Process for preparing statin precursor
The present invention relates to a process for preparing a statin precursor, which process comprises a first reaction step, wherein a hydroxy-pyrimidine-carbonitrile is reacted with an organic sulfonyl halide to form the sulfonate-pyrimidine-carbonitrile; a second reaction step, wherein the sulfonate-pyrimidine-carbonitrile is reacted with N-methylmethane sulfonamide to form a pyrimidinyl-sulfonamide; and optionally a third reaction step, wherein the pyrimidinyl-sulfonamide is reacted with a reducing agent. All steps are conducted in toluene as the main solvent.
1. A process for preparing the compound of formula (IV), the process comprising the steps of:
(a) providing a starting mixture comprising the compound of formula (II) and toluene
(b) a first reaction step, wherein the starting mixture is contacted with an organic sulfonyl halide and the resulting first reaction mixture is kept at a first temperature of below 110° C., thereby forming an intermediate mixture comprising the compound of formula (III)
wherein R is an organic group having from 1 to 15 carbons; and
(c) a second reaction step, wherein the intermediate mixture is contacted with N-methylmethane sulfonamide and the resulting second reaction mixture is kept at a second temperature, thereby forming a second mixture comprising the compound of formula (IV)
2. The process according to claim 1 wherein toluene is present in steps (a), (b) and (c).
3. The process according to claim 1 , further comprising a reduction step, wherein the compound of formula (IV) obtained in the second reaction step is reacted with a reducing agent in toluene to form the compound of formula (I)
4. The process according to claim 1 , wherein the first and second temperature are independently chosen to lie in the range of 50 to 110° C.
5. The process according to claim 1 , wherein the intermediate mixture is contacted with N-methylmethane sulfonamide by adding the intermediate mixture to a sulfonamide mixture comprising N-methylmethane sulfonamide in toluene.
6. The process according to claim 5 , wherein the intermediate mixture is added to the mixture comprising N-methylmethane sulfonamide over a period of at least 1 hour.
7. The process according to claim 5 , wherein the mixture comprising N-methylmethane sulfonamide further comprises a base.
8. The process according to claim 5 , wherein the sulfonamide mixture comprises 1-60 wt. % N-methylmethane sulfonamide, relative to the total weight of toluene in the sulfonamide mixture.
9. The process according to claim 1 , wherein the organic sulfonyl halide is selected from the group consisting of methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl bromide, p-toluenesulfonyl chloride, p-toluenesulfonyl bromide, p-toluenesulfonyl fluoride, 4-chlorobenzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 2-naphtalenesulfonyl chloride and 2,4,6-trimethylbenzenesulfonyl chloride.
10. The process according to claim 1 , wherein the first and second reaction steps are conducted in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol and potassium tert-amyl alcohol.
11. The process according to claim 1 , wherein R having from 1 to 15 carbons is an aromatic hydrocarbon, alkane or cycloalkane, optionally substituted with one or more of C1-C4 alkyl, halide or nitro.
12. The process according to claim 1 , wherein at least 95 wt. % of the organic solvent present in the starting mixture, first reaction mixture and second reaction mixture is toluene.
13. The process according to claim 1 , wherein the starting mixture is a suspension of the compound of formula (II) in toluene.
14. The process according to claim 3 , wherein the reducing agent is diisobutylaluminium hydride.
15. The process according to claim 14 , wherein the reduction reaction is conducted by contacting a mixture of the compound of formula (IV) in toluene with a solution of DIBALH in toluene at a temperature below 20° C. and keeping the resulting mixture at said temperature below 20° C. for an amount of time.
16. The process according to claim 15 , wherein the amount of time that the resulting mixture is kept at a temperature below 20° C. is about 10-120 minutes.
17. The process according to claim 1 , wherein in the starting mixture at least 90% of any solvent present is toluene.
18. The process according to claim 1 , wherein in the first reaction mixture at least 90% of any solvent present is toluene.
19. The process according to claim 1 , wherein in the intermediate mixture at least 90% of any solvent present is toluene.
20. The process according to claim 1 , wherein in the second reaction mixture at least 90% of any solvent present is toluene.