Preparation method of ezetimibe intermediate

Abstract

The invention relates to a preparation method of an ezetimibe intermediate, and belongs to the technical field of drug intermediate synthesis. In order to reduce the production of by-products and improve the product yield, the invention provides the preparation method of the ezetimibe intermediate, and the preparation method comprises the following steps: carrying out amidation reaction on a raw material 4-(4-fluorobenzoyl) butyric acid and a chiral auxiliary material (R)-4-phenyl-2-oxazolidinone in a reaction solvent under the catalysis of a phosphine oxide compound to obtain the ezetimibe intermediate. The preparation method comprises the following steps: taking ezetimibe as a raw material, removing water generated in the reaction process to obtain a compound III, carrying out addition reaction and condensation on the compound III and [4-(tert-butyldimethylsiloxy)-benzylidene]-(4-fluorophenyl)-amine under the catalysis of a titanium-based catalyst to generate a compound II, and carrying out cyclization reaction on the compound II under the catalysis of the catalyst to obtain a compound I, namely the intermediate ezetimibe. The method provided by the invention has the advantages of less and single by-product generation, high product yield, recyclable catalyst and the like.

Description

Technical Field

[0001] The invention relates to a method for preparing an ezetimibe intermediate, and belongs to the field of drug intermediate preparation. 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] In patent WO2000034240, fluorobenzene is reacted with cyclopentane dicarboxylic anhydride to obtain 4-(4-fluorobenzoyl)butyric acid, and then 4-(4-fluorobenzoyl)butyric acid is reacted with 4-phenyl-2-oxazolidinone to obtain (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone, and one of the carbonyl groups in the compound is reduced to a hydroxyl group using oxazolidinone catalytic reduction, and then condensed with an imine derivative to generate ezetimibe ring-opened product, and then cyclized under the catalysis of bistrimethylsilylacetamide and tetrabutylammonium fluoride, and the protecting group is removed to generate ezetimibe. The reaction route adopts the method of first reacting and then reducing the carbonyl group, which makes the reaction easy to produce by-products and the yield is low. Its synthesis route is as follows:

[0004]

[0005] Patent CN104892537B 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:

[0006]

[0007] 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, the reaction yield is low, etc. At the same time, the catalyst used in the reaction cannot be recycled, which further increases the production cost.

[0008] Therefore, there is an urgent need to find a synthesis method with less by-product generation, high product yield and low production cost. Summary of the invention

[0009] In view of the defects existing in the above prior art, the present invention provides a method for preparing an ezetimibe intermediate, and solves the problem of how to achieve a preparation method that reduces the generation of by-products, improves product yield, and reduces production costs.

[0010] The object of the present invention is achieved by the following technical scheme, a method for preparing an ezetimibe intermediate, the preparation method comprising:

[0011] S1: in a reaction solvent, the raw material 4-(4-fluorobenzoyl)butyric acid and the chiral auxiliary material (R)-4-phenyl-2-oxazolidinone are subjected to an amidation reaction under the catalysis of a phosphine oxide compound, and water generated during the reaction is removed to obtain compound III;

[0012] S2: Compound III and [4-(tert-butyldimethylsilyloxy)-benzylidene]-(4-fluorophenyl)-amine undergo an addition reaction condensation under the catalysis of a titanium-based catalyst to generate compound II;

[0013] S3: Compound II undergoes a cyclization reaction under the catalysis of a catalyst to obtain compound I, which is the intermediate ezetimibe.

[0014] The preparation route of compound I is:

[0015]

[0016] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in the step S1, the reaction solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and ethyl acetate.

[0017] Most preferably, the reaction solvent is N,N-dimethylformamide.

[0018] In the above-mentioned preparation method of the ezetimibe intermediate, preferably, in the step S1, the phosphine oxide compound is a catalyst containing a pentavalent phosphine, the feed mass ratio of the raw material to the phosphine oxide compound is 1:0.1-0.15, and the phosphine oxide compound is diphenyl (2-hydroxyphenylmethyl) phosphine oxide.

[0019] Most preferably, the mass ratio of the raw material to the phosphine oxide compound is 1:0.15.

[0020] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in the step S1, after adding the phosphine oxide compound, at least one of toluene and xylene is added as an initiator.

[0021] Most preferably, xylene is selected as the initiator.

[0022] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, the mass ratio of the raw material to the initiator is 1:0.06-0.1.

[0023] As the most preferred embodiment, the mass ratio of the raw material to the initiator is 1:0.1.

[0024] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in the step S1, the reaction temperature is 15 to 75°C.

[0025] Most preferably, the reaction temperature is 65°C.

[0026] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in step S2, the reaction is carried out in an alkaline environment, and at least one of DIPEA and TEA is added. Most preferably,.

[0027] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in step S2, the titanium-based catalyst is at least one of tetraisopropoxytitanium and titanium tetrachloride.

[0028] Most preferably, the titanium-based catalyst is tetraisopropoxytitanium.

[0029] In the above-mentioned method for preparing the ezetimibe intermediate, preferably, in step S3, the catalyst is at least one of tetrabutylammonium fluoride and N,O-bis(trimethylsilyl)acetamide.

[0030] Most preferably, tetrabutylammonium fluoride is used as the catalyst in step S3.

[0031] In summary, compared with the prior art, the present invention has the following advantages:

[0032] 1. In the scheme of the present invention, a phosphine oxide compound is used as a catalyst for the amidation reaction, wherein the selectivity for the hydroxyl group in the reaction can be improved without using a carbonyl protecting group, and the only by-product of the reaction is water, thereby increasing the yield of the product and reducing the difficulty of handling the by-product;

[0033] 2. In the scheme of the present invention, only a small amount of diphenyl (2-hydroxyphenylmethyl) phosphine oxide is needed to catalyze a highly selective amidation reaction, while also solving the defects of high steric hindrance and difficulty in leaving the hydroxyl group. Compared with the conventional reaction catalytic process of using 2 times the equivalent of triphenylphosphine oxide and requiring additional addition of an oxidant, the amount of catalyst added in the present application is lower, and the cost of raw materials is also reduced accordingly;

[0034] 3. In the scheme of the present invention, after testing, diphenyl (2-hydroxyphenylmethyl) phosphine oxide still exists in the waste liquid in the form of a single molecule after the reaction is completed, and can be recycled after simple separation. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the overall synthesis route of the present invention. DETAILED DESCRIPTION

[0036] 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.

[0037] Example 1

[0038] In a reaction flask, add 21g 4-(4-fluorobenzoyl)butyric acid (0.1mol), 5.06g TEA (0.05mol) and 100mL DMF, stir until completely dissolved, add 4.62g diphenyl (2-hydroxyphenylmethyl) phosphine oxide (0.015mol), heat to 65°C and stir, then add 19.56g (S)-4-phenyl-2-oxazolidinone (0.12mol) and 1.18mL xylene (0.01mol), and keep warm for 6h. Pour the reaction solution into dilute hydrochloric acid to quench, stir and separate, extract the aqueous layer, combine the organic layers and wash with 100mL saturated sodium bicarbonate solution and 100mL saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 33.44g compound III, the product yield is 94.7%, and the product purity is 99.4%.

[0039] Example 2

[0040] In a reaction bottle, add 28.25 g of compound II (0.08 mol), 29.62 g of [4-(tert-butyldimethylsilyloxy)-benzylidene]-(4-fluorophenyl)-amine (0.09 mol), 4.05 g of TEA (0.04 mol) and 120 mL of DMSO, add 5.92 mL of tetraisopropoxytitanium (0.02 mol) dropwise, and stir at room temperature for 3 h. Acetic acid was added dropwise to quench the mixture, the solution was extracted, 200 ml of ethyl acetate was added for extraction, the mixture was allowed to stand for stratification, the aqueous layer was extracted with solvent, the organic layers were combined, washed with saturated brine, 3 / 4 of the solvent was removed from the organic layer under reduced pressure, 12.71 mL of N, O-bis(trimethylsilyl)acetamide (0.075 mol) was added, and the mixture was stirred to reflux. The reaction solution was then removed to dryness, n-hexane was added, stirred and heated until completely dissolved, the temperature was slowly lowered for crystallization, the mixture was filtered, and the filtered solid was dried to obtain 47.82 g of compound II. The product yield was 87.6%, and the product purity was 99%.

[0041] Example 3

[0042] In the reaction bottle, add 34.12g of compound II (0.05mol) and 100mL of dichloromethane, stir to dissolve, heat to 45°C, add 7.37mL of tetrabutylammonium fluoride (0.025mol), and keep warm for reaction. After 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, and obtain 22.62g of compound I, with a product yield of 86.8% and a product purity of 99.5%.

[0043] Example 4

[0044] In a reaction flask, add 21g 4-(4-fluorobenzoyl)butyric acid (0.1mol), 5.06g TEA (0.05mol) and 100mL DMF, stir until completely dissolved, add 3.08g diphenyl (2-hydroxyphenylmethyl) phosphine oxide (0.01mol), heat to 65°C and stir, then add 19.56g (S)-4-phenyl-2-oxazolidinone (0.12mol) and 1.18mL xylene (0.01mol), and keep warm for 9h. Pour the reaction solution into dilute hydrochloric acid to quench, stir and separate, extract the aqueous layer, combine the organic layers and wash with 100mL saturated sodium bicarbonate solution and 100mL saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 33.37g compound III, the product yield is 94.5%, and the product purity is 99.4%.

[0045] Example 5

[0046] In a reaction flask, add 21g 4-(4-fluorobenzoyl)butyric acid (0.1mol), 5.06g TEA (0.05mol) and 100mL DMF, stir until completely dissolved, add 4.62g diphenyl (2-hydroxyphenylmethyl) phosphine oxide (0.015mol), heat to 65°C and stir, then add 19.56g (S)-4-phenyl-2-oxazolidinone (0.12mol) and 0.92mL toluene (0.01mol), and keep warm for 8h. Pour the reaction solution into dilute hydrochloric acid to quench, stir and separate, extract the aqueous layer, combine the organic layers and wash with 100mL saturated sodium bicarbonate solution and 100mL saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 33.12g compound III, the product yield is 93.8%, and the product purity is 99.4%.

[0047] Example 6

[0048] In a reaction flask, add 21g 4-(4-fluorobenzoyl)butyric acid (0.1mol), 5.06g TEA (0.05mol) and 100mL DMF, stir until completely dissolved, add 4.62g diphenyl (2-hydroxyphenylmethyl) phosphine oxide (0.015mol), heat to 65°C and stir, then add 19.56g (S)-4-phenyl-2-oxazolidinone (0.12mol) and 0.71mL xylene (0.006mol), and keep warm for 7h. Pour the reaction solution into dilute hydrochloric acid to quench, stir and separate, extract the aqueous layer, combine the organic layers and wash with 100mL saturated sodium bicarbonate solution and 100mL saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 33.23g compound III, the product yield is 94.1%, and the product purity is 99.4%.

[0049] Example 7

[0050] In a reaction bottle, add 28.25 g of compound II (0.08 mol), 29.62 g of [4-(tert-butyldimethylsilyloxy)-benzylidene]-(4-fluorophenyl)-amine (0.09 mol), 4.05 g of TEA (0.04 mol) and 120 mL of DMSO, add 2.2 mL of titanium tetrachloride (0.02 mol) dropwise, and stir at room temperature for 3 h. Acetic acid was added dropwise to quench the mixture, the solution was extracted, 200 ml of ethyl acetate was added for extraction, the mixture was allowed to stand for stratification, the aqueous layer was extracted with solvent, the organic layers were combined, washed with saturated brine, 3 / 4 of the solvent was removed from the organic layer under reduced pressure, 12.71 mL of N, O-bis(trimethylsilyl)acetamide (0.075 mol) was added, and the mixture was stirred to reflux. The reaction solution was then removed to dryness, n-hexane was added, stirred and heated until completely dissolved, the temperature was slowly lowered for crystallization, the mixture was filtered, the filtered solid was dried to obtain 47.6 g of compound II, the product yield was 87.2%, and the product purity was 98.8%.

[0051] 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 method for preparing an ezetimibe intermediate, characterized in that: The preparation method comprises: S1: in a reaction solvent, the raw material 4-(4-fluorobenzoyl)butyric acid and the chiral auxiliary material (R)-4-phenyl-2-oxazolidinone are subjected to an amidation reaction under the catalysis of a phosphine oxide compound, and water generated during the reaction is removed to obtain compound III; S2: Compound III and [4-(tert-butyldimethylsilyloxy)-benzylidene]-(4-fluorophenyl)-amine undergo an addition reaction condensation under the catalysis of a titanium-based catalyst to generate compound II; S3: Compound II undergoes a cyclization reaction under the catalysis of a catalyst to obtain compound I, i.e., the intermediate ezetimibe; The structural formula of compound III is: The structural formula of compound II is: The structural formula of compound I is:

2. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that: In the step S1, the reaction solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, and ethyl acetate.

3. The method for preparing an ezetimibe intermediate according to claim 2, characterized in that: In the step S1, the phosphine oxide compound is a catalyst containing pentavalent phosphine, the mass ratio of the raw material to the phosphine oxide compound is 1:0.1-0.15, and the phosphine oxide compound is diphenyl (2-hydroxyphenylmethyl) phosphine oxide.

4. The method for preparing an ezetimibe intermediate according to claim 3, characterized in that: In the step S1, after adding the phosphine oxide compound, at least one of toluene and xylene is added as an initiator.

5. The method for preparing an ezetimibe intermediate according to claim 4, characterized in that: The mass ratio of the raw material to the initiator is 1:0.06-0.

1.

6. The method for preparing an ezetimibe intermediate according to claim 5, characterized in that: In the step S1, the reaction temperature is 15-75°C.

7. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the reaction is carried out in an alkaline environment, and at least one of DIPEA and TEA is added.

8. The method for preparing an ezetimibe intermediate according to claim 7, characterized in that: In the step S2, the titanium-based catalyst is at least one of tetraisopropoxytitanium and titanium tetrachloride.

9. The method for preparing an ezetimibe intermediate according to claim 1, characterized in that: In the step S3, the catalyst is at least one of tetrabutylammonium fluoride and N,O-bis(trimethylsilyl)acetamide.

Images