Method for preparing a key intermediate for the synthesis of statins

11708,363

17/488276

September 28, 2021

Disclosed herein relates to organic synthesis, and more particularly to a method for preparing a key intermediate for the synthesis of statins. The key intermediate is 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2,2-disubstituted-1,3-dioxan-4-yl] acetate of formula (I): [chemical expression included] where R1 is a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a monosubstituted or polysubstituted aryl group, or monosubstituted or polysubstituted aralkyl group; R2 is hydrogen, or monosubstituted or polysubstituted C1-C3 alkyl group, or halogen; and R3 and R4 are each independently a C1-C5 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group, a C1-C3 alkoxy group, a C6-C10 aryl group, or C7-C12 aralkyl group. In the method, a halomethyl compound and a thiol reagent are subjected to nucleophilic substitution in an organic solvent to synthesize a thioether, which then undergoes ketal exchange reaction with a carbonyl compound (V) in the presence of an organic acid to obtain a target product.

Fudan University (Shanghai, CN)

Fudan University (Shanghai, CN)

1. A method for preparing 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2,2-disubstituted-1,3-dioxan-4-yl] acetate of formula (I): [chemical expression included] wherein R 1 is a C 1 -C 8 alkyl group, a C 3 -C 8 cycloalkyl group, a C 6 -C 10 aryl group, or a C 7 -C 12 aralkyl group; R 2 is hydrogen, a C 1 -C 3 alkyl group, or halogen; and R 3 and R 4 are each independently a C 1 -C 5 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group, a C 1 -C 3 alkoxy group, a C 6 -C 10 aryl group, or a C 7 -C 12 aralkyl group; wherein the method comprising: (1) subjecting 2-[(4R,6S)-6-halomethyl-2-oxo-1,3-dioxan-4-yl] acetate (II) and a 2-mercaptobenzothiazole compound (III) to nucleophilic substitution in an organic solvent to synthesize 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl] acetate (IV), [chemical expression included] [chemical expression included] [chemical expression included] wherein X is halogen; and M is hydrogen, alkali metal cation, ammonium ion or phosphonium ion; and wherein the organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, acetonitrile, a ketone solvent, N-alkylpyridinium salt, 1,3-dialkyl imidazolium salt and a combination thereof; and (2) subjecting 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl]acetate (IV) and a carbonyl compound (V) to ketal exchange reaction in the presence of an organic acid to synthesize the 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2,2-disubstituted-1,3-dioxan-4-yl] acetate (I), [chemical expression included]

2. The method of claim 1 , wherein 2-mercaptobenzothiazole compound (III) is 2-mercaptobenzothiazole; the step (1) specifically comprises: subjecting 2-[(4R,6S)-6-halomethyl-2-oxo-1,3-dioxan-4-yl] acetate (II) and 2-mercaptobenzothiazole to nucleophilic substitution in the organic solvent in the presence of a base to synthesize 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl] acetate (IV); wherein the base is an inorganic base or an organic base; the inorganic base is alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide or a combination thereof; and the organic base is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine or a combination thereof.

3. The method of claim 1 , wherein when the M in the formula (III) is hydrogen, the nucleophilic substitution in step (1) is performed in the presence of a base; the base in step (1) is an inorganic base; the inorganic base such is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide; or when the 2 mercaptobenzothiazole compound (III) is a 2-mercaptobenzothiazole salt, the nucleophilic substitution in step (1) is performed in the absence of the base.

4. The method of claim 1 , wherein the ketone solvent is selected from the group consisting of symmetric alkyl ketone, symmetric cycloalkyl ketone, asymmetric alkyl ketone, asymmetric cycloalkyl ketone, symmetric aryl ketone, symmetric aralkyl ketone, asymmetric aryl ketone, asymmetric aralkyl ketone and a combination thereof.

5. The method of claim 1 , wherein in step (1), a concentration of 2-[(4R,6S)-6-halomethyl-2-oxo-1,3-dioxan-4-yl] acetate (II) is 0.1-5 mol/L.

6. The method of claim 1 , wherein in step (1), a molar ratio of 2 [(4R,6S)-6-halomethyl-2-oxo-1,3-dioxan-4-yl] acetate (II) to 2 mercaptobenzothiazole compound (III) is 1:0.5-5.

7. The method of claim 6 , wherein in step (1), the molar ratio of 2 [(4R,6S)-6-halomethyl-2-oxo-1,3-dioxan-4-yl] acetate (II) to 2 mercaptobenzothiazole compound (III) is 1:1-3.

8. The method of claim 1 , wherein in step (1), the nucleophilic substitution is performed at 20-180° C. for 1-18 h.

9. The method of claim 8 , wherein in step (1), the nucleophilic substitution is performed at 30-90° C. for 4-10 h.

10. The method of claim 1 , wherein in step (2), the organic acid is p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or camphor sulfonic acid.

11. The method of claim 10 , wherein in step (2), the organic acid is p-toluenesulfonic acid or benzenesulfonic acid.

12. The method of claim 1 , wherein in step (2), a concentration of 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl] acetate (IV) is 0.1-5 mol/L.

13. The method of claim 1 , wherein in step (2), a molar ratio of 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl] acetate (IV) to the organic acid is 1:0.01-5.

14. The method of claim 13 , wherein in step (2), the molar ratio of 2-[(4R,6S)-6-[(benzo[d]thiazol-2-ylthio)methyl]-2-oxo-1,3-dioxan-4-yl] acetate (IV) to the organic acid is 1:0.1-1.

15. The method of claim 1 , wherein in step (2), the ketal exchange reaction is performed at 10-80° C. for 1-48 h.

16. The method of claim 15 , wherein the ketal exchange reaction in step (2) is performed at 15-50° C. for 3-10 h.

20120136151 May 2012 Lee
102459196 May 2012
103328470 September 2013
104356109 February 2015
20090050044 May 2009
0196311 December 2001
02098854 December 2002
2010140765 December 2010

edspgr.11708363