Preparation method for Ezetimibe

Abstract

The invention relates to the technical field of preparation methods for Ezetimibe. The preparation method for Ezetimibe disclosed by the invention comprises the following steps of: preparing via SHI oxidation reaction on the basis of an olefin compound to obtain a new intermediate, namely, an epoxy compound 1, and performing loop opening and hydrogenation on the compound 1 to prepare a high-chiral-selectivity Ezetimibe product. Via the preparation method, an expensive and unstable chiral catalyst is avoided, and replaced by a cheap and easily-gotten fructose derivative, so that the preparation method is economic, efficient, cost-saving, simple and practical in aftertreatment, and suitable for industrialized production.

Description

technical field

[0001] The invention relates to the technical field of ezetimibe preparation methods. Background technique

[0002] Cardiovascular and cerebrovascular diseases are currently the most serious disease that endangers human life and health, and are common and frequently-occurring diseases among middle-aged and elderly people. It ranks first in morbidity and mortality in many countries. Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases. A large number of experimental and clinical data prove that atherosclerosis is closely related to abnormal blood lipid metabolism. Therefore, lipid-regulating drugs have become an important field of current drug research.

[0003] Through prospective, random and controlled clinical studies, it has been proved that some statins can reduce the occurrence of atherosclerosis and coronary heart disease, reduce the mortality caused by coronary heart disease, and reduce the incidence of myocardial infarcti...

Examples

Embodiment 1

[0046] Embodiment 1: the preparation of compound 1 (R 1 for tetrahydro-2H-pyranyl)

[0047] Add 5g of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, dry, filter, Evaporate to dryness and recrystallize from ethanol to obtain 1.41g of compound c with a yield of 27.3% and a de value of 95%.

Embodiment 2

[0048] Embodiment 2: the preparation of compound 1 (R 1 Dimethyl tert-butylsilyl)

[0049] Add 5g (10.4mmol) of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, Dry, filter, evaporate to dryness, and recrystallize from ethanol to obtain 1.55 g of compound c with a yield of 30% and a de value of 95.5%.

Embodiment 3

[0051] Embodiment 3: the preparation of compound 1

[0052] Add 5g (10.4mmol) of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, Dry, filter, evaporate to dryness, and recrystallize from ethanol to obtain 1.45 g of compound c with a yield of 28% and a de value of 95.3%.

[0053] MS (ESI): 500 (M+H + )

[0054] 1 H NMR (400MHz, DMSO) δ (ppm): 1.645-1.799 (m, 2H); 3.126-3.157 (m, 1H); 3.366-3.407 (m, 1H); 4.170-4.180 (d, 1H); 4.804- 4.809 (d, 1H), 5.061 (s, 2H); 6.993-7.424 (m, 17H).

technical field

[0001] The invention relates to the technical field of ezetimibe preparation methods. Background technique

[0002] Cardiovascular and cerebrovascular diseases are currently the most serious disease that endangers human life and health, and are common and frequently-occurring diseases among middle-aged and elderly people. It ranks first in morbidity and mortality in many countries. Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases. A large number of experimental and clinical data prove that atherosclerosis is closely related to abnormal blood lipid metabolism. Therefore, lipid-regulating drugs have become an important field of current drug research.

[0003] Through prospective, random and controlled clinical studies, it has been proved that some statins can reduce the occurrence of atherosclerosis and coronary heart disease, reduce the mortality caused by coronary heart disease, and reduce the incidence of myocardial infarcti...

Examples

Embodiment 1

[0046] Embodiment 1: the preparation of compound 1 (R 1 for tetrahydro-2H-pyranyl)

[0047] Add 5g of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, dry, filter, Evaporate to dryness and recrystallize from ethanol to obtain 1.41g of compound c with a yield of 27.3% and a de value of 95%.

Embodiment 2

[0048] Embodiment 2: the preparation of compound 1 (R 1 Dimethyl tert-butylsilyl)

[0049] Add 5g (10.4mmol) of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, Dry, filter, evaporate to dryness, and recrystallize from ethanol to obtain 1.55 g of compound c with a yield of 30% and a de value of 95.5%.

Embodiment 3

[0051] Embodiment 3: the preparation of compound 1

[0052] Add 5g (10.4mmol) of compound 2 and 50mL of dichloromethane into a 100mL three-necked flask, add 2.74g of m-chloroperoxybenzoic acid under magnetic stirring in an ice-water bath, TLC judges that the reaction is complete, add 1mol / L potassium carbonate aqueous solution to wash twice, Dry, filter, evaporate to dryness, and recrystallize from ethanol to obtain 1.45 g of compound c with a yield of 28% and a de value of 95.3%.

[0053] MS (ESI): 500 (M+H + )

[0054] 1 H NMR (400MHz, DMSO) δ (ppm): 1.645-1.799 (m, 2H); 3.126-3.157 (m, 1H); 3.366-3.407 (m, 1H); 4.170-4.180 (d, 1H); 4.804- 4.809 (d, 1H), 5.061 (s, 2H); 6.993-7.424 (m, 17H).

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