Process for the preparation of pyrimidine derivatives
An improved process for the preparation of pyrimidine derivatives is provided comprising reacting a Wittig reagent of the general formula wherein R is an alkyl of from 1 to 10 carbon atoms, aryl or arylalkyl, R 1 is a substituted or unsubstituted hydrocarbon group, R 2 and R 3 are the same or different and are hydrogen or a substituted or unsubstituted hydrocarbon group; Z is sulfur, oxygen, sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, and sulfonyl substituted by alkyl, amino or alkylamino and X is a halogen; with an aldehyde of the general formula wherein R 4 is hydrogen, a lower alkyl or a cation capable of forming a non-toxic pharmaceutically acceptable salt and each R 5 are the same or different and are hydrogen or a hydrolyzable protecting group, or each R 5 , together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group, or each R 5 is bonded to the same substituent which is bonded to each oxygen atom to form a hydrolyzable protecting group; in the presence of a base.
1. A process for the preparation of pyrimidine derivatives comprising reacting a Wittig reagent of the general formula
wherein R is an alkyl of from 1 to 10 carbon atoms, aryl or arylalkyl, R 1 is a substituted or unsubstituted hydrocarbon group, R 2 and R 3 are the same or different and are hydrogen or a substituted or unsubstituted hydrocarbon group; Z is sulfur, oxygen, sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, and sulfonyl substituted by alkyl, amino or alkylamino and X is a halogen; with an aldehyde of the general formula
wherein R 4 is hydrogen, a lower alkyl or a cation capable of forming a non-toxic pharmaceutically acceptable salt and each R 5 are the same or different and are hydrogen or a hydrolyzable protecting group, or each R 5 , together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group, or each R 5 is bonded to the same substituent which is bonded to each oxygen atom to form a hydrolizable protecting group; in the presence of a base to provide a pyrimidine derivative of the general formula
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , X and Z have the aforestated meanings or a racemic mixture, an enantiomer, a diastereoisomer or a mixture thereof.
2. The process of claim 1 , wherein R 1 is a substituted or unsubstituted hydrocarbon group of 1 to about 10 carbon atoms, R 2 and R 3 are the same or different and are a substituted or unsubstituted hydrocarbon group of 1 to about 10 carbon atoms and R 4 is a lower alkyl of 1 to 6 carbon atoms.
3. The process of claim 1 , wherein R 1 is selected from the group consisting of lower alkyl which may have 1 to 3 substitutents independently selected from the group consisting of halogen, amino, and cyano, a C 6 to C 12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano, and C 1 to C 6 lower alkyl substituted by C 6 to C 12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano; R 2 is a lower alkyl which may have 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano, or a C 6 to C 12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano; R 3 is a lower alkyl which may have 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano, R 4 is hydrogen or a lower alkyl which may have 1 to 3 substituents independently selected from the group consisting of halogen, amino, and cyano.
4. The process of claim 1 , wherein R 1 is a lower alkyl of 1 to 6 carbon atoms; R 2 is a C 6 to C 12 aromatic group which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, and cyano; R 3 is a lower alkyl of 1 to 6 carbon atoms, R 4 is a lower alkyl of 1 to 6 carbon atoms.
5. The process of claim 1 , wherein Z is an amino substituted by sulfonyl or alkylsulfonyl wherein the alkyl group contains from 1 to 6 carbon atoms.
6. The process of claim 1 , wherein Z is methanesulfonyl amino.
7. The process of claim 1 , wherein the Wittig reagent is triphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphonium bromide or tributyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphonium bromide and the aldehyde is of the general formula
wherein R 4 has the aforestated meaning and each R 5 is the same or different and is a lower alkyl group.
8. The process of claim 1 , wherein the base is selected from the group consisting of alkali metal carbonates, alkali metal hydroxides and mixtures thereof.
9. The process of claim 1 , wherein the base is an alkali metal carbonate selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate and mixtures thereof.
10. The process of claim 1 , wherein the reaction is carried out at a temperature of about 40° C. to about 90° C.
11. The process of claim 1 , wherein the reaction is carried out at a temperature of about 60° C. to about 80° C.
12. The process of claim 1 , wherein the base is present in an amount of about 2.5 to about 4.5 equivalents per equivalent of the Wittig reagent.
13. The process of claim 1 , wherein the base is present in an amount of about 3.5 equivalents per equivalent of the Wittig reagent.
14. The process of claim 1 , wherein the aldehyde is added to the Wittig reagent in an excess amount.
15. The process of claim 1 , wherein the aldehyde is present in an amount of about 1 to about 1.3 equivalents per equivalent of the Wittig reagent.
16. The process of claim 1 , wherein the reaction is carried out in one or more aprotic solvents.
17. The process of claim 16 , wherein the aprotic solvent is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, dimethylacetamide and mixtures thereof.
18. The process of claim 16 wherein the solvent is present in a ratio of Wittig reagent to solvent of about 1:3 w/v to about 1:5 w/v.
19. The process of claim 1 , further comprising hydrolyzing the pyrimidine derivative to produce a hydrolyzed pyrimidine derivative of the general formula:
wherein R, R 1 , R 2 , R 3 , R 4 and Z have the aforestated meanings or a racemic mixture, an enantiomer a diastereoisomer or a mixture thereof.
20. The process of claim 19 , wherein the step of hydrolyzing the pyrimidine derivative comprises contacting the pyrimidine derivative with a dilute acid.
21. The process of claim 20 , wherein the dilute acid is hydrochloric acid.
22. The process of claim 19 , wherein the hydrolyzed pyrimidine derivative is converted to a pharmaceutically acceptable salt of the pyrimidine derivative.
23. The process of claim 19 , wherein the hydrolyzed pyrimidine derivative is converted to a calcium salt of the pyrimidine derivative.
24. The process of claim 19 , wherein the hydrolyzed pyrimidine derivative is purified.
25. The process of claim 1 , wherein the pyrimidine derivative is converted to a pharmaceutically acceptable salt of the pyrimidine derivative.
26. The process of claim 1 , wherein the pyrimidine derivative is converted to a calcium salt of the pyrimidine derivative.
27. The process of claim 1 , wherein the pyrimidine derivative is contacted with a sufficient amount of a source of calcium in the presence of a dilute acid to provide a calcium salt of the pyrimidine derivative.
28. The process of claim 1 , wherein the pyrimidine derivative is contacted with a sufficient amount of a calcium acetate in the presence of a dilute acid to provide a calcium salt of the pyrimidine derivative.
29. The process of claim 1 , further comprising contacting the pyrimidine derivative with an amine of the general formula R 6 NH 2 wherein R 6 is an alkyl of from 1 to about 6 carbon atoms in the presence of a dilute acid to produce an alkylammonium salt of the pyrimidine derivative of the general formula:
wherein R, R 1 , R 2 , R 3 , and Z have the aforestated meanings.
30. The process of claim 29 , wherein the dilute acid is hydrochloric acid.
31. The process of claim 29 , wherein the amine is present in an amount of from about 1.6 to about 1.8 equivalents per equivalent of the pyrimidine derivative.
32. The process of claim 29 , wherein the alkylammonium salt of the pyrimidine derivative is converted to a pharmaceutically acceptable salt.
33. The process of claim 32 , wherein the pharmaceutically acceptable salt is a calcium salt of the pyrimidine derivative.
34. The process of claim 29 , further comprising contacting the alkylammonium salt of the pyrimidine derivative with a sufficient amount of a source of calcium to provide a calcium salt of the pyrimidine derivative.
35. The process of claim 29 , further comprising contacting the alkyl ammonium salt of the pyrimidine derivative with a sufficient amount of calcium chloride to provide a calcium salt of the pyrimidine derivative.
36. The process of claim 1 , further comprising contacting the pyrimidine derivative with an amine of the general formula R 6 NE 2 wherein R 6 can be an alkyl of from 1 to about 6 carbon atoms in the presence of a dilute acid to produce an alkylammonium salt of the pyrimidine derivative of the general formula:
wherein R, R 1 , R 2 , R 3 , and Z have the aforestated meanings; and contacting the alkylammonium salt of the pyrimidine derivative with a sufficient amount of calcium chloride to provide a calcium salt of the pyrimidine derivative.
37. The process of claim 36 , wherein the amine is present in an amount of about 1.6 to about 1.8 equivalents per equivalent of the pyrimidine derivative.
38. A process for the preparation of tert-butyl[E]-(6-{2-[4-(4-fluorophenyl]-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate (BEM) comprising reacting a Wittig reagent of the general formula:
wherein R is the same or different and can be an alkyl of from 1 to 10 carbon atoms, aryl or an arylalkyl and X is a halogen, with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (BFA) of the general formula
in the presence of a base.
39. The process of claim 38 , wherein the Wittig reagent is triphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphonium bromide.
40. The process of claim 38 , wherein the Wittig reagent is tributyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphonium bromide.
41. The process of claim 38 , wherein the reaction is carried out at a temperature of about 40° C. to about 90° C.
42. The process of claim 38 , wherein the reaction is carried out at a temperature of about 60° C. to about 80° C.
43. The process of claim 38 , wherein the base is present in an amount of about 2.5 to about 4.5 equivalents per equivalent of the Wittig reagent.
44. The process of claim 38 , wherein the base is present in an amount of about 3.5 equivalents per equivalent of the Wittig reagent.
45. The process of claim 38 , wherein BFA is present in an amount of about 1.0 to about 1.3 equivalents per equivalent of the Wittig reagent.
46. The process of claim 38 , wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate and mixtures thereof.
47. The process of claim 38 , wherein the reaction is carried out in the presence of one or more aprotic solvents.
48. The process of claim 47 , wherein the solvent is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, dimethylacetamide and mixtures thereof.
49. The process of claim 38 , further comprising converting BEM to a calcium salt of rosuvastatin.
50. The process of claim 49 , wherein the step of converting comprises contacting BEM with a sufficient amount of a source of calcium in the presence of a dilute acid to provide the calcium salt of rosuvastatin.
51. The process of claim 49 , wherein the step of converting comprises contacting BEM with a sufficient amount of calcium acetate in the presence of a dilute acid to provide the calcium salt of rosuvastatin.
52. A process for the preparation of a rosuvastatin salt comprising the steps of:
(a) reacting a Wittig reagent of the general formula:
wherein R is an alkyl of from 1 to 10 carbon atoms, aryl or arylalkyl and X is a halogen, with BFA in the presence of a base to form BEM; and
(b) converting BEM to a salt of rosuvastatin.
53. The process of claim 52 , wherein the salt is the calcium salt of rosuvastatin.
54. A compound of the general formula
wherein R is an alkyl of from 1 to 10 carbon atoms, aryl or arylalkyl, R 1 is a substituted or unsubstituted hydrocarbon group, R 2 and R 3 are the same or different and are hydrogen or a substituted or unsubstituted hydrocarbon group; Z is sulfur, oxygen, sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, and sulfonyl substituted by alkyl, amino or alkylamino and X is a halogen.
55. The compound of claim 54 , which is of the formula:
wherein R and X have the aforestated meanings.