A method for preparing a remigipam intermediate

Abstract

The present invention provides a method for preparing a remigipam intermediate, belonging to the field of medicinal chemistry. The method provided herein utilizes asymmetric hydrogenation of a compound of Formula I in an organic solvent using a very low amount of catalyst to directly obtain a compound of Formula II with high purity and high ee value. The reaction does not require additional additives, such as large amounts of base or chiral resolution aids, resulting in good atom economy, consistent with the high efficiency and low emission characteristics of green chemistry, and easily scalable, making it an ideal method for the industrial preparation of the compound of Formula II.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for preparing a remigipam intermediate. Background Art

[0002] Rimegepant (formula below, CAS number 1289023-67-1) is a calcitonin gene-related peptide (CGRP) receptor antagonist developed by Biohaven Pharmaceutical Ireland DAC (acquired by Pfizer in 2021). It is indicated for the acute treatment of migraine with or without aura in adults and for the preventive treatment of episodic migraine in adults. The product was approved for marketing by the FDA on February 27, 2020, approved for marketing in Europe on April 25, 2022, and filed for marketing approval in China on September 6, 2022.

[0003]

[0004] The compound of formula II is a key intermediate in the synthesis of remdelin. The currently reported methods for synthesizing the compound of formula II mainly involve first synthesizing the compound of formula I and then further splitting it to obtain the compound of formula II. For example, WO2009126530 and Organic Letters (2012), 14(18), 4938-4941 disclose that the preparation of the compound of formula II requires enzyme-catalyzed reduction or transition metal-catalyzed reduction. During the enzyme-catalyzed reduction process, the two carbonyl groups of the compound of formula I are over-reduced or reduced in the wrong position, resulting in impurities shown in the following formula III or formula IV; while the transition metal-catalyzed asymmetric hydrogenation requires the use of precious metal rhodium and a ligand, binapine, which is not available on the market and has a complex synthesis process and very harsh synthesis conditions. The above reasons make this method difficult to achieve industrial production.

[0005]

[0006] Patent application CN113717103A discloses a method for obtaining a compound of Formula II by chiral reduction of a compound of Formula I using a Noyori-series catalyst in the presence of a hydrogen donor / base. However, this method requires the use of an additional reducing agent and a large amount of base, and the catalyst dosage is generally no less than 1% by mass of the compound of Formula I, resulting in poor economic efficiency. Summary of the Invention

[0007] The present invention provides a method for preparing a remegpam intermediate (i.e., a compound of Formula II). This method utilizes a simple, commercially available chiral phosphine ligand in the presence of a transition metal to perform chiral hydrogenation on a compound of Formula I. This method directly yields the target product, Compound II, with high optical purity sufficient for industrial use and an ee value exceeding 99%. Furthermore, the catalyst dosage is extremely low, and the reaction can proceed to completion with an amount as low as 0.1% by mass of the compound of Formula I.

[0008] The present invention provides a method for preparing a compound of formula II, comprising the following steps: mixing a compound of formula I, a catalyst, and a solvent, and reacting them under a H2 atmosphere to obtain a compound of formula II;

[0009]

[0010] The catalyst is shown in Formula A or Formula B:

[0011]

[0012] in, represents a bidentate phosphine ligand, wherein the bidentate phosphine ligand is one of the following ligands:

[0013]

[0014] Furthermore, the molar ratio of the compound of formula I to the catalyst is 1:(0.0001-0.020), preferably 1:(0.0005-0.012), and more preferably 1:(0.0012-0.005).

[0015] The above catalyst can be prepared in advance or generated in situ during the reaction.

[0016] When prepared in advance, the catalyst preparation method includes the following steps: mixing a bidentate phosphine ligand, a metal complex, and a solvent, and reacting to obtain a catalyst. The molar ratio of the bidentate phosphine ligand to the metal complex is (1.1-2.2):1 or (0.99-1.50):1, preferably (1.02-1.15):1. The metal complex is represented by Formula C or Formula D:

[0017]

[0018] When the compound is generated in situ during the reaction, the present invention also provides another method for preparing the compound of formula II, which comprises the following steps: mixing the compound of formula I, a bidentate phosphine ligand, a metal complex and a solvent, and reacting them under a H2 atmosphere to obtain the compound of formula II;

[0019]

[0020] The metal complex is shown in Formula C or Formula D:

[0021]

[0022] The bidentate phosphine ligand is one of the following ligands:

[0023]

[0024] Furthermore, the molar ratio of the bidentate phosphine ligand to the metal complex is (0.99-1.50):(0.5-1); preferably, the molar ratio of the bidentate phosphine ligand to the metal complex C is (0.99-1.50):0.5, preferably (1.02-1.15):0.5, and the molar ratio of the bidentate phosphine ligand to the metal complex D is (0.99-1.50):1, preferably (1.02-1.15):1;

[0025] The molar ratio of the compound of formula I to the metal complex is 1:(0.0001-0.020), preferably 1:(0.0005-0.012), and more preferably 1:(0.0012-0.005).

[0026] Furthermore, the pressure of H2 is 0.5-100 standard atmospheres, preferably 1-10 atmospheres, more preferably 1-5 atmospheres;

[0027] The reaction time is 5-72 hours, preferably 10-24 hours;

[0028] The reaction temperature is 0-140°C, preferably 10-65°C, more preferably 30-40°C.

[0029] Furthermore, the solvent is an organic solvent, and the organic solvent is preferably one or a mixture of two or more of a halogenated hydrocarbon solvent, an alcohol solvent, an ester solvent, an ether solvent, and an aromatic hydrocarbon solvent;

[0030] The mass volume ratio of the compound of formula I to the solvent is 1:(1-20) g / mL, preferably 1:(3-10) g / mL.

[0031] Furthermore, the halogenated hydrocarbon solvent is dichloromethane, the alcohol solvent is one of methanol and ethanol or a mixture of two of them, the ester solvent is ethyl acetate, the ether solvent is one of tetrahydrofuran, methyl tert-butyl ether, methyltetrahydrofuran or a mixture of two or more thereof, and the aromatic hydrocarbon solvent is toluene.

[0032] Furthermore, after the reaction is completed, the method further comprises the following steps: concentrating the reaction solution.

[0033] Furthermore, after the reaction solution is concentrated, one or more of the following post-treatment operations are further included: decolorization, adsorption, washing, crystallization, recrystallization, and column chromatography purification.

[0034] Furthermore, the eluent used in the column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate.

[0035] Furthermore, in the mixed solvent of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 2:1.

[0036] Furthermore, the present invention also provides the use of a catalyst in catalyzing the reaction of a compound of formula I in a H2 atmosphere to prepare a compound of formula II, wherein the catalyst is represented by formula A or formula B:

[0037]

[0038] in, represents a bidentate phosphine ligand, wherein the bidentate phosphine ligand is one of the following ligands:

[0039]

[0040] Utilizing the method of the present invention, after the reaction is completed, the reaction mixture is directly vacuum concentrated to remove the solvent to obtain a crude compound of formula II with high chemical purity and optical purity, which can be directly used in subsequent applications without post-treatment. Alternatively, a compound of formula II with higher chemical purity and optical purity can be obtained through post-treatment. The crude compound of formula II obtained by concentrating the reaction solution is sufficient for subsequent applications. At the highest, the chemical purity can reach more than 98%, and the optical purity can reach more than 99% ee value. In order to further improve the purity of the compound of formula II, any suitable method or method that can improve the purity of the target product can be adopted, including but not limited to decolorization, adsorption, washing, crystallization, recrystallization, etc. In some embodiments, the post-treatment includes: concentrating the reaction solution to obtain a crude compound of formula II, and then subjecting the crude product to column chromatography purification or recrystallization to obtain a compound of formula II with higher chemical purity and optical purity.

[0041] In some embodiments, the aforementioned method for preparing the compound of Formula II has an ee value of no less than 95%. In some embodiments, the aforementioned method for preparing the compound of Formula II has an ee value of no less than 97%. In some embodiments, the aforementioned method for preparing the compound of Formula II has an ee value of no less than 98%. In some embodiments, the aforementioned method for preparing the compound of Formula II has an ee value of no less than 99%.

[0042] The method provided herein directly yields high-purity, high-ee compound II by asymmetric hydrogenation of compound I in an organic solvent using minimal catalyst. The reaction requires no additional additives, such as large amounts of base or chiral resolution agents, resulting in excellent atom economy, consistent with the high efficiency and low emissions of green chemistry, and easily scalable, making it an ideal method for the industrial preparation of compound II.

[0043] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0044] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0045] The raw materials used in the present invention are all known products, which can be obtained by purchasing commercial products or preparing them by conventional methods in the art.

[0046] Unless otherwise specified, the operations of the present invention are carried out at room temperature, which refers to 25±5°C.

[0047] In the present invention, optical purity is characterized by ee value, and the calculation method of ee (enantiomeric excess) value is: ee = ([R] - [S]) / ([R] + [S]) * 100%, wherein R represents the content of R-configuration product, and S represents the content of S-configuration product.

[0048] Example 1: Preparation of the first type of catalyst

[0049] Rh(COD)2BF4 (406 mg, 1 mmol, 1 equiv) and chiral phosphine ligand (1.1 equiv) were dissolved in 40 mL of dichloromethane and stirred at room temperature for 6 hours to obtain a catalyst solution (0.025 M) which was directly used in the next step or directly used in the next step after drying.

[0050] The structure of Rh(COD)2BF4 is:

[0051] The chiral phosphine ligand is one of the following ligands:

[0052]

[0053] The first type of catalyst obtained is in,

[0054] Example 2: Preparation of the second type of catalyst

[0055] Metal complex 2 (406 mg, 1 mmol, 1 equiv) and chiral phosphine ligand (2.2 equiv) were dissolved in 40 mL of dichloromethane and stirred at room temperature for 6 hours to obtain a catalyst solution (0.025 M) which was used directly in the next step or dried and used directly in the next step.

[0056] The structure of metal complex 2 is:

[0057] The chiral phosphine ligand is one of the following ligands:

[0058]

[0059] The second type of catalyst obtained is in,

[0060]

[0061] Example 3: Preparation of compound of formula II

[0062]

[0063] Under a nitrogen atmosphere, 3.5 g of the compound of Formula I, 17.5 mg of cat01 (prepared in Example 1, in an amount of 0.5% by mass and 0.12% by mole of the compound of Formula I), and 35 mL of dichloromethane were added to a reaction kettle. The reaction kettle was then sealed, replaced with H2, and the H2 pressure was adjusted to 5 standard atmospheres. The reaction solution was heated to 40°C and stirred under these conditions for 10 hours. After the reaction was completed, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.4 g of the pure product, with a yield of 96%, a purity of 99.7%, and an ee of 99.4%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0064] Example 4: Preparation of compound of formula II

[0065] The reaction was carried out according to the method of Example 3, except that the solvent, dichloromethane, was replaced with tetrahydrofuran. After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.3 g of the pure product, with a yield of 93%, a purity of 99.4%, and an ee of 98.8%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0066] Example 5: Preparation of compound of formula II

[0067]

[0068] The reaction was carried out according to the method of Example 3, except that cat01 was replaced with cat02 (prepared in Example 1). After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.2 g of the pure product, with a yield of 90%, a purity of 99.2%, and an ee of 98.4%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0069] Example 6: Preparation of compound of formula II

[0070] The reaction was carried out according to the method of Example 5, except that dichloromethane was replaced with tetrahydrofuran. After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >97%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.1 g of the pure product, with a yield of 87%, a purity of 99.0%, and an ee of 98.0%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0071] Example 7: Preparation of compound of formula II

[0072]

[0073] The reaction was carried out according to the method of Example 3, except that cat01 was replaced with cat03 (prepared in Example 1). After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.1 g of the pure product, with a yield of 87%, a purity of 99.1%, and an ee of 98.2%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0074] Example 8: Preparation of compound of formula II

[0075] The reaction was carried out according to the method of Example 7, except that dichloromethane was replaced with tetrahydrofuran. After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.0 g of the pure product, with a yield of 85%, a purity of 98.9%, and an ee of 97.8%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0076] Example 9: Preparation of compound of formula II

[0077]

[0078] Under a nitrogen atmosphere, 3.5 g of the compound of Formula I, 175 mg of cat04 (prepared in Example 2, in an amount of 5% by mass and 1.2% by mole of the compound of Formula I), and 35 mL of dichloromethane were added to a reaction kettle. The reaction kettle was then sealed, replaced with H2, and the H2 pressure was adjusted to 5 standard atmospheres. The reaction solution was heated to 40°C and stirred under these conditions for 10 hours. After the reaction was completed, the reaction solution was sampled and analyzed by LCMS. The purity of the reaction solution was >96%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether / ethyl acetate = 2:1) to obtain 3.2 g of the pure product, with a yield of 90%, a purity of 99.0%, and an ee of 98.0%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0079] Example 10: Preparation of compound of formula II

[0080] The reaction was carried out according to the method of Example 9, except that the solvent, dichloromethane, was replaced with tetrahydrofuran. After completion of the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.1 g of the pure product, with a yield of 87%, a purity of 98.8%, and an ee of 97.6%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0081] Example 11: Preparation of compound of formula II

[0082]

[0083] The reaction was carried out according to the method of Example 9, except that the catalyst Cat04 was replaced with Cat05 (prepared in Example 2). After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.0 g of the pure product, with a yield of 85%, a purity of 98.9%, and an ee of 97.8%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0084] Example 12: Preparation of compound of formula II

[0085] The reaction was carried out according to the method of Example 11, except that the solvent, dichloromethane, was replaced with tetrahydrofuran. After completion of the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 2.9 g of the pure product, with a yield of 82%, a purity of 98.6%, and an ee of 97.2%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0086] Example 13: Preparation of compound of formula II

[0087]

[0088] The reaction was carried out according to the method of Example 9, except that the catalyst Cat04 was replaced with Cat06 (prepared in Example 2). After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 2.9 g of the pure product, with a yield of 82%, a purity of 98.3%, and an ee of 96.6%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0089] Example 14: Preparation of Compound of Formula II

[0090] The reaction was carried out according to the method of Example 13, except that the solvent, dichloromethane, was replaced with tetrahydrofuran. After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.0 g of the pure product, with a yield of 85%, a purity of 98.1%, and an ee of 96.2%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0091] Example 15: Preparation of compound of formula II

[0092]

[0093] The reaction was carried out according to the method of Example 3, except that the catalyst Cat01 was replaced with Cat07 (prepared in Example 1). After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity of >98%. The reaction solution was concentrated and purified on a silica gel column (eluent: a mixture of petroleum ether and ethyl acetate = 2:1) to obtain 3.3 g of the pure product, with a yield of 93%, a purity of 99.4%, and an ee of 98.8%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0094] Example 16: Preparation of compound of formula II

[0095] The reaction was carried out according to the method of Example 15, except that the solvent, dichloromethane, was replaced with tetrahydrofuran. After the reaction, the reaction solution was sampled and analyzed by LCMS, revealing a purity >98%. The reaction solution was concentrated and purified on a silica gel column to obtain 3.2 g of the pure product, with a yield of 90%, a purity of 99.2%, and an ee of 98.4%. [α] 20 D -35.37. 1 H-NMR (400MHz, CDCl3) δ8.67(dd,J=5.0,1.7Hz,1H),8.11(dd,J=7.7,1.9Hz,1H),7.38(dd,J=7.7,4.8Hz,1H),5.37 (bs,1H),4.96(dd,J=10.2,4.8Hz,1H),2.87-2.73(m,2H),2.51-2.45(m,1H),2.10-2.02(m,1H),1.86-1.70(m,2H). LCMS: [M+1]=178.1.

[0096] In summary, the present invention provides a method for preparing a remigipam intermediate. This method utilizes asymmetric hydrogenation of a compound of Formula I in an organic solvent using a very low amount of catalyst to directly yield a compound of Formula II with high purity and high ee. The reaction does not require additional additives, such as large amounts of base or chiral resolution aids, resulting in excellent atom economy, consistent with the high efficiency and low emission characteristics of green chemistry, and easily scalable, making it an ideal method for the industrial preparation of the compound of Formula II.

Claims

1. A method for preparing a compound of formula II, characterized in that It includes the following steps: Mixing a compound of formula I, a catalyst and a solvent, and reacting them under a H2 atmosphere to obtain a compound of formula II; The catalyst is one of the following structures:

2. The method according to claim 1, characterized in that The molar ratio of the compound of formula I to the catalyst is 1:(0.0001-0.020).

3. The method according to claim 2, characterized in that The molar ratio of the compound of formula I to the catalyst is 1:(0.0005-0.012).

4. The method according to claim 3, characterized in that The molar ratio of the compound of formula I to the catalyst is 1:(0.0012-0.005).

5. The method according to claim 1, characterized in that The pressure of H2 is 0.5-100 standard atmospheres; The reaction time is 5-72 hours; The reaction temperature is 0-140°C.

6. The method according to claim 5, characterized in that The pressure of H2 is 1-10 atmospheres; The reaction time is 10-24 hours; The reaction temperature is 10-65°C.

7. The method according to claim 6, characterized in that The pressure of H2 is 1-5 atmospheres; The reaction temperature is 30-40°C.

8. The method according to claim 1, characterized in that The solvent is an organic solvent; The mass volume ratio of the compound of formula I to the solvent is 1:(1-20) g / mL.

9. The method according to claim 8, characterized in that The organic solvent is one or a mixture of two or more of a halogenated hydrocarbon solvent, an alcohol solvent, an ester solvent, an ether solvent, or an aromatic hydrocarbon solvent; The mass volume ratio of the compound of formula I to the solvent is 1:(3-10) g / mL.

10. The method according to claim 9, characterized in that The halogenated hydrocarbon solvent is dichloromethane, the alcohol solvent is methanol, ethanol or a mixture of two thereof, the ester solvent is ethyl acetate, the ether solvent is tetrahydrofuran, methyl tert-butyl ether, methyltetrahydrofuran or a mixture of two or more thereof, and the aromatic hydrocarbon solvent is toluene.

11. The method according to any one of claims 1 to 10, characterized in that After the reaction is completed, the following step is further included: concentrating the reaction solution.

12. The method according to claim 11, characterized in that After the reaction solution is concentrated, one or more of the following post-treatment operations are further included: decolorization, adsorption, washing, crystallization, recrystallization, and column chromatography purification.

13. Use of a catalyst in catalyzing the reaction of a compound of formula I in a H2 atmosphere to prepare a compound of formula II, characterized in that: The compound of formula I is The compound of formula II is The catalyst is one of the following structures:

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