Preparation method of Milvexian

Abstract

The invention discloses a preparation method of Milvexian, and belongs to the technical field of synthesis of organic compounds. The invention provides a novel preparation method of Milvexian. The preparation method mainly comprises the following steps: nucleophilic addition and elimination of imine, coupling of aryl ammonia and olefine acid, and double bond reduction of olefin. The method is simple in preparation step, high in yield, low in price, convenient to operate and environment-friendly, and has a relatively wide industrial production prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of Milvexian. Background Art

[0002] Milvexian was developed by Bristol-Myers Squibb (BMS) and has now reached the third phase of clinical trials. As an antithrombotic drug, Milvexian mainly acts on the activated form of factor XI (FXIa) in the physiological natural blood coagulation pathway. By inhibiting the activity of FXIa, it achieves the effect of preventing thrombus formation. Compared with previous antithrombotic drugs, this compound has the advantages of being orally available, having a long in vivo metabolic half-life, and a low probability of causing major bleeding in the body. Therefore, it is of great significance to find an economical and green synthesis method.

[0003] An article published by Bristol-Myers Squibb in the Journal of Medicinal Chemistry in 2021: Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy reported the synthesis of Milvexian. The reaction time of the first step is overnight, which is relatively long; the coupling agent used for the condensation of amino group and carboxyl group in the seventh step is T3P (2,4,6-tripropyl-1,3,5,2λ5,4λ5,6λ5-trioxatriphosphane-2,4,6-trione), and this reagent belongs to the scope of drugs precursor and explosive precursor control, so other coupling agents are used instead; the reduction reaction in the ninth step uses palladium-carbon-catalyzed high-pressure hydrogenation, which has great safety hazards and a long reaction time, and is not conducive to industrial production. US Patent WO2020 / 21063 reported another synthesis method of Milvexian. The steps are very cumbersome (a total of 13 steps). In short, it is of great value to develop a new method for preparing Milvexian with high efficiency, environmental protection and low cost. Summary of the Invention

[0004] Object of the Invention: Aiming at the problems existing in the prior art, the present invention provides a method for preparing Milvexian that is economical, simple, environmentally friendly, has a high yield and is suitable for industrial production, effectively solving the problems of complex preparation and long reaction time of existing Milvexian.

[0005] Technical Solution: To achieve the above object, the present invention provides a method for preparing Milvexian, comprising the following steps:

[0006] Step (1): 4-chloropyridinecarbaldehyde shown in Formula I and S-tert-butylsulfinamide shown in Formula II are subjected to a nucleophilic addition reaction under the action of a borate ester, and then dehydrated to obtain (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide shown in Formula III;

[0007]

[0008] Step (2): Allylmagnesium bromide shown in Formula IV reacts with indium trichloride to form an indium allyl reagent, and then undergoes a nucleophilic addition reaction with (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide shown in Formula III prepared in Step (1), directly generating (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide shown in Formula V;

[0009]

[0010] Step (3): The compound of Formula V is hydrolyzed to directly generate (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride shown in Formula VI;

[0011]

[0012] Step (4): The compound of Formula VI is dehydrochlorinated to obtain a free amine, and then undergoes a nucleophilic addition with di-tert-butyl dicarbonate shown in Formula VII and elimination to generate tert-butyl (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula VIII;

[0013]

[0014] Step (5): Under the activation of a coupling agent, the compound of Formula VIII undergoes a C-H activation type coupling reaction with 1-(difluoromethyl)-4-nitro-1H-pyrazole shown in Formula IX under basic conditions and catalytic action to generate tert-butyl (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula X;

[0015]

[0016] Step (6): The compound of Formula X is reduced under weakly acidic conditions to (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula XI;

[0017]

[0018] Step (7): Under alkaline conditions, the compound of formula ⅩⅠ undergoes coupling with (R)-2-methylbut-3-enoic acid shown in formula ⅩⅡ through a condensing agent to obtain tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in formula ⅩⅢ;

[0019]

[0020] Step (8): Under the catalysis, the compound of formula ⅩⅢ undergoes olefin metathesis reaction to remove one molecule of ethylene to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolo-cyclonon-6-en-9-yl]carbamate shown in formula ⅩⅣ;

[0021]

[0022] Step (9): In a hydrazine solution, the compound of formula ⅩⅣ is reduced to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolo-cyclonon-9-yl]carbamate shown in formula ⅩⅤ;

[0023]

[0024] Step (10): The compound of formula ⅩⅤ is hydrolyzed to form a hydrochloride salt, and then hydrogen chloride is removed to obtain (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolo-cyclonon-4-one shown in formula ⅩⅥ;

[0025]

[0026] Step (11): Under alkaline conditions, the compound of formula ⅩⅥ undergoes condensation with 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol shown in formula ⅩⅦ through a condensing agent to form (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolo-cyclonon-4-one (Milvexian) shown in formula ⅩⅧ;

[0027]

[0028] Among them, in step (1), (S)-tert-butanesulfinamide forms a borate intermediate with the catalyst borate ester. This intermediate adds to 4-chloropyridinecarboxaldehyde shown in formula I and eliminates one molecule of water to obtain formula III. The borate ester used is tris(2,2,2-trifluoroethyl) borate or tris(hexafluoroisopropyl) borate. The molar ratio range of the borate ester used to the compound of formula I is 1.0 - 1.5∶1; when (S)-tert-butanesulfinamide reacts with tris(2,2,2-trifluoroethyl) borate in step (1), the reaction solvent used in step (1) is any one or a mixture of acetone, acetonitrile, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylacetamide, dimethyl sulfoxide.

[0029] Among them, in step (3), the compound of formula V is hydrolyzed with hydrogen chloride ethyl acetate solution to directly generate (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride shown in formula VI.

[0030] Among them, in step (4), the compound of formula VI is dehydrochlorinated with triethylamine to obtain the free amine, and then undergoes nucleophilic addition with di-tert-butyl dicarbonate shown in formula VII and elimination to generate tert-butyl (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate shown in formula VIII.

[0031] Among them, in step (5), under the activation of the coupling agent palladium acetate, under the alkaline condition provided by potassium carbonate and the catalytic action of pivalic acid (PivOH), the compound of formula VIII undergoes a C-H activation type coupling reaction with 1-(difluoromethyl)-4-nitro-1H-pyrazole shown in formula IX to generate tert-butyl (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in formula X.

[0032] Among them, in step (7), tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in formula ⅩⅠ and (R)-2-methylbut-3-enoic acid shown in formula ⅩⅡ undergo coupling by eliminating one molecule of water under the catalysis of a condensing agent to obtain tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate of formula ⅩⅢ. The bases used are pyridine (Py), 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), and the molar ratio range of the base used to the compound of formula ⅩⅠ is 1.5 - 3∶1; the condensing agents are O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylazanium, hexafluorophosphate (HBTU), diethyl (4-oxo-1,2,3-benzotriazin-3(4H)-yl)phosphate (DEPBT), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), bis(1H-imidazol-1-yl)methanone (CDI), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ), N,N′-dicyclohexylmethanediimine (DCC), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N′-dicyclohexylmethanediimine (DCC) and 1H-1,2,3-benzotriazol-1-ol (HOBt), N,N'-di(propan-2-yl)methanediimine (DIC) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N'-di(propan-2-yl)methanediimine (DIC), 1H-1,2,3-benzotriazol-1-ol (HOBt). The molar ratio range of the condensing agent to the compound of formula ⅩⅠ is 1.0 - 1.2∶1; the solvents used are any one or a mixture of acetone, acetonitrile, toluene, chloroform, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylacetamide, dimethyl sulfoxide.

[0033] Among them, in step (8), the compound of formula ⅩⅢ undergoes olefin metathesis under the catalysis of Grubbs second-generation catalyst to eliminate one molecule of ethylene to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolo[1,5-a]cyclonon-6-en-9-yl]carbamate shown in formula ⅩⅣ.

[0034] Among them, in step (9), the olefin double bond of tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazacyclonon-6-en-9-yl] carbamate shown in formula XIV is reduced to an alkane single bond by hydrazine. The reducing agent used is any one or more of hydrazine, methylhydrazine, ethylhydrazine, propylhydrazine, isopropylhydrazine, cyclopropylhydrazine, cyclomethylpropylhydrazine, phenylhydrazine, o-tolylhydrazine, m-tolylhydrazine, p-tolylhydrazine, o-fluorophenylhydrazine, m-fluorophenylhydrazine, p-fluorophenylhydrazine, p-toluenesulfonylhydrazine. The molar ratio range of the reducing agent used to the compound of formula XIV is 8-12∶1; the solvent used is any one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide.

[0035] Among them, in step (10), the compound of formula XV is first hydrolyzed with a hydrochloric acid 1,4-dioxane solution to form a hydrochloride, and then the hydrochloride is removed by an ammonia methanol solution to obtain (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazacyclonon-4-one of formula XVI.

[0036] Among them, in step (11), under alkaline conditions, the compound of formula XVI reacts with 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol shown in formula XVII through a condensing agent to condense and form the compound of formula XVIII, (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-4-one (Milvexian); the condensing agent is any one or more of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylazanium hexafluorophosphate (HBTU), diethyl (4-oxo-1,2,3-benzotriazin-3(4H)-yl)phosphate (DEPBT), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), bis(1H-imidazol-1-yl)methanone (CDI), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ), N,N'-dicyclohexylmethanediimine (DCC), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N'-dicyclohexylmethanediimine (DCC) and 1H-1,2,3-benzotriazol-1-ol (HOBt), N,N'-bis(propan-2-yl)methanediimine (DIC) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N'-bis(propan-2-yl)methanediimine (DIC) and 1H-1,2,3-benzotriazol-1-ol (HOBt).

[0037] Preferably, the preparation method of Milvexian comprises the following steps:

[0038] Step (1): 4-chloropyridinecarbaldehyde shown in formula I and S-tert-butylsulfinamide shown in formula II are subjected to a nucleophilic addition reaction under the catalysis of a borate ester, and then dehydrated to obtain (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide shown in formula III;

[0039]

[0040] Step (2): React Compound IV with indium trichloride to form an indium allyl reagent, and then perform a nucleophilic addition reaction with the (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide shown in Formula III prepared in Step (1) to directly generate (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide shown in Formula V;

[0041]

[0042] Step (3): Hydrolyze the Compound V with a 4N hydrogen chloride ethyl acetate solution to directly generate (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride shown in Formula VI.

[0043]

[0044] Step (4): Remove hydrogen chloride from the Compound VI with triethylamine to obtain a free amine, and then perform a nucleophilic addition and elimination reaction with di-tert-butyl dicarbonate shown in Formula VII to generate tert-butyl (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula VIII;

[0045]

[0046] Step (5): Under the activation of the coupling agent palladium acetate, under the alkaline condition provided by potassium carbonate and the catalytic action of pivalic acid (PivOH), the Compound VIII undergoes a C-H activation type coupling reaction with 1-(difluoromethyl)-4-nitro-1H-pyrazole shown in Formula IX to generate tert-butyl (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula X;

[0047]

[0048] Step (6): Under the weak acidic condition provided by ammonium chloride solution, the Compound X is reduced by iron powder to generate tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in Formula XI;

[0049]

[0050] Step (7): The compound of formula ⅩⅠ undergoes coupling with (R)-2-methylbut-3-enoic acid shown in formula ⅩⅡ under alkaline conditions through a condensing agent to obtain tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate shown in formula ⅩⅢ;

[0051]

[0052] Step (8): The compound of formula ⅩⅢ undergoes olefin metathesis reaction under the catalysis of Grubbs second-generation catalyst to remove one molecule of ethylene to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-6-en-9-yl]carbamate shown in formula ⅩⅣ;

[0053]

[0054] Step (9): The compound of formula ⅩⅣ is reduced to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-9-yl]carbamate shown in formula ⅩⅤ;

[0055]

[0056] Step (10): The compound of formula ⅩⅤ is first hydrolyzed with 1,4-dioxane solution of hydrochloric acid to form a hydrochloride salt, and then the hydrochloride is removed with methanol solution of ammonia to obtain (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-4-one shown in formula ⅩⅥ;

[0057]

[0058] Step (11): The compound of formula ⅩⅥ under alkaline conditions, through a condensing agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol shown in formula ⅩⅦ, is condensed to form (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-4-one (Milvexian) shown in formula ⅩⅧ;

[0059]

[0060] Based on the existing Milvexian synthesis method, the present invention provides a completely new preparation process for Milvexian. In step 1 of the present invention, borate ester is used to replace the strong base cesium carbonate used in the prior art, which can shorten the reaction time from 12 h to 6 h; in step 7, HATU is used to equivalently replace the explosive precursor-controlled condensing agent T3P, while effectively improving the yield of this step; in step 9, hydrazine solution is used to replace the hydrogen palladium carbon reduction system, which can avoid high-pressure conditions, shorten the reaction duration from 24 h to 6 h, and increase the yield from 72% to 90%. The method of the present invention not only bypasses restricted reagents, increases the reaction yield, but also reduces the reaction time and reaction risk.

[0061] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0062] (1) The raw materials used in the present invention are widely sourced and inexpensive, which is beneficial to cost reduction and industrial production.

[0063] (2) The reaction operation is simple, the reaction time is short, the synthesis efficiency is high, and it is safe, environmentally friendly.

[0064] (3) The synthesis method of the present invention has a wide substrate range and broad applicability. Specific embodiments

[0065] The content of the present invention will be specifically described below through examples. The following examples are for better illustrating the present invention and are not intended to limit the scope of the present invention. Various changes and modifications can be made to the present invention without departing from the purpose and scope of the present invention.

[0066] Unless otherwise specified, the starting materials used in the embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0067] Example 1

[0068] (1) Preparation of (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (Formula III)

[0069] Under normal temperature conditions, 4-chloropyridinecarboxaldehyde (142 mg) and S-tert-butylsulfinamide (121 mg of formula II) were added to a two-necked flask. The flask was evacuated, filled with argon, evacuated again, and this was repeated three times. Finally, an argon balloon was used to maintain an argon atmosphere inside the flask. Tetrahydrofuran (1 mL) was injected to dissolve the substances, and tris(2,2,2-trifluoroethyl) borate (0.215 mL) was injected. After addition, the mixture was stirred at room temperature for 6 h until the reaction was complete (monitored by TLC). 4 mL of ethyl acetate was added to dilute the reaction solution, and the reaction solution was washed with 10 mL of saturated ammonium chloride solution and 10 mL of saturated sodium chloride solution respectively. The reaction solution was dried over anhydrous sodium sulfate overnight, filtered, and an appropriate amount of silica gel was added and loaded onto a silica gel column by dry method. The eluent used was ethyl acetate and petroleum ether 10%-20% for column chromatography to obtain a pale yellow thick liquid. Ethyl acetate (0.5 mL) was added to dissolve it, and n-hexane (25 mL) was added. The temperature was lowered for crystallization to precipitate white crystals of the compound of formula III (76%).

[0070] The HPLC purity is above 99%. 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 5.3, 2.0 Hz, 1H), 1.29 (s, 9H).

[0071] (2) Preparation of (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (formula V)

[0072] Under normal temperature conditions, indium(III) chloride (6.6 g) was added to anhydrous tetrahydrofuran (120 mL), and the mixture was stirred for 30 min and cooled to 0 °C. A solution of allylmagnesium bromide in diethyl ether (1 N, 45 mL of formula IV) was slowly added dropwise, and the mixture was stirred for 1 h. (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (formula III) was dissolved in 57 mL of absolute ethanol and added to the reaction system. The mixture was stirred for 3 h until the reaction was complete as monitored by TLC. 20 mL of ethyl acetate was added to dilute the reaction solution, and 20 mL of water was added to wash the reaction solution. The aqueous phase was extracted twice with ethyl acetate (20 mL), and the organic phases were combined and washed once with saturated brine (80 mL). The reaction solution was dried over anhydrous sodium sulfate overnight, filtered, and an appropriate amount of silica gel was added and loaded onto a silica gel column by dry method. The eluent used was ethyl acetate and petroleum ether 20%-50% for column chromatography to obtain a colorless thick liquid, the compound of formula V (91%). The HPLC purity is above 99%. 11H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.19 (dd, J = 5.3, 1.9 Hz, 1H), 5.75–5.62 (m, 1H), 5.10–4.99 (m, 2H), 4.74 (d, J = 7.3 Hz, 1H), 4.44 (q, J = 6.8 Hz, 1H), 2.61–2.54 (m, 2H), 1.25 (s, 9H).

[0073] (3) Preparation of (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride (VI)

[0074] Under room temperature conditions, dissolve (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.1 g, 3.835 mmol, formula V) in 11.8 mL of methanol, and add ethyl acetate solution of hydrogen chloride with a concentration of 4N (4.79 mL). Stir for 2 h until the reaction is completed as monitored by TLC. Evaporate the reaction solution under vacuum, add 20 mL of ethyl acetate for pulping, filter, wash the filter cake with ethyl acetate, and dry the filter cake to obtain the crude product of compound (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride of formula VI, and directly proceed to the next reaction.

[0075] (4) Preparation of tert-butyl (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (formula VIII)

[0076] Under room temperature conditions, place (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride (VI, 3.835 mmol) in 11.8 mL of acetonitrile, add 5.35 mL of triethylamine, and then add 1.76 mL of di-tert-butyl dicarbonate (formula VII). Stir for 3 h until the reaction is complete as monitored by TLC. Evaporate the reaction solution under vacuum, add 20 mL of ethyl acetate for dilution, wash the reaction solution with 80 mL of saturated ammonium chloride solution, wash the aqueous phase twice with ethyl acetate (20 mL × 2), combine the organic phases, wash once with 100 mL of saturated brine, dry the reaction solution with anhydrous sodium sulfate overnight, filter, add an appropriate amount of silica gel and load it onto a silica gel column by dry method, and elute with ethyl acetate and petroleum ether 10 - 20% to obtain the white solid compound of formula VIII (72%). The HPLC purity is above 99%. 1HNMR(400MHz,Chloroform-d)δ8.45(d,J=5.3Hz,1H),7.24(d,J=2.0Hz,1H),7.18(dd,J=5.3,2.0Hz,1H),5.71–5.59(m,1H),5.47(d,J=8.2Hz,1H),5.13–5.00(m,2H),4.78(q,J=7.1Hz,1H),2.64–2.49(m,2H),1.43(s,9H).

[0077] (5) Preparation of tert-butyl (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (Formula X)

[0078] Under room temperature conditions, palladium acetate (57.9 mg), n-butyldi(1-adamantyl)phosphine (183.4 mg), potassium carbonate (1060 mg), and pivalic acid (78.4 mg) were placed in a two-necked flask. The flask was purged with an argon balloon and a water pump three times, and finally filled and protected with argon. tert-Butyl (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (Ⅷ 723.4 mg) and 1-(difluoromethyl)-4-nitro-1H-pyrazole (Formula IX 0.268 mL) were dissolved in anhydrous 1,4-dioxane (7.2 mL) and injected into the two-necked flask. The two-necked flask was placed in an oil bath at 100 °C and heated under reflux for 5 h until the reaction was monitored by TLC to be complete. After cooling to room temperature, the reaction solution was washed with 50 mL of water. The aqueous phase was washed twice with ethyl acetate (20 mL × 2). The organic phases were combined, washed once with 100 mL of saturated brine, and the reaction solution was dried over anhydrous sodium sulfate overnight, filtered, and an appropriate amount of silica gel was added for dry loading onto a silica gel column. The eluent used ethyl acetate and petroleum ether 10 - 20% for column chromatography to obtain a reddish-brown thick liquid of Compound of Formula X (58%). The HPLC purity was above 99%. 1 H NMR(400MHz,Chloroform-d)δ8.77(d,J=5.1Hz,1H),8.33(s,1H),7.32(s,1H),7.28(dd,J=5.0,1.7Hz,1H),7.08(td,J=17.6,3.2Hz,1H),5.75–5.62(m,1H),5.11–5.00(m,2H),4.96–4.81(m,1H),2.63(t,J=6.9Hz,2H),1.43(s,9H).

[0079] (6) Preparation of tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (Formula XI)

[0080] Under normal temperature conditions, dissolve tert-butyl (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (formula Ⅹ, 518 mg) in 8.35 mL, add 6.3 N aqueous ammonium chloride solution (2 mL), add iron powder (353.15 mg) activated with dilute hydrochloric acid, transfer the reaction vessel to an oil bath at 65 °C, heat under reflux for 8 h until the reaction is complete as monitored by TLC. Filter the reaction solution through diatomaceous earth while it is hot, wash the filter cake with methanol, evaporate the reaction solution under vacuum, wash the reaction solution with 30 mL of water, wash the aqueous phase twice with ethyl acetate (20 mL × 2), combine the organic phases, wash once with 80 mL of saturated brine, dry the reaction solution over anhydrous sodium sulfate overnight, filter, add an appropriate amount of silica gel and load it onto a silica gel column dryly. Use ethyl acetate and petroleum ether 30 - 50% for column elution to obtain a pale yellow thick liquid, the compound of formula XI (69%). The HPLC purity is above 99%. 1 H NMR(400MHz,Chloroform-d)δ8.67(d,J=5.1Hz,1H),7.40(s,1H),7.33(s,1H),7.30(d,J=4.5Hz,1H),7.24–6.95(m,1H),5.76–5.64(m,1H),5.58(d,J=7.8Hz,1H),5.06(d,J=11.4Hz,2H),4.85(p,J=7.2Hz,1H),3.18(s,2H),2.63(t,J=6.2Hz,2H),1.43(s,10H).

[0081] (7) Preparation of tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (formula ⅩⅢ)

[0082] Under normal temperature conditions, in a round-bottom flask, add tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (6.95 g of Formula ⅩⅠ), pyridine (2.96 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 9.05 g). Add 52 mL of dichloromethane and stir to dissolve it completely. Add (R)-2-methylbut-3-enoic acid (2.46 mL of Formula ⅩⅡ), stir for 8 h until the reaction is complete (monitored by TLC). After the reaction is complete, add 150 mL of saturated ammonium chloride solution to wash the reaction solution. The aqueous phase is washed twice with ethyl acetate (50 mL). Combine the organic phases and wash once with saturated sodium chloride solution (100 mL). Add an appropriate amount of anhydrous sodium sulfate and dry overnight. Filter, add an appropriate amount of silica gel to the filtrate, load the sample dry onto a silica gel column, and elute with ethyl acetate and petroleum ether 15%-25% to obtain a yellowish-brown thick liquid. After further treatment by adding water and trituration, a yellow solid of Compound of Formula XIII (81%) is obtained. The HPLC purity is above 99%. 1 H NMR(400MHz,Chloroform-d)δ8.71(d,J=5.1Hz,1H),8.33(d,J=2.1Hz,1H),7.31(d,J=8.2Hz,1H),7.10(d,J=7.8Hz,2H),5.94–5.81(m,1H),5.76–5.60(m,1H),5.53(s,1H),5.26–5.15(m,2H),5.07(d,J=11.8Hz,2H),4.84(s,1H),3.14(dt,J=13.8,6.9Hz,1H),2.64(d,J=7.0Hz,2H),1.42(s,9H),1.30(d,J=3.1Hz,3H).

[0083] (8) Preparation of tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazacyclonon-6-en-9-yl]carbamate (Formula ⅩⅣ)

[0084] Under normal temperature conditions, in a two-necked flask, the air was replaced 3 times with an argon balloon and a water pump, and the flask was filled with argon for protection. A solution of tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (0.5 g of formula XIII) in 1,2-dichloroethane (150 mL) was injected into the flask. Argon was bubbled into the solution for 10 - 15 min. Grubbs second-generation catalyst (0.23 g) was added. The mixture was heated under reflux in an oil bath at 108 °C for 24 h and monitored by TLC until the reaction was complete. It was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. An appropriate amount of silica gel was added for dry-column chromatography on a silica gel column, and the eluent was ethyl acetate and petroleum ether 25 - 50% for column chromatography to obtain a grayish-brown solid of compound of formula XIV (41%). The HPLC purity was above 99%. The HPLC purity was above 99%. 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J=5.2Hz,1H),7.75(d,J=8.2Hz,1H),7.42–7.36(m,1H),7.34(d,J=5.1Hz,1H),7.25–7.07(m,1H),6.86(d,J=5.0Hz,1H),6.50–6.22(m,1H),5.82–5.65(m,1H),4.84–4.65(m,2H),3.10(d,J=7.7Hz,1H),3.06–2.91(m,1H),2.11–1.93(m,1H),1.47(s,9H),1.15(d,J=6.2Hz,3H).

[0085] (9) Preparation of tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-9-yl]carbamate (formula XV).

[0086] Under normal temperature conditions, in an eggplant-shaped flask, ethanol (6.3 mL), tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazolacyclonon-6-en-9-yl]carbamate (97 mg), and a 55% hydrazine hydrate solution (0.177 mL) were added. The mixture was heated under reflux in an oil bath at 90 °C for 3 h until the reaction was complete (monitored by TLC). It was cooled to room temperature, an appropriate amount of silica gel was added to the reaction solution for dry-column chromatography on a silica gel column, and the eluent was ethyl acetate and petroleum ether 30% - 60% for column chromatography. A white solid of compound of formula XV (80%) was obtained. The HPLC purity was above 99%. 11H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 5.6 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J = 3.6 Hz, 1H), 5.92 (d, J = 7.9 Hz, 1H), 4.89 (s, 1H), 2.63 (t, J = 5.7 Hz, 1H), 1.80 (t, J = 12.1 Hz, 2H), 1.72–1.58 (m, 2H), 1.45 (s, 9H), 1.27 (d, J = 10.5 Hz, 3H).

[0087] (10) Preparation of (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazacyclonon-4-one (Formula XVI)

[0088] Under normal temperature conditions, dissolve tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazacyclonon-9-yl]carbamate (Formula XV, 0.0531 mmol) in 0.354 mL of methanol, add 39.8 μL of 4N hydrochloric acid 1,4-dioxane solution, stir and react for 2 h. Monitor the reaction by TLC until it is complete. Add 7N ammonia methanol solution (200 μL) and react for 5 min. Filter, wash the filter cake with methanol, and evaporate the reaction solution under vacuum to obtain a white solid of Compound XVI. The HPLC purity is above 99%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.73 (d, J = 5.0 Hz, 1H), 7.87 (t, J = 35 Hz, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 6.3 Hz, 1H), 3.76 (dd, J = 8.3, 5.1 Hz, 1H), 2.63 - 2.53 (m, 1H), 1.90 - 1.69 (m, 2H), 1.58 - 1.37 (m, 2H), 1.16 - 1.00 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H)

[0089] (11) Preparation of (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyrido-2(5,4)-pyrazacyclonon-4-one (Milvexian)

[0090] Under normal temperature conditions, dissolve 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (11 mg of formula XVII) in 0.32 mL of anhydrous acetonitrile, add 20 mg of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and 9.1 μL of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), and stir for 30 min. Dissolve (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolacyclonon-4-one (13.1 mg of formula XVI) in a mixed solvent of 0.32 mL of acetonitrile and 80 μL of N,N-dimethylformamide, add it to the reaction system, stir and react for 4 h, and monitor with TLC until the reaction is complete. Add 1 mL of ethyl acetate to dilute the reaction solution, add 1 mL of saturated ammonium chloride solution to wash the organic phase, extract the aqueous phase with ethyl acetate 1-2 times, combine the organic phases, wash once with saturated sodium chloride solution, add an appropriate amount of anhydrous sodium sulfate and dry overnight. Filter, load the sample wetly, pass through a silica gel column, and use ethyl acetate and petroleum ether 20%-50% to elute the column to obtain a white solid (Milvexian) (21%). The HPLC purity is above 99%. 1 H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 7.74–7.71 (m, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.63–7.56 (m, 3H), 7.52–7.42 (m, 3H), 7.24–6.97 (m, 3H), 6.34 (s, 1H), 6.16 (dd, J = 12.8, 4.8 Hz, 1H), 4.16–4.03 (m, 1H), 2.06–1.96 (m, 4H), 1.44–1.41 (m, 2H), 1.01 (d, J = 6.8 Hz, 3H)

[0091] Comparative Example 1

[0092] Comparative Example 1 adopted the preparation method in Example 1, except that tris(2,2,2-trifluoroethyl) borate in step (1) was replaced with an equal amount of cesium carbonate, and it was necessary to react for 12 h under the same conditions to produce an equal amount of the compound of formula III.

[0093] Comparative Example 2

[0094] Comparative Example 2 adopted the preparation method in Example 1, except that in step (7), the condensing agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was respectively replaced with an equal amount of [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylazanium hexafluorophosphate (HBTU), diethyl (4-oxo-1,2,3-benzotriazin-3(4H)-yl) phosphate (DEPBT), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), bis(1H-imidazol-1-yl)methanone (CDI), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ), N,N′-dicyclohexylmethanediimine (DCC) and 1H-1,2,3-benzotriazol-1-ol (HOBt), N,N'-di(propan-2-yl)methanediimine (DIC) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), and the yield of the compound of formula XIII decreased significantly.

[0095] Among them, when using an equal amount of HBTU, the yield of the compound of formula XIII was 8.41%; DEPBT was 41.01%; PyBOP was 40.56%; CDI was 2.04%; EEDQ was 8.72%, DCC and HOBt (in equimolar amounts) was 38.44%; DIC and HOAt (in equimolar amounts) was 4.93%; while using HATU in Example 1 of the present invention was 81%.

[0096] Comparative Example 3

[0097] Comparative Example 3 adopted the preparation method in Example 1, except that in step (9), hydrazine hydrate was replaced with 10% palladium on carbon (0.25 equivalent), 4 bar pressure of hydrogen was required, and the reaction time was 24 h, and the yield of formula XV was only 72%.

Claims

1. A method for preparing Milvexian, comprising the following steps: Step (1): subjecting 4-chloropyridinecarboxaldehyde of formula I to a nucleophilic addition reaction with S-tert-butylsulfenamide of formula II under borate conditions, followed by dehydration to obtain (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfenamide of formula III; Step (2): reacting the allylmagnesium bromide represented by formula IV with indium trichloride to form an indium allyl reagent, and then subjecting the indium allyl reagent to a nucleophilic addition reaction with the (S)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfenamide represented by formula III prepared in step (1), thereby directly generating the (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfenamide represented by formula V; Step (3): hydrolyzing the compound of formula V to directly generate (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride of formula VI; Step (4): removing hydrogen chloride from the compound of formula VI to obtain free amine, followed by nucleophilic addition reaction with di-tert-butyl dicarbonate of formula VII and elimination reaction to generate (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester of formula VIII; Step (5): the compound of formula VIII, under the activation of a coupling agent, undergoes a carbon-hydrogen activation type coupling reaction with 1-(difluoromethyl)-4-nitro-1H-pyrazole of formula IX under alkaline conditions and under catalysis to produce (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester of formula X; Step (6): The compound of formula X is reduced under weakly acidic conditions to tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate of formula X; Step (7): The compound of formula XⅠ is coupled with (R)-2-methylbut-3-enoic acid of formula XII in the presence of a condensing agent under alkaline conditions to obtain tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enoylamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-ene-1-yl)carbamate of formula XIII; Step (8): the compound of formula XIII undergoes olefin metathesis reaction under the action of a catalyst to remove one molecule of ethylene to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolecyclononane-6-ene-9-yl]carbamate of formula XIV; Step (9): The compound of formula XIV is reduced to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolocyclononane-9-yl]carbamate represented by formula XV; Step (10): hydrolyzing the compound of formula XV to form a hydrochloride, and then removing hydrogen chloride to obtain (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolocyclononane-4-one of formula XVI; Step (11): The compound of formula XVI is condensed with 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol of formula XVII in the presence of a condensing agent under alkaline conditions to generate a compound of formula XVIII (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolocyclononane-4-one (Milvexian); 2. The preparation method according to claim 1, characterized in that: In step (1), (S)-tert-butylsulfenamide reacts with boric acid ester to form a boric acid ester intermediate, and the intermediate is added with 4-chloropyridine carboxaldehyde shown in formula I and one molecule of water is removed to obtain formula III, the boric acid ester used is tris(2,2,2-trifluoroethyl) borate or tris(hexafluoroisopropyl) borate, and the molar ratio of the boric acid ester to formula I is in the range of 1.0-1.5:1; when S-tert-butylsulfenamide reacts with tris(2,2,2-trifluoroethyl) borate in step (1), the reaction solvent used in step (1) is any one of acetone, acetonitrile, toluene, chloroform, n-hexane, cyclohexane, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, ether, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, or a mixture of multiple solvents.

3. The preparation method according to claim 1, characterized in that: In step (3), the compound of formula V is preferably hydrolyzed with a hydrogen chloride ethyl acetate solution to directly generate (S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine hydrochloride represented by formula VI.

4. The preparation method according to claim 1, characterized in that: In step (4), the compound of formula VI is dehydrochlorinated with triethylamine to obtain a free amine, which is then subjected to nucleophilic addition and elimination with di-tert-butyl dicarbonate of formula VII to generate (S)-(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester of formula VIII.

5. The preparation method according to claim 1, characterized in that: In step (5), the compound of formula VIII undergoes a carbon-hydrogen activation type coupling reaction with 1-(difluoromethyl)-4-nitro-1H-pyrazole shown in formula IX under the activation effect of coupling agent palladium acetate, under the alkaline conditions provided by potassium carbonate and under the catalysis of pivalic acid (PivOH) to produce (S)-(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester shown in formula X.

6. The preparation method according to claim 1, characterized in that: In step (7), tert-butyl (S)-(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate represented by formula XⅠ and (R)-2-methylbut-3-enoic acid represented by formula XII are coupled by removing one molecule of water under the catalytic action of a condensing agent to obtain butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enoylamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate represented by formula XIII, wherein the base used is pyridine (Py) , 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) or any one of a plurality of solvent mixtures, the molar ratio of the base to the compound of formula XⅠ is 1.5-3:1; the condensing agent is O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylazonium hexafluorophosphate (HBTU), 4-oxo-1,2,3-benzotriazine-3(4H)- diethyl phosphate (DEPBT), (benzotriazol-1-yloxy)tripyrrolidinophosphine hexafluorophosphate (PyBOP), di(1H-imidazol-1-yl)methanone (CDI), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ), N,N′-dicyclohexylmethanediimide (DCC) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N′-dicyclohexylmethanediimide (DCC) and 1H-1,2,3-benzotriazol-1-ol (HOBt), N,N′-di(propan-2-yl)methanediimide (D IC) and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-ol (HOAt), N,N'-di(propan-2-yl)methanediimide (DIC), 1H-1,2,3-benzotriazole-1-ol (HOBt), the molar ratio of the condensing agent to the compound of formula XⅠ is in the range of 1.0-1.2:1; the solvent used is any one of acetone, acetonitrile, toluene, chloroform, dichloromethane, 1,2-dichloroethane, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, ether, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture of multiple thereof.

7. The preparation method according to claim 1, characterized in that: In step (8), the compound of formula XIII undergoes olefin metathesis reaction under the catalysis of Grubbs II catalyst to remove one molecule of ethylene to obtain tert-butyl [(5R,9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolecyclononane-6-ene-9-yl]carbamate represented by formula XIV.

8. The preparation method according to claim 1, characterized in that: In step (9), the tert-butyl [(5R, 9S)-21-(difluoromethyl)-5-methyl-4-oxo-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolocyclononane-6-ene-9-yl] carbamate olefin double bond represented by formula XIV is reduced to an alkane single bond by hydrazine, and the reducing agent used is hydrazine, methylhydrazine, ethylhydrazine, propylhydrazine, isopropylhydrazine, cyclopropylhydrazine, cyclomethylpropylhydrazine, phenylhydrazine, o-tolylhydrazine, m-tolylhydrazine, p-tolylhydrazine, o-fluorophenylhydrazine, m-fluorophenylhydrazine, p-fluorophenylhydrazine, p-toluenesulfonylhydrazine, and the molar ratio of the reducing agent used to the compound of formula XIV is in the range of 8-12:1; the solvent used is any one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, or a mixture of multiple solvents.

9. The preparation method according to claim 1, characterized in that: In step (10), the compound of formula XV is first hydrolyzed with a hydrochloric acid 1,4-dioxane solution to form a hydrochloride, and then the hydrogen chloride is removed by a methanol solution of ammonia to obtain the compound of formula XVI (5R,9S)-9-amino-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolecyclononane-4-one.

10. The preparation method according to claim 1, characterized in that: In step (11), the compound of formula XVI is condensed with 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol shown in formula XVII under alkaline conditions by using a condensing agent to generate a compound of formula XVIII (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)- 5-methyl-21H-3-aza-1(4,2)-pyridine-2(5,4)-pyrazolocyclononane-4-one (Milvexian); the condensing agent is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethylazonium hexafluorophosphate (HBTU), 4-oxo-1,2,3-benzotriazine- 3(4H)-diethyl phosphate (DEPBT), (benzotriazol-1-yloxy)tripyrrolidinophosphine hexafluorophosphate (PyBOP), di(1H-imidazol-1-yl)methanone (CDI), ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ), N,N′-dicyclohexylmethanediimide (DCC), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N′- Any one or more of dicyclohexylmethanediimide (DCC) and 1H-1,2,3-benzotriazol-1-ol (HOBt), N,N'-di(propan-2-yl)methanediimide (DIC) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N'-di(propan-2-yl)methanediimide (DIC) and 1H-1,2,3-benzotriazol-1-ol (HOBt).

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