Title of Invention

"PROCESS FOR THE PREPARATION OF AMINOPYRIMIDINES"

Abstract

A process for the preparation of a compound of formula (I): wherein X is halogen; Y is ZR1; Z is oxygen or sulphur; and R1 is C1-6 alkyl, C1-6 haloalkyl or C3-7 cycloalkyl; the process comprising: hydrogenating a compound of formula (II): with a transition metal catalyst selected from platinum, palladium and a combination of platinum with another transition metal in a C1-6 aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent.

Full Text

CHEMICAL PROCESS 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-(1 ct, 2cc, 3 f3 (18* ,2R* ),5 13)]-3-[7-[2-(3 ,4-difluorophenyl)-cyclopropyl] amino] -5-(propylthio)-3H- 1 ,2,3-triazo1oI4,5-d]pynmidin-3-y1)-5~(2-hydroxyetlioxy>-cyclopentaned,2-diol (Compound A), and similar such compounds, are disclosed in WO 00/34283 and WO 99/05 143 as pli.annaceutically active P2~ (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used as, inter alia, inhibitors of platelet activation, aggregation or degnanulation. 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 US6096924. The present invention provides a process for the preparation of a compound of formula (I): or wherein X is halogen; Y is ZR'; Z is oxygen or sulphur; and R1 C1..6 alkyl, C1..6 haloalkyl C3.7 cycloalkyl; the process comprising either: a. hydrogenating a compound of formula (II): with a suitable transition metal catalyst in a C1..6 aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent; or, b. conducting a one-pot hydrogenation of a compound of formula (III): N wherein R2 is phenyl optionally substituted by chioro, C1..6 alkyl, c1..6 alkoxy or (C16 allyl)2N; i. firstly at about 200C to form a compound of formula (IV): ii. and then at about 400C; 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 aIlcyl groups are methyl, ethyl, n-propyl, isopropyl or ~i-buty1. 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, CLIP2, CF3, CJI2CF3 and 3,3,3-trifluoroprop-1 -yl. Cycloalkyl is, for example, C3~ cycloalkyl, 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 Xis halogen; ~ is ZRIZ is oxygen or sulphur; and R' is alkyl, haloalkyl or C3.1 cycloalkyl; the process comprising hydrogenating a compound of formula (in: _ with a suitable transition metal catalyst i:n C,.6 aliphatic 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, fc~r example carbon. A suitable solvent for the hydrogenation of a compound of formula (II) is a C1~ aliphatic alcohol (such as ethanol and iso-propyl alcohol), an ether (for example a di(C,6 alkyl) ether, such as diethylether or mefli yl tort-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 (in is conducted at a temperature in the range 10 to 900C, for example 20 to 400C. In yet another aspect the hydrogenation of a compound of formula (in 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): is or wherein X is halogen; Y is ZR'; Z is oxygen or sulphur; and R' ~ alkyl, C,~ haloalkyl C3..7 cycloalkyl; the process comnpmising c onducting a one-pot hydrogenation of a compound of formula CIII): 4 wherein R2 is phenyl optionally substituted by chioro, C,..6 alkyl, C1.6 alkoxy or (C1~6 alkyl)2N; i. firstly at 10 to 250C to form a compound of formula (IV): (IV) ii. and then hydrogenating at about 35 to 500C; 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 (JIlT) 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 2-1O%w/w (for example 3-7%wlw) and vanadium O.2-3%w/w on carbon. A suitable solvent for the one-pot hydrogenation is a C1.6 aliphatic alcohol (for example ethanol or iso-propyl alcohol), an ester (for example ethyl acetate), an ether (such as tetrahydrofuran or methyl ~-buty1 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 (UT) 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 R' is alkyl or (s (such as ~-propyl) C14 ha1oa~~I uch as 3,3,3- trifluoroprop-1 -yI). 40CC 5 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 of4,6-dichloro-2-(propylthio)pyrimidin-5-aniine. A Pt[VIC catalyst (available from Degussa; about 3% Pt and 0.6% V adsorbed on charcoal, 30g) was charged to a vessel and the vessel was purged with nitrogen. 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine (302g) 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 300C 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-jI(E)..(4-methylphenyl)diazenyl] -2-. (propylsnlfanyl)pyrimidine Cl CI The Pt/C catalyst (33.3g, 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)pyiimidine (1 SOg, 430.1 rumol) in ethyl acetate (3000m1) was added to the reaction vessel containing the catalyst and agitation was initiated. The inner temperature was adjusted to 200C, 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 200C for about 30 minutes and then it was increased to 400C and maintained for 150 minutes. When the reaction was complete (full conversion) the reaction solution was cooled to 200C and the catalyst filtered off under a nitrogen atmosphere. The catalyst was washed with ethyl acetate (300m1) and the filtered wash-solution was combined with the filtered reaction solution. The ethyl acetate solution was concentrated to Smi (ethyl acetate)/g (amine) under vacuum at a maximum temperature of 400C. The resulting solution was extracted twice with aqueous hydrochloric acid (about 3M; 700m1 and 375m1) until a pH of 1.5-2 was obtained. The concentration of the ethyl acetate layer, under vacuum, yielded about 93g of the 4,6-dichloro-2-(propylthio)pyrimidin-5-amine as a yellow oil. WE CLAIM: 1. A process for the preparation of a compound of formula (I): (Formula Removed) wherein X is halogen; Y is ZR1; Z is oxygen or sulphur; and R1 is C1-6 alkyl, C1-6 haloalkyl or C3-7 cycloalkyl; the process comprising: hydrogenating a compound of formula (II): (Formula Removed) with a transition metal catalyst selected from platinum, palladium and a combination of platinum with another transition metal in a C1-6 aliphatic alcohol, an ether, an ester or a hydrocarbon as solvent. 2. The process as claimed in claim 1 wherein X is chloro. 3. The process as claimed in claim 1 or 2 wherein Z is sulphur. 4. The process as claimed in claim 1,2 or 3 wherein R1 is C1-4 alkyl or C1-4 haloalkyl. 5. The process as claimed in claim 1, 2, 3 or 4 wherein Y is ZR1; Z is sulphur; and R1 is n-propyl. 6. The process as claimed in any one of claims 1 to 5 wherein the transition metal catalyst for the hydrogenation of a compound of formula (II) is a combination of platinum with a transition metal selected from vanadium, iron and manganese. 7. The process as claimed claim 6 wherein the transition metal catalyst is on a carbon support. 8. The process as claimed in any one of claims 1 to 7 wherein the solvent for the hydrogenation of a compound of formula (II) is a C1-6 aliphatic alcohol, an ether, an ester or a hydrocarbon solvent. 9. The process as claimed in any one of claims 1 to 8 wherein the hydrogenation of a compound of formula (II) is conducted at a temperature in the range 10 to 90°C. 10. The 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. The process as claimed in any one of claims 1 to 10 wherein the hydrogenation of a compound of formula (II) is conducted at a pressure of 1 to 10 bar. 12. The process as claimed in claim 11 wherein the hydrogenation of a compound of formula (II) is conducted at a pressure of 2 to 4 bar. 13. The 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 R1 is 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.

Documents:

5343-DELNP-2006-Abstract-(25-05-2012).pdf

5343-DELNP-2006-Claims-(25-05-2012).pdf

5343-DELNP-2006-Correspondence Others-(25-05-2012).pdf

5343-DELNP-2006-Form-3-(25-05-2012).pdf

5343-DELNP-2006-GPA-(25-05-2012).pdf

5343-DELNP-2006-Petition-137-(25-05-2012).pdf

5348-delnp-2006-abstract.pdf

5348-delnp-2006-claims.pdf

5348-delnp-2006-correspondence-others.pdf

5348-delnp-2006-description(complete).pdf

5348-delnp-2006-form-1.pdf

5348-delnp-2006-form-2.pdf

5348-delnp-2006-form-3.pdf

5348-delnp-2006-gpa.pdf

5348-delnp-2006-pct-search report.pdf

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