Green preparation process of ezetimibe bulk drug

Abstract

The invention relates to a green preparation process of an ezetimibe bulk drug, and belongs to the technical field of synthesis of drug intermediates. The invention provides a green preparation process of an ezetimibe bulk drug, which comprises the following steps: S1, mixing a compound as shown in a formula III, ZTM, TMSCl and a reaction solvent I at the temperature of below 0 DEG C, then sequentially adding diisopropylethylamine and titanium tetrachloride into a catalytic reaction system until a substrate is used up, quenching the reaction system, extracting the reaction system, washing an organic phase, and drying to obtain a compound as shown in a formula III; after 3 / 4 of the solvent is removed, N, O-bis (trimethylsilyl) acetamide is added for continuous reflux reaction, the solution is removed again after completion of the reflux reaction, cooling crystallization is performed to obtain a compound shown in a formula II, the compound shown in the formula II, a reaction solvent II and tetrabutylammonium fluoride are subjected to primary reaction, the solution of a reaction system is removed, then the compound is dissolved in isopropanol, diluted hydrochloric acid is added for reaction, crystallization is performed to obtain a crude product, and the compound shown in the formula II is obtained. And recrystallizing to obtain the ezetimibe bulk drug. The method integrally has the advantages of high product yield, mild reaction conditions, less by-products and environmental protection.

Description

Technical Field

[0001] The invention relates to a green preparation process of an ezetimibe raw material drug, and belongs to the technical field of drug intermediate synthesis. Background Art

[0002] Ezetimibe Tablets is a cholesterol absorption inhibitor developed jointly by Merck & Co. and Schering-Plough Corporation of the United States. Unlike other lipid-lowering drugs, it can be used in combination with statins to treat primary hypercholesterolemia. It does not increase bile secretion, nor inhibit the synthesis of cholesterol in the liver, and has a long duration of effect. It is an ideal lipid-lowering drug and has occupied an important position in the market since its launch, with broad prospects.

[0003] Patent CN104892537A discloses an intermediate of ezetimibe and a method for synthesizing ezetimibe. Compound 1 and compound 2 are simultaneously added with a protective group to obtain a compound of formula 3 and a compound of formula 4 to prepare a feed solution, and then a catalyst is added to react the compound of formula 3 with the compound of formula 4 to generate a compound of formula 5. In this reaction route, adding a protective group to the compound before reacting can reduce the generation of by-products. However, compound 1 and compound 2 are in the same reaction system, which easily leads to misalignment of the protective group to produce additional by-products, thereby reducing the reaction yield. The synthesis route is as follows: From the above literature, it can be seen that the shortcomings of the current production and preparation process of ezetimibe intermediates are that by-products are easily produced during the reaction process and the reaction yield is low. Summary of the invention

[0004] In view of the defects existing in the above prior art, the present invention provides a green preparation process of ezetimibe raw material, which solves the problems of more by-products, low yield and greater pollution to the environment.

[0005] The object of the present invention is achieved by the following technical scheme, a green preparation process of ezetimibe raw material, the method comprising the following steps: S1: After mixing the compound of formula III, ZTM, TMSCl and reaction solvent I at below 0° C., diisopropylethylamine and titanium tetrachloride are sequentially added to the catalytic reaction system until the substrate is exhausted; S2: After quenching the reaction system, extract the reaction system and wash the organic phase, remove 3 / 4 of the solvent, then add N, O-bis(trimethylsilyl)acetamide to continue reflux reaction, and after completion, remove the solution again and cool and crystallize to obtain a compound of formula II; S3: The compound of formula II is initially reacted with reaction solvent II and tetrabutylammonium fluoride, the reaction system is desolvated and dissolved in isopropanol, dilute hydrochloric acid is added and reacted, and then crystallization is performed to obtain a crude product, and the compound of formula I, i.e., ezetimibe raw material, is obtained after recrystallization; In the step S2, after the reaction system is quenched, the reaction solution is poured into a 5% tartaric acid solution, stirred, and then a 15% sodium bisulfite solution is added to continue to be heated and stirred, and the reaction solution is allowed to stand for stratification. After the reaction solution is stratified, the aqueous layer is extracted with ethyl acetate, and the organic phases are combined and washed with saturated brine; The structural formula of the compound of formula I is: ; The structural formula of the compound of formula II is: ; The structural formula of the compound of formula III is: .

[0006] Preferably, the reaction solvent I includes at least one of dimethyl sulfoxide, tetrahydrofuran, and dichloromethane; and the reaction solvent II includes at least one of dichloromethane, tetrahydrofuran, or ethyl acetate.

[0007] Preferably, in step S1, the reaction temperature is -5~0°C.

[0008] Most preferably, the lower the reaction temperature, the less by-products are generated.

[0009] Preferably, in the step S1, the mass ratio of the compound of formula III, the ZTM and the TMSCl is 1:1.1~1.3:1~1.1.

[0010] Most preferably, the mass ratio of the compound of formula III, the ZTM, and the TMSCl is 1:1.1:1.1.

[0011] Preferably, in step S1, the mass ratio of the compound of formula III, the diisopropylethylamine and the titanium tetrachloride is 1:1-1.2:0.2-0.4.

[0012] Most preferably, the mass ratio of the compound of formula III, the diisopropylethylamine and the titanium tetrachloride is 1:1:0.2.

[0013] Preferably, in step S2, acetic acid is used as a reagent to quench the reaction, and the reaction system is returned to room temperature after quenching the reaction.

[0014] Preferably, in step S2, the crystallization solution is at least one of dichloromethane, toluene and n-hexane.

[0015] Preferably, in step S2, the amount of N,O-bis(trimethylsilyl)acetamide used is 75% of the mass of the compound of formula III.

[0016] Preferably, in step S4, the mass ratio of the compound of formula II to the tetrabutylammonium fluoride is 1:0.5-0.7.

[0017] Most preferably, the mass ratio of the compound of formula II to the tetrabutylammonium fluoride is 1:0.5.

[0018] Preferably, in step S3, the crystallization solution is selected from at least one of n-hexane, cyclohexane and ethyl acetate.

[0019] In summary, compared with the prior art, the present invention has the following advantages: 1. In the scheme of the present invention, by optimizing the reaction conditions and process, the synthesis efficiency and quality of the ezetimibe API are improved, and the efficient use of raw materials and the minimization of energy consumption are achieved. It has the advantages of short reaction time, simple operation, and easy scale-up production; 2. In the scheme of the present invention, by precisely controlling parameters such as reaction temperature, pressure and flow rate, the selectivity and yield of the reaction can be effectively improved and the generation of by-products can be reduced; it can also achieve the recycling of raw materials and solvents, reduce production costs, and reduce environmental impact. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION

[0021] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0022] Example 1 In a reaction flask, add 35.7 g (0.1 mol) of compound III, 23.67 g (0.11 mol) of ZTM, 11.95 g (0.11 mol) of TMSCl and 200 mL of dimethyl sulfoxide, cool to -5 °C and stir to react, add 17.42 mL (0.1 mol) of diisopropylethylamine dropwise, keep warm until the compound III reacts, then add 2.19 mL (0.02 mol) of titanium tetrachloride dropwise, keep warm until the reaction is completed.

[0023] Acetic acid was added dropwise to quench the mixture, and the mixture was stirred to room temperature. The reaction solution was poured into a 5% tartaric acid solution and stirred. A 15% sodium bisulfite solution was added and the mixture was continued to be heated and stirred. The mixture was allowed to stand for stratification. The aqueous layer was extracted with a solvent. The organic layers were combined and washed with saturated brine. 3 / 4 of the solvent was removed from the organic layer under reduced pressure. 15.26 g (0.075 mol) of N,O-bis(trimethylsilyl)acetamide was added and stirred to reflux. The reaction solution was then removed to dryness. Hexane was added and stirred and heated until completely dissolved. The temperature was then slowly reduced to crystallize. The mixture was filtered and the solid was dried to obtain 56.2 g of compound II. The yield of the product was 87.3% and the purity of the product was 99.1%.

[0024] In a reaction flask, add 32.16g (0.05mol) of compound II and 100mL of dichloromethane, stir and heat, add 7.37mL (0.025mol) of tetrabutylammonium fluoride, and keep warm until the reaction is completed. Cool to room temperature, add acetic acid dropwise to quench, stir, decompress the reaction solution to dryness, add 70mL of isopropanol, stir until completely dissolved, add 5mL of dilute hydrochloric acid dropwise, keep warm and stir until the reaction is completed. Add water, stir at room temperature until a large amount of solid precipitates, filter, filter and dry to obtain a crude compound of formula I.

[0025] The crude compound of formula I was added with n-hexane, stirred and heated until completely dissolved, slowly stirred and cooled to crystallize, filtered, filtered and dried to obtain 17.72 g of ezetimibe raw material, i.e., compound of formula I, with a product yield of 86.6%, a product purity of 99.5%, and a total yield of 75.6%.

[0026] Example 2 In a reaction flask, add 35.7 g (0.1 mol) of compound III, 27.98 g (0.13 mol) of ZTM, 10.86 g (0.1 mol) of TMSCl and 200 mL of dimethyl sulfoxide, cool to -5 °C and stir to react, add 20.9 mL (0.12 mol) of diisopropylethylamine dropwise, keep warm to react until compound III reacts, then add 4.38 mL (0.04 mol) of titanium tetrachloride dropwise, keep warm until the reaction is completed.

[0027] Acetic acid was added dropwise to quench the mixture, and the mixture was stirred to room temperature. The reaction solution was poured into a 5% tartaric acid solution and stirred. A 15% sodium bisulfite solution was added and the mixture was kept warm and stirred. The mixture was allowed to stand for stratification. The aqueous layer was extracted with a solvent. The organic layers were combined and washed with saturated brine. 3 / 4 of the solvent was removed from the organic layer under reduced pressure. 15.26 g (0.075 mol) of N,O-bis(trimethylsilyl)acetamide was added and stirred to reflux. The reaction solution was then removed to dryness. Hexane was added and stirred and heated until the mixture was completely dissolved. The reaction solution was then slowly cooled for crystallization. The mixture was filtered and dried to obtain 56.22 g of compound II. The yield of the product was 87.4% and the purity of the product was 99.1%. In a reaction flask, add 32.16g (0.05mol) of compound II and 100mL of dichloromethane, stir and heat, add 10.32mL (0.035mol) of tetrabutylammonium fluoride, and keep warm until the reaction is completed. Cool to room temperature, add acetic acid to quench, stir, decompress the reaction solution to dryness, add 70mL of isopropanol, stir until completely dissolved, add 5mL of dilute hydrochloric acid, keep warm and stir until the reaction is completed. Add water, stir at room temperature until a large amount of solid precipitates, filter, filter and dry to obtain a crude compound of formula I; The crude compound of formula I was added with n-hexane, stirred and heated until completely dissolved, slowly stirred and cooled to crystallize, filtered, filtered solid and dried to obtain 17.72 g of ezetimibe raw material, i.e., compound of formula I, with a product yield of 86.6%, a product purity of 99.6%, and a total yield of 75.6%.

[0028] Example 3 In a reaction flask, add 35.7 g (0.1 mol) of compound III, 23.67 g (0.11 mol) of ZTM, 11.95 g (0.11 mol) of TMSCl and 200 mL of tetrahydrofuran, cool to -5 °C and stir to react, add 17.42 mL (0.1 mol) of diisopropylethylamine dropwise, keep warm until the compound III reacts, then add 2.19 mL (0.02 mol) of titanium tetrachloride dropwise, keep warm until the reaction is complete.

[0029] Acetic acid was added dropwise to quench the mixture, and the mixture was stirred to room temperature. The reaction solution was poured into a 5% tartaric acid solution and stirred. A 15% sodium bisulfite solution was added and the mixture was continued to be heated and stirred. The mixture was allowed to stand for stratification. The aqueous layer was extracted with a solvent. The organic layers were combined and washed with saturated brine. 3 / 4 of the solvent was removed from the organic layer under reduced pressure. 15.26 g (0.075 mol) of N,O-bis(trimethylsilyl)acetamide was added and stirred to reflux. The reaction solution was then removed to dryness. Toluene was added and stirred and heated until completely dissolved. The temperature was then slowly reduced to crystallize. The mixture was filtered and the solid was dried to obtain 56.02 g of compound II. The yield of the product was 87.1% and the purity of the product was 99.1%.

[0030] Example 4 In a reaction flask, add 35.7 g (0.1 mol) of compound III, 23.67 g (0.11 mol) of ZTM, 11.95 g (0.11 mol) of TMSCl and 200 mL of dichloromethane, cool to -5 °C and stir to react, add 17.42 mL (0.1 mol) of diisopropylethylamine dropwise, keep warm to react until compound III reacts, then add 2.19 mL (0.02 mol) of titanium tetrachloride dropwise, keep warm until the reaction is completed.

[0031] Acetic acid was added dropwise to quench the mixture, and the mixture was stirred to room temperature. The reaction solution was poured into a 5% tartaric acid solution and stirred. A 15% sodium bisulfite solution was added and the mixture was continued to be heated and stirred. The mixture was allowed to stand for stratification. The aqueous layer was extracted with a solvent. The organic layers were combined and washed with saturated brine. 3 / 4 of the solvent was removed from the organic layer under reduced pressure. 15.26 g (0.075 mol) of N,O-bis(trimethylsilyl)acetamide was added and stirred to reflux. The reaction solution was then removed to dryness. Dichloromethane was added and stirred and heated until completely dissolved. The temperature was slowly lowered for crystallization. The mixture was filtered and the solid was dried to obtain 56.02 g of compound II. The yield of the product was 87.1% and the purity of the product was 99%.

[0032] Example 5 In a reaction flask, add 32.16g (0.05mol) of compound II and 100mL of tetrahydrofuran, stir and heat, add 7.37mL (0.025mol) of tetrabutylammonium fluoride, and keep warm until the reaction is completed. Cool to room temperature, add acetic acid dropwise to quench, stir, decompress the reaction solution to dryness, add 70mL of isopropanol, stir until completely dissolved, add 5mL of dilute hydrochloric acid dropwise, keep warm and stir until the reaction is completed. Add water, stir at room temperature until a large amount of solid precipitates, filter, filter and dry to obtain a crude compound of formula I.

[0033] The crude compound of formula I was added to cyclohexane, stirred and heated until completely dissolved, slowly stirred and cooled to crystallize, filtered, filtered and dried to obtain 17.67 g of ezetimibe raw material, i.e., compound of formula I, with a product yield of 86.4% and a product purity of 99.2%.

[0034] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.

Claims

1. A green preparation process for ezetimibe API, characterized in that: The method comprises the following steps: S1: After mixing the compound of formula III, ZTM, TMSCl and reaction solvent I at below 0° C., diisopropylethylamine and titanium tetrachloride are sequentially added to the catalytic reaction system until the substrate is exhausted; S2: After quenching the reaction system, extract the reaction system and wash the organic phase, remove 3 / 4 of the solvent, then add N, O-bis(trimethylsilyl)acetamide to continue reflux reaction, and after completion, remove the solution again and cool and crystallize to obtain a compound of formula II; S3: The compound of formula II is initially reacted with reaction solvent II and tetrabutylammonium fluoride, the reaction system is desolvated and dissolved in isopropanol, dilute hydrochloric acid is added and reacted, and then crystallization is performed to obtain a crude product, and the compound of formula I, i.e., ezetimibe raw material, is obtained after recrystallization; In the step S2, after the reaction system is quenched, the reaction solution is poured into a 5% tartaric acid solution, stirred, and then a 15% sodium bisulfite solution is added to continue to be heated and stirred, and the reaction solution is allowed to stand for stratification. After the reaction solution is stratified, the aqueous layer is extracted with ethyl acetate, and the organic phases are combined and washed with saturated brine; The structural formula of the compound of formula I is: ； The structural formula of the compound of formula II is: ； The structural formula of the compound of formula III is: 。 2. A green preparation process of ezetimibe API according to claim 1, characterized in that: The reaction solvent I includes at least one of dimethyl sulfoxide, tetrahydrofuran, and dichloromethane; the reaction solvent II includes at least one of dichloromethane, tetrahydrofuran, or ethyl acetate.

3. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S1, the reaction temperature is -5~0°C.

4. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S1, the mass ratio of the compound of formula III, the ZTM, and the TMSCl is 1:1.1-1.3:1-1.

1.

5. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S1, the mass ratio of the compound of formula III, the diisopropylethylamine and the titanium tetrachloride is 1:1-1.2:0.2-0.

4.

6. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S2, acetic acid is used as a reagent to quench the reaction, and the reaction system is returned to room temperature after quenching the reaction.

7. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S2, the crystallization solution is selected from at least one of dichloromethane, toluene and n-hexane.

8. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S2, the amount of N,O-bis(trimethylsilyl)acetamide used is 75% of the mass of the compound of formula III.

9. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S4, the mass ratio of the compound of formula II to the tetrabutylammonium fluoride is 1:0.5-0.

7.

10. The green preparation process of the ezetimibe API according to claim 1, characterized in that: In the step S3, the crystallization solution is selected from at least one of n-hexane, cyclohexane and ethyl acetate.

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