US20100324289A1

US20100324289A1 - Chemical Process

Info

Publication number: US20100324289A1
Application number: US12/871,993
Authority: US
Inventors: Ulf Larsson; Kajsa Rådevik
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-03-31
Filing date: 2010-08-31
Publication date: 2010-12-23
Also published as: AU2005227727B2; IL177998A0; ZA200607708B; CN101851212A; WO2005095358A2; DK1751117T3; WO2005095358A3; JP2007530650A; CY1111847T1; SE0401001D0; NZ587999A; CN1938284B; PL1751117T3; KR101164265B1; JP5059599B2; ATE517096T1; EP1751117A2; CA2560094A1; CN1938284A; NO20064117L

Abstract

The present invention provides a process for the preparation of a compound of formula (I); wherein X is halogen; Y is ZR¹; Z is oxygen or sulphur; and R¹is C_1-6alkyl, C_1-6haloalkyl or C_3-7cloalkyl; the process comprising either: hydrogenating a compound of formula (II); with a suitable transition metal catalyst in a C_1-6aliphatic alcohol, an ether, an hydrocarbon as solvent; or, conducting a one-pot hydrogenation of a compound of formula (III): wherein R²is phenyl optionally substituted by chloro, C_1-6alkyl, C_1-6alkoxy or (C_1-6alkyl)₂N; firstly at about 20° C. to form a compound of formula (IV): and then at about 40° C.; both steps (I) and (ii) being carried out in the presence of a suitable catalyst and in the presence of a suitable solvent.

Description

The present invention concerns a process fox the preparation of 5-aminopyrimidines which are useful intermediates in the preparation of pharmaceutically active triazolo[4,5-d]pyrimidine cyclopentanes.
The compound [1S-(1α, 2α, 3β (1S*,2R*),5β)]-3-[7-[2-(3,4-difluorophenyl)-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 as pharmaceutically active P_2T(which is now usually referred to as P₂Y₁₂) 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 and analogues thereof (see example 3 of WO 01/92263).
Catalytic hydrogenation of aromatic nitro compounds is disclosed in U.S. Pat. No. 6,09,6924.
The present invention provides a process for the preparation of a compound of formula (I):
wherein X is halogen; Y is ZR¹; Z is oxygen or sulphur; and R¹is C_1-6alkyl, C_1-6haloalkyl or C_3-7cycloalkyl; the process comprising either:

a. hydrogenating a compound of formula (II):

with a suitable transition metal catalyst in a C_1-6aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent;
or,
b. conducting a one-pot hydrogenation of a compound of formula (III):

wherein R²is phenyl optionally substituted by chloro, C_1-6alkyl, C_1-6alkoxy or (C_1-6alkyl)₂N;
- i. firstly at about 20° C. to form a compound of formula (IV):

- ii. and then at about 40° C.;
both steps (i) and (ii) being carried out in the presence of a suitable catalyst and in the presence of a suitable solvent.

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.
Haloalkyl groups and moieties are straight or branched chain and comprise, for example, 1 to 6 (such as 1 to 4) carbon atoms, and 1 to 6 halogen atoms (for example fluorine or chlorine atoms). Examples of haloalkyl are CH₂F, CHF₂, CF₃, CH₂CF₃and 3,3,3-trifluoroprop-1-yl.
Cycloalkyl is, for example, C_3-6cycloalkyl, such as cyclopropyl, cyclopentyl or cyclohexyl.
In one particular aspect the present invention provides a process for the preparation of a compound of formula (I):
wherein X is halogen; Y is ZR¹; Z is oxygen or sulphur; and R¹is C_1-6alkyl, C_1-6haloalkyl or C_3-7cycloalkyl; the process comprising hydrogenating a compound of formula (II):
with a suitable transition metal catalyst in C_1-6aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent.
Suitable transition metal catalyst for the hydrogenation of a compound of formula (II) is, for example, platinum or palladium, or a combination of platinum with another transition metal such as vanadium, iron or manganese. In a further aspect of the invention the transition metal catalyst is on a suitable support, for example carbon.
A suitable solvent for the hydrogenation of a compound of formula (II) is a C_1-6aliphatic alcohol (such as ethanol and iso-propyl alcohol), an ether (for example a di(C_1-6alkyl) ether, such as diethylether or methyl tert-butyl ether; or a cyclic ether such as tetrahydrofuran), an ester (for example ethyl acetate) or a hydrocarbon solvent (such as an aromatic hydrocarbon, for example benzene, toluene or a xylene).
In another aspect the hydrogenation of a compound of formula (II) is conducted at a temperature in the range 10 to 90° C., for example 20 to 40° C.
In yet another aspect the hydrogenation of a compound of formula (II) is conducted at a pressure of 1 to 10 bar, for example 2 to 4 bar.
In a further aspect the present invention provides a process for the preparation of a compound of formula (I):
wherein X is halogen; Y is ZR¹; Z is oxygen or sulphur; and R¹is C_1-6alkyl, C_1-6haloalkyl or C_3-7cycloalkyl; the process comprising conducting a one-pot hydrogenation of a compound of formula (III):
wherein R²is phenyl optionally substituted by chloro, C_1-6alkyl, C_1-6alkoxy or (C_1-6alkyl)₂N;

i. firstly at 10 to 25° C. to form a compound of formula (IV):

ii. and then hydrogenating at about 35 to 50° C.;
both steps (i) and (ii) being carried out in the presence of a suitable catalyst and in the presence of a suitable solvent.

Highly effective mixing (for example stirring) is used during the one-pot hydrogenation as this aids effective mass transfer during the process. Highly effective mixing is used to obtain good contact between the gaseous hydrogen, the solid catalyst and the compound of formula (III) or (IV).
A suitable catalyst for the one-pot hydrogenation is either a single transition metal or a mixture of two or more transition metals. Suitable catalysts are platinum or a mixture of platinum and vanadium. It is usual for the catalyst to be on a suitable support (for example carbon). Examples of these catalysts are platinum on carbon 5-15% w/w; platinum 2-10% w/w (for example 3-7% w/w) and vanadium 0.2-3% w/w on carbon.
A suitable solvent for the one-pot hydrogenation is a C_1-6aliphatic alcohol (for example ethanol or iso-propyl alcohol), an ester (for example ethyl acetate), an ether (such as tetrahydrofuran or methyl tert-butyl ether), a hydrocarbon (such as an aromatic hydrocarbon, for example benzene, toluene or a xylene) or a ketone (such as acetone).
In yet another aspect the hydrogenation of a compound of formula (III) or (IV) is conducted at a pressure of 0.5 to 10 bar, for example 2 to 4 bar.
In a still further aspect the present invention provides a process as hereinbefore described wherein X is chloro.
In another aspect the present invention provides a process as hereinbefore described wherein Z is sulphur.
In yet another aspect the present invention provides a process as hereinbefore described wherein R¹is C_1-4alkyl (such as n-propyl) or C_1-4haloalkyl (such as 3,3,3-trifluoroprop-1-yl).
In yet another aspect the present invention provides a process as herein described where in 5-15% w/w catalyst is used based on compound of formula (II) or (III).
The following Examples illustrate the invention.

EXAMPLE 1

This Example illustrates a process for the preparation of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine.
A Pt/V/C catalyst (available from Degussa; about 3% Pt and 0.6% V adsorbed on charcoal, 30 g) was charged to a vessel and the vessel was purged with nitrogen. 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine (302 g) dissolved in tert-butyl methyl ether (31) was charged to the vessel and agitation was started. The resulting mixture was heated to an initial temperature of 30° C. and then the vessel was pressurised with hydrogen to 3 bar for 3 hours. After the completion of the hydrogenation the catalyst was filtered off. The filtrate was concentrated under reduced pressure to provide the title compound (254 g).

EXAMPLE 2

This Example illustrates a process for the preparation of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine from 4,6-dichloro-5-[(E)-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine
The Pt/C catalyst (33.3 g, 10% w/w) was added to a reaction vessel that had been purged with nitrogen and maintained under an atmosphere of nitrogen. The solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (150 g, 430.1 mmol) in ethyl acetate (3000 ml ) was added to the reaction vessel containing the catalyst and agitation was initiated. The inner temperature was adjusted to 20° C., the nitrogen atmosphere was evacuated, and the vessel was pressurized with 3 bar of hydrogen (hydrogen pressure of 3 bar was maintained throughout the reaction). The temperature was maintained at 20° C. for about 30 minutes and then it was increased to 40° C. and maintained for 150 minutes. When the reaction was complete (full conversion) the reaction solution was cooled to 20° C. and the catalyst filtered off under a nitrogen atmosphere. The catalyst was washed with ethyl acetate (300 ml ) and the filtered wash-solution was combined with the filtered reaction solution. The ethyl acetate solution was concentrated to 5m1 (ethyl acetate)/g (amine) under vacuum at a maximum temperature of 40° C. The resulting solution was extracted twice with aqueous hydrochloric acid (about 3M; 700 ml and 375 ml ) until a pH of 1.5-2 was obtained. The concentration of the ethyl acetate layer, under vacuum, yielded about 93 g of the 4,6-dichloro-2-(propylthio)pyrimidin-5-amine as a yellow oil.

Claims

1. A process for the preparation of a compound of formula (I):

wherein

X is halogen;

Y is ZR¹;

Z is oxygen or sulphur; and

R¹is C_1-6alkyl, C_1-6haloalkyl or C_3-7cycloalkyl;

the process comprising either:

hydrogenating a compound of formula (II):

with a suitable transition metal catalyst in a C_1-6aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent; or,

conducting a one-pot hydrogenation of a compound of formula (III):

wherein R²is phenyl optionally substituted by chloro, C_1-6alkyl, C_1-6alkoxy or (C_1-6alkyl)₂N;

(i) firstly at about 20° C. to form a compound of formula (IV):

(ii) and then at about 40° C.;

both steps (i) and (ii) being carried out in the presence of a suitable catalyst and in the presence of a suitable solvent.

2. A process as claimed in claim 1 wherein X is chloro.

3. A process as claimed in claim 1 wherein Z is sulphur.

4. A process as claimed in claim 1, wherein R¹is C_1-4alkyl or C_1-4haloalkyl.

5. A process as claimed in claim 1, wherein Y is ZR¹; Z is sulphur; and R¹is n-propyl.

6. A process as claimed in claim 1 wherein the transition metal catalyst for the hydrogenation of a compound of formula (II) is selected from platinum, palladium and a combination of platinum with a transition metal selected from vanadium, iron and manganese.

7. A process as claimed claim 6 wherein the transition metal catalyst is on a carbon support.

8. A process as claimed in claim 1 wherein the solvent for the hydrogenation of a compound of formula (II) is a C_1-6aliphatic alcohol, an ether, an ester or a hydrocarbon solvent.

9. A process as claimed in claim 1 wherein the hydrogenation of a compound of formula (II) is conducted at a temperature in the range 10 to 90° C.

10. A process as claimed in claim 9 wherein the hydrogenation of a compound of formula (II) is conducted at a temperature in the range 20 to 40° C.

11. A process as claimed in claim 1 wherein the hydrogenation of a compound of formula (II) is conducted at a pressure of 1 to 10 bar.

12. A process as claimed in claim 10 wherein the hydrogenation of a compound of formula (II) is conducted at a pressure of 2 to 4 bar.

13. A process as claimed in claim 1 for the preparation of a compound of formula (I) in which X is chloro, Y is ZR¹; Z is sulphur; and R¹is n-propyl; the process comprising hydrogenating a compound of formula (II) in solvent comprising an ether at a pressure of 2 to 4 bar, a temperature in the range 20 to 40° C. and a Pt/V/C catalyst.

14. A process as claimed in claim 1 wherein the catalyst for the one-pot hydrogenation is selected from platinum and a mixture of platinum and vanadium.

15. A process as claimed in claim 13 wherein the catalyst for the one-pot hydrogenation is selected from platinum on carbon 5-15% w/w; platinum 2-10% w/w and vanadium 0.2-3% w/w on carbon.

16. A process as claimed in claim 12, wherein the solvent for the one-pot hydrogenation is selected from a C_1-6aliphatic alcohol, an ester, an ether, a hydrocarbon and a ketone.

17. A process as claimed in claim 13, wherein the hydrogenation of a compound of formula (III) or (IV) is conducted at a pressure of 2 to 4 bar.

18. A process as claimed in claim 1 for the preparation of a compound of formula (I) in which X is chloro, Y is ZR¹; Z is sulphur; and R¹is n-propyl; the process comprising a one-pot hydrogenation of a compound of formula (III) wherein the hydrogenation is conducted in a solvent of ethyl acetate at a pressure of 2 to 4 bar and using a Pt/C catalyst.

19. A process as claimed in claim 1 wherein:

X is chloro;

Z is sulphur;

R¹is n-propyl;

the transition metal catalyst for the hydrogenation of a compound of formula (II) is selected from platinum, palladium and a combination of platinum with a transition metal selected from vanadium, iron and manganese; and

the solvent for the hydrogenation of a compound of formula (II) is a C_1-6aliphatic alcohol, an ether, an ester or a hydrocarbon solvent;

20. A process as claimed in claim 19 wherein:

the hydrogenation of the compound of formula (II) is conducted at a temperature in the range 20 to 40° C.;

the hydrogenation of the compound of formula (II) is conducted at a pressure of 2 to 4 bar;

the catalyst for the one-pot hydrogenation is selected from platinum on carbon 5-15% w/w, platinum 2-10% w/w and vanadium 0.2-3% w/w on carbon; and

the hydrogenation of the compound of formula (III) or (IV) is conducted at a pressure of 2 to 4 bar.