Preparation midbody for Ezetimibe and preparation method of preparation midbody

Abstract

The invention provides a preparation midbody for Ezetimibe which is shown in a general formula I, wherein PG is an acetyl group, a T-butyloxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, a trityl group, a trimethylsilyl group or a diphenylmethyl group silicon group. The invention further provides a preparation method of the midbody I, and the application for preparing the medicine Ezetimibe. The method for preparing the Ezetimibe by adopting the compounds shown in the general formula I is different from the method in the conventional document, the newer chirality assistant (S)-4-(2-chlorphenyl)-2-oxazolone is adopted, the productive rate reaches 91%, and the optical purity reaches 100%, so that the productive rate and the optical purity are higher than those of the previously applied (S)-4-phenyl-2-oxazolone. Besides, the selected chirality assistant (S)-4-(2-chlorphenyl)-2- oxazolone can be conveniently prepared by the original commercialized ((S)-2-chlorobenzene glycine potassium).

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation intermediate of a lipid-lowering drug-ezetimibe and a preparation method thereof. Background technique

[0002] Ezetimibe, chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4-(4-hydroxyphenyl)-2-azetidinone is a blood lipid-lowering drug and belongs to selective cholesterol absorption inhibitors. The drug binds to the membrane protein on the small intestinal brush border membrane vesicles, inhibits the body's absorption of cholesterol, thereby lowering the cholesterol level and lowering blood lipids.

[0003]

[0004] Structurally, ezetimibe has three chiral centers, which are the 3 and 4 positions of azetidinone and the 3'-position chiral carbon atom connected to the hydroxyl group on the side chain connected to the 3 position. The synthesis of ezetimibe focuses on the ability to form these three chiral centers...

Examples

Embodiment 1

[0032] Embodiment 1. The synthesis of compound IV

[0033]

[0034] Add 5-(4-fluorophenyl)-5-oxopentanoic acid (20g, 95mmol), (S)-4-(2-chlorophenyl)-2-oxazolone (19g, 96mmol) into a 500ml three-necked flask ), N,N'-dicyclohexylcarbodiimide (19.8g, 96mmol) and dichloromethane 200ml, stirred at room temperature for 12 hours. Filter and wash the organic layer with 3% dilute hydrochloric acid (80ml). The organic layer was concentrated and the product was crystallized from isopropanol (150ml), filtered and dried. 31 g of the product was obtained with a yield of 83.7%. 1 H NMR (400MHz, CDCl 3 ):δ2.05(m,2H),2.94(m,2H),3.05(m,2H),4.26(m,1H),4.67(t,1H),5.42(m,1H),7.08(m, 2H),7.30(m,4H),7.89(m,2H).

Embodiment 2

[0035] Embodiment 2. Synthesis of Compound II

[0036]

[0037]Dry dichloromethane (20ml) and borane dimethyl sulfide (2.82ml, 28.2mmol) were added to a 250ml three-necked flask, and the mixture was cooled to -5-0°C. Add (R)-MeCBS toluene solution (1.4ml, 1.4mmol, 5%mol), and stir at 0°C for 15 minutes, slowly add compound IV (10g, 25.7mmol) in dichloromethane within 3-4 hours (30ml) solution, the reaction temperature is controlled at -5~0 degree. Stirring was continued for 1-2 hours. The reaction was quenched by the slow addition of methanol (4ml) while maintaining the temperature below 0°C. 5% hydrogen peroxide (20ml) was added followed by 4N sulfuric acid (1.5ml). The mixture was stirred for 15 minutes, the organic layer was separated and washed with 2N sulfuric acid (20ml), 5% sodium bisulfite (50ml) and 10% sodium chloride (50ml). The organic layer was concentrated to low volume until the water content was less than 0.05%. The product was used directly in the next...

Embodiment 3

[0038] Example 3. Synthesis of compound I (PG trimethylsilyl)

[0039]

[0040] A dichloromethane solution of compound II (10 g equivalent of compound 6, 25 mmol) and compound III (12.05 g) obtained from the previous step were added to a 500 ml three-necked flask, and the total volume of the reaction mixture was adjusted to 150 ml using anhydrous dichloromethane. The mixture was cooled to 1 H NMR (400MHz, CDCl3): δ-0.07(s,9H),0.28(s,9H),1.41(m,1H),1.55(m,3H),4.21(m,1H),4.29(m,1H ),4.46(m,2H),4.47(m,1H),5.43(m,1H),6.43(m,2H),6.77(m,4H),6.98(m,2H),7.06(m,2H) ,7.18(m,7H).

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation intermediate of a lipid-lowering drug-ezetimibe and a preparation method thereof. Background technique

[0002] Ezetimibe, chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4-(4-hydroxyphenyl)-2-azetidinone is a blood lipid-lowering drug and belongs to selective cholesterol absorption inhibitors. The drug binds to the membrane protein on the small intestinal brush border membrane vesicles, inhibits the body's absorption of cholesterol, thereby lowering the cholesterol level and lowering blood lipids.

[0003]

[0004] Structurally, ezetimibe has three chiral centers, which are the 3 and 4 positions of azetidinone and the 3'-position chiral carbon atom connected to the hydroxyl group on the side chain connected to the 3 position. The synthesis of ezetimibe focuses on the ability to form these three chiral centers...

Examples

Embodiment 1

[0032] Embodiment 1. The synthesis of compound IV

[0033]

[0034] Add 5-(4-fluorophenyl)-5-oxopentanoic acid (20g, 95mmol), (S)-4-(2-chlorophenyl)-2-oxazolone (19g, 96mmol) into a 500ml three-necked flask ), N,N'-dicyclohexylcarbodiimide (19.8g, 96mmol) and dichloromethane 200ml, stirred at room temperature for 12 hours. Filter and wash the organic layer with 3% dilute hydrochloric acid (80ml). The organic layer was concentrated and the product was crystallized from isopropanol (150ml), filtered and dried. 31 g of the product was obtained with a yield of 83.7%. 1 H NMR (400MHz, CDCl 3 ):δ2.05(m,2H),2.94(m,2H),3.05(m,2H),4.26(m,1H),4.67(t,1H),5.42(m,1H),7.08(m, 2H),7.30(m,4H),7.89(m,2H).

Embodiment 2

[0035] Embodiment 2. Synthesis of Compound II

[0036]

[0037]Dry dichloromethane (20ml) and borane dimethyl sulfide (2.82ml, 28.2mmol) were added to a 250ml three-necked flask, and the mixture was cooled to -5-0°C. Add (R)-MeCBS toluene solution (1.4ml, 1.4mmol, 5%mol), and stir at 0°C for 15 minutes, slowly add compound IV (10g, 25.7mmol) in dichloromethane within 3-4 hours (30ml) solution, the reaction temperature is controlled at -5~0 degree. Stirring was continued for 1-2 hours. The reaction was quenched by the slow addition of methanol (4ml) while maintaining the temperature below 0°C. 5% hydrogen peroxide (20ml) was added followed by 4N sulfuric acid (1.5ml). The mixture was stirred for 15 minutes, the organic layer was separated and washed with 2N sulfuric acid (20ml), 5% sodium bisulfite (50ml) and 10% sodium chloride (50ml). The organic layer was concentrated to low volume until the water content was less than 0.05%. The product was used directly in the next...

Embodiment 3

[0038] Example 3. Synthesis of compound I (PG trimethylsilyl)

[0039]

[0040] A dichloromethane solution of compound II (10 g equivalent of compound 6, 25 mmol) and compound III (12.05 g) obtained from the previous step were added to a 500 ml three-necked flask, and the total volume of the reaction mixture was adjusted to 150 ml using anhydrous dichloromethane. The mixture was cooled to 1 H NMR (400MHz, CDCl3): δ-0.07(s,9H),0.28(s,9H),1.41(m,1H),1.55(m,3H),4.21(m,1H),4.29(m,1H ),4.46(m,2H),4.47(m,1H),5.43(m,1H),6.43(m,2H),6.77(m,4H),6.98(m,2H),7.06(m,2H) ,7.18(m,7H).

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