Preparation method of ezetimibe and intermediate thereof

Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of ezetimibe and an intermediate thereof. According to the synthetic route, the chiral catalyst 4-pyrrolidinyl pyridine derivative is utilized, a beta-lactam mother ring in the molecular structure of ezetimibe is efficiently constructed, and the use of chiral prothetic groups in the process at the present stage is avoided, so that the cost of the product is reduced. The improved route is good in process stability, high in product total yield and optical purity and more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to a preparation method of ezetimibe and its intermediates. Background Art

[0002] As a novel cholesterol absorption inhibitor, ezetimibe has been widely used in clinical treatment due to its pharmaceutical characteristics such as low toxicity and high efficiency. Whether used alone or in combination, ezetimibe has good efficacy in reducing blood lipids. It was first developed by Schering-Plough Corporation, was first launched in Germany in 2002, and entered the domestic market in 2007, having broad market prospects and economic value.

[0003] Based on the huge application prospects of ezetimibe, scientists have conducted a large number of studies and improvements on the synthesis method of ezetimibe (CN100509058C / CN102850390A). Analyzing the structure, it can be seen that the main difficulties in synthesis lie in the construction of the β-lactam ring and the introduction of the S-configured side-chain hydroxyl group. The main industrial synthesis route of ezetimibe at present is as follows. This preparation method uses fluorobenzene as the starting material, first undergoes a Friedel-Crafts reaction with glutaric anhydride to generate 4-(4-fluorobenzoyl)butyric acid, then is activated with pivaloyl chloride and reacts with chiral oxazolidinone, then is asymmetrically reduced with (R)-MeCBS to obtain a chiral alcohol intermediate, and then undergoes a Mannich condensation with an imine, ring closure, hydrolysis and deprotection to finally obtain the target product ezetimibe. The key of this synthesis method is to induce the formation of the β-lactam ring through the Evans auxiliary agent (S)-4-phenyl-2-oxazolidinone. Among them, the yield of the Mannich condensation step is relatively low, generally 55-60%, but the introduction and removal of chiral groups make the cost of this route relatively high. Due to the problems mainly existing in this technical route such as low yield and poor atom economy, seeking a more efficient synthesis method to construct the β-lactam ring in the molecular structure is the key to process improvement.

[0004] Summary of the Invention

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

[0006] The technical solution of the present invention to solve the above technical problems is as follows:

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

[0008]

[0009] The specific steps are as follows:

[0010] (1) Using Compound of Formula I as the raw material to prepare the Compound of Formula II;

[0011] (2) Using Compound of Formula III as the raw material to prepare the Compound of Formula IV;

[0012] (3) Reacting the Compound of Formula II and the Compound of Formula IV to generate the Compound of Formula V;

[0013] (4) Reacting the Compound of Formula V with hydrochloric acid in an organic solvent to prepare the compound shown in Formula VI;

[0014] (5) Reacting the compound of Formula VI with borane dimethyl sulfide and a chiral catalyst to obtain ezetimibe of Formula VII.

[0015] Furthermore, the second object of the present invention is to provide a method for preparing a compound of Formula II, and the structural formula of Compound II is:

[0016]

[0017] The method for preparing the compound of Formula II includes the following steps:

[0018] Using the compound of Formula I as the raw material, reacting with tert-butyldimethylchlorosilane in an organic phase under the catalysis of an organic base, stirring at room temperature for 3 - 7 hours, and after the reaction is completed, separating and purifying to obtain the compound shown in Formula II.

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

[0020] The third object of the present invention is to provide a method for preparing a compound of Formula IV, and the structural formula of Compound IV is:

[0021]

[0022] The method for preparing the compound of Formula IV includes the following steps:

[0023] Using the compound of Formula III as the raw material, reacting with thionyl chloride in an organic phase, the reaction temperature is 35 - 40 °C, and the stirring time is 4 - 7 hours. After the reaction is completed, separating and preparing to obtain the organic phase solution of Formula IV.

[0024] Wherein the organic solvent is dichloromethane, dichloroethane, toluene, chloroform or tetrahydrofuran, preferably dichloromethane.

[0025] The fourth object of the present invention is to provide a method for preparing a compound of Formula V, and the structural formula of Compound V is:

[0026]

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

[0028] Take the organic phase solution of formula IV, add an organic base dropwise at 20 - 30°C, and keep the temperature for reaction for 1 - 2 hours. Then cool down to 0 - 10°C, add the chiral catalyst L, add the organic phase solution of formula II dropwise, and keep the temperature for reaction for 12 - 20 hours. After the reaction is completed, separate and purify to obtain the compound shown in formula V.

[0029] Wherein the organic base is triethylamine, N,N - diisopropylethylamine, pyridine or imidazole, preferably triethylamine. The preferred structural formula of the chiral catalyst L is:

[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, wash with alkali, concentrate, and recrystallize to obtain the intermediate V. The alkali washing is preferably carried out with a saturated sodium bicarbonate aqueous solution. The recrystallization preferably adopts the following steps: dissolve the crude intermediate V in an organic solvent, heat to dissolve clearly, add a poor solvent dropwise, and cool down to crystallize. The organic solvent is preferably isopropanol or ethanol, and the poor solvent is preferably water. The temperature for heating to dissolve clearly is preferably 50 - 60°C, and the temperature for cooling to crystallize is preferably 0 - 10°C.

[0034] The fifth object of the present invention is to provide a preparation method of a compound of formula VI, and the structural formula of the compound VI is:

[0035]

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

[0037] Add formula V and hydrochloric acid to the organic phase, stir at 55 - 65°C for 4 - 8 hours. After the reaction is completed, separate and prepare to obtain the compound shown in formula VI.

[0038] Wherein the organic solvent is isopropanol, ethanol, methanol or tetrahydrofuran, preferably isopropanol.

[0039] The sixth object of the present invention is to provide a preparation method of ezetimibe of formula VII, and the structural formula of ezetimibe is:

[0040]

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

[0042] Add an organic phase solution of borane dimethyl sulfide and a chiral catalyst into a reaction flask, dropwise add an organic phase solution of formula VI at 0 - 10°C. After the addition is completed, raise the temperature to 10 - 20°C and keep the temperature for reaction for 2 - 4 hours. After the reaction is completed, separate and purify to obtain the product ezetimibe of formula VII. The organic phase solution of borane dimethyl sulfide is a tetrahydrofuran solution or a toluene solution or an ether solution, preferably a tetrahydrofuran solution; the organic phase solution of formula VI is a dichloromethane solution or a tetrahydrofuran solution or a chloroform solution, preferably a dichloromethane solution; 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 invention, if there is a conflict between the Chinese naming and the structural formula of the compound, the structural formula shall prevail, except when the structural formula has obvious errors.

[0044] The beneficial effects of the present invention are as follows:

[0045] (1) There is no need to use a chiral auxiliary group, which greatly reduces the production cost, has good process stability, and is more suitable for industrial production.

[0046] (2) The product ezetimibe prepared by the present invention has a high total yield and optical purity. Description of the Drawings

[0047] Figure 1 For the 1 1H NMR spectrum of ezetimibe. Detailed Embodiments

[0048] The following examples illustrate the present invention, but do not limit the present invention. In the art, simple substitutions or improvements made by those skilled in the art to the present invention fall within the scope of the technical solutions protected by the present invention.

[0049] Example 1:

[0050] Under nitrogen protection, compound I (100 g, 0.46 mol) was added to a three-necked flask, and then dry dichloromethane (500 mL) and triethylamine (141 g, 1.39 mol) were added successively. The mixture was cooled to 5 °C. While controlling the temperature at 0 - 5 °C, tert-butyldimethylchlorosilane (84 g, 0.56 mol) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at 5 °C for 1 hour, then warmed to room temperature and stirred for another 5 hours. The reaction endpoint was monitored by TLC. After the reaction was completed, the reaction solution was washed once with 1 mol / L aqueous sodium hydroxide solution (300 mL) and then once with saturated aqueous sodium chloride solution (300 mL), and concentrated under reduced pressure to dryness to obtain a pale yellow solid of compound II, 146.3 g, with a yield of 95.6%.

[0051] Example 2:

[0052] Under nitrogen protection, compound III (150 g, 0.71 mol) and dry dichloromethane (750 mL) were added to a three-necked flask. The mixture was cooled to 5 °C. While controlling the temperature at 0 - 5 °C, thionyl chloride (110.4 g, 0.93 mol) was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 40 °C and gently refluxed with stirring for 5 hours. The reaction endpoint was monitored by TLC. After the reaction was completed, the reaction solution was washed once with saturated aqueous sodium bicarbonate solution (300 mL) and, without separation and purification, a dichloromethane solution of compound IV was obtained and directly used for the next reaction.

[0053] Example 3:

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

[0055] Example 4:

[0056] Under nitrogen protection, compound V (150 g, 0.29 mol), isopropyl alcohol (750 mL) and 2N hydrochloric acid (150 mL) were successively added to a three-necked flask. The reaction solution was heated to 60 °C and stirred for 5 hours, and the reaction end point was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness, 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 compound VI. The crude product was recrystallized with 450 mL of isopropyl alcohol to obtain compound VI as a white solid, 108.6 g, with a yield of 92.7%, an HPLC purity of 99.3%, and an ee value greater than 99.9%.

[0057] Example 5:

[0058] Under nitrogen protection, a solution of borane dimethyl sulfide in tetrahydrofuran (18.6 g, 0.25 mol, 2 mol / L), dichloromethane (300 mL) and chiral catalyst (R)-2-methyl-CBS-oxazaborolidine (3.4 g, 0.01 mol) were added to a three-necked flask. The mixture was cooled to 0 - 5 °C, and a solution of compound VI (100 g, 0.25 mol) in dichloromethane (400 mL) was slowly added dropwise. After the addition was completed, the reaction solution was heated to 15 °C and stirred for another 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 then 1 mol / L dilute hydrochloric acid (300 mL) was added. The mixture was stirred and allowed to stand for layer separation. The organic phase was washed once with saturated sodium chloride aqueous 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, with a yield of 86.0%, an HPLC purity of 99.8%, and an optical purity of 99.8%.

[0059] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention.

Claims

1. A preparation method of ezetimibe, characterized in that, the preparation method is as follows: The specific steps are as follows: (1) Using the compound of formula I as a raw material to prepare the compound of formula II; (2) Using the compound of formula III as a raw material to prepare the compound of formula IV; (3) Reacting the compound of formula II and the compound of formula IV to generate the compound of formula V; (4) Reacting the compound of formula V with hydrochloric acid in an organic solvent to prepare the compound shown in formula VI; (5) Reacting the compound of formula VI with borane dimethyl sulfide and a chiral catalyst to obtain ezetimibe of formula VII.

2. The preparation method according to claim 1, characterized in that, the specific operation of the step (1) is as follows: Using the compound of formula I as a raw material, reacting with tert-butyldimethylchlorosilane in an organic phase under the catalysis of an organic base, stirring and reacting at room temperature, 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, in the step (1), the organic phase 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 the step (2) is as follows: Using the compound of formula III as a raw material, reacting with thionyl chloride in an organic phase, the reaction temperature is 35 - 40 °C, the stirring time is 4 - 7 hours, after the reaction is completed, separating and preparing to obtain the organic phase solution of formula IV.

5. The preparation method according to claim 4, characterized in that, in the 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, the specific operation of the step (3) is as follows: Taking the organic phase solution of formula IV, dropping an organic base at 20 - 30 °C, keeping warm and reacting for 1 - 2 hours. Then cooling to 0 - 10 °C, adding a chiral catalyst L, dropping the organic phase solution of formula II, keeping warm and reacting for 12 - 20 hours, after the reaction is completed, separating and purifying to obtain the compound shown in formula V.

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

8. The preparation method according to claim 6, characterized in that, in the step (3), the molar ratio of the chiral catalyst L to the compound of formula II is 0.01 - 0.

05.

9. The preparation method according to claim 6, characterized in that, in the step (3), the organic phase of the formula II is selected from one of dichloromethane, dichloroethane, toluene, chloroform and tetrahydrofuran.

10. The preparation method according to claim 6, characterized in that, in the step (3), the preparation method of the compound of formula V adopts the following post-treatment steps: After the reaction is completed, washing with alkali, concentrating, and recrystallizing to obtain the compound of formula V.

11. The preparation method according to claim 10, characterized in that, In the post-treatment step of the preparation method of the compound of formula V, saturated sodium bicarbonate aqueous solution is used for alkali washing; the recrystallization is carried out by the following steps: the crude product of the compound of formula V is dissolved in an organic solvent, heated to dissolve clearly, a poor solvent is added dropwise, and then 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 clearly is 50-60 °C, and the temperature for cooling to crystallize is 0-10 °C.

12. According to the preparation method described in claim 1, it is characterized in that the specific operation of the step (4) is as follows: formula V and hydrochloric acid are added to an organic solvent, and stirred at 55-65 °C for 4-8 hours. After the reaction is completed, the compound shown in formula VI is separated and prepared; the organic solvent is: isopropanol, ethanol, methanol or tetrahydrofuran.

13. According to the preparation method described in claim 1, it is characterized in that in step (5), the compound of formula VI reacts with borane dimethyl sulfide and a chiral catalyst to obtain ezetimibe of formula 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 formula VI is added dropwise at 0-10 °C. After the addition is completed, the temperature is raised to 10-20 °C and the reaction is kept for 2-4 hours. After the reaction is completed, the product ezetimibe of formula VII is separated and purified; the organic phase solution of borane dimethyl sulfide is a tetrahydrofuran solution or a toluene solution or an ether solution, the organic phase solution of formula VI is a dichloromethane solution or a tetrahydrofuran solution or a chloroform solution, and the chiral catalyst is (R)-2-methyl-CBS-oxazaborole or (R)-2-butyl-CBS-oxazaborole or (R)-2-phenyl-CBS-oxazaborole.

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