CN114621299B - Preparation method of ezetimibe intermediate - Google Patents

Preparation method of ezetimibe intermediate Download PDF

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CN114621299B
CN114621299B CN202011471817.9A CN202011471817A CN114621299B CN 114621299 B CN114621299 B CN 114621299B CN 202011471817 A CN202011471817 A CN 202011471817A CN 114621299 B CN114621299 B CN 114621299B
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CN114621299A (en
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石利平
叶金星
徐春涛
程瑞华
何义
孙伟振
张维冰
李大伟
庞小召
陆梦云
王欢
施莉莉
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Jiangsu Alpha Pharmaceutical Co ltd
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Abstract

The invention relates to a preparation method of ezetimibe intermediate, which comprises the following steps: the preparation method comprises the steps of catalyzing 4- (4-fluorobenzoyl) butyric acid to carry out asymmetric hydrogenation reaction to obtain S-5- (4-fluorophenyl) -5-hydroxyvaleric acid by adopting a catalyst prepared from a metallic iridium (Ir) complex and a chiral tridentate ligand L with a ferrocene structure, and carrying out amidation reaction to obtain the intermediate of ezetimibe with high selectivity by adopting the TBS protection of the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid prepared by asymmetric hydrogenation. The catalyst of the present invention has high catalyst activity, low catalyst consumption, high selectivity, 90% yield and 90% ee value during asymmetric hydrogenation. The preparation method disclosed by the invention is mild in reaction condition, high in yield and purity, environment-friendly and free from complex post-treatment process. Wherein, the structural formula of the chiral ligand L is as follows.

Description

Preparation method of ezetimibe intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ezetimibe intermediate.
Background
Ezetimibe (Ezetimibe) is a novel hypolipidemic drug developed by the company Mr. Nalingbao and Merck, approved by the FDA in the United states in 2012 and is marketed under the chemical name (3R, 4S) -1-4- (4-fluorophenyl) -3- (3S) -3- [3- (4-fluorophenyl) -3-hydroxyphenylpropyl)]-4- (4-hydroxyphenyl) -2-azetidinone of formula C 24 H 21 F 2 NO 3 Molecular weight 409.4, its structural formula is as follows:
ezetimibe is the first selective inhibitor of cholesterol absorption approved by the FDA in the united states to act as a novel hypolipidemic agent with a different effect from other hypolipidemic agents, acting primarily on the small intestine, reducing intestinal cholesterol transport to the liver by inhibiting cholesterol absorption without affecting other nutrient absorption; the ezetimibe and statin drugs can be combined to reduce the usage amount of the statin drugs, overcome the defect that the usage amount of the statin drugs is increased but the effect is not obvious, and show a strong application prospect when the ezetimibe and the statin drugs are combined.
Whether the ezetimibe is used singly or in combination, the ezetimibe has good treatment effect on hyperlipidemia, and along with the wide use of the ezetimibe, the existing preparation method can not meet the requirements, and a new preparation method of the ezetimibe intermediate is urgently needed to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of ezetimibe intermediate on the basis of the prior art.
The technical scheme of the invention is as follows:
a preparation method of ezetimibe intermediate comprises the following steps:
(1) Uniformly mixing a metal iridium complex, a chiral ligand L and a solvent A, and then carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
the structural formula of the compound shown by the chiral ligand L is as follows:
wherein R is 1 Represents methyl, ethyl, tert-butyl, phenyl or adamantyl; r is R 2 Selected from hydrogen, methyl or ethyl;
(2) Uniformly mixing a compound I, alkali, the catalyst solution prepared in the step (1) and a solvent B, and introducing hydrogen to perform asymmetric hydrogenation reaction at 25-100 ℃ under the condition that the pressure is controlled to be 0.1-10.0MPa to prepare a compound II;
(3) Dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, uniformly mixing, and then carrying out chemical reaction at 20-40 ℃ to prepare a compound III;
(4) Dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, stirring and reacting for 1-3 hours at the temperature of-5-10 ℃ after uniformly mixing, adding a compound IV, and heating to 20-40 ℃ for chemical reaction to prepare an intermediate compound V; the specific synthetic route is as follows:
wherein, the compound I is 4- (4-fluorobenzoyl) butyric acid, the compound II is S-5- (4-fluorophenyl) -5-hydroxyvaleric acid, and the compound IV is S-4-phenyloxazolidine-2-ketone.
According to the invention, 4- (4-fluorobenzoyl) butyric acid (compound I) is used as a raw material, after a metal iridium (Ir) complex and a chiral tridentate ligand L with a ferrocene structure are subjected to chemical reaction, an asymmetric hydrogenation reaction is carried out under the condition that the obtained reaction liquid is used as a catalyst to prepare S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), and then the compound II is subjected to TBS protection and amidation reaction to prepare the ezetimibe intermediate compound V with high selectivity.
When the catalyst disclosed by the invention is used for preparing S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II) by taking 4- (4-fluorobenzoyl) butyric acid (compound I) as a raw material, the asymmetric hydrogenation reaction activity is high, the dosage of the catalyst is low, and the catalyst has the advantages of high selectivity and high yield.
In a preferred embodiment, in step (1), the iridium metal complex may be, but is not limited to, [ Ir (COD) Cl ] in the preparation of the catalyst] 2 、[Ir(COE) 2 Cl] 2 Or [ Ir (COD) OMe] 2 . The molar ratio of the metal Ir complex to the chiral ligand L may be adjusted according to practical needs, and it may be formulated that the molar ratio of the metal Ir complex to the chiral ligand L is 1:1.0 to 4.0, for example, but not limited to, 1:1, 1:1.5, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.5, 1:3.0, 1:3.5 or 1:4.0, and further preferably 1:2.0 to 3.0, particularly preferably 1:2.2, in order to obtain higher yield and cost saving.
In the step (1), the solvent A is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, solvent a is isopropanol.
In step (1), the structural formula of the compound represented by the chiral ligand L mentioned in the present invention is as follows:
wherein R is 1 Represents methyl, ethyl, tert-butyl, phenyl or adamantyl; r is R 2 Selected from hydrogen, methyl or ethyl.
In a preferred embodiment, R 1 Represents phenyl or adamantyl. R is R 2 Selected from hydrogen or methyl.
In a more preferred embodiment, the chiral ligand L is selected from the following compounds:
the chiral ligand L can be prepared according to the following synthetic route, and the chiral ligand L is specifically as follows:
when the chiral ligand is L1, the preparation method comprises the following more detailed steps:
when the chiral ligand is L2, the preparation method thereof comprises the following more detailed steps:
in the step (2), in the preparation of the compound II, the base used is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide; preferably, the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide or sodium methoxide.
In the preparation of the compound II, the solvent B is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent B is isopropanol, methanol or ethanol.
In a preferred embodiment, the molar ratio of compound I to base in the preparation of compound II may be adjusted according to the actual need, and it may be assumed that the molar ratio of compound I to base is 40 to 60:1, for example, but not limited to, 40:1, 45:1, 50:1, 55:1 or 60:1, and further preferably 45 to 50:1, particularly preferably 50:1, for obtaining higher yields and cost saving.
In a preferred embodiment, the amount of catalyst used in the preparation of compound II is determined according to the amount of iridium metal complex used in step (1), and the molar ratio of compound I to iridium metal complex may be 5-15:1, for example, but not limited to, 5:1, 8:1, 10:1, 12:1 or 15:1, more preferably 8-12:1, particularly preferably 10:1, for higher yields and cost savings.
In the step (2), the asymmetric hydrogenation is carried out in the preparation of the compound II, and the pressure during the reaction is controlled to be 1.0 to 3.0MPa, preferably 2.0MPa.
Further, the reaction temperature is controlled to 40 to 60 ℃, preferably 50 ℃.
Further, the reaction time is controlled to be 20 to 30 hours, preferably 24 hours.
In the present invention, in the step (3), in the preparation of the compound III, the reaction temperature is controlled to 25℃and the reaction time is controlled to 10 to 20 hours, for example, 12 hours. In the course of the reaction, the molar ratio of the compound II to imidazole may be adjusted according to actual needs, and it may be assumed that the molar ratio of the compound II to imidazole is 1:2 to 8, for example, but not limited to, 1:2, 1:2.5, 1:3.0, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7 or 1:8, and may further preferably be 1:3 to 5, and particularly preferably 1:4.
Further, the molar ratio of compound II to TBSCl during the reaction is 1:1.0 to 2.5, preferably 1:1.2 to 1.8, more preferably 1:1.5.
In the reaction process, the solvent C is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, solvent C is N, N-dimethylformamide.
In the step (4), the compound III prepared in the step (3) is dissolved in a solvent D, triethylamine and pivaloyl chloride are added, after being uniformly mixed, the mixture is stirred and reacted for 1 to 3 hours at the temperature of between 5 ℃ below zero and 10 ℃, then the compound IV is added, and the temperature is raised to between 20 and 40 ℃ for chemical reaction, so that an intermediate compound V is prepared.
The molar ratio of triethylamine to pivaloyl chloride prior to addition of compound IV is 1:0.5 to 1.0, preferably 1:0.7 to 0.8, more preferably 1:0.75.
In a preferred embodiment, the reaction temperature is controlled to be 0 ℃; the reaction time is 1 to 3 hours, preferably 2 hours.
After the addition of compound IV, the reaction time is controlled to be 3 to 8 hours, preferably 5 hours.
In the whole reaction process, the solvent D is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, solvent D is N, N-dimethylformamide.
For the present invention, the preparation method of ezetimibe intermediate comprises the following more detailed steps:
(1) Uniformly mixing a metal iridium complex, a chiral ligand L and a solvent A, and then carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
(2) Uniformly mixing the compound I, alkali, the catalyst solution prepared in the step (1) and the solvent B, and then introducing hydrogen to control the pressure to be between 0.1 and 10.0MPa (for example, 2 MPa), and carrying out asymmetric hydrogenation reaction at 25 to 100 ℃ (for example, 50 ℃), so as to prepare a compound II;
(3) Dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, carrying out chemical reaction at 20-40 ℃ after uniform mixing, adding saturated ammonium chloride aqueous solution for quenching after the reaction is completed, extracting with dichloromethane, concentrating an organic layer under reduced pressure, dissolving the obtained crude product by using methyl tertiary butyl ether, washing with saturated NaCl aqueous solution, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to obtain a compound III, and directly using the compound III in the next step without further purification;
(4) Dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, stirring and reacting for 1-3 hours under the condition of-5-10 ℃ (for example, 0 ℃) after uniformly mixing, adding the compound IV, heating to 20-40 ℃ for chemical reaction, adding water and methyl tertiary butyl ether for extraction after the reaction is finished, collecting an organic phase, washing with a saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an intermediate compound V.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) The invention adopts a catalyst prepared from a metal iridium (Ir) complex and a chiral tridentate ligand L with a ferrocene structure to catalyze 4- (4-fluorobenzoyl) butyric acid to carry out asymmetric hydrogenation reaction to obtain S-5- (4-fluorophenyl) -5-hydroxyvaleric acid, the catalyst has high activity, the catalyst dosage is low, the selectivity is high, the yield reaches 90%, and the ee value reaches 90%.
(2) The S-5- (4-fluorophenyl) -5-hydroxyvaleric acid prepared by asymmetric hydrogenation is subjected to TBS protection and amidation reaction to prepare the ezetimibe intermediate with high selectivity, the reaction condition is mild, the complex post-treatment process is not needed, the yield and the purity are high, and the environment is protected.
Detailed Description
The preparation method of ezetimibe intermediate of the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.
Example 1: synthesis of chiral ligand L1
(1) Compound 1 (46.6 mmol,12 g) was placed in a three-necked flask and under nitrogen blanket, dehydrated ether was added to 80mL as a solvent, the resulting mixed solution was stirred at-40℃and sec-butyllithium (35 mL, 1.6M) was slowly added dropwise thereto while stirring, followed by stirring for 20-30min. After the completion of the dropwise addition, the obtained reaction solution was transferred to 25℃and stirred for 2 hours. Then, diphenyl phosphorus chloride (20.5 g,93 mmol) was dissolved in 40mL diethyl ether, slowly added dropwise to the reaction solution obtained above, and after the addition was completed, the reaction solution obtained again was transferred to an oil bath and heated under reflux for 4 hours; the reaction was quenched with saturated aqueous sodium bicarbonate, the reaction mixture was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the yellow solid 2 was purified by column chromatography in 53% yield. 1 H NMR(400MHz，Chloroform-d)δ7.59(dq，J＝7.6，3.1，2.3Hz，2H)，7.44-7.29(m，3H)，7.23-7.10(m，5H)，4.36(q，J＝1.9Hz，1H)，4.24(d，J＝2.5Hz，1H)，4.15(qd，J＝6.8，2.6Hz，1H)，3.94(s，5H)，3.88-3.82(m，1H)，1.76(s，6H)，1.25(d，J＝6.7Hz，3H)。
(2) Compound 2 (3 g) obtained in step (1) was dissolved in 6mL of acetic anhydride, and reacted overnight at 60℃under nitrogen. After the reaction was completed, most of acetic anhydride was distilled off under reduced pressure to obtain crude product 3, which was directly used in the next step without purification and preservation at low temperature.
(3) At N 2 To a mixed solution of 40mL of THF and 40mL of methanol, 40mL of ammonia water was added under protection, and the reaction was carried out at 60℃for 4 hours. TLC detection reaction is complete, redundant solvent is removed through reduced pressure distillation, EA and water are added for layering treatment, organic phases are combined, anhydrous sodium sulfate is dried, and yellow product 4 is obtained through column chromatography, and the yield is 64%. 1 H NMR(400MHz，Chloroform-d)δ7.68-7.49(m，1H)，7.47-7.30(m，2H)，7.25(d，J＝3.5Hz，4H)，4.44(dt，J＝3.0，1.7Hz，1H)，4.27(t，J＝2.5Hz，1H)，4.21(qd，J＝6.6，2.4Hz，1H)，4.01(s，3H)，3.80-3.74(m，1H)，1.44(d，J＝6.7Hz，2H)。
(4) Compound 5 (1.08 g,4.4 mmol) was dissolved in anhydrous dichloromethane at-78deg.C under nitrogen and Tf was slowly added 2 O (1.47 g,5.2 mmol), 2, 6-lutidine (0.68 mL,5.2 mmol), after 30min of reaction, a dichloromethane solution of compound 4 (1.65 g,4 mmol) obtained in step (3) and triethylamine (1.1 mL,8 mmol) were added, the reaction was allowed to stand at 25℃until it was completed, after completion of the reaction, water quenching reaction was added, dichloromethane extraction was performed, the organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product, which was subjected to column chromatography to give 1.08g of the objective product L1 in 42% yield. 1 H NMR(400MHz，Chloroform-d)δ7.60-7.48(m，2H)，7.43-7.33(m，3H)，7.25-7.18(m，5H)，4.48(s，1H)，4.29(d，J＝2.6Hz，1H)，4.10-4.01(m，2H)，3.98(s，5H)，3.82-3.75(m，1H)，3.29(td，J＝9.0，5.3Hz，1H)，2.71(dd，J＝11.3，5.3Hz，1H)，2.38(dd，J＝11.3，9.1Hz，1H)，1.97(s，3H)，1.84-1.74(m，6H)，1.74-1.66(m，6H)，1.50(d，J＝6.6Hz，3H)，0.82(d，J＝6.4Hz，3H)。
Example 2: synthesis of ligand L2
Preparation of Compound 4 As in example 1
Compound 5 (0.78 g,4.4 mmol) was dissolved in anhydrous dichloromethane at-78deg.C under nitrogen and Tf was slowly added 2 O (1.47 g,5.2 mmol), 2, 6-lutidine (0.68 mL,5.2 mmol), after 30min of reaction, a solution of Compound 4 (1.65 g,4 mmol) in dichloromethane and triethylamine (1.1 mL,8 mmol) were added, the temperature was raised to 25℃for reaction,monitoring the reaction, adding water for quenching reaction after the reaction is completed, extracting with dichloromethane, collecting an organic phase, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, and distilling under reduced pressure to obtain a crude product, wherein 1.03g of target product L2 is obtained through column chromatography, and the yield is 45%. 1 H NMR(400MHz，Chloroform-d)δ8.02-7.67(m，2H)，7.57-7.48(m，2H)，7.48-7.42(m，1H)，7.40-7.34(m，5H)，7.27(d，J＝4.0Hz，5H)，4.63-4.35(m，1H)，4.29(t，J＝2.5Hz，1H)，4.11(dd，J＝6.6，2.9Hz，1H)，3.99(s，5H)，3.85(dd，J＝9.4，8.0Hz，1H)，3.81-3.68(m，2H)，3.51(t，J＝7.7Hz，1H)，2.79(dd，J＝11.1，4.5Hz，1H)，2.34(dd，J＝11.2，8.5Hz，1H)，1.47(d，J＝6.5Hz，3H)。
Example 3: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L1 (0.22 mmol,141 mg) were added to the reaction tube, and after air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere and reacted at 25℃for 2 hours to prepare a catalyst solution.
(2) 4- (4-fluorobenzoyl) butyric acid (Compound I,210g,1 mol), 1L of isopropanol, potassium tert-butoxide (2.24 g,20 mmol) and the catalyst solution prepared in the above step (1) were added to a hydrogen reaction vessel, and stirred uniformly. And (3) replacing the hydrogen in the reaction kettle for three times, finally flushing the hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0 MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 92%, and the ee value is 94%. 1 H NMR(400MHz，Chloroform-d)δ7.30-7.06(m，4H)，5.40(d,J＝4.9Hz,2H),4.89(dt,J＝5.1,1.1Hz,1H)，2.32-2.28(m,2H),1.81-1.64(m,3H),1.61-1.51(m,1H)。
Example 4: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L2 (0.22 mmol,126 mg) were added to a reaction tube, the air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and the mixture was reacted at 25℃for 2 hours to obtain a catalyst solutionAnd (3) liquid.
(2) 4- (4-fluorobenzoyl) butanoic acid (Compound I,210g,1 mol), 1L of isopropanol, potassium t-butoxide (2.24 g,20 mmol), and the catalyst solution prepared in step (1) above were charged into a hydrogen reactor. After stirring uniformly, replacing the hydrogen in the reaction kettle for three times, finally flushing hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0 MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 92%, and the ee value is 94%.
Example 5: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L2 (0.22 mmol,126 mg) were added to the reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and the mixture was reacted at 25℃for 2 hours to prepare a catalyst solution.
(2) To a hydrogen reactor was added 4- (4-fluorobenzoyl) butanoic acid (compound I,210g,1 mol), 1L of isopropanol, sodium t-butoxide (1.92 g,20 mmol), and the catalyst solution prepared in step (1) above. After stirring uniformly, replacing the hydrogen in the reaction kettle for three times, finally flushing hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0 MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 93%, and the ee value is 91%.
Example 6: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L2 (0.22 mmol,126 mg) were added to the reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and the mixture was reacted at 25℃for 2 hours to prepare a catalyst solution.
(2) To a hydrogen reactor was added 4- (4-fluorobenzoyl) butanoic acid (compound I,210g,1 mol), 1L of isopropanol, sodium methoxide (1.08 g,20 mmol), and the catalyst solution prepared in step (1) above. The reaction kettle is replaced by hydrogen for three times, finally, hydrogen (2.0 MPa) is flushed, the reaction is carried out for 24 hours at 50 ℃, the reduced pressure concentration is carried out, the isopropanol is recovered, and the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II) is obtained, the yield is 93%, and the ee value is 91%.
Example 7: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L2 (0.22 mmol,126 mg) were added to the reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and the mixture was reacted at 25℃for 2 hours to prepare a catalyst solution.
(2) 4- (4-fluorobenzoyl) butanoic acid (Compound I,210g,1 mol), 1L of methanol, sodium methoxide (1.08 g,22 mmol), and the catalyst solution prepared in step (1) above were charged into a hydrogen reactor. After stirring uniformly, replacing the hydrogen in the reaction kettle for three times, finally flushing hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0 MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 94%, and the ee value is 94%.
Example 8: preparation of catalyst and its catalysis of asymmetric hydrogenation of 4- (4-fluorobenzoyl) butyric acid
(1) Metal complex [ Ir (COD) Cl] 2 (0.10 mmol,70 mg) and ligand L2 (0.22 mmol,126 mg) were added to the reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and the mixture was reacted at 25℃for 2 hours to prepare a catalyst solution.
(2) To a hydrogen reactor was added 4- (4-fluorobenzoyl) butanoic acid (compound I,210g,1 mol), 1L ethanol, lithium t-butoxide (1.60 g,20 mmol), and the catalyst solution prepared in step (1) above. After stirring uniformly, replacing the hydrogen in the reaction kettle for three times, finally flushing hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0 MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 87%, and the ee value is 94%.
Example 9: preparation of ezetimibe intermediate IV from S-5- (4-fluorophenyl) -5-hydroxyvaleric acid
(1) S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (Compound II,170g,0.8 mol) prepared in example 8 was added to 1.5L DMF at 25℃followed by imidazole (217 g,3.2 mol), and after stirring well, TBSCl (180 g,1.2 mol) was added in portions, and then the reaction temperature was controlled at 25℃for 12h. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane, and the organic layer was concentrated under reduced pressure, and the obtained crude product was dissolved with methyl tert-butyl ether, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound III, which was used directly in the next step without further purification.
(2) Compound III prepared in step (1) was dissolved in 3L THF at 0deg.C, triethylamine (222 mL,1.6 mol) and pivaloyl chloride (148 mL,1.2 mol) were added, the temperature was kept constant, stirred for 2 hours, and then S-4-phenyloxazolidin-2-one (compound IV,130g,0.8 mol) was added in portions, and the temperature was raised to 25deg.C and the reaction time was 5 hours. Water and methyl tert-butyl ether were added for extraction, and the organic phase was collected, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the objective intermediate compound V335 g in 89% yield. 1 H NMR(400MHz，Chloroform-d)δ7.47-7.40(m,2H),7.38-7.29(m,2H),7.26-7.03(m,5H),5.82(t,J＝0.9Hz,1H),4.65(t,J＝0.9Hz,2H),3.57(d,J＝13.5Hz,1H),3.02(t,J＝8.0Hz,2H),1.73-1.59(m,4H),0.86(s,9H),0.15(s,6H)。
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.

Claims (10)

1. The preparation method of the ezetimibe intermediate is characterized by comprising the following steps of:
(1) Uniformly mixing a metal iridium complex, a chiral ligand L2 and a solvent A, and then carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
wherein the iridium complex is [ Ir (COD) Cl ]] 2 The molar ratio of the metal iridium complex to the chiral ligand L is 1:2.0-3.0; the solvent A is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide;
the synthetic route of the compound shown by the chiral ligand L2 is as follows:
(2) Uniformly mixing a compound I, alkali, the catalyst solution prepared in the step (1) and a solvent B, and introducing hydrogen to perform asymmetric hydrogenation reaction at 40-60 ℃ under the condition that the pressure is controlled to be 1.0-3.0MPa to prepare a compound II;
wherein the alkali is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide or sodium methoxide; the solvent B is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; the mol ratio of the compound I to the alkali is 45-50:1; the molar ratio of the compound I to the metal iridium complex is 8-12:1;
(3) Dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, uniformly mixing, and then carrying out chemical reaction at 20-40 ℃ to prepare a compound III;
wherein, the mol ratio of the compound II to the imidazole is 1:3-5; the mol ratio of the compound II to TBSCl is 1:1.2-1.8; the solvent C is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide;
(4) Dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, stirring and reacting for 1-3 hours at the temperature of 0 ℃ after uniformly mixing, adding a compound IV, and heating to 20-40 ℃ for chemical reaction to prepare an intermediate compound V;
wherein, the mol ratio of the triethylamine to the pivaloyl chloride is 1:0.7-0.8; the solvent D is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide;
the specific synthetic route is as follows:
2. the method for preparing ezetimibe intermediate according to claim 1, wherein in step (1), the molar ratio of the iridium complex to chiral ligand L is 1:2.2; the solvent A is isopropanol.
3. The method for preparing ezetimibe intermediate according to claim 1, wherein in step (2), the solvent B is isopropyl alcohol, methanol or ethanol.
4. The method for preparing ezetimibe intermediate according to claim 1, wherein in step (2), the molar ratio of compound I to base in step (2) is 50:1; the molar ratio of the compound I to the iridium complex is 10:1.
5. The method for producing ezetimibe intermediate according to claim 1, wherein in step (2), the pressure is 2.0MPa during the asymmetric hydrogenation reaction in step (2); the reaction temperature is 50 ℃; the reaction time is 20 to 30 hours.
6. The method for producing ezetimibe intermediate according to claim 5, wherein in the step (2), the reaction time is 24 hours at the time of the asymmetric hydrogenation reaction in the step (2).
7. The method for preparing ezetimibe intermediate according to claim 1, wherein in step (3), the reaction temperature is 25 ℃; the reaction time is 10 to 20 hours; the molar ratio of the compound II to the imidazole is 1:4; the molar ratio of the compound II to TBSCl is 1:1.5; the solvent C is N, N-dimethylformamide.
8. The method for preparing ezetimibe intermediate according to claim 1, wherein in step (4), the molar ratio of triethylamine to pivaloyl chloride is 1:0.75; the reaction time was 2 hours.
9. The method for preparing ezetimibe intermediate according to claim 8, wherein in step (4), the reaction time is 3 to 8 hours after adding compound IV; the solvent D is N, N-dimethylformamide.
10. The process for the preparation of ezetimibe intermediate according to claim 9, wherein in step (4), the reaction time is 5 hours after the addition of compound IV.
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JP2010083880A (en) * 2008-09-05 2010-04-15 Teijin Pharma Ltd 1-biaryl azetidinone derivative
CN104513187A (en) * 2015-01-09 2015-04-15 安润医药科技（苏州）有限公司 Ezetimibe synthesis method and Ezetimibe intermediate synthesis method
CN109293547A (en) * 2018-12-10 2019-02-01 无锡福祈制药有限公司 A new class of Ezetimibe derivative and preparation method thereof

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JP2010083880A (en) * 2008-09-05 2010-04-15 Teijin Pharma Ltd 1-biaryl azetidinone derivative
CN104513187A (en) * 2015-01-09 2015-04-15 安润医药科技（苏州）有限公司 Ezetimibe synthesis method and Ezetimibe intermediate synthesis method
CN109293547A (en) * 2018-12-10 2019-02-01 无锡福祈制药有限公司 A new class of Ezetimibe derivative and preparation method thereof

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