub.2X at -15 to -25.degree. 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-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[2,2-dimethyl-6-((ethoxycar- bonyl)methoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester.

##STR00003##

A solution (Solution A) of [3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[tetrahydro-6-hydroxy-2,2-d- imethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester (80 g, 260 mmol) in THF (160 ml), under a nitrogen atmosphere, was cooled to -22.degree. C. A solution of potassium tert-butoxide (36.1 g, 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 -20.degree. C. This provided a reaction mixture.

A pre-made solution of ethyl bromoacetate (53.2 g, 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.degree. C. The resulting mixture was stirred for approximately an hour at -22.degree. C. HPLC analysis showed that there was a 98% conversion to the desired product.

Table below shows variations on this process.

TABLE-US-00001 t-BuOK EtBrAc Mole ratios of Addition Addition reagents to (II) Time Temp. Time Temp. Hold time Ex t-BuOK EtBrAc (min.) (.degree. C.) (min.) (.degree. C.) (min.) 2 1.40 1.46 13 -20 34 -20 23 3 1.15 1.15 22 -22 42 -22 20 4 1.20 1.20 30 -20 45 -20 15 5 1.10 1.10 20 -30 30 -30 20 6 1.20 1.20 20 -22 30 -22 20 7 1.10 1.10 20 -10 30 -10 20 8* 1.20 1.20 20 -22 30 -22 20 9 1.20 1.20 30 -22 180 -22 150 10 1.20 1.20 25 -21 45 -21 10 11 1.20 1.20 30 -22 40 -20 10 12 1.2 1.2 13 -23/-28 10 -22/-28 30 13 1.15 1.15 12 -20/-22 15 -19/-24 30 Ex = Example number (II) = [3aS-(3a.alpha.,4.alpha.,6.alpha.,6a.alpha.)]-[tetrahydro-6-hydroxy- -2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester t-BuOK = potassium tert-butoxide EtBrAc = ethyl bromoacetate * = Both the THF solution of compound of formula (II) and potassium tert-butoxide were filtered before use

*