A process for the preparation of ezetimibe and intermediates thereof

Abstract

The present application relates to the field of drug synthesis, and more particularly to a preparation method of ezetimibe and intermediates thereof. The synthetic route of the present application utilizes a chiral catalyst 4-pyrrolidinyl pyridine derivative to efficiently construct a beta-lactam parent ring in the molecular structure of ezetimibe, thereby avoiding the use of chiral auxiliary groups in the current process and reducing the cost of the product. The improved route has good process stability, high product total yield and optical purity, and is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of ezetimibe and intermediates thereof. BACKGROUND

[0002] Ezetimibe, as a new type of cholesterol absorption inhibitor, has been widely used in clinical treatment due to its low toxicity and high efficiency. Ezetimibe has good curative effect on reducing blood lipids whether used alone or in combination. It was first developed by Schering-Plough Corporation, and was first marketed in Germany in 2002 and entered the domestic market in 2007, and has broad market prospects and economic value.

[0003] Based on the huge application prospect of ezetimibe, scientists have made a lot of research and improvement on the synthesis method of ezetimibe (CN100509058C / CN102850390A). It can be known from the analysis of the structure that the difficulties in synthesis mainly lie in the construction of the beta-lactam mother ring and the introduction of the S configuration side chain hydroxyl. At present, the main industrial synthesis route of ezetimibe is as shown in the following, which is prepared from fluorobenzene as a starting material, first subjected to a Friedel-Crafts reaction with glutaric anhydride to generate 4-(4-fluorobenzoyl) butyric acid, then activated with pivaloyl chloride and reacted with a chiral oxazolidinone, followed by asymmetric reduction with (R)-MeCBS to obtain a chiral alcohol intermediate, then subjected to Mannich condensation with an imine, ring closure, hydrolysis and deprotection to finally obtain the target product ezetimibe. The key of the synthesis method is to induce the generation of the beta-lactam mother ring through the Evans auxiliary agent (S)-4-phenyl-2-oxazolidinone, wherein the yield of the Mannich condensation step is relatively low, generally 55-60%, but the introduction and removal of the chiral group make the cost of the route relatively high. Based on the problems of the technical route, such as low yield and poor atom economy, it is the key to process improvement to seek a more efficient synthesis method to construct the beta-lactam mother ring in the molecular structure.

[0004] SUMMARY

[0005] In order to overcome the problems of the existing industrial route, such as low yield, poor atom economy and high production cost, the synthesis route of the present application has short steps, mild reaction conditions and easy operation, and the total yield and purity of the prepared product are high, which is suitable for industrial production.

[0006] The technical scheme for solving the above technical problems of the present application is as follows:

[0007] The present application discloses a preparation method of ezetimibe, and the preparation method is as follows:

[0008]

[0009] The specific steps are as follows:

[0010] (1) the compound of formula II is prepared from the compound of formula I;

[0011] (2) the compound of formula IV is prepared from the compound of formula III;

[0012] (3) the compound of formula V is prepared by reacting the compound of formula II and the compound of formula IV;

[0013] (4) the compound of formula VI is prepared by reacting the compound of formula V with hydrochloric acid in an organic solvent;

[0014] (5) the compound of formula VII is prepared by reacting the compound of formula VI with borane dimethyl sulfide and a chiral catalyst.

[0015] Further, a second object of the present application is to provide a preparation method of the compound of formula II.

[0016]

[0017] The preparation method of the compound of formula II comprises the following steps:

[0018] The compound of formula II is prepared by reacting the compound of formula I with tert-butyldimethylsilyl chloride in an organic phase under the catalysis of an organic base, stirring at room temperature for 3-7 hours, and then separating and purifying the compound of formula II after the reaction is completed.

[0019] The organic solvent is dichloromethane, dichloroethane, chloroform, tetrahydrofuran or 2-methyltetrahydrofuran, and dichloromethane is preferred; and the organic base is triethylamine, pyridine or imidazole, and triethylamine is preferred.

[0020] A third object of the present application is to provide a preparation method of the compound of formula IV.

[0021]

[0022] The preparation method of the compound of formula IV comprises the following steps:

[0023] The compound of formula IV is prepared by reacting the compound of formula III with dichlorosulfoxide in an organic phase, stirring for 4-7 hours at a reaction temperature of 35-40 ℃, and then separating and preparing the organic phase solution of formula IV after the reaction is completed.

[0024] The organic solvent is dichloromethane, dichloroethane, toluene, chloroform or tetrahydrofuran, and dichloromethane is preferred.

[0025] A fourth object of the present application is to provide a preparation method of the compound of formula V.

[0026]

[0027] The preparation method of the compound of formula V comprises the following steps:

[0028] The organic phase solution of formula IV is taken, and an organic base is added dropwise at 20-30°C, and the reaction is kept for 1-2 hours. Then the temperature is lowered to 0-10°C, a chiral catalyst L is added, and an organic phase solution of formula II is added dropwise, and the reaction is kept for 12-20 hours. After the reaction is completed, the compound of formula V is separated and purified.

[0029] The organic base is triethylamine, N,N-diisopropyl ethylamine, pyridine or imidazole, preferably triethylamine. The chiral catalyst L preferably has the following structure:

[0030]

[0031] In the preparation method of the compound of formula V, the molar ratio of the chiral catalyst to formula II is preferably 0.01-0.05.

[0032] The organic phase of formula II is selected from one of dichloromethane, dichloroethane, toluene, chloroform and tetrahydrofuran, preferably dichloromethane.

[0033] The preparation method of the intermediate V preferably adopts the following post-treatment steps: after the reaction is completed, the reaction solution is washed with a base, concentrated, and recrystallized to obtain the intermediate V. The base washing preferably uses a saturated sodium bicarbonate aqueous solution. The recrystallization preferably adopts the following steps: the crude intermediate V is dissolved in an organic solvent, heated to dissolve, dropwise added with a poor solvent, and cooled to crystallize. The organic solvent is preferably isopropyl alcohol or ethanol, and the poor solvent is preferably water. The heating temperature for dissolving is preferably 50-60°C, and the cooling temperature for crystallization is preferably 0-10°C.

[0034] A fifth object of the present application is to provide a preparation method of a compound of formula VI, and the structural formula of the compound VI is as follows:

[0035]

[0036] The preparation method of the compound of formula VI comprises the following steps:

[0037] In the organic phase, formula V and hydrochloric acid are added, and stirred at 55-65°C for 4-8 hours. After the reaction is completed, the compound of formula VI is separated and prepared.

[0038] The organic solvent is isopropyl alcohol, ethanol, methanol or tetrahydrofuran, preferably isopropyl alcohol.

[0039] A sixth object of the present application is to provide a preparation method of ezetimibe of formula VII, and the structural formula of the ezetimibe is as follows:

[0040]

[0041] The preparation method of the compound of formula VII comprises the following steps:

[0042] The organic phase solution of borane dimethyl sulfide and chiral catalyst are added into a reaction bottle, the organic phase solution of formula VI is added dropwise at 0-10 DEG C, after the dropping, the temperature is increased to 10-20 DEG C, and the reaction is kept for 2-4 hours, after the reaction is completed, the product ezetimibe of formula VII is obtained after separation and purification. The organic phase solution of borane dimethyl sulfide is tetrahydrofuran solution or toluene solution or diethyl ether solution, preferably tetrahydrofuran solution; the organic phase solution of formula VI is dichloromethane solution or tetrahydrofuran solution or chloroform solution, preferably dichloromethane solution; and the chiral catalyst is (R)-2-methyl-CBS-oxazaborolidine or (R)-2-butyl-CBS-oxazaborolidine or (R)-2-phenyl-CBS-oxazaborolidine, preferably (R)-2-methyl-CBS-oxazaborolidine.

[0043] In the present application, the Chinese name of the compound conflicts with the structural formula, and the structural formula is used as the criterion; except for the structural formula with obvious errors.

[0044] The present application has the following advantages:

[0045] (1) The chiral auxiliary is not needed, the production cost is greatly reduced, the process stability is good, and the industrial production is more suitable.

[0046] (2) The total yield and optical purity of the product ezetimibe prepared by the present application are high. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 The present application is the preparation method of ezetimibe 1 H NMR spectrum. DETAILED DESCRIPTION

[0048] The present application is described below by combining with examples, but the present application is not limited by the examples. In the art, the simple replacement or improvement of the present application by the skilled person is within the technical solution protected by the present application.

[0049] Example 1:

[0050] Under nitrogen protection, formula I (100 g, 0.46 mol) was added into a three-necked flask, then dry dichloromethane (500 mL) and triethylamine (141 g, 1.39 mol) were added in turn, the mixture was cooled to 5 °C. The temperature was controlled at 0-5 °C, and then the reaction solution was slowly added with dropwise tert-butyl dimethyl chlorosilane (84 g, 0.56 mol). After the dropwise addition was completed, the mixture was continuously stirred at 5 °C for 1 hour, then the temperature was increased to room temperature, and the mixture was continuously stirred for 5 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was washed with 1 mol / L sodium hydroxide aqueous solution (300 mL) once, and then washed with saturated sodium chloride aqueous solution (300 mL) once. The mixture was concentrated under reduced pressure to dryness to obtain formula II as a light yellow solid, 146.3 g, with a yield of 95.6%.

[0051] Example 2:

[0052] Under nitrogen protection, formula III (150 g, 0.71 mol) and dry dichloromethane (750 mL) were added into a three-necked flask, and the mixture was cooled to 5 °C. The temperature was controlled at 0-5 °C, and then the reaction solution was slowly added with dropwise dichlorosulfoxide (110.4 g, 0.93 mol). After the dropwise addition was completed, the temperature was increased to 40 °C, and the mixture was stirred for 5 hours under reflux. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate aqueous solution (300 mL) once. The dichloromethane solution of formula IV was obtained without isolation and purification, and was directly used in the next reaction.

[0053] Example 3:

[0054] Under nitrogen protection, the dichloromethane solution of formula IV (100 g, 0.44 mol) was added into a three-necked flask. The temperature was controlled at 20-25 °C, and then triethylamine was slowly added dropwise. After the dropwise addition was completed, the mixture was continuously stirred at 25 °C for 1 hour. Then the mixture was cooled to 5 °C, and then chiral catalyst (S)-(-)-4-pyrrolidine pyridyl L (pentamethylcyclopentadienyl) iron (1.65 g, 4.4 mmol) was added. The temperature was controlled at 0-5 °C, and then the dichloromethane solution of formula II (144.1 g of formula II was dissolved in 430 mL of dichloromethane, 0.44 mol) was slowly added dropwise. After the dropwise addition was completed, the temperature was increased to room temperature, and the mixture was continuously stirred for 16 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate aqueous solution (300 mL) once, and then concentrated under reduced pressure to dryness to obtain the crude product of formula V. Ethanol (1200 mL) was added into the crude product, and the temperature was increased to 55 °C. The mixture was stirred until it was clear, and then deionized water (2400 mL) was added dropwise at the temperature. After the dropwise addition was completed, the temperature was decreased to 5 °C, and then the mixture was filtered and dried to obtain formula V as a light yellow solid, 179.2 g, with a yield of 78.5%, an HPLC purity of 98.5%, and an ee value of greater than 99.9%.

[0055] Example 4:

[0056] Under nitrogen protection, formula V (150 g, 0.29 mol), isopropyl alcohol (750 mL) and 2N hydrochloric acid (150 mL) were added into a three-neck flask in turn. The reaction liquid was warmed to 60°C, and stirred for 5 hours, and the reaction end point was monitored by TLC. After the reaction was completed, the reaction liquid was cooled to room temperature, concentrated to dryness, and ethyl acetate (1050 mL) and water (450 mL) were added, and the organic phase was separated by stirring. The organic phase was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product of formula VI. The crude product was recrystallized with 450 mL of isopropyl alcohol to obtain formula VI as a white solid, 108.6 g, yield 92.7%, HPLC purity 99.3%, ee value greater than 99.9%.

[0057] Example 5:

[0058] Under nitrogen protection, 2 mol / L borane dimethyl sulfide in tetrahydrofuran solution (18.6 g, 0.25 mol), dichloromethane (300 mL) and chiral catalyst (R)-2-methyl-CBS-oxazaborolidine (3.4 g, 0.01 mol) were added into a three-neck flask. The mixture was cooled to 0-5°C, and a solution of formula VI (100 g, 0.25 mol) in dichloromethane (400 mL) was slowly added dropwise. After the dropwise addition was completed, the reaction liquid was warmed to 15°C, and stirring was continued for 2 hours, and the reaction end point was monitored by TLC. After the reaction was completed, 40 mL of methanol was added to quench the reaction, and 1 mol / L dilute hydrochloric acid (300 mL) was further added. The layers were separated after stirring and standing, and the organic phase was washed once with saturated aqueous sodium chloride solution (300 mL), and concentrated to dryness under reduced pressure to obtain the crude product of ezetimibe. The crude product was recrystallized with isopropyl alcohol / water (300 mL:200 mL) to obtain the final product ezetimibe as a white solid, 86.4 g, yield 86.0%, HPLC purity 99.8%, optical purity 99.8%.

[0059] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the inventive concept, several modifications and improvements can be made, which are all within the scope of the present application.

Claims

1. A method for preparing ezetimibe, characterized in that, The preparation method is as follows: The specific steps are as follows: (1) Formula I is used to prepare compound II from raw materials; (2) Formula III is used as a raw material to prepare compound IV; (3) Compound II and compound IV react to generate compound V; the specific operation of step (3) is as follows: take the organic phase solution of formula IV, add an organic base dropwise at 20-30℃, and keep the reaction at this temperature for 1-2 hours; then cool down to 0-10℃, add chiral catalyst L, add the organic phase solution of formula II dropwise, keep the reaction at this temperature for 12-20 hours, and after the reaction is completed, separate and purify to obtain the compound shown in formula V; the structural formula of the chiral catalyst L is: (4) Compound V was reacted with hydrochloric acid in an organic solvent to prepare the compound shown in Formula VI; (5) The reaction of compound VI with boron dimethyl sulfide and a chiral catalyst yields ezetimibe compound VII.

2. The preparation method according to claim 1, characterized in that, The specific operation of step (1) is as follows: using Formula I as raw material, reacting it with tert-butyldimethylchlorosilane in an organic phase under the catalysis of an organic base, stirring the reaction at room temperature, and after the reaction is completed, separating and purifying to obtain the compound shown in Formula II.

3. The preparation method according to claim 2, characterized in that, The organic phase in step (1) is selected from one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran and 2-methyltetrahydrofuran, and the organic base is selected from one of triethylamine, pyridine or imidazole.

4. The preparation method according to claim 1, characterized in that, The specific operation of step (2) is as follows: using formula III as raw material, react with thionyl chloride in an organic phase at a reaction temperature of 35-40℃ and a stirring time of 4-7 hours. After the reaction is completed, separate and prepare an organic phase solution of formula IV.

5. The preparation method according to claim 4, characterized in that, In step (2), the organic phase is selected from one of dichloromethane, dichloroethane, toluene, chloroform and tetrahydrofuran.

6. The preparation method according to claim 1, characterized in that, In step (3), the organic base is selected from one of triethylamine, N,N-diisopropylethylamine, pyridine and imidazole.

7. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of the chiral catalyst L to the compound of formula II is 0.01-0.

05.

8. The preparation method according to claim 1, characterized in that, In step (3), the organic phase of formula II is selected from one of dichloromethane, dichloroethane, toluene, chloroform and tetrahydrofuran.

9. The preparation method according to claim 1, characterized in that, In step (3), the preparation method of compound V adopts the following post-processing steps: after the reaction is completed, the compound is washed with alkali, concentrated, and recrystallized to obtain compound V.

10. The preparation method according to claim 9, characterized in that, In the post-processing steps of the preparation method of compound V, the alkaline washing uses a saturated sodium bicarbonate aqueous solution; the recrystallization adopts the following steps: the crude compound V is dissolved in an organic solvent, heated to dissolve completely, a poor solvent is added dropwise, and the mixture is cooled to crystallize; the organic solvent is selected from isopropanol or ethanol, and the poor solvent is selected from water; the temperature for heating to dissolve completely is 50-60℃, and the temperature for cooling to crystallize is 0-10℃.

11. The preparation method according to claim 1, characterized in that, The specific operation of step (4) is as follows: add formula V and hydrochloric acid to an organic solvent, stir at 55-65℃ for 4-8 hours, and after the reaction is completed, separate and prepare the compound shown in formula VI; the organic solvent is: isopropanol, ethanol, methanol or tetrahydrofuran.

12. The preparation method according to claim 1, characterized in that, Step (5) involves reacting compound VI with borane dimethyl sulfide and a chiral catalyst to obtain ezetimibe compound VII. Specifically, the organic phase solution of borane dimethyl sulfide and the chiral catalyst are added to a reaction flask, and the organic phase solution of compound VI is added dropwise at 0-10°C. After the addition is complete, the temperature is raised to 10-20°C and the reaction is maintained for 2-4 hours. After the reaction is completed, the product ezetimibe compound VII is obtained by separation and purification. The organic phase solution of borane dimethyl sulfide is a tetrahydrofuran solution, a toluene solution, or a diethyl ether solution. The organic phase solution of compound VI is a dichloromethane solution, a tetrahydrofuran solution, or a chloroform solution. The chiral catalyst is (R)-2-methyl-CBS-oxazolium borane or (R)-2-butyl-CBS-oxazolium borane or (R)-2-phenyl-CBS-oxazolium borane.

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