Industrial preparation method of high optical purity remegipam intermediate

Abstract

The present invention provides an industrial preparation method of a high optical purity remegipam intermediate. Specifically, the present invention provides a chiral separation method of an isomeric mixture of a compound of formula III, wherein R is H or a hydroxyl protecting group; and the method comprises the steps of: (a) using optically active camphorsulfonic acid as a resolving agent, chiral separation of the isomeric mixture of the compound of formula III, thereby obtaining a single configuration of the compound of formula III or its camphorsulfonic acid salt; wherein the optically active camphorsulfonic acid is L-camphorsulfonic acid or D-camphorsulfonic acid. The method of the present invention has mild reaction conditions, simple operation, high yield, especially high total yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to an industrial preparation method of an optically pure remigipam intermediate. Background Art

[0002] NURTEC TM ODT (Rimegepant) is an effective, selective, competitive, orally active calcitonin gene-related peptide (CGRP) antagonist used for the acute treatment of migraine in adults. On February 27, 2020, it was approved for marketing by the U.S. Food and Drug Administration (FDA).

[0003] CN102656159A discloses two methods for synthesizing Remigipam, and the process routes are shown in Route 1 and Route 2 respectively:

[0004]

[0005] (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cyclohepta[b]pyridin-5-one (compound of formula II) is the molecular core skeleton of remegipam and is a key intermediate for synthesizing the starting materials of the above-mentioned routes 1 and 2. Its synthesis method has only been reported in two literatures.

[0006]

[0007] WO2009126530 reported the selective reduction of cyclohepta[b]pyridine-5,9-dione to prepare hydroxypyridone by enzyme preparation:

[0008]

[0009] WO2009126530 does not disclose specific reaction conditions, nor does it disclose the ratio of (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one to the compound of formula II in the product. However, based on the method disclosed therein for converting (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one into the compound of formula II, it can be inferred that the ratio of (9S)-6,7,8,9-tetrahydro-9-hydroxy-5H-cycloheptan[b]pyridine-5-one is not low, which indicates that the selectivity of the enzymatic reduction to obtain the compound of formula II is not high.

[0010] In 2012, David K. Lealy et al. (Organic Letters (2012), 14 (18), 4938-4941) reported two asymmetric reduction methods for compounds of formula II: using ketone reductase catalyst ESKRED-119 and metal catalyst Rh-(R-Binapine)(COD)BF4, the ee values ​​of the obtained reaction products were 98% and above 99.9%, respectively. The reaction formula is as follows.

[0011]

[0012] Ketoreductase catalyst ESKRED-119 has few suppliers on the market and is expensive. Metal catalyst Rh-(R-Binapine)(COD)BF4 is not available on the market, and the ligand R-Binapine used in the synthesis of Rh-(R-Binapine)(COD)BF4 is also difficult to prepare. The preparation method has very harsh reaction conditions (such as requiring a hydrogen pressure of up to 100 psi), and uses a dangerous reagent hexachlorodisilane, see Angew.Chem.Int.Ed.2003,42,3509.

[0013] In summary, there is an urgent need in the art to develop a new method for preparing a compound of formula II or its derivatives (such as the starting materials of routes 1 and 2) with high chiral purity that is low-cost, easy to operate, and suitable for industrial production. Summary of the invention

[0014] The purpose of the present invention is to provide a novel method for preparing compound II or its derivatives with high chiral purity, which is low-cost, easy to operate and suitable for industrial production.

[0015] In a first aspect of the present invention, a method for chiral separation of an isomeric mixture of a compound of formula III is provided.

[0016]

[0017] Wherein, R is H or a hydroxyl protecting group;

[0018] Furthermore, the method comprises the steps of:

[0019] (a) using optically active camphorsulfonic acid as a resolving agent to chiral resolve the isomeric mixture of the compound of formula III, thereby obtaining a single-configuration compound of formula III or its camphorsulfonic acid salt; wherein the optically active camphorsulfonic acid is L-camphorsulfonic acid or D-camphorsulfonic acid.

[0020] In another preferred embodiment, the isomer mixture of the compound of formula III is a mixture including any isomers of the compound of formula III.

[0021] In another preferred embodiment, the isomeric mixture of the compound of formula III is a mixture comprising a compound of formula V (as shown below) and its isomers.

[0022] In another preferred embodiment, in the isomeric mixture of the compound of formula III, the optical purity of any single configuration of the compound of formula III is ≥50%; preferably, ≥75%; most preferably, ≥85%.

[0023] In another preferred embodiment, in the isomeric mixture of the compound of formula III, the optical purity of any single configuration of the compound of formula III is ≤95%; preferably, ≤90%.

[0024] In another preferred embodiment, the hydroxyl protecting group is selected from the following group: TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethyl), Me (methyl), Et (ethyl), Pr (propyl), or Bn (benzyl), CH3CO (acetyl), CH3CH2CO (propionyl), PhCO (benzoyl), CH3SO2 (methylsulfonyl), PhSO2 (phenylsulfonyl).

[0025] In another preferred embodiment, the propyl group includes: n-Pr (normal-propyl) or i-Pr (isopropyl).

[0026] In another preferred embodiment, the single-configuration compound of formula III is a compound of formula V

[0027]

[0028] Wherein, R is H or a hydroxyl protecting group.

[0029] In another preferred embodiment, when R is H, the compound of formula V is as shown in formula II

[0030]

[0031] In another preferred embodiment, the camphorsulfonate of the compound of formula III in a single configuration is a compound of formula IV

[0032]

[0033] Wherein, R is H or a hydroxyl protecting group, and It is of L configuration or D configuration.

[0034] In another preferred embodiment, when R is H, the compound of formula IV is as shown in formula IV-a

[0035]

[0036] In another preferred embodiment, in step (a), the molar ratio of the isomer mixture of the compound of formula III to the optically active camphorsulfonic acid is 1:(0.5-2), preferably, 1:(0.9-1.1).

[0037] In another preferred embodiment, step (a) comprises the steps of:

[0038] (a1) reacting the compound of formula III with optically active camphorsulfonic acid to form a salt, thereby obtaining a mixture containing camphorsulfonic acid salt; and

[0039] (a2) separating the mixture obtained in step (a1) to obtain a camphorsulfonate salt of the compound of formula III having a single configuration; and

[0040] Optionally, (a3) ​​liberating the camphorsulfonate of the single-configuration compound of formula III obtained in step (a2) in the presence of a base to obtain a single-configuration compound of formula III.

[0041] In another preferred embodiment, in step (a1), the salt-forming reaction is carried out in an organic solvent 1; preferably, the organic solvent 1 is selected from the following group: a halogenated hydrocarbon solvent (preferably, a C1-3 halogenated hydrocarbon solvent, more preferably, dichloromethane), an alcohol solvent (preferably, a C1-3 alcohol solvent, more preferably, methanol and / or ethanol), a ketone solvent (preferably, a C3-6 ketone solvent, more preferably, acetone and / or butanone), an ester solvent (preferably, a C2-6 ester solvent, more preferably, ethyl acetate), an ether solvent (preferably, a C2-6 ether solvent, more preferably, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, or a combination thereof), an aromatic solvent (preferably, toluene), or a combination thereof; preferably, a halogenated hydrocarbon solvent; more preferably, dichloromethane.

[0042] In another preferred embodiment, in step (a1), the mass volume (g:mL) ratio of the compound of formula III to the organic solvent 1 is 1:(1-20); preferably, 1:(2-15).

[0043] In another preferred embodiment, in step (a2), the separation treatment is recrystallization or slurrying.

[0044] In another preferred embodiment, in step (a2), the solvent used for the separation treatment (such as recrystallization or slurrying) is an organic solvent 2, and the organic solvent 2 is selected from the following group: a halogenated hydrocarbon solvent (preferably, a C1-3 halogenated hydrocarbon solvent, more preferably, dichloromethane), an alcohol solvent (preferably, a C1-3 alcohol solvent, more preferably, methanol and / or ethanol), a ketone solvent (preferably, a C3-6 ketone solvent, more preferably, acetone and / or butanone), an ester solvent Preferably, the solvent is a mixed solvent of an ester solvent and an alcohol solvent or a mixed solvent of a ketone solvent and an ether solvent; More preferably, the solvent is a mixed solvent of ethyl acetate and methanol or a mixed solvent of methyl tert-butyl ether and acetone.

[0045] In another preferred embodiment, the organic solvent 2 is a mixed solvent of an ester solvent and an alcohol solvent, and the volume ratio of the ester solvent to the alcohol solvent is: (3-15):1.

[0046] In another preferred embodiment, the organic solvent 2 is a mixed solvent of a ketone solvent and an ether solvent, and the volume ratio of the ester solvent to the alcohol solvent is: 1:(3-15).

[0047] In another preferred embodiment, when the optically active camphorsulfonic acid is L-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of an ester solvent and an alcohol solvent, and preferably, the volume ratio of the ester solvent to the alcohol solvent is: (3-15):1.

[0048] In another preferred embodiment, when the optically active camphorsulfonic acid is D-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of a ketone solvent and an ether solvent, and preferably, the volume ratio of the ester solvent to the alcohol solvent is: 1:(3-15).

[0049] In another preferred embodiment, in step (a2), the mass volume ratio (g:mL) of the mixture containing camphorsulfonate to the organic solvent 2 is 1:(5-50); preferably, 1:(5-30). In another preferred embodiment, in step (a3), the dissociation is carried out in the organic solvent 3; preferably, the organic solvent 3 is selected from the following group: halogenated hydrocarbon solvents (preferably, C1-3 halogenated hydrocarbon solvents, more preferably, dichloromethane), alcohol solvents (preferably, C1-3 alcohol solvents, more preferably, methanol and / or ethanol), ester solvents (preferably, C2-6 ester solvents, more preferably, ethyl acetate), ether solvents (preferably, C2-6 ether solvents, more preferably, tetrahydrofuran, ether, methyl tert-butyl ether, or a combination thereof), aromatic solvents (preferably, toluene), preferably, halogenated hydrocarbon solvents; more preferably, dichloromethane.

[0050] In another preferred embodiment, in step (a3), the base is selected from the group consisting of imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, or a combination thereof; preferably, imidazole.

[0051] In another preferred embodiment, in step (a3), the mass volume ratio (g:mL) of the camphorsulfonic acid salt of the single-configuration compound of formula III to the organic solvent 3 is 1:(1-20). In another preferred embodiment, in step (a3), the molar ratio of the compound of formula V to the base is 1:(0.5-2), preferably, 1:(0.9-1.1).

[0052] In another preferred embodiment, the isomer mixture of the compound of formula III is prepared by asymmetric hydrogenation of the compound of formula I and optionally protecting the hydroxyl group;

[0053]

[0054] In a second aspect of the present invention, there is provided a compound of formula IV,

[0055]

[0056] Wherein, R is H or a hydroxyl protecting group, and It is of L configuration or D configuration.

[0057] In another preferred embodiment, the optical purity of the compound of formula IV is ≥98%; preferably, ≥99%; more preferably, ≥99.5%.

[0058] In another preferred embodiment, the compound of formula IV can be used in the synthesis of Rimegepant or a Rimegepant intermediate after being freed in the presence of a base.

[0059] In another preferred embodiment, the compound of formula IV can be directly used in the synthesis of Rimegepant or a Rimegepant intermediate without being liberated.

[0060] In the third aspect of the present invention, there is provided a method for preparing the compound of formula IV as described in the second aspect, the preparation method comprising the steps of:

[0061] (1) subjecting cycloheptane [b] pyridine-5,9-dione (compound of formula I) and H2 to an asymmetric hydrogenation reaction in the presence of a metal catalyst to obtain an isomeric mixture of a compound of formula III-a; and, optionally, protecting the hydroxyl group to obtain an isomeric mixture of a compound of formula III;

[0062]

[0063] (2) Chiral resolution of the isomeric mixture of the compound of formula III is performed by the chiral resolution method described in the first aspect to obtain the compound of formula IV.

[0064] In another preferred embodiment, step (1) is as defined in step (1) in the fifth aspect.

[0065] In another preferred embodiment, step (2) comprises the steps of:

[0066] (2.1) reacting the compound of formula III with optically active camphorsulfonic acid to form a salt, thereby obtaining a mixture containing camphorsulfonic acid salt; and

[0067] (2.2) The mixture obtained in step (2.1) is separated to obtain a compound of formula IV.

[0068] In another preferred example, steps (2.1) and (2.2) are defined as steps (2.1) and (2.2) of the fifth aspect.

[0069] In the fourth aspect of the present invention, there is provided use of the compound of formula IV as described in the second aspect for the synthesis of Rimegepant or a Rimegepant intermediate.

[0070] In a fifth aspect of the present invention, a method for preparing a compound of formula V with high optical purity is provided, the preparation method comprising the steps of:

[0071] (1) subjecting cycloheptane [b] pyridine-5,9-dione (compound of formula I) and H2 to an asymmetric hydrogenation reaction in the presence of a metal catalyst to obtain an isomeric mixture of a compound of formula III-a; and, optionally, protecting the hydroxyl group to obtain an isomeric mixture of a compound of formula III;

[0072]

[0073] (2) performing chiral resolution on the isomeric mixture of the compound of formula III by the chiral resolution method described in the first aspect to obtain the compound of formula V;

[0074]

[0075] In each formula, R is H or a hydroxyl protecting group.

[0076] In another preferred embodiment, the ee value of the compound of formula V obtained in step (2) is ≥98%; preferably, ≥99%.

[0077] In another preferred embodiment, the metal catalyst is Rh-(S-Binap)(COD)BF4, Rh-(Wingphos)(COD)BF4, Rh-(MeO-BIBOP)(COD)BF4, Rh-(MeO-POP)(COD)BF4 or a combination thereof.

[0078] In another preferred embodiment, the metal catalyst is Rh-(S-Binap)(COD)BF4.

[0079] In another preferred embodiment, in step (1), the ee value of the compound of formula II in the isomer mixture of compound III-a is ≥50%; more preferably, ≥75%; most preferably, ≥85%;

[0080]

[0081] In another preferred embodiment, the asymmetric hydrogenation reaction is carried out in a hydrogen environment, preferably, the pressure of the hydrogen is 0.5 to 100 standard atmospheres (more preferably, 1 to 5 standard atmospheres, most preferably, 2 to 4 standard atmospheres).

[0082] In another preferred embodiment, the molar ratio of the compound of formula I to the metal catalyst is 1:(0.005-0.010); preferably, it is 1:(0.007-0.008).

[0083] In another preferred embodiment, the molar ratio of the compound of formula I to Rh-(S-Binap)(COD)BF4 is 1:(0.005-0.010); preferably, it is 1:(0.007-0.008).

[0084] In another preferred embodiment, the reaction time of the asymmetric hydrogenation reaction is 12-72 hours; preferably, 12-36 hours.

[0085] In another preferred embodiment, the asymmetric hydrogenation reaction is carried out in an organic solvent A. Preferably, the organic solvent A is selected from the following group: a halogenated hydrocarbon solvent (preferably, a C1-3 halogenated hydrocarbon solvent, more preferably, dichloromethane), an alcohol solvent (preferably, a C1-3 alcohol solvent, more preferably, methanol and / or ethanol), an ester solvent (preferably, a C2-6 ester solvent, more preferably, ethyl acetate), an ether solvent (preferably, a C2-6 ether solvent, more preferably, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, or a combination thereof), an aromatic solvent (preferably, toluene), or a combination thereof; preferably, a halogenated hydrocarbon solvent; more preferably, dichloromethane.

[0086] In another preferred embodiment, in step (1), before obtaining the isomeric mixture of the compound of formula III-a, the step further includes filtering and concentrating to remove the solvent.

[0087] In another preferred embodiment, in step (1), before obtaining the isomeric mixture of the compound of formula III, the process further comprises the steps of extraction, separation, optional washing and concentration.

[0088] In another preferred embodiment, the mass volume ratio of the compound of formula I to the organic solvent A is 1:(1-10); preferably, 1:(3-5).

[0089] In another preferred embodiment, when R is H, the compound of formula V is a compound of formula II, and step (1) is: subjecting the compound of formula I and H2 to an asymmetric hydrogenation reaction in the presence of a metal catalyst to obtain an isomeric mixture of a compound of formula III-a.

[0090] In another preferred embodiment, when R is a hydroxyl protecting group, step (1) is: subjecting the compound of formula I to an asymmetric hydrogenation reaction with H2 in the presence of a metal catalyst to obtain an isomeric mixture of a compound of formula III-a; and, optionally protecting the hydroxyl group to obtain an isomeric mixture of a compound of formula III.

[0091] In another preferred embodiment, step (2) comprises the steps of:

[0092] (2.1) reacting the compound of formula III with optically active camphorsulfonic acid to form a salt, thereby obtaining a mixture containing camphorsulfonic acid salt;

[0093] (2.2) separating the mixture obtained in step (2.1) to obtain a camphorsulfonate salt of the compound of formula V; and

[0094] (2.3) In the presence of a base, the camphorsulfonate of the compound of formula V obtained in step (2.2) is liberated to obtain the compound of formula V.

[0095] In another preferred embodiment, step (2.1), step (2.2) and step (2.3) are respectively defined as step (a1), step (a2) and step (a3) ​​in the first aspect.

[0096] In another preferred embodiment, the camphorsulfonate of the compound of formula V is as shown in formula IV,

[0097]

[0098] Wherein, R is H or a hydroxyl protecting group, and It is of L configuration or D configuration.

[0099] In a sixth aspect of the present invention, a method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cyclohepta[b]pyridine-5-one (compound of formula II) with high optical purity is provided, the preparation method comprising the steps of:

[0100]

[0101] in, It is of L configuration or D configuration;

[0102] (i) asymmetric hydrogenation of cyclohepta[b]pyridine-5,9-dione (compound of formula I) and H2 in the presence of Rh-(S-Binap)(COD)BF4 to obtain a mixture of isomers of a compound of formula III-a; and

[0103] (ii) chiral separation of the isomeric mixture of the compound of formula III-a by the separation method described in the first aspect to obtain the compound of formula II.

[0104] In another preferred embodiment, the optical purity of the compound of formula II obtained in step (ii) is ≥98%; preferably, ≥99%; more preferably, ≥99.5%.

[0105] In another preferred embodiment, in step (i), in the isomer mixture of the compound of formula III-a, the ee value of the compound of formula II is ≥50%; more preferably, ≥75%; most preferably, ≥85%.

[0106] In another preferred embodiment, in step (i), in the isomer mixture of the compound of formula III-a, the ee value of the compound of formula II is ≤95%; preferably, ≤90%.

[0107] In another preferred embodiment, the asymmetric hydrogenation reaction in step (i) is defined as the asymmetric hydrogenation reaction described in the second aspect.

[0108] In another preferred embodiment, step (ii) comprises the steps of:

[0109] (ii-1) reacting the compound of formula III-a with optically active camphorsulfonic acid to form a salt, thereby obtaining a mixture containing camphorsulfonate;

[0110] (ii-2) separating the mixture obtained in step (ii-1) to obtain a compound of formula IV-a;

[0111] (ii-3) In the presence of a base, the compound of formula IV-a obtained in step (ii-2) is liberated to obtain a compound of formula II.

[0112] In another preferred embodiment, the optical purity of the compound of formula IV-a obtained in step (ii-2) is ≥98%; preferably, ≥99%; more preferably, ≥99.5%.

[0113] In another preferred embodiment, step (ii-1), step (ii-2) and step (ii-3) are respectively defined as step (a1), step (a2) and step (a3) ​​in the first aspect.

[0114] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0115] After extensive and in-depth research, the inventor unexpectedly found that optically active camphorsulfonic acid is very suitable as a chiral resolving agent for the compound of formula III, and camphorsulfonic acid can form easily separable diastereoisomer salts with the compound of formula III, thereby obtaining the compound of formula V with high optical purity in high yield. Based on this, the inventor completed the present invention.

[0116] the term

[0117] As used herein, Rh-(S-Binap)(COD)BF4 is represented by

[0118]

[0119] As used herein, the term "optical purity" is also known as optical purity. It is usually expressed as %op and is a measure of the amount of one enantiomer that exceeds the other enantiomer in an optically active sample.

[0120] As used herein, the term "ee value" refers to the excess of one enantiomer over another, usually expressed as a percentage.

[0121] Unless otherwise specified, in this article, the term "isomer mixture" refers to a mixture of any isomers that can be represented by a specified structural formula (such as Formula III), or a mixture of a compound represented by a specified structural formula and its isomers. Each isomer in the isomer mixture can exist in any proportion. Preferably, in the isomer mixture, the optical purity of any single configuration isomer is ≤90%.

[0122] Unless otherwise specified, herein, when the bonds in a structural formula are represented by lines (rather than wedges), that is, when represented in a manner not specifying specific isomers, the structure includes any isomer that can be represented by the structural formula, or a mixture of these isomers in any proportion (which may also be referred to as an isomeric mixture of the structural formula).

[0123] Unless otherwise specified, in this document, the term "single configuration" refers to a compound that can be represented by a specified structural formula (such as Formula III) and has a specific configuration. Generally, when a certain structural formula (such as Formula III) is described as "single configuration" or "single configuration", it means that there are basically no other configurations of the compound, for example, the optical purity of the single configuration compound is ≥95%, preferably, ≥98; more preferably, ≥99%.

[0124] Unless otherwise specified, herein, when there is a bond represented by a wedge in a structural formula, that is, when it is represented in a manner that specifies an isomer, the structure represents that other isomeric forms are essentially absent, for example, the optical purity is ≥95%, preferably, ≥98; more preferably, ≥99%, and most preferably, ≥99.5%.

[0125] As used herein, isomers refer to stereoisomers (eg, enantiomers and diastereomers) unless otherwise specified.

[0126] Preparation method

[0127] In order to solve the technical problems existing in the prior art, an object of the present invention is to provide an industrial preparation method of (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cyclohepta[b]pyridine-5-one with high optical purity.

[0128] In a specific embodiment, the present invention provides a method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cyclohepta[b]pyridin-5-one (compound of formula II) with high optical purity, comprising the following steps:

[0129] i) in the presence of a catalyst Rh-(S-Binap)(COD)BF4, cyclohepta[b]pyridine-5,9-dione (Formula I) is subjected to asymmetric hydrogenation to obtain a crude compound of Formula II (or a mixture of isomers of a compound of Formula III-a) (preferably, the ee value of the crude product is greater than 85%);

[0130] ii) The crude compound of formula II is resolved with camphorsulfonic acid to obtain a compound of formula II with an ee value of more than 99%.

[0131] The reaction formula is as follows:

[0132]

[0133] Preferably, step i is carried out in an organic solvent, and the organic solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, n-heptane, ethyl acetate, methanol, ethanol, diethyl ether, methyl tert-butyl ether, and toluene, and dichloromethane is more preferred.

[0134] Preferably, in step i, the reaction temperature is 10°C-100°C; and / or the hydrogen pressure is 0.5-100 atmospheres, more preferably 3-5 atmospheres; and / or the reaction time is 12-36 hours.

[0135] Preferably, the catalyst Rh-(S-Binap)(COD)BF4 used in step i is available in large quantities on the market because the ligand S-Binap is easy to prepare.

[0136] In another specific embodiment, the present invention provides a compound of formula IV, the structural formula is as follows:

[0137]

[0138] Wherein R=H, TMS, TIPS, TBS, Me, Et, Pr, i-Pr, Bn, CH3CO, CH3CH2CO, PhCO, CH3SO2 or PhSO2.

[0139] In another specific embodiment, the present invention provides a method for preparing a compound of formula IV, comprising the following steps:

[0140] 1) reacting a compound of formula III having an ee value ≥ 50% (i.e., a mixture of a compound of formula V and an isomer thereof) with optically active camphorsulfonic acid to form a camphorsulfonate of the compound of formula III;

[0141] 2) The camphorsulfonate of the compound of formula III is purified by recrystallization or beating to separate the compound of formula IV.

[0142] The reaction formula is as follows:

[0143]

[0144] Wherein R=H, TMS, TIPS, TBS, Me, Et, Pr, i-Pr, Bn, CH3CO, CH3 CH2CO, PhCO, CH3SO2 or PhSO2.

[0145] Preferably, the compound of formula III is prepared by the following steps:

[0146] In the presence of Rh-(S-Binap)(COD)BF4, cycloheptane[b]pyridine-5,9-dione (compound of formula I) and H2 are subjected to an asymmetric hydrogenation reaction to obtain a crude compound of formula II (or a mixture of isomers containing the compound of formula II); and, optionally, the hydroxyl group is protected to obtain a compound of formula III.

[0147] Preferably, the camphorsulfonic acid is D-camphorsulfonic acid or L-camphorsulfonic acid.

[0148] Preferably, the optical purity of the compound of formula IV is above 98%, preferably above 99%, and more preferably above 99.5%.

[0149] Preferably, step 1 is carried out in an organic solvent 1, wherein the organic solvent 1 is selected from any one or more of dichloromethane, methanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetone, butanone, and toluene, and dichloromethane is more preferred.

[0150] Preferably, the organic solvent 2 used for recrystallization or slurrying in step 2 is selected from any one or more of dichloromethane, methanol, ethanol, ethyl acetate, tetrahydrofuran, ether, methyl tert-butyl ether, acetone, butanone, and toluene, and is further preferably a mixed solution of ethyl acetate and methanol or a mixed solvent of methyl tert-butyl ether (MTBE) and acetone.

[0151] Preferably, step 3 is carried out in an organic solvent 3, wherein the organic solvent 3 is selected from any one or more of dichloromethane, methanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and toluene, and dichloromethane is further preferred.

[0152] Preferably, the base in step 3 is selected from any one or more of imidazole, DBU, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate, and imidazole is more preferred.

[0153] Preferably, the preparation method further comprises the following steps: the compound of formula IV is freed by alkali to obtain the compound of formula V. The reaction formula is as follows:

[0154]

[0155] Wherein R=H, TMS, TIPS, TBS, Me, Et, Pr, i-Pr, Bn, CH3CO, CH3CH2CO, PhCO, CH3SO2 or PhSO2.

[0156] Preferably, the optical purity of the compound of formula V is above 98%, preferably above 99%, and more preferably above 99.5%.

[0157] The main advantages of the present invention include:

[0158] (a) The separation method of the present invention has mild conditions, and the separation product has high optical purity and high yield.

[0159] (b) The method of the present invention has mild reaction conditions, is easy to operate, has high yield, especially high total yield, and is suitable for industrial production.

[0160] (c) The preferred embodiment of the present invention also uses the easily available and relatively low-priced metal catalyst Rh-(S-Binap)(COD)BF4, which provides a raw material with relatively high optical purity for chiral resolution, thereby providing a method for preparing an optically pure Remigipam intermediate with low cost and high chiral compound yield.

[0161] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0162] Example 1 Preparation of Compound of Formula III-a

[0163] Cycloheptane [b] pyridine-5,9-dione 80.0 g (0.46 mol, 1.0 eq.), Rh-(S-Binap)(COD)BF4 3.2 g (0.0034 mol, 0.0075 eq.) and dichloromethane 300 mL were added to the hydrogenation reaction bottle in sequence, nitrogen was replaced three times, hydrogen was replaced three times, hydrogen was passed to the pressure of 40-50 psi, 20-30°C, and the reaction was carried out for 24 hours. HPLC monitoring showed that the raw material: product was less than 1.0%, the reaction was stopped, filtered on a 30 wt% silica gel pad, and concentrated to obtain 77.8 g of the target product, with a yield of 97% and an ee value of 90.0%.

[0164] Example 2 Preparation of Compound of Formula IV-a

[0165] Add 20.0 g (0.11 mol, 1.0 eq.) of the compound of formula III-a obtained in Example 1, 26.5 g (0.11 mol, 1.0 eq.) of L-camphorsulfonic acid and 80 mL of dichloromethane to the reaction flask, and heat to reflux for 2 hours. Cool to room temperature, concentrate to remove the solvent, and obtain 45.5 g of solid. Add 450 mL of ethyl acetate, heat to reflux, and reflux for 0.5 hours. Add 70 mL of methanol, continue to reflux for 1 hour, and completely dissolve the solid. Cool to 0-5 ° C, stir for 0.5 hours, filter, and dry to obtain 39.1 g of the product, with a yield of 87% and an ee value of 99.5%.

[0166] Example 3 Preparation of high optical purity compound of formula II

[0167] 37.5 g (0.09 mol, 1.0 eq.) of the compound IV-a obtained in Example 2, 6.12 g (0.09 mol, 1.0 eq.) of imidazole and 375 mL of dichloromethane were added to the reaction flask in sequence and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated and filtered through a 30 wt% silica gel pad to obtain 14.6 g of the product with a yield of 95.1% and an ee value of 99.5%.

[0168] Example 4 Preparation of Compound of Formula III-a

[0169] Cycloheptan[b]pyridine-5,9-dione 20.0 g (0.12 mol, 1.0 eq.), Rh-(S-Binap)(COD)BF4 0.08 g (0.0009 mol, 0.0075 eq.) and tetrahydrofuran 80 mL were added to the hydrogenation reaction bottle in sequence, nitrogen was replaced three times, hydrogen was replaced three times, hydrogen was introduced to a pressure of 40-50 psi, 20-30°C, and the reaction was carried out for 48 hours. Filtered through a 30 wt% silica gel pad, concentrated to obtain 16.2 g of the target product, with a yield of 80.1% and an ee value of 85%.

[0170] Example 5 Preparation of Compound of Formula IV-a

[0171] Add 16.0 g (0.092 mol, 1.0 eq.) of the compound of formula III-a obtained in Example 4, 21.2 g (0.092 mol, 1.0 eq.) of L-camphorsulfonic acid and 50 mL of methanol to the reaction flask, heat to reflux, and reflux for 2 hours. Cool to room temperature, concentrate to remove the solvent, and obtain 36.8 g of solid. Add 350 mL of ethyl acetate, heat to reflux, and reflux for 0.5 hour. Add 65 mL of methanol and continue to reflux for 0.5 hour to dissolve all the solids. Cool to 0-5 ° C, stir for 1 hour, filter, and dry to obtain 24.1 g of the product, with a yield of 80.0% and an ee value of 99.0%.

[0172] Example 6 Preparation of high optical purity compound of formula II

[0173] 22.5 g (0.054 mol, 1.0 eq.) of the compound IV-a obtained in Example 5, 2.2 g (0.054 mol, 1.0 eq.) of sodium hydroxide and 250 mL of tetrahydrofuran were added to the reaction flask in sequence and reacted at room temperature for 0.5 hours. After the reaction was completed, the mixture was filtered through a 30 wt% silica gel pad and concentrated to obtain 8.8 g of the product with a yield of 94.9% and an ee value of 99.0%.

[0174] Example 7 Preparation of Compound III (R = TIPS)

[0175] Add 50.0 g (0.28 mol, 1.0 eq.) of the compound of formula III-a obtained in Example 1, 250 mL of DMF, 63.5 g (0.33 mol, 1.2 eq.) of TIPSCl and 37.3 g (0.55 mol, 2.0 eq.) of imidazole to the reaction flask in sequence and stir at room temperature for 24 hours. Detect the reaction by TLC. After the reaction is complete, add 200 mL of water and 500 mL of ethyl acetate. Separate the liquids, wash the organic layer twice with water, and concentrate to obtain 82.5 g of the product with a yield of 90% and an ee value of 90%.

[0176] Example 8 Preparation of Compound of Formula IV (R = TIPS)

[0177] Add 76.7 g (0.23 mol, 1.0 eq) of the compound of formula III obtained in Example 7, 52.9 g (0.23 mol, 1.0 eq.) of L-camphorsulfonic acid and 220 mL (3.0 vol.) of dichloromethane into the reaction flask, heat to reflux, react for 2 hours, cool to room temperature, concentrate to remove the solvent, and obtain 129.0 g of solid. Add 650 mL of ethyl acetate, heat to reflux, and reflux for 0.5 hours. Add 64 mL of methanol and continue to reflux for 0.5 hours. Cool to 0-5°C, stir for 1 hour, filter, and dry to obtain 98.7 g of the product, with a yield of 76.5% and an ee value of 99.5%.

[0178] Example 9 Preparation of Compound of Formula IV (R = TIPS)

[0179] 38.3 g (0.12 mol, 1.0 eq.) of the compound of formula III obtained in Example 7, 26.5 g (0.12 mol, 1.0 eq.) of D-camphorsulfonic acid and 383 mL (10.0 vol.) of acetone were added to the reaction flask in sequence, heated to reflux, reacted for 1 hour, cooled to room temperature, concentrated to 2 vol., heated to reflux, MTBE (10 vol.) was added dropwise, refluxed for 1 hour, cooled to 0-5 ° C, stirred for 1 hour, filtered, and dried to obtain 31.4 g of the product with a yield of 82.0% and an ee value of 99.8%.

[0180] Example 10 Preparation of Compound of Formula V (R = TIPS)

[0181] 84.7 g (0.15 mol, 1.0 eq.) of the compound IV obtained in Example 8, 10.2 g (0.15 mol, 1.0 eq.) of imidazole and 420 mL of dichloromethane were added to the reaction flask in sequence and reacted at room temperature for 2 hours. After the reaction, 160 mL of water was added, the liquid was separated, filtered through a 30 wt% silica gel pad, and concentrated to obtain 46.5 g of the product, with a yield of 93% and an ee value of 99.5%.

[0182] Example 11: Experimental separation of compound III with other chiral acids

[0183] In a reaction flask, compound III (R = TIPS) (1.0 eq.) prepared according to the method of Example 7, the chiral acid in Table 1 (1.0 eq.) and DCM (10 vol.) were added, heated to reflux for 1 hour, cooled, concentrated to remove the solvent, and a solid crude product (ee value 90%) was obtained. 2 vol of acetone was added, heated to reflux, MTBE (15 vol.) was added, stirred for 1 hour, cooled to 0-5°C, filtered to obtain a solid, and the ee value of the solid was tested (the results are shown in Table 1).

[0184] Table 1

[0185]

[0186]

[0187] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for chiral resolution of an isomeric mixture of a compound of formula III, in, R is H or a hydroxyl protecting group; Wherein, in the isomeric mixture of the compound of formula III, the optical purity of the compound of formula III with a single configuration is ≥75%; and in the isomeric mixture of the compound of formula III, the optical purity of any single configuration of the compound of formula III is ≤95%; Furthermore, the method comprises the steps of: (a1) subjecting the compound of formula III to a salt-forming reaction with optically active camphorsulfonic acid to obtain a mixture containing camphorsulfonic acid salts; wherein the optically active camphorsulfonic acid is L-camphorsulfonic acid or D-camphorsulfonic acid, the salt-forming reaction is carried out in an organic solvent 1, and when the optically active camphorsulfonic acid is L-camphorsulfonic acid, the organic solvent 1 is dichloromethane, methanol, or a combination thereof; when the optically active camphorsulfonic acid is D-camphorsulfonic acid, the organic solvent 1 is acetone; and (a2) purifying and separating the mixture obtained in step (a1) to obtain a camphorsulfonic acid salt of the compound of formula III with a single configuration; wherein the purification and separation is recrystallization or beating; wherein the solvent used for the purification and separation is an organic solvent 2; and when the optically active camphorsulfonic acid is L-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of ethyl acetate and methanol; when the optically active camphorsulfonic acid is D-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of acetone and MTBE; and Optionally, (a3) ​​in the presence of a base, freeing the camphorsulfonate of the single-configuration compound of formula III obtained in step (a2) to obtain a single-configuration compound of formula III; wherein the base is selected from the group consisting of imidazole, sodium hydroxide, potassium hydroxide, lithium hydroxide or a combination thereof; Wherein, the single configuration compound of formula III is a compound of formula V Wherein, R is H or a hydroxyl protecting group; The camphorsulfonate salt of the compound of formula III in a single configuration is a compound of formula IV Wherein, R is H or a hydroxyl protecting group, and It is of L configuration or D configuration.

2. The method according to claim 1, characterized in that In step (a3), the base is imidazole.

3. The method according to claim 1, characterized in that R=H, TMS, TIPS, TBS, Me, Et, Pr, i-Pr, Bn, CH3CO, CH3CH2CO, PhCO, CH3SO2 or PhSO2.

4. The method according to claim 1, characterized in that R = H, TMS or TIPS.

5. The method according to claim 1, characterized in that In step (a), the molar ratio of the isomer mixture of the compound of formula III to the optically active camphorsulfonic acid is 1:(0.5-2).

6. The method according to claim 1, characterized in that In step (a), the molar ratio of the isomer mixture of the compound of formula III to the optically active camphorsulfonic acid is 1:(0.9-1.1).

7. The method according to claim 1, characterized in that In step (a3), the dissociation is carried out in an organic solvent 3, and the organic solvent 3 is selected from the following group: halogenated hydrocarbon solvents, alcohol solvents, ester solvents, ether solvents, and aromatic solvents.

8. The method according to claim 7, characterized in that iv) The organic solvent 3 is a halogenated hydrocarbon solvent.

9. The method according to claim 7, characterized in that iv) The organic solvent 3 is dichloromethane.

10. The method according to claim 1, characterized in that The organic solvent 2 is a mixed solvent of ethyl acetate and methanol, wherein the volume ratio of ethyl acetate to methanol is: (3-15): 1; or, The organic solvent 2 is a mixed solvent of acetone and MTBE, wherein the volume ratio of acetone to MTBE is: 1:(3-15).

11. The method according to claim 1, characterized in that In step (a1), the mass volume g:mL ratio of the compound of formula III to the organic solvent 1 is 1:(1-20); and In step (a2), the mass volume g:mL ratio of the mixture containing camphorsulfonate to the organic solvent 2 is 1:(5-50).

12. The method according to claim 1, characterized in that In step (a1), the mass volume g:mL ratio of the compound of formula III to the organic solvent 1 is 1:(2-15); and In step (a2), the mass volume g:mL ratio of the mixture containing camphorsulfonate to the organic solvent 2 is 1:(5-30).

13. The method according to claim 1, characterized in that In the isomeric mixture of the compound of formula III, the optical purity of the compound of formula III with a single configuration is ≥85%; and in the isomeric mixture of the compound of formula III, the optical purity of any single configuration of the compound of formula III is ≤90%.

14. A method for preparing a compound of formula V with high optical purity, characterized in that: The preparation method comprises the steps of: (1) subjecting cyclohepta[b]pyridine-5,9-dione (compound of formula I) and H2 to an asymmetric hydrogenation reaction in the presence of Rh-(S-Binap)(COD)BF4 to obtain an isomeric mixture of a compound of formula III-a; and protecting the hydroxyl group to obtain an isomeric mixture of the compound of formula III; (2) chiral separation of the isomeric mixture of the compound of formula III by the chiral separation method as described in claim 1 to obtain the compound of formula V; In each formula, R is a hydroxyl protecting group.

15. The preparation method according to claim 14, characterized in that: Step (1) has one or more of the following characteristics: i) the asymmetric hydrogenation reaction is carried out under a hydrogen environment, preferably, the pressure of the hydrogen is 0.5 to 100 standard atmospheres; ii) the molar ratio of the compound of formula I to the metal catalyst is 1:(0.005-0.010); iii) The reaction time of the asymmetric hydrogenation reaction is 12-72 hours.

16. The preparation method according to claim 15, characterized in that: Step (1) has one or more of the following characteristics: ii) the pressure of the hydrogen is 0.5 to 100 standard atmospheres; iii) the molar ratio of the compound of formula I to the metal catalyst is 1:(0.007-0.008); iv) The reaction time of the asymmetric hydrogenation reaction is 12-36 hours.

17. The preparation method according to claim 15, characterized in that: Step (1) has one or more of the following characteristics: ii) The pressure of the hydrogen is 1-5 standard atmospheres.

18. The preparation method according to claim 15, characterized in that: The asymmetric hydrogenation reaction is carried out in an organic solvent A, wherein the organic solvent A is selected from the following group: halogenated hydrocarbon solvents, alcohol solvents, ester solvents, ether solvents, aromatic solvents, or a combination thereof.

19. The preparation method according to claim 18, characterized in that: The organic solvent A is selected from the following group: C1-3 halogenated hydrocarbon solvents, C1-3 alcohol solvents, C2-6 ester solvents, C2-6 ether solvents, toluene, or a combination thereof.

20. The preparation method according to claim 18, characterized in that: The organic solvent A is a halogenated hydrocarbon solvent.

21. The preparation method according to claim 20, characterized in that: The organic solvent A is dichloromethane.

22. A method for preparing (9R)-6,7,8,9-tetrahydro-9-hydroxy-5H-cyclohepta[b]pyridin-5-one of formula II with high optical purity, characterized in that: The preparation method comprises the steps of: in, It is of L configuration or D configuration; (i) asymmetric hydrogenation of cyclohepta[b]pyridine-5,9-dione (compound of formula I) and H2 in the presence of Rh-(S-Binap)(COD)BF4 to obtain a mixture of isomers of a compound of formula III-a; and (ii) performing chiral resolution on the isomeric mixture of the compound of formula III-a by a chiral resolution method to obtain a compound of formula II; Wherein, the step (ii) comprises the steps of: (ii-1) reacting the compound of formula III-a with optically active camphorsulfonic acid to form a salt, thereby obtaining a mixture containing camphorsulfonic acid salt; wherein the salt-forming reaction is carried out in an organic solvent 1, and when the optically active camphorsulfonic acid is L-camphorsulfonic acid, the organic solvent 1 is dichloromethane, methanol, or a combination thereof; when the optically active camphorsulfonic acid is D-camphorsulfonic acid, the organic solvent 1 is acetone; (ii-2) purifying and separating the mixture obtained in step (ii-1) to obtain a compound of formula IV-a; wherein the purification and separation is recrystallization or pulping; wherein the solvent used for the purification and separation is an organic solvent 2; and when the optically active camphorsulfonic acid is L-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of ethyl acetate and methanol; when the optically active camphorsulfonic acid is D-camphorsulfonic acid, the organic solvent 2 is a mixed solvent of acetone and MTBE; (ii-3) in the presence of a base, freeing the compound of formula IV-a obtained in step (ii-2) to obtain a compound of formula II; wherein the base is selected from the group consisting of imidazole, sodium hydroxide, potassium hydroxide, lithium hydroxide or a combination thereof; Wherein, the optically active camphorsulfonic acid is L-camphorsulfonic acid or D-camphorsulfonic acid.

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