Method for preparing NK3r antagonist intermediate

Abstract

The present invention relates to a method for preparing an NK3R antagonist intermediate, which method comprises method 1 and method 2. In method 1, compound I-11 is subjected to a chiral ligand-induced asymmetric hydrogenation reaction to construct a chiral center, thereby obtaining a target chiral compound represented by formula I, which has a chiral purity of 95% or more, and a product yield of 55% or more. In method 2, compound 9 is directly subjected to a chiral ligand-induced asymmetric hydrogenation reaction to construct a chiral center, thereby obtaining a target chiral compound represented by formula I, which has a chiral purity of 90% or more, and a product yield of 90% or more. Compared with the original synthesis process (the method disclosed in WO 2022 / 222963), the yield is increased by about seven times, and one reaction step is reduced in the overall reaction process of the compound represented by formula I. The two methods avoid the defect that the original resolution process requires multiple rounds of slurrying and purification operations, greatly lower the preparation cost, and are expected to achieve the cost reduction and large-scale production of the compound of formula I.

Description

Preparation method of NK3R antagonist intermediate

[0001] This application claims priority to the following earlier application: Patent application No. 2024115729910, filed with the China National Intellectual Property Administration on November 5, 2024, entitled "Method for preparing NK3R antagonist intermediate". The entire contents of that earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of compound preparation technology, specifically relating to a method for preparing NK3R antagonist intermediates. Background Technology

[0003] NK3R stands for Neurokinin-3 Receptor. NK3R antagonists are a class of compounds that can inhibit NK3R activity. NK3R is a G protein-coupled receptor (GPCR) mainly distributed in the central nervous system (such as the limbic system and basal ganglia of the brain), the peripheral nervous system, and some peripheral tissues (including reproductive organs and the gastrointestinal tract).

[0004] Neurokinin B (NKB) is an endogenous ligand of NK3R. When NKB binds to NK3R, it activates a series of intracellular signaling pathways, including activating phospholipase C (PLC) through the Gq / 11 protein, which in turn increases inositol triphosphate (IP3) and diacylglycerol (DAG), leading to the release of intracellular calcium ions, thereby regulating cellular physiological functions.

[0005] Currently, NK3R antagonists are primarily used in clinical trials for the treatment of mental illnesses and gastrointestinal disorders. In the treatment of schizophrenia, several clinical trials are evaluating the efficacy and safety of NK3R antagonists in improving patient symptoms. Regarding gastrointestinal disorders, NK3R antagonists have entered clinical research stages for conditions such as IBS, with some studies showing potential in alleviating IBS symptoms.

[0006] PCT / WO2022 / 2222963 (application date April 20, 2022) discloses an NK3R antagonist compound (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyrrolo-2-one. The key intermediate for synthesizing this compound is compound 12. Existing processes for synthesizing compound 12 involve a one-step hydrogenation reduction of compound 9 to obtain a racemic compound 10 (yield approximately 65%), followed by resolution of the racemic compound 10 to obtain the chiral compound 12. This resolution process requires multiple slurry purifications, with a one-step yield of only about 20%, and the multiple purification operations are unsuitable for large-scale production.

[0007] PCT / WO2022 / 2222963 discloses the following reaction route for preparing compound 12:

[0008] Therefore, it is necessary to improve the preparation method of compound 12. Summary of the Invention

[0009] To address the aforementioned technical problems, the present invention provides a method for preparing the compound represented by Formula I, comprising:

[0010] Method 1. Compound I-11 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral ruthenium complex and / or rhodium complex 1 to give the compound shown in Formula I;

[0011] or,

[0012] Method 2. Compound I-9 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral phosphine ligand and an iridium complex and / or a rhodium complex 2 to give the compound shown in Formula I;

[0013] Among them, R1 and R2 may be the same or different, and are independently selected from H, halogens, and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3- 20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups;

[0014] The "*" indicates that the carbon at that position in the compound shown in formula I is a chiral carbon, and it is either an R configuration or an S configuration.

[0015] In Method 1, when it is necessary to prepare the compound of Formula I with the R configuration, a chiral ruthenium complex and / or rhodium complex 1 with the S,S configuration is used;

[0016] In some embodiments of the present invention, when preparing the compound of formula I with R configuration, the product contains an er value of 80:20 or more for the compound of formula I with R configuration and 90:10 or more for the compound of formula I with S configuration, and even more preferably 95:5 or more.

[0017] Alternatively, when it is necessary to prepare the S-configuration compound of Formula I, a chiral ruthenium complex and / or rhodium complex 1 with an R,R configuration is used;

[0018] In some embodiments of the present invention, when preparing the S-configuration compound of Formula I, the product contains an er value of 80:20 or more for the S-configuration compound of Formula I and 90:10 or more for the R-configuration compound of Formula I, and even more preferably 95:5 or more.

[0019] In Method 2, when it is necessary to prepare the S-configuration compound shown in Formula I, the R-configuration chiral phosphine ligand and iridium complex and / or rhodium complex 2 are used;

[0020] In some embodiments of the present invention, when preparing the S-configuration compound of Formula I, the product contains an er value of 80:20 or more for the S-configuration compound of Formula I and 90:10 or more for the R-configuration compound of Formula I, and even more preferably 95:5 or more.

[0021] Alternatively, when it is necessary to prepare the R-configuration compound of Formula I, the S-configuration chiral phosphine ligand and iridium complex and / or rhodium complex 2 are used;

[0022] In some embodiments of the present invention, when preparing the compound of formula I with R configuration, the product contains an er value of 80:20 or more for the compound of formula I with R configuration and 90:10 or more for the compound of formula I with S configuration, and even more preferably 95:5 or more.

[0023] According to embodiments of the present invention, R1 and R2 may be the same or different, and are independently selected from H, fluorine, bromine, chlorine, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl compounds.

[0024] According to an embodiment of the present invention, R1 is selected from H, bromine, methyl, ethyl, or bromomethyl;

[0025] R2 is selected from H, chloro, methyl, ethyl, or chloromethyl.

[0026] As an example, the compound shown in Formula I is selected from the following compounds:

[0027] According to an embodiment of the present invention, the chiral ruthenium complex is selected from chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(mesene)ruthenium(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)ruthenium(II), and chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene). Ruthenium (II); or, at least one of the following: chlorine {N-[(1R,2R)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium (II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(trimethylbenzene)ruthenium (II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)ruthenium (II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)ruthenium (II).

[0028] According to an embodiment of the present invention, the chiral rhodium complex 1 is selected from chloro{N-[(1R,2R)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)Rh(II), chloro{(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(metamethylbenzene)Rh(II), chloro{(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)Rh(II), and chloro{(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)Rh(II);

[0029] Alternatively, chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(trimethylbenzene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)Rh(II).

[0030] According to an embodiment of the present invention, the chiral phosphine ligand is selected from at least one of R-SegPhos, (R)-(+)-(6,6′-dimethoxybiphenyl-2,2′-yl)bis(diphenylphosphine), (11aR)-1,11-di(diphenylphosphine)dibenzo[d,f][1,3]dioxane, (R)-(-)-2,2,6,6-tetramethoxy-4,4-bis(diphenylphosphine)-3,3-bipyridine, and (R)-(+)-2,2′-bis(di-4-methylphenylphosphine)-1,1′-binaphthylene;

[0031] Alternatively, at least one of S-SegPhos, (S)-(+)-(6,6′-dimethoxybiphenyl-2,2′-yl)bis(diphenylphosphine), (11aS)-1,11-bis(diphenylphosphine)dibenzo[d,f][1,3]dioxane, (S)-(-)-2,2,6,6-tetramethoxy-4,4-bis(diphenylphosphine)-3,3-bipyridine, and (S)-(+)-2,2′-bis(di-4-methylphenylphosphine)-1,1′-binaphthyl.

[0032] According to an embodiment of the present invention, the iridium complex is [Ir(COD)]Cl]2.

[0033] According to an embodiment of the present invention, the rhodium complex 2 is Rh(COD)2BF4.

[0034] According to an embodiment of the present invention, in method 1, the reaction is carried out in the presence of an organic base-ammonium formate or an organic base-formic acid as a cocatalyst.

[0035] According to an embodiment of the present invention, in method 1, the organic base in the co-catalyst is selected from at least one of triethylamine, dimethylamine, diethylamine, dipropylamine, tripropylamine, or tributylamine.

[0036] According to an embodiment of the present invention, in method 1, the co-catalyst is selected from triethylamine-ammonium formate or triethylamine-formic acid.

[0037] According to an embodiment of the present invention, the molar ratio of ammonium formate or formic acid to organic base in organic base-ammonium formate or organic base-formic acid is (1-20):1, for example (2-10):1, such as (2.5-8):1.

[0038] According to an embodiment of the present invention, the amount of the chiral ruthenium complex and / or rhodium complex 1 used is 0.1 to 50 g of chiral ruthenium complex and / or rhodium complex 1 per mol of organic base, such as 1 to 20 g of chiral ruthenium complex and / or rhodium complex 1.

[0039] According to an embodiment of the present invention, the molar ratio of compound I-11 to organic base is (0.001-10):1, such as (0.01-2):1.

[0040] According to an embodiment of the present invention, the asymmetric hydrogenation reaction in method 1 is carried out at 0–30°C.

[0041] According to an embodiment of the present invention, the asymmetric hydrogenation reaction described in method 1 is carried out in an alcohol solvent, such as methanol or ethanol.

[0042] According to an embodiment of the present invention, method 1 includes the following steps:

[0043] S1. Compound I-10 undergoes an oxidation reaction to yield compound I-11;

[0044] S2. Compound I-11 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral ruthenium complex and / or rhodium complex 1 to give the compound shown in Formula I;

[0045] R1 and R2 have the definitions described above.

[0046] The chiral ruthenium complex and rhodium complex 1 have the definitions described above.

[0047] According to an embodiment of the present invention, the oxidation reaction in step S1 is carried out in the presence of oxidants such as hydrogen peroxide, trichloroisocyanuric acid, and dichlorodicyanobenzoquinone.

[0048] According to an embodiment of the present invention, method 1 further includes a preparation process for compound I-10, comprising the following steps:

[0049] Step A1. Compound I-9 undergoes a reduction reaction to obtain compound I-10;

[0050] R1 and R2 have the definitions described above.

[0051] According to an embodiment of the present invention, the reduction reaction in step A1 is carried out in the presence of a reducing agent such as sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, or lithium borohydride.

[0052] According to an embodiment of the present invention, in method 2, the molar ratio of compound I-9, chiral phosphine ligand, iridium complex and / or rhodium complex 2 is (100-1):(10-0.1):1, preferably (50-10):(1-5):1, more preferably (50-20):(2.5-5):1.

[0053] According to an embodiment of the present invention, in method 2, the reaction is carried out in a hydrogen atmosphere at a hydrogen pressure of 1 psi or higher, for example, 10 psi or higher, such as 100 psi or higher.

[0054] According to an embodiment of the present invention, in method 2, the reaction temperature is 30–100°C, for example 40–90°C, such as 50–80°C.

[0055] According to an embodiment of the present invention, in method 2, the reaction is carried out in an aromatic solvent, wherein the aromatic solvent is selected from toluene and xylene.

[0056] According to an embodiment of the present invention, compound I-9 is prepared by the following method:

[0057] Compound I-2 reacts with compound I-7 to give compound I-8; compound I-8 undergoes a cyclization reaction to give compound I-9.

[0058] R1 and R2 have the definitions described above.

[0059] According to an embodiment of the present invention, the reaction between compound I-2 and compound I-7 is carried out at 20–60 °C.

[0060] According to an embodiment of the present invention, the reaction of compound I-2 with compound I-7 is carried out in an alcohol solvent.

[0061] According to an embodiment of the present invention, the cyclization reaction of compound I-8 is carried out at 40–140 °C.

[0062] According to an embodiment of the present invention, compound I-8 undergoes a cyclization reaction in the presence of phosphorus oxychloride.

[0063] According to an embodiment of the present invention, compound I-8 undergoes a cyclization reaction in an ether solvent. Beneficial effects

[0064] Method 1 of this invention involves subjecting compound I-11 to a chiral ligand-induced asymmetric hydrogenation reaction to construct a chiral center, thereby obtaining the target chiral compound of formula I with a chiral purity of over 95% and a product yield of over 55%. Compared to the original synthetic process (the method disclosed in PCT / WO2022 / 2222963), the yield is increased by more than four times, and the cost is significantly reduced. This method holds promise for achieving cost reduction and large-scale production of compound I.

[0065] Method 2 of this invention involves directly subjecting compound 9 to a chiral ligand-induced asymmetric hydrogenation reaction to construct a chiral center, yielding the target chiral compound of Formula I with a chiral purity of over 90% and a yield of over 90%. Compared to the original synthetic process (disclosed in PCT / WO2022 / 2222963), the yield is increased by approximately 7 times, and one reaction step is reduced in the entire reaction process for the compound of Formula I. Furthermore, this method avoids the multiple pulping and purification operations required by the original resolution process, significantly reducing preparation costs. This method holds promise for cost reduction and large-scale production of the compound of Formula I.

[0066] Terms and Definitions

[0067] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains.

[0068] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0069] Term "C" 1-12 "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably "C". 1- 6-alkyl. "C 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0070] The term "halogenated C" 1-12 "alkyl" should be understood as C 1-12 A group in which one, two, three, four, five, or six H atoms on an alkyl group are replaced by halogen atoms, wherein C 1-12 Alkyl groups have the above definition.

[0071] Term "C" 3-20"Cycloalkyl" should be understood as representing a saturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring (also called a fused ring hydrocarbon ring) with 3-20 carbon atoms. Bicyclic or polycyclic cycloalkyl includes fused cycloalkyl, bridged cycloalkyl, and spirocyclic cycloalkyl; fused ring refers to a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). Bridged ring refers to a fused ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Spirocyclic refers to a fused ring structure formed by two or more cyclic structures sharing a single ring atom. For example, the C 3-20 Cycloalkyl groups can be C 3-8 Monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7-12 Circoalkyl, such as decahydronaphthalene ring; or C 7-12 Bridged cycloalkyl groups, such as norbornene, adamantane, and bicyclo[2,2,2]octane.

[0072] The term "3-20 membered heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O, and S, preferably a "3-12 membered heterocyclic group". The term "3-10 membered heterocyclic group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O, and S. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). In particular, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl, oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one, two, or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl, 1,3-benzooxazolyl, or 1,3-benzodioxacyclopentenyl. According to the invention, the heterocyclic group is non-aromatic.

[0073] Term "C" 6-20"Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms that is monovalent and partially aromatic, preferably "C". 6-14 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0074] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc. Attached Figure Description

[0075] Figure 1 shows the LCMS spectrum of compound 8.

[0076] Figure 2 shows the LCMS spectrum of compound 9.

[0077] Figure 3 shows the MS spectrum of compound 10.

[0078] Figure 4 shows the MS spectrum of compound 11.

[0079] Figure 5 shows the chiral HPLC spectrum of compound 12.

[0080] Figure 6 shows the MS spectrum of compound 12.

[0081] Figure 7 shows the MS spectrum of compound A02.

[0082] Figure 8 shows the MS spectrum of compound A03.

[0083] Figure 9 shows the MS spectrum of compound A04.

[0084] Figure 10 shows the MS spectra of compounds A05 and A07.

[0085] Figure 11 shows the MS spectrum of compound A06. Detailed Implementation

[0086] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0087] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0088] Unless otherwise specified, the yields in the following examples are all included yields.

[0089] The enantiomeric ratios (molar ratios) in the following examples were obtained by chiral HPLC determination.

[0090] Example 1

[0091] Under nitrogen protection, 20.00 g of compound 2, 200 mL of methanol, and 17.24 g of compound 7 were added to a 250 mL three-necked flask. The reaction solution was heated to 40 °C and reacted for 5 h. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated, 200 mL of DCM was added, and the mixture was washed with water 100 mL × 3 times. After drying the organic phase, it was concentrated to dryness and then slurried with 3 times its volume of ethanol for 1 h. The mixture was filtered, and the filter cake was washed with EtOH / MTBE (V:V = 1 / 1). The solid was dried to obtain a pale yellow solid, compound 8, with a purity of 96% and a yield of 70%. LCMS (ESI, m / z): 250.02 [M+H]+ As shown in Figure 1.

[0092] Example 2

[0093] Under nitrogen protection, 18.90 g of compound 8 and 200 mL of 1,4-dioxane were added to a 500 mL three-necked flask. The temperature was raised to 50-60 °C, and 23.00 g of POCl3 was added dropwise. After the addition was complete, the temperature was raised to reflux at an internal temperature of 103 °C (120 °C in an oil bath) and maintained at reflux for 6 hours. The reaction was then checked for completion, cooled, and the reaction solution was quenched in 400 mL of 5 M NaOH solution (dropwise addition controlled below 10 °C). A large amount of solid precipitated out. The solution was filtered, and the filter cake was washed with water 20 mL × 3 times. The filter cake was dissolved in 400 mL of DCM, and the organic phase was washed with water 100 mL × 3 times. The organic phase was dried and concentrated to dryness to obtain a yellow solid compound 9 with a purity of 98% and a yield of 90%. LCMS (ESI, m / z): 232.02 [M+H] + As shown in Figure 2.

[0094] Example 3

[0095] Under nitrogen protection, compound 9 (20 g, 86.5 mmol) and 3 equivalents of acetic acid were dissolved in dichloromethane (400 mL) in a 100 mL round-bottom flask, and sodium borohydride (0.5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium borohydride (1.8 eq, 0.15 mol). Stirring was continued at room temperature for another hour. After the reaction was complete, 8 times the volume of water was added to quench the reaction, resulting in separation of the aqueous phase. The organic phase was washed once more with 8 times the volume of water, and the aqueous phases were combined. The pH of the aqueous phase was adjusted to 5–9 with saturated sodium hydroxide solution, and then extracted with 16 times the volume of chloroform. The mixture was allowed to stand for separation, dried over anhydrous sodium sulfate, concentrated, and filtered to give compound 10 in 80% yield. MS (ESI, m / z): 236.04 [M+H] + As shown in Figure 3. 1 ¹H NMR (500 MHz, deuterated chloroform) δ 7.66 (s, 1H), 4.38–4.29 (m, 4H), 3.15–3.04 (m, 3H), 3.08–3.02 (m, 1H), 2.47 (s, 3H), 1.53 (s, 2H).

[0096] Example 4

[0097] 10.00 g of compound 10, 0.084 mol (2.0 eq.) of hydrogen peroxide, and 100 mL of dichloromethane were added to a 250 mL three-necked flask at room temperature. 10.90 g of N,N-diisopropylethylamine (0.084 mol, 2.0 eq.) was added dropwise. The mixture was heated to 40 °C and stirred for 1 h. LC-MS analysis showed the reaction was complete. The mixture was then cooled, and 50 mL of 20% Na₂S₂O₃ solution was added and stirred for 0.5 h. The mixture was separated, and the organic phase was washed twice with 5 mL of water. The organic phase was dried and concentrated to give a yellow solid, compound 11, with a purity of 95% and a yield of 99%. MS (ESI, m / z): 234.01 [M+H] + As shown in Figure 4.

[0098] Example 5

[0099] At room temperature, weigh 10 g (42.86 mmol) of compound 11 into a 500 mL single-necked flask and add it to the flask. Then add 400 mL of MeOH to the flask. Weigh 8.67 g (85.7 mmol, 2 eq) of NEt3 into a 50 mL beaker and add 9.86 g (214.3 mmol, 5 eq) of HCOOH into the beaker under ice bath conditions. Stir and allow to return to room temperature. Transfer the solution from the beaker to a 500 mL single-necked flask and add 510 mg of chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium(II). The reaction solution was initially turbid. After stirring overnight at room temperature, the solution became clear. After the reaction was complete, the methanol in the system was concentrated by rotary evaporation, and 200 mL of water (20V) and 200 mL of DCM (20V) were added. The aqueous phase was separated, and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. Extraction was then performed with 200 mL of DCM (20V), and the extract was dried over anhydrous sodium sulfate. The final product was obtained by rotary evaporation with a yield of 92%, HPLC: 99.1%; er: 95:5. The chiral HPLC is shown in Figure 5. MS (ESI, m / z): 236.04 [M+H] + As shown in Figure 6.

[0100] Example 6

[0101] Compound 9 (10 g, 42.86 mmol), ligand L12 (S-SegPhos, 3.3 g, 5.36 mmol, 0.125 eq.), and [Ir(COD)]Cl]2 (1.43 g, 2.14 mmol, 0.05 eq.) and 400 mL of toluene were weighed at room temperature and added to a hydrogenation reactor. After purging with hydrogen three times, the reactor was pressurized to 100 psi and heated in an oil bath to 60-70 °C to initiate the reaction. The reaction was carried out overnight. After the reaction was completed, 200 mL of water (20 V) was added to adjust the pH to 1-2. The aqueous phase was separated and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. 200 mL of DCM (20 V) was added for extraction, and the mixture was dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound 12, yield 90%, HPLC: 98%, ER: 90:10. LCMS (ESI, m / z): 236.04 [M+H] + As shown in Figure 6.

[0102] Comparative Example 1

[0103] At room temperature, weigh 5 g (21.43 mmol) of compound 11 into a 250 mL single-necked flask and add it to the flask. Then add 200 mL of MeOH to the flask. Weigh 4.4 g (43 mmol, 2 eq) of NEt3 into a 50 mL beaker and add 4.93 g (107.3 mmol, 5 eq) of HCOOH into the beaker while it is in an ice bath. Stir and then allow the mixture to return to room temperature. The solution in the beaker was transferred to a 250 mL single-necked flask, and 265 mg of chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonylamino}(p-cymene)ruthenium(II) was added. At this point, the reaction solution was turbid. The mixture was stirred overnight at room temperature until the solution became clear. After the reaction was completed, the methanol in the system was concentrated by rotary evaporation, and 100 mL of water (20V) and 100 mL of DCM (20V) were added. The aqueous phase was separated and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. 100 mL of DCM (20V) was added for extraction, and the mixture was dried over anhydrous sodium sulfate. The final product was obtained by rotary evaporation with a yield of 80%, HPLC: 95%, ER: 60:40.

[0104] Comparative Example 2

[0105] At room temperature, weigh 5 g (21.43 mmol) of compound 11 into a 250 mL single-necked flask and add 200 mL of MeOH to the system. Weigh 4.4 g (43 mmol, 2 eq) of NEt3 into a 50 mL beaker and add 4.93 g (107.3 mmol, 5 eq) of HCOOH into the beaker under ice bath conditions. Stir and allow to return to room temperature. The solution in the beaker was transferred to a 250 mL single-necked flask, and 265 mg of chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonylamino}(trimethylbenzene)ruthenium(II) was added. At this point, the reaction solution was turbid. The mixture was stirred overnight at room temperature until the solution became clear. After the reaction was completed, the methanol in the system was concentrated by rotary evaporation, and 100 mL of water (20V) and 100 mL of DCM (20V) were added. The aqueous phase was separated and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. 100 mL of DCM (20V) was added for extraction, and the mixture was dried over anhydrous sodium sulfate. The final product was obtained by rotary evaporation with a yield of 84%, HPLC: 96%, ER: 66:34.

[0106] Comparative Example 3

[0107] Compound 9 (10 g, 42.86 mmol), ligand L1 (2.2 g, 5.36 mmol, 0.125 eq.), [Ir(COD)]Cl]2 (1.43 g, 2.14 mmol, 0.05 eq.), and 400 mL of toluene were weighed at room temperature and added to a hydrogenation reactor. After purging with hydrogen three times, the pressure was increased to 100 psi, and the oil bath was heated to 60-70 °C to start the reaction. The reaction was carried out overnight. After the reaction was completed, 200 mL of water (20 V) was added to adjust the pH to 1-2. The aqueous phase was separated and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. 200 mL of DCM (20 V) was added for extraction, and the mixture was dried over anhydrous sodium sulfate. The extract was then evaporated to dryness to obtain compound 12, with a yield of 50% (HPLC: 98%, ER: 52:48).

[0108] Comparative Example 4

[0109] Compound 9 (10 g, 42.86 mmol), ligand L1 (3.7 g, 5.36 mmol, 0.125 eq.), [Ir(COD)]Cl]2 (1.43 g, 2.14 mmol, 0.05 eq.), and 400 mL of toluene were weighed at room temperature and added to a hydrogenation reactor. After purging with hydrogen three times, the pressure was increased to 100 psi, and the oil bath was heated to 60-70 °C to start the reaction. The reaction was carried out overnight. After the reaction was completed, 200 mL of water (20 V) was added to adjust the pH to 1-2. The aqueous phase was separated and the pH of the aqueous phase was adjusted to greater than 10 with NaOH aqueous solution. 200 mL of DCM (20 V) was added for extraction, and the mixture was dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound 12, with a yield of 56% (HPLC: 98%, ER: 60: 40).

[0110] Example 7

[0111] Step 1 & Step 2 consecutive throws

[0112] Compound A01 (10 g, 64.52 mmol) was added to a reaction vessel and dissolved in methanol (100 ml, 10V). Then, 0.025 equivalents of Pd(OAc)₂ (0.364 g), dppf (0.753 g), and 1 equivalent of potassium carbonate solid were added sequentially. CO gas was then introduced to replace the air in the system twice. The pressure was then increased to 0.8-1.0 MPa by introducing CO gas, and the reaction was heated and stirred at 40°C. The reaction was allowed to proceed for 3.5-4 h, with the pressure inside the vessel maintained for 30 min. The reaction was then stopped, and samples were taken for LC-MS analysis. 97.55% of the starting material was converted to the product, with 2.45% of the starting material remaining. The reaction solution was filtered to remove the solids, and the mother liquor was analyzed. MS m / z (ESI): 178.8 / 180.7 (3:1) (M+1, see Figure 7).

[0113] The filtered solution containing A02 (approximately 9.8 g, 55.05 mmol) was concentrated to dryness, then dissolved in THF (100 ml, 10 V), and 1.1 equivalents of compound 7 were added, followed by 5 equivalents of sodium carbonate solid. The mixture was heated and stirred at 40 °C, and the reaction was monitored by central LC-MS until completion. A small amount of impurities were generated, which were removed by slurrying with water. The reaction system was concentrated to dryness, and then 150 ml of water was added for slurrying twice. The solid was filtered and dried to obtain 14.38 g of solid product. The QNMR content was 85.6%, yielding the final product A03. The overall yield of compounds A01 to A03 was 71%. MS m / z (ESI): 270.01 / 271.92 (3:1) (M+1, see Figure 8).

[0114] Step 3

[0115] Compound A03 (1.2 g, 2.25 mmol) was dissolved in 1,4-dioxane (1200 mL). The reaction solution was heated to 60 °C under nitrogen protection and stirred, and phosphorus oxychloride (132.85 g, 866.41 mmol) was added. The temperature was raised to 80-90 °C and stirred for 16 hours. After the reaction was completed, solid precipitates and black oil at the bottom of the flask were separated. Black oil product: The remaining black oil at the bottom of the flask was dissolved in methanol (250 mL), 60 g of diatomaceous earth was added and stirred for 0.5 hours, filtered, and the filtrate was evaporated to dryness. It was then combined with the collected precipitated solid product for subsequent water and ethanol slurrying. Solid product: After cooling to room temperature, the reaction solution was added to a cooled 5M NaOH aqueous solution (2400 mL) for quenching. Filtered, and the filter cake was washed with water (120 mL). The filter cake was then slurried with water (1200 mL), filtered, and then slurried with ethanol (600 mL). The solid was filtered to obtain the product compound A04, with a yield of 91%. MS m / z (ESI): 252.0 (M+1, see Figure 9).

[0116] Step 4

[0117] Compound A04 (94.05 g, 373.67 mmol) was dissolved in 3 equivalents of acetic acid in dichloromethane (2000 mL), and sodium borohydride (373.67 mmol) was added in portions under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (500 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to remove dichloromethane and acetic acid. 1.25 M NaOH aqueous solution (2000 mL) was added, and the mixture was stirred at room temperature for 0.5 hours, resulting in the precipitation of a large amount of yellow solid. Dichloromethane (1000 mL × 3) was added for extraction, and the organic phases were combined, washed with water (1000 mL), dried, and concentrated. Acetone (120 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed with acetone (20 mL), and then washed with acetone / n-heptane (150 mL, v / v) at a ratio of 1:3. The mixture was filtered, dried, and the product compound A05 was obtained in 85% yield. MS m / z (ESI): 256.0 (M+1, see Figure 10).

[0118] Step 5

[0119] Compound A05 (95.35 g) was dissolved in dichloromethane (1000 mL), and H2O2 (20 mL) was added. Triethylamine (75.46 g) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated, and the crude product was slurried with 10% sodium thiosulfate aqueous solution (1000 mL), filtered, and the solid was slurried again with water (1000 mL). The filter cake was washed with water and n-heptane and dried to obtain the product compound A06, with a yield of 94%. MS m / z (ESI): 254.0 (M+1, see Figure 11).

[0120] Step 6

[0121] Compound A06 (85.26 g) was added to methanol (1700 mL), followed by triethylamine (68.01 g). Formic acid (77.33 g) was added under ice bath conditions, and the mixture was stirred until it returned to room temperature. Then, chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](1,1,1,-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium(II) (4.79 g) was added to the system, and the mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the solution was concentrated and dissolved in dichloromethane (1000 mL) and water (1000 mL). The pH was weakly acidic. The system was adjusted to pH 2-3 with hydrochloric acid, stirred, and separated. The organic phase was extracted with water (1000 mL × 2) at pH 2-3. The aqueous phases were combined and the pH was adjusted to 10 with 5M NaOH aqueous solution. The aqueous phase was then extracted with dichloromethane (1000 mL × 3). The organic phases were combined, washed with water (1000 mL × 2), dried, and evaporated to dryness to obtain 76.43 g of solid. The solid was added to a flask, and ethanol (1540 mL) was added. The mixture was heated to 50 °C until it dissolved and became clear. The mixture was then allowed to cool to room temperature, during which seed crystals were added, and the mixture was stirred overnight at room temperature. The solid precipitated, was filtered, and the mother liquor was evaporated to dryness to obtain solid compound A07 (er = 98.1 / 1.9), with a yield of 60%. MS m / z (ESI): 256.0 (M+1, see Figure 10).

[0122] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A method for preparing the compound shown in Formula I, characterized in that, include: Method 1. Compound I-11 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral ruthenium complex and / or a chiral rhodium complex 1 to give the compound shown in Formula I; or, Method 2. Compound I-9 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral phosphine ligand and an iridium complex and / or a rhodium complex 2 to give the compound shown in Formula I; Among them, R1 and R2 may be the same or different, and are independently selected from H, halogens, and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3- 20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups; The "*" indicates that the carbon at that position in the compound shown in formula I is a chiral carbon, and it is either an R configuration or an S configuration. In Method 1, when it is necessary to prepare the compound of Formula I with the R configuration, a chiral ruthenium complex and / or rhodium complex 1 with the S,S configuration is used; Alternatively, when it is necessary to prepare the S-configuration compound of Formula I, a chiral ruthenium complex and / or rhodium complex 1 with an R,R configuration is used; In Method 2, when it is necessary to prepare the S-configuration compound shown in Formula I, the R-configuration chiral phosphine ligand and iridium complex and / or rhodium complex 2 are used; Alternatively, when it is necessary to prepare the R-configuration compound of Formula I, the S-configuration chiral phosphine ligand and iridium complex and / or rhodium complex 2 are used.

2. The method according to claim 1, characterized in that, R1 and R2 may be the same or different, and are independently selected from H, fluorine, bromine, chlorine, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl compounds.

3. The method according to claim 1 or 2, characterized in that, R1 is selected from H, bromine, methyl, ethyl, or bromomethyl; R2 is selected from H, chloro, methyl, ethyl, or chloromethyl.

4. The method according to any one of claims 1-3, characterized in that, The compound shown in Formula I is selected from the following compounds:

5. The method according to any one of claims 1-4, characterized in that, The chiral ruthenium complex is selected from chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(trimethylbenzene)ruthenium(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)ruthenium(II), and chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)ruthenium(II); Alternatively, at least one of the following: chlorine {N-[(1R,2R)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)ruthenium(II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(trimethylbenzene)ruthenium(II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)ruthenium(II), chlorine {[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)ruthenium(II); Preferably, the chiral rhodium complex 1 is selected from chloro{N-[(1R,2R)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)Rh(II), chloro{[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(metobenzene)Rh(II), chloro{[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)Rh(II), and chloro{[(1R,2R)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)Rh(II); Alternatively, chloro{N-[(1S,2S)-2-amino-1,2-diphenylethyl](1,1,1-trifluoromethanesulfonyl)amino}(p-cymene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(trimethylbenzene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-trifluorobenzenesulfonyl)amino}(p-cymene)Rh(II), chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](pentafluorobenzenesulfonyl)amino}(hexamethylbenzene)Rh(II).

6. The method according to any one of claims 1-4, characterized in that, The chiral phosphine ligand is selected from at least one of R-SegPhos, (R)-(+)-(6,6′-dimethoxybiphenyl-2,2′-yl)bis(diphenylphosphine), (11aR)-1,11-bis(diphenylphosphine)dibenzo[d,f][1,3]dioxane, (R)-(-)-2,2,6,6-tetramethoxy-4,4-bis(diphenylphosphine)-3,3-bipyridine, and (R)-(+)-2,2′-bis(di-4-methylphenylphosphine)-1,1′-binaphthyl; Or, at least one of S-SegPhos, (S)-(+)-(6,6′-dimethoxybiphenyl-2,2′-yl)bis(diphenylphosphine), (11aS)-1,11-bis(diphenylphosphine)dibenzo[d,f][1,3]dioxane, (S)-(-)-2,2,6,6-tetramethoxy-4,4-bis(diphenylphosphine)-3,3-bipyridine, and (S)-(+)-2,2′-bis(di-4-methylphenylphosphine)-1,1′-binaphthyl; Preferably, the iridium complex is [Ir(COD)]Cl]2; Preferably, the rhodium complex 2 is Rh(COD)2BF4.

7. The method according to any one of claims 1-5, characterized in that, Method 1 possesses at least one of the following features: 1) The reaction is carried out in the presence of an organic base-ammonium formate or an organic base-formic acid as a cocatalyst; 2) The amount of the chiral ruthenium complex and / or rhodium complex 1 used is 0.1 to 50 g of chiral ruthenium complex and / or rhodium complex 1 per mol of organic base; 3) The asymmetric hydrogenation reaction is carried out at 0–30°C; 4) The asymmetric hydrogenation reaction is carried out in an alcohol solvent.

8. The method according to claim 7, characterized in that, Method 1 includes the following steps: S1. Compound I-10 undergoes an oxidation reaction to yield compound I-11; S2. Compound I-11 was subjected to an asymmetric hydrogenation reaction in the presence of a chiral ruthenium complex and / or rhodium complex 1 to give the compound shown in Formula I; Preferably, the oxidation reaction in step S1 is carried out in the presence of oxidants such as hydrogen peroxide, trichloroisocyanuric acid, and dichlorodicyanobenzoquinone.

9. The method according to claim 8, characterized in that, Method 1 also includes the preparation process of compound I-10, comprising the following steps: Step A1. Compound I-9 undergoes a reduction reaction to obtain compound I-10; Wherein, R1 and R2 have the definitions described in any one of claims 1-3; Preferably, the reduction reaction in step A1 is carried out in the presence of a reducing agent such as sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, or lithium borohydride.

10. The method according to claim 1 or 9, characterized in that, Compound I-9 was prepared by the following method: Compound I-2 reacts with compound I-7 to give compound I-8; compound I-8 undergoes a cyclization reaction to give compound I-9. Wherein, R1 and R2 have the definitions described in any one of claims 1-3.

Images