Method for synthesizing lenacagvir sodium and series of intermediate compounds of lenacagvir sodium

Abstract

The invention provides a method for synthesizing lenacagpasvir sodium, which comprises the following steps: reacting a lenacagpasvir N2 solvent compound 14 with a compound 15 under the action of alkali to complete sulfonylation reaction, and finally forming sodium salt to obtain a target product lenacagpasvir sodium compound 16. M in the compound 15 is chlorine, methanesulfonyloxy or an N-heterocyclic compound, Z is C, N, O or S, the compound 14 is a new compound, and the complexing solvent (solvate) is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2, 2-dimethoxypropane or methylbenzene. The synthesis method improves the purity of the final product and is suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for synthesizing lenacapvir sodium and a series of intermediate compounds thereof. Background Art

[0002] Lenacapavir (trade name Sunlenca) is an oral or injectable reverse transcriptase inhibitor developed by Gilead Sciences for the treatment of AIDS. It blocks the replication and spread of HIV-1 virus by inhibiting the activity of HIV-1 reverse transcriptase. Its mechanism of action helps to reduce HIV load, slow viral replication, and thus slow disease progression. In clinical trials, Lenacapavir has shown excellent therapeutic effects on suppressing AIDS, especially for patients who have tried other HIV virus treatments but the virus has not yet reached undetectable levels in blood tests, and its pharmacokinetic properties in the body show its long-lasting effects. Lenacapavir was first approved for marketing in Europe in August 2022, and was subsequently approved for marketing by the FDA in December of the same year. Lenacapavir is also in the research stage for HIV prevention, and is expected to be successful in HIV prevention.

[0003] The chemical name of lenacapvir is: N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetamide, which is generally used in the form of sodium salt. Their structural formulas are as follows:

[0004]

[0005] PCT patent WO2018035359A1 reports the synthetic route of lenacapvir: first, bicyclo[3.1.0]hexan-3-one and ethyl trifluoroacetate are condensed under the action of lithium hexamethyldisilazide, and then a cyclization reaction is carried out with ethyl hydrazinoacetate under the action of hydrochloric acid to obtain a bicyclopyrazole intermediate, and then the benzylic methylene is oxidized with sodium chlorite to form a carbonyl group, and the ester group is hydrolyzed to generate a carboxylic acid intermediate, and the double bond is protected by ethanedithiol, and then the racemic product of the key acid intermediate of lenacapvir is obtained by fluorination with hydrogen fluoride and pyridine, and finally the key chiral acid intermediate of lenacapvir 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid is obtained by chiral resolution.

[0006]

[0007]

[0008] This patent uses the imine formed by 3,6-dibromopyridine-2-carboxaldehyde and (S)-tert-butylsulfenamide to react with 3,5-difluorobenzylzinc bromide for addition reaction, and then acidolysis removes the (S)-tert-butylsulfenyl group, and then uses Boc to protect the amino group to obtain (S)-tert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate, which is then coupled with 3-methyl-3-(methylsulfonyl)-1-butyne to obtain the key chiral amine intermediate of lenacapvir (S)-tert-butyl (1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate. The key chiral amine intermediate is then subjected to Suzuki coupling with the key boronate intermediate of lenacapvir, 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine, followed by protection of the amino group with a bis-mesyl group, followed by acidolysis with trifluoroacetic acid to remove the Boc protection, and finally condensed with 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazol-1-yl)acetic acid in the presence of a condensation agent HATU, and alkaline cleavage with lithium hydroxide to remove one molecule of the mesyl group to obtain the target product lenacapvir. The key chiral acid intermediate of this method needs to be separated by a preparative column for chiral splitting, which has low atom economy, low synthesis efficiency and low yield. The synthesis of the key parent core intermediate of lenacapvir has many steps, and the raw materials used for the addition reaction of (S)-tert-butylsulfenamide are expensive, the reaction yield is low and the selectivity is average, so the cost is high.

[0009]

[0010] In general, this method for synthesizing lenacapvir has a low total yield and is too costly, and there is still a need to find a method with a simple process route, low cost, and suitable for industrial production. Summary of the invention

[0011] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for synthesizing lenacapvir which has a short synthetic route, simple operation, high yield, high product purity and is suitable for industrial production.

[0012] To achieve the purpose of the invention, the present invention provides a series of new intermediate compounds for synthesizing lenacapvir, adopting the following technical scheme:

[0013] Lenacapvir N2 intermediate solvent compound 14 has the following structural formula:

[0014]

[0015] Wherein, the complexing solvent (solvate) in compound 14 is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene.

[0016] A preparation method of lenacapvir N2 intermediate solvent compound 14, comprising the steps of crystallizing the lenacapvir N2 intermediate using a crystallization solvent, wherein the crystallization solvent is selected from a single complexing solvent or a complexing solvent and methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, tert-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol A 1+1 mixed solvent combination formed by one of the following solvents: alcohol dimethyl ether, acetonitrile, n-propionitrile, n-butyl, acetone, butanone, methyl isobutyl ketone, n-pentane, n-hexane, n-heptane, dichloromethane, chloroform, and water, or a 1+2 mixed solvent combination formed by any two of these solvents; the complexing solvent is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane, or toluene; and the crystallization temperature is -20 to 110°C.

[0017] Preferably, the present invention provides an ether solvent compound 14a of a Nacapavir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​measured using Cu-Kα rays have characteristic peaks at 4.93±0.2°, 8.36±0.2°, 14.50±0.2°, 18.90±0.2°, 21.04±0.2° and 23.18±0.2°; and its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-115°C, the melting point peak is at 110.4±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 309.9±3.0°C.

[0018] Preferably, the present invention provides an n-propyl ether solvent compound 14b of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 7.36±0.2°, 8.39±0.2°, 14.18±0.2°, 14.55±0.2°, 14.89±0.2°, 21.40±0.2° and 23.40±0.2°; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-120°C, the melting point peak is at 108.4±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 310.3±3.0°C.

[0019] Preferably, the present invention provides an isopropyl ether solvent compound 14c of a lenacapvir N2 intermediate, the single crystal structure of the isopropyl ether solvent compound of the lenacapvir N2 intermediate is confirmed by single crystal analysis, wherein the single crystal unit cell parameters of the isopropyl ether solvent compound of the lenacapvir N2 intermediate are: α=γ=90°, β=98.558(2)°, Monoclinic system, space group is P21;

[0020] Preferably, the present invention provides an isopropyl ether solvent compound 14c of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 6.57±0.2°, 14.07±0.2°, 14.79±0.2°, 17.71±0.2°, 21.13±0.2° and 22.17±0.2°; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 95.0-125°C, the melting point peak is at 116.5°C±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 314.4°C±3.0°C.

[0021] Preferably, the present invention provides an n-butyl ether solvent compound 14d of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 12.87°, 17.27°, 17.95°, 20.21°, 20.38° and 20.92°; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 100.0-125°C, the melting point peak is at 120.6±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 310.2±3.0°C.

[0022] Preferably, the present invention provides a methyl tert-butyl ether solvent compound 14e of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2 Theta values ​​14.79°, 17.22°, 20.32°, 20.51°, 21.55° and 23.23° obtained by Cu-Kα ray measurement have characteristic peaks; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-120°C, the melting point peak is at 111.5±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 309.5±3.0°C.

[0023] Preferably, the present invention provides a methyl cyclopentyl ether solvent compound 14f of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 6.82±0.2°, 14.09±0.2°, 14.53±0.2°, 14.87±0.2°, 18.25±0.2° and 20.30±0.2°; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 96.0-133°C, the melting point peak is at 120.3±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 309.3±3.0°C.

[0024] Preferably, the present invention provides 14 g of a 2,2-dimethoxypropane solvent compound of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 17.85°, 20.32°, 21.16°, 21.91°, 22.63° and 24.66°; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-115°C, the melting point peak is at 109.0±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 310.7±3.0°C.

[0025] Preferably, the present invention provides a toluene solvent compound 14h of a lenacapvir N2 intermediate, wherein the X-ray powder diffraction pattern 2Theta values ​​obtained by Cu-Kα ray measurement have characteristic peaks at 7.35°, 14.50°, 15.28°, 15.70°, 18.53° and 20.37; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 95.0-120°C, the melting point peak is at 106.5±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 309.6±3.0°C.

[0026] The present invention also provides a method for synthesizing a lenacapvir N2 intermediate solvent compound 14, which adopts the following technical scheme:

[0027] A method for synthesizing a lenacapvir N2 intermediate solvent compound 14, comprising subjecting a free base or salt form of a compound 7 to a condensation reaction with a compound 12 under the action of a base and a condensing agent to obtain a free base, and then reacting with a complexing solvent to obtain a solvent compound 14;

[0028]

[0029] Among them, the HY acid in compound 7 is selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid; in compound 14, the complexing solvent (solvate) is selected from ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene.

[0030] Preferably, the condensing agent is selected from carbonyldiimidazole (CDI), isobutyl chloroformate (ICBF), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester (HATU), dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC), T3P, T4P, BOP or PyBOP; the base is selected from diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine or N-methylmorpholine; the reaction solvent is selected from dimethylformamide, dimethylacetamide, NMP, tetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them; the reaction temperature is -20 to 60°C.

[0031] The present invention also provides another method for synthesizing lenacapvir N2 intermediate solvent compound 14, which adopts the following technical scheme:

[0032] A method for synthesizing a lenacapvir N2 intermediate solvent compound 14 comprises the following steps:

[0033] (1) Compound 5 in free base or salt form is subjected to condensation reaction with compound 12 in the presence of a base and a condensing agent to obtain compound 13;

[0034]

[0035] (2) Compound 13 and borate intermediate compound 6 are coupled under the action of a palladium catalyst, and then reacted with a complexing solvent to obtain a solvent compound 14;

[0036]

[0037] Among them, in compound 5, the HX acid is selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid; in compound 14, the complexing solvent (solvate) is selected from ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene.

[0038] Preferably, the condensing agent in step 1 is selected from carbonyl diimidazole (CDI), isobutyl chloroformate (ICBF), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HA The method comprises the following steps: the step of: preparing the reaction mixture of the present invention; the step of preparing the reaction mixture of the present invention comprises ...

[0039] The present invention also provides a method for synthesizing the above-mentioned key chiral acid intermediate compound 12 of lenacapvir, which adopts the following technical scheme:

[0040] The synthesis method of the key chiral acid intermediate compound 12 of Nacapavir comprises the following steps:

[0041] (1) Compound 8 is treated with an oxidant to obtain compound 9;

[0042]

[0043] (2) condensing compound 9 with ethyl trifluoroacetate in the presence of a lithium salt to obtain an intermediate compound 10;

[0044]

[0045] (3) Compound 10 and ethyl hydrazinoacetate are subjected to a cyclization reaction under the action of an acid to obtain an intermediate compound 11;

[0046]

[0047] (4) alkaline hydrolysis and acidification of compound 11 to obtain the key chiral acid intermediate compound 12;

[0048]

[0049] Preferably, in the oxidation reaction of step (1), no catalyst is added or a catalyst selected from TEMPO is added; the oxidant is selected from Dess-Martin reagent, iodobenzene acetate, sodium hypochlorite, TCCA, NBS, NCS, DBDMH, liquid bromine or sodium hypobromite; no additive is added or an additive is added selected from one or a mixture of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bromide and TBAB; the reaction solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, ethyl acetate or isopropyl acetate or a mixed solvent system formed by any one of these solvents and water; and the reaction temperature ranges from -30 to 60°C.

[0050] Preferably, in the condensation reaction of step (2), the lithium salt is selected from lithium tert-butoxide, n-butyl lithium, lithium diisopropylamide or LiHMDS; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, NMP, DMPU or a mixed solvent formed by any two of these solvents; and the reaction temperature is -90 to 60°C.

[0051] Preferably, in the cyclization reaction of step (3), the acid added is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride etherate or pyridinium p-toluenesulfonate; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or a mixed solvent formed by any two of these solvents; and the reaction temperature is -20 to 110°C.

[0052] Preferably, in the alkaline hydrolysis reaction of step (4), lithium chloride or lithium bromide is added to an organic base for alkaline hydrolysis, wherein the organic base is selected from diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, acetonitrile, toluene, acetone, tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is -20 to 110°C; and the acidifying acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid or tartaric acid.

[0053] The present invention also provides a method for synthesizing lenacapvir sodium, which adopts the following technical scheme:

[0054] A method for synthesizing lenacapvir sodium, comprising reacting a lenacapvir N2 solvent compound 14 with a compound 15 under the action of a base to complete a sulfonylation reaction, and finally forming a sodium salt to obtain a target product lenacapvir sodium compound 16;

[0055]

[0056] Among them, the complexing solvent (solvate) in compound 14 is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene; in compound 15, M is chlorine, methanesulfonyloxy or N-heterocyclic compound, wherein Z is C, N, O or S.

[0057] Preferably, in the sulfonylation reaction, the base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, triethylamine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine or N-methylmorpholine; the reaction solvent is selected from dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl The invention relates to a method for preparing the present invention wherein the present invention comprises the following steps: the step of preparing the present invention comprises the following steps: forming a sodium salt of at least one tert-butyl alcohol, a ...

[0058] The present invention also provides a series of compounds for synthesizing lenacapvir, a key chiral amine intermediate compound 5 salt form and an intermediate compound 7 salt form, the structural formula of which is as follows:

[0059]

[0060] Among them, the ratio of free base to acid in compound 5 is 1:1 or 1:2; the ratio of free base to acid in compound 7 is 1:1 or 1:2; wherein HX acid and HY acid are respectively selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0061] The present invention relates to a method for synthesizing a key chiral amine intermediate compound 5 of lenacapvir, and adopts the following technical scheme:

[0062] The synthesis method of the key chiral amine intermediate compound 5 of lenacapvir comprises the following steps:

[0063] (1) Compound 2 is exchanged with a Grignard reagent and then condensed with 3,6-dibromopyridine-2-carboxylic acid methyl ester compound 1 to obtain an intermediate compound 3;

[0064]

[0065] (2) coupling compound 3 with 3-methyl-3-(methylsulfonyl)-1-butyne in the presence of a catalyst to obtain an intermediate compound 4;

[0066]

[0067] (3) Compound 4 is reacted with an aminating agent under the catalysis of transaminase and coenzyme to obtain a free base of Compound 5 or is salified with HX acid to obtain a salt form of Compound 5;

[0068]

[0069]

[0070] Preferably, in the condensation reaction of step (1), the Grignard reagent is selected from isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, isopropylmagnesium bromide, tert-butylmagnesium chloride, cyclohexylmagnesium chloride, and n-hexylmagnesium chloride; the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a mixed solvent of any two of N-methylpyrrolidone; and the reaction temperature is -80 to 60°C.

[0071] Preferably, in the coupling reaction of step (2), the catalyst is selected from palladium carbon, palladium acetate, palladium dichloride, sodium palladate, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)palladium, Pd(dppf)Cl2, di-tert-butylphenylphosphine palladium dichloride; no copper salt is added or the copper salt added is selected from cuprous iodide, cuprous bromide or cuprous chloride; no ligand is added or a ligand is added, and the ligand is selected from triphenylphosphine, tricyclohexylphosphine, bisphenylcyclohexylphosphine or bis-tert-butylphenylphosphine; the base is selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, carbon Cesium nitrate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or water and a mixed solvent formed by any two of them; the reaction temperature is 0 to 130°C.

[0072] Preferably, the aminotransferase in step (3) is selected from commercial ω-aminotransferase or immobilized ω-aminotransferase attached to amino resin, and the ω-aminotransferase is preferably MY-ATA-233, MY-ATA-238, MY-ATA-258; the amino resin model is preferably SEPABEADS, EC-HFA / S, LX-1000HFA, LX-HFA001; the coenzyme is pyridoxal 5-phosphate; the amination reagent is selected from isopropylamine or isopropylamine hydrochloride; the reaction solvent is selected from dimethyl sulfoxide, methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, ethyl acetate, isopropyl acetate, n-butyl acetate or water, and a mixed solvent formed by any two of them; the buffer used in the reaction adjusts the pH, and the buffer The buffer is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, phosphoric acid, tris(hydroxymethyl)aminomethane hydrochloride and a mixed buffer solution system composed of any two of them; the reaction temperature is 0-70°C; the salt-forming acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0073] The present invention relates to a method for synthesizing a key chiral amine intermediate compound 7 of lenacapvir, and adopts the following technical scheme:

[0074] A method for synthesizing a key chiral amine intermediate compound 7 of lenacapvir, comprising coupling a free base or salt form of compound 5 with a borate intermediate compound 6 under the action of a palladium catalyst to obtain a free base of compound 7 or forming a salt with HY acid to obtain a salt form of compound 7;

[0075]

[0076] Preferably, in the coupling reaction, the palladium catalyst is selected from palladium acetate, palladium chloride, palladium pivalate, Pd(dppf)Cl2, ditriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium or Pd2(dba)3, di-tert-butylphenylphosphine palladium dichloride; no ligand is added or the ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine or di-tert-butylphenylphosphine; the base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium hydroxide, carbonate The reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them; the reaction temperature is 0 to 150°C. The acid for salt formation is selected from hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0077] The present invention relates to a method for synthesizing lenacapvir sodium, which adopts the following technical scheme:

[0078] A synthesis method of lenacapvir sodium comprises taking 3,6-dibromopyridine-2-carboxylic acid methyl ester compound 1 and 3,5-difluorobenzyl bromide compound 2 as starting materials, performing Grignard addition reaction to obtain compound 3, docking with 3-methyl-3-(methylsulfonyl)-1-butyne compound 4 through coupling reaction, and then using transaminase amination reaction to obtain lenacapvir key chiral amine intermediate compound 5, and then coupling with lenacapvir key boric ester compound 6 to obtain compound 7; compound 8 is firstly oxidized by hydroxyl group to obtain carbonyl compound 9, and then reacted with ethyl trifluoroacetate under the action of strong base lithium reagent to obtain compound 7; The compound 10 is obtained by ester reaction, and then the compound 11 is cyclized with ethyl hydrazinoacetate to obtain the compound 11, and then hydrolyzed to obtain the key chiral acid intermediate compound 12 of lenacapvir; the compound 7 and the compound 12 are directly condensed, and the compound 7 and the compound 12 are used to form a solvate with a complexing solvent to obtain the lenacapvir N2 intermediate solvent compound 14, and finally the compound 14 is sulfonylated with 15 to form a sodium salt to obtain the target product lenacapvir sodium; the compound 12 and the compound 5 are first condensed to generate the compound 13, and then coupled with the compound 6 to obtain the lenacapvir N2 intermediate solvent compound 14; the reaction route is:

[0079]

[0080] Among them, the complexing solvent (solvate) of compound 14 is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene; in compound 15, M is chlorine, methanesulfonyloxy or N-heterocyclic compound, wherein Z is C, N, O or S; HX acid and HY acid are respectively selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0081] The present invention relates to a method for synthesizing a lenacapvir N2 intermediate solvent compound 14, which reduces the difficulty of synthesis, reduces the number of synthesis steps, and has a simple route, and the total yield of the route is also improved, thereby reducing the process cost. The present invention makes full use of the salt-forming properties of compound 5 and compound 7 to improve the crystallization properties of the intermediate, provides an N2 intermediate solvent compound 14, optimizes the sulfonylation reagent from N2 to the API finished product, improves the purity of the final finished product, and is suitable for scaled-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate ether solvent compound 14a;

[0083] Figure 1b is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate ether solvent compound 14a;

[0084] Figure 2a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate n-propyl ether solvent compound 14b;

[0085] Figure 2b This is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate n-propyl ether solvent compound 14b;

[0086] Figure 3a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate isopropyl ether solvent compound 14c;

[0087] Figure 3b This is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate isopropyl ether solvent compound 14c;

[0088] Figure 3c This is the single crystal structure diagram of the isopropyl ether solvent compound 14c, the intermediate of lenacapvir N2;

[0089] Figure 4a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate n-butyl ether solvent compound 14d;

[0090] Figure 4b This is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate n-butyl ether solvent compound 14d;

[0091] Figure 5a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate methyl tert-butyl ether solvent compound 14e;

[0092] Figure 5b This is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate methyl tert-butyl ether solvent compound 14e;

[0093] Figure 6a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate methyl cyclopentyl ether solvent compound 14f;

[0094] Figure 6b This is a differential scanning calorimetry analysis curve of lenacapvir N2 intermediate methyl cyclopentyl ether solvent compound 14f;

[0095] Figure 7a This is the X-ray powder diffraction pattern of lenacapvir N2 intermediate 2,2-dimethoxypropane solvent compound 14g;

[0096] Figure 7bThis is a differential scanning calorimetry analysis curve of 14 g of lenacapvir N2 intermediate 2,2-dimethoxypropane solvent compound;

[0097] Figure 8a is the X-ray powder diffraction pattern of lenacapvir N2 intermediate toluene solvent compound 14h;

[0098] Figure 8b This is the differential scanning calorimetry analysis curve of lenacapvir N2 intermediate toluene solvent compound 14h. DETAILED DESCRIPTION

[0099] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0100] Example 1

[0101]

[0102] Compound 2 (21.74 g, 105 mmol) and tetrahydrofuran (148 mL) were added to a three-necked flask, stirred and dissolved, and then cooled to -10-0°C in an ice-salt bath. 2.0 M isopropyl magnesium chloride tetrahydrofuran solution (105 mmol, 52.5 mL) was added dropwise under nitrogen protection, and the mixture was kept warm for 1 hour for standby use. Compound 1 (29.49 g, 100 mmol) was added to another reaction flask, and tetrahydrofuran (148 mL) was added under nitrogen protection to dissolve, cooled to 0-10°C, and the prepared Grignard reagent solution was added dropwise to the reaction flask, and then kept warm at 0-10°C for 3-5 hours. After the reaction, saturated ammonium chloride (236 mL) was added to quench the reaction, and the mixed solution was extracted 3 times with ethyl acetate (148 mL), and the organic phase was combined and washed with water 2 times (59 mL), concentrated, and recrystallized with isopropanol and water to obtain compound 3 (34.21 g, 87.5%).

[0103] In Example 1, isopropyl magnesium chloride can be replaced by isopropyl magnesium chloride lithium chloride complex, isopropyl magnesium bromide, tert-butyl magnesium chloride, cyclohexyl magnesium chloride or n-hexyl magnesium chloride; the solvent tetrahydrofuran can be replaced by 2-methyltetrahydrofuran, toluene, N-methylpyrrolidone or a mixed solvent composed of any two of them.

[0104] Example 2

[0105]

[0106] Compound 3 (39.10 g, 100 mmol), 3-methyl-3-(methylsulfonyl)-1-butyne (17.54 g, 120 mmol), N,N-diisopropylethylamine (38.77 g, 300 mmol) and N,N-dimethylformamide (196 mL) were added to a three-necked flask. After stirring evenly, the vacuum was switched to nitrogen three times. Cuprous iodide (190 mg, 1.0 mmol) and bis(triphenylphosphine)palladium dichloride (702 mg, 1.0 mmol) were added under nitrogen protection. After the addition, the temperature was raised to 85-90°C and the reaction was carried out for 10-16 hours. After the reaction was completed, the temperature was cooled to room temperature, and 391 mL of water was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate (196 mL), and the organic phases were combined, washed once with water (138 mL), dried with sodium sulfate, concentrated, and recrystallized with ethyl acetate and n-heptane to obtain intermediate 4 (40.97 g, 89.8%).

[0107] In Example 2, the catalyst bis(triphenylphosphine)palladium dichloride can be replaced by palladium carbon, palladium acetate, palladium dichloride, sodium palladate, tris(dibenzylideneacetone)palladium, Pd(dppf)Cl2 or di(tert-butylphenylphosphine)palladium dichloride; cuprous iodide can be omitted, or cuprous iodide can be replaced by cuprous bromide or cuprous chloride; the alkaline substance N,N-diisopropylethylamine can be replaced by potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, DBU, DABCO or N-methylmorpholine can be used instead; the reaction solvent N,N-dimethylformamide can be replaced by N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or water, and a mixed solvent formed by any two of them.

[0108] Example 3

[0109]

[0110] Compound 3 (39.10 g, 100 mmol), 3-methyl-3-(methylsulfonyl)-1-butyne (17.54 g, 120 mmol), triethylamine (30.36 g, 300 mmol) and acetonitrile (196 mL) were added to a three-necked flask. After stirring evenly, the nitrogen was switched under vacuum for 3 times. Di(triphenylphosphine)palladium dichloride (702 mg, 1.0 mmol) was added under nitrogen protection. After the addition, the temperature was raised to 75-80°C and the reaction was carried out for 10-16 hours. After the reaction was completed, most of the salt and filter residue were removed by filtration. The filtrate was concentrated to a small volume, heated to 50-60°C, 391 mL of water was slowly added, and the mixture was slowly cooled to 0-5°C and recrystallized to obtain intermediate 4 (38.97 g, 85.4%).

[0111] In Example 3, the catalyst bis(triphenylphosphine)palladium dichloride can be replaced by palladium on carbon, palladium acetate, palladium dichloride, sodium palladate, tridibenzylideneacetone dipalladium, Pd(dppf)Cl2 or di-bis-tert-butylphenylphosphine palladium dichloride; the alkaline substance triethylamine can be replaced by potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent acetonitrile can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, 1,4-dioxane or water and a mixed solvent formed by any two of them.

[0112] Example 4

[0113]

[0114] Compound 4 (45.63 g, 100 mmol) and dimethyl sulfoxide (91 mL) were added to a three-necked flask, and after stirring and dissolving, 70% isopropylamine aqueous solution (42.22 g, 500 mmol) was added, and 1M potassium dihydrogen phosphate solution was added to adjust the pH to 8.8-9.0. After the addition, ω-aminotransferase MY-ATA-258 (100 mg) was added, and 5-pyridoxal phosphate (90 mg) was added, and the mixture was kept at 35-38°C for 16-24 hours. After the reaction was completed, ethyl acetate (456 mL) was added for extraction, and the organic phase was collected, heated to 45-50°C, methylsulfonic acid (11.53 g, 120 mmol) was added, and the mixture was slowly cooled to 0°C for crystallization, filtered, and the solid was collected and dried to obtain product 5a (50.75 g, 91.7%).

[0115] MS (ESI) m / z = 457.1 [M + H] +

[0116] 1H NMR (500MHz, DMSO) δ8.67-8.24(m,2H),8.19(d,J=8.3Hz,1H),7.62(d,J=8.3Hz,1H),7.14(tt,J=9.4,2.2Hz,1H),6.89(dd,J=8 .0,1.9Hz,2H),4.95(t,J=7.1Hz,1H),3.24(s,3H),3.23-3.18(m,1H),3.13(dd,J=13.5,6.9Hz,1H),2.38(s,3H),1.70(s,6H).

[0117] In Example 4, the aminotransferase in step (3) is selected from commercial ω-aminotransferase or immobilized ω-aminotransferase attached to amino resin, ω-aminotransferase MY-ATA-258 can be replaced by MY-ATA-233 or MY-ATA-238; the amination reagent isopropylamine can be replaced by isopropylamine hydrochloride; the reaction solvent dimethyl sulfoxide can be replaced by methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, ethyl acetate, isopropyl acetate, n-butyl acetate or water, and a mixed solvent formed by any two of them; potassium dihydrogen phosphate can be replaced by sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dihydrogen phosphate The methylsulfonic acid can be replaced by hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0118] Example 5

[0119]

[0120] Compound 4 (45.63 g, 100 mmol) and isopropyl acetate (91 mL) were added to a three-necked flask, and after stirring and dissolving, 70% isopropylamine aqueous solution (42.22 g, 500 mmol) was added, and 1 M phosphoric acid was added to adjust the pH to 8.6-8.8. After the addition, ω-aminotransferase MY-ATA-238 (100 mg) was added, and 5-pyridoxal phosphate (90 mg) was added, and the mixture was kept at 38-40°C for 16-24 hours. After the reaction was completed, isopropyl acetate (456 mL) was added for extraction, and the organic phase was collected, heated to 45-50°C, p-toluenesulfonic acid (20.66 g, 120 mmol) was added, and the mixture was slowly cooled to 0°C for crystallization, filtered, and the solid was collected and dried to obtain product 5b (58.74 g, 93.3%).

[0121] MS (ESI) m / z = 457.1 [M + H] +

[0122] 1H NMR (500MHz, DMSO) δ8.18(d,J=8.3Hz,1H),7.60(d,J=8.3Hz,1H),7.50(d,J=8.1Hz,2H),7.13(d,J=7.8Hz ,3H),6.93-6.81(m,2H),4.90(t,J=7.1Hz,1H),3.23(s,3H),3.20-3.04(m,2H),2.29(s,3H),1.69(s,6H).

[0123] In Example 5, ω-aminotransferase MY-ATA-238 can be replaced by MY-ATA-233 or MY-ATA-258; isopropylamine can be replaced by isopropylamine hydrochloride; the reaction solvent isopropyl acetate can be replaced by dimethyl sulfoxide, methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, ethyl acetate, n-butyl acetate, water or a mixed solvent formed by any two of them; the buffer phosphoric acid can be replaced by sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, trihydroxymethyl The p-toluenesulfonic acid of the salt-forming acid can be replaced by hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0124] Example 6

[0125]

[0126] Compound 4 (45.63 g, 100 mmol) and methyl tert-butyl ether (91 mL) were added to a three-necked flask, and after stirring and dissolving, 70% isopropylamine aqueous solution (42.22 g, 500 mmol) was added, and 1M dilute hydrochloric acid was added to adjust the pH to 8.6-9.0. After the addition, ω-aminotransferase MY-ATA-238 (100 mg) was added, and 5-pyridoxal phosphate (90 mg) was added, and the mixture was kept at 35-38°C for 16-24 hours. After the reaction was completed, methyl tert-butyl ether (456 mL) was added for extraction, and the organic phase was collected, heated to 45-50°C, acetic acid (9.01 g, 150 mmol) was added, and the mixture was slowly cooled to 0°C for crystallization, filtered, and the solid was collected and dried to obtain product 5c (47.86 g, 92.5%).

[0127] MS (ESI) m / z = 457.1 [M + H] +

[0128] 1H NMR (500MHz, DMSO) δ8.07(d,J=8.2Hz,1H),7.44(d,J=8.2Hz,1H),7.03(ddd,J=9.5,5.9,2.3Hz,1H),6.90(dt,J=5.9,2.9Hz,2H) ,4.43(dd,J=8.4,5.3Hz,1H),3.21(s,3H),2.93(dd,J=13.3,5.3Hz,1H),2.81(dd,J=13.3,8.5Hz,1H),1.90(s,3H),1.69(s,6H).

[0129] In Example 6, the ω-aminotransferase MY-ATA-238 can be replaced by MY-ATA-233 or MY-ATA-258; the amination reagent isopropylamine can be replaced by isopropylamine hydrochloride; the reaction solvent methyl tert-butyl ether can be replaced by dimethyl sulfoxide, methanol, ethanol, isopropanol, isopropyl ether, ethyl acetate, isopropyl acetate, n-butyl acetate, water or a mixed solvent formed by any two of them; the buffer solution hydrochloric acid can be replaced by sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, The acetic acid for forming the salt can be replaced by hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0130] Example 7

[0131]

[0132] Compound 4 (45.63 g, 100 mmol) and ethyl acetate (91 mL) were added to a three-necked flask, and after stirring and dissolving, 70% isopropylamine aqueous solution (42.22 g, 500 mmol) was added, and 1M dilute hydrochloric acid was added to adjust the pH to 8.8-9.0. After the addition, ω-aminotransferase MY-ATA-238 (100 mg) was added, and 5-pyridoxal phosphate (90 mg) was added, and the mixture was kept at 36-38°C for 16-24 hours. After the reaction was completed, ethyl acetate (456 mL) was added for extraction, and the organic phase was collected and heated to 45-50°C, and L-di-p-toluoyl tartaric acid (40.57 g, 105 mmol) was added, and the mixture was slowly cooled to 0°C for crystallization, filtered, and the solid was collected and dried to obtain product 5d (78.55 g, 93.1%).

[0133] MS (ESI) m / z = 457.1 [M + H] +

[0134] 1H NMR (500MHz, DMSO) δ8.09(d,J=8.3Hz,1H),7.85(d,J=8.0Hz,4H),7.54(d,J=8.3Hz,1H),7.30(d,J=8.0Hz,4H),7.06(t,J=9.4Hz,1H),6.72(d,J=6 .3Hz,2H),5.67(s,2H),4.96(t,J=7.1Hz,1H),3.22(s,3H),3.18(dd,J=1 3.2, 6.3Hz, 1H), 2.99 (dd, J=13.0, 8.0Hz, 1H), 2.36 (s, 6H), 1.68 (s, 6H).

[0135] In Example 7, ω-aminotransferase MY-ATA-238 can be replaced by MY-ATA-233 and MY-ATA-258; isopropylamine can be replaced by isopropylamine hydrochloride; the reaction solvent ethyl acetate can be replaced by dimethyl sulfoxide, methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, isopropyl acetate, n-butyl acetate, water or a mixed solvent formed by any two of them; hydrochloric acid can be replaced by sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, tris(hydroxymethyl)aminomethane hydrochloride or a mixed buffer solution system composed of any two of them; L -Di-p-toluoyltartaric acid can be replaced by hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid; ω-aminotransferase MY-ATA-238 can be attached to the amino resin of SEPABEADS, EC-HFA / S, LX-1000HFA or LX-HFA001.

[0136] Example 8

[0137]

[0138] Compound 5a (55.34 g, 100 mmol), compound 6 (41.31 g, 110 mmol), potassium carbonate (41.46 g, 300 mmol), 1,4-dioxane (277 mL) and water (55 mL) were added to a three-necked flask. After stirring evenly, the vacuum was switched to nitrogen three times. Pd(dppf)Cl2 (730 mg, 1.0 mmol) was added under nitrogen protection. After the addition was complete, the temperature was raised to 80-90°C. ℃ for 4-6 hours, after the reaction is completed, cool to room temperature, add 550mL of water to quench the reaction, extract the aqueous phase with isopropyl acetate (277mL) 3 times, combine the organic phases and wash once with water (277mL), concentrate to a small volume, heat to 55-60℃, add methanesulfonic acid (21.14g, 220mmoL), slowly cool to 0-5℃ for crystallization, filter, collect the solid and dry in vacuum to obtain intermediate 7a (75.44g, 92.2%). MS (ESI) m / z=626.1[M+H] +

[0139] 1H NMR (500MHz, DMSO) δ7.90 (s, 2H), 7.17 (d, J = 7.7Hz, 1H), 7.10 (tt, J = 9.4, 2.1Hz, 1H),6.90(d,J=7.7Hz,1H),6.32(d,J=6.1Hz,2H),4.59(dd,J=16.5,8.3Hz,1H), 4.02(d,J=3.1Hz,1H),3.92(dq,J=17.1,8.6Hz,1H),3.28(s,3H),3.00(dd,J=14 .0,8.3Hz,1H),2.92(dt,J=10.0,4.7Hz,1H),2.48(s,6H),1.74(d,J=1.7Hz,6H).

[0140] In Example 8, in the coupling reaction, Pd(dppf)Cl2 can be replaced by palladium acetate, palladium chloride, palladium pivalate, ditriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium or Pd2(dba)3, di-bis-tert-butylphenylphosphine palladium dichloride; potassium carbonate can be replaced by triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium phosphate or cesium carbonate; the reaction solvent 1,4-dioxane can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetic acid The methylsulfonic acid can be replaced by hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, toluenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0141] Example 9

[0142]

[0143] Compound 5b (62.95 g, 100 mmol), compound 6 (41.31 g, 110 mmol), sodium carbonate (31.80 g, 300 mmol), DMF (315 mL) and water (63 mL) were added to a three-necked flask. After stirring, the mixture was switched to nitrogen three times under vacuum. Di(triphenylphosphine)palladium dichloride (702 mg, 1.0 mmol) was added under nitrogen protection. After the addition, the mixture was heated to 90-95°C and reacted for 4-6 hours. After the reaction was completed, the mixture was cooled to room temperature and 630 mL of water was added to quench the reaction. The aqueous phase was extracted three times with isopropyl acetate (315 mL). The organic phases were combined and washed once with water (315 mL), concentrated to a small volume, heated to 55-60°C, p-toluenesulfonic acid (37.88 g, 220 mmol) was added, and the mixture was slowly cooled to 0-5°C for crystallization. The mixture was filtered and the solid was collected and dried under vacuum to obtain intermediate 7b (88.99 g, 91.7%).

[0144] MS (ESI) m / z = 626.1 [M + H] +

[0145] 1H NMR(500MHz,DMSO)δ7.90(s,2H),7.50(d,J=7.7Hz,4H),7.17(d,J=7.7Hz,5H),7.10(t t,J=9.4,2.1Hz,1H),6.90(d,J=7.7Hz,1H),6.32(d,J=6.1Hz,2H),4.59(dd,J=16.5,8 .3Hz,1H),4.02(d,J=3.1Hz,1H),3.92(dq,J=17.1,8.6Hz,1H),3.28(s,3H),3.00(dd, J=14.0,8.3Hz,1H),2.92(dt,J=10.0,4.7Hz,1H),2.48(s,6H),1.74(d,J=1.7Hz,6H).

[0146] In Example 9, bis(triphenylphosphine)palladium dichloride can be replaced by palladium acetate, palladium chloride, palladium pivalate, Pd(dppf)Cl2, tetrakistriphenylphosphine palladium, Pd2(dba)3 or di-bis-tert-butylphenylphosphine palladium dichloride; sodium carbonate can be replaced by triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate or cesium carbonate; N,N-dimethylformamide DMF can be replaced by N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, tert ... Butyl ester, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them; p-toluenesulfonic acid can be replaced by hydrobromic acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0147] Example 10

[0148]

[0149] Compound 5c (51.74 g, 100 mmol), compound 6 (41.31 g, 110 mmol), N,N-diisopropylethylamine (38.77 g, 300 mmol), toluene (260 mL) and water (52 mL) were added to a three-necked flask. After stirring evenly, the mixture was switched to nitrogen three times under vacuum. Di-bis-tert-butylphenylphosphine palladium dichloride (311 mg, 0.5 mmol) was added under nitrogen protection. After the addition was complete, the temperature was raised to 75-80°C and the mixture was reacted for 4-6 min. The reaction was continued for 2 hours, and the mixture was cooled to room temperature. 520 mL of water was added to quench the reaction. The aqueous phase was extracted with toluene (260 mL) three times. The combined organic phases were washed with water once (260 mL), concentrated to dryness, and isopropanol (517 mL) was added. The mixture was heated to 55-60°C, and L-di-p-toluoyltartaric acid (40.57 g, 105 mmol) was added. The mixture was slowly cooled to 0-5°C for crystallization, filtered, and the solid was collected and dried under vacuum to obtain intermediate 7d (91.22 g, 90.1%).

[0150] MS (ESI) m / z = 627.1 [M + H] +

[0151] 1H NMR(500MHz,DMSO)δ8.01(d,J=7.3Hz,8H),7.88(s,2H),7.69(d,J=7.4Hz,2H), 7.55(t,J=7.7Hz,8H),7.09(m,2H),6.77(d,J=7.7Hz,1H),6.28(d,J=6.2Hz,2H ),5.80(s,2H),4.54(dt,J=16.5,8.4Hz,1H),4.04(dd,J=7.2,5.8Hz,1H),3.88 (dt,J=16.8,8.5Hz,1H),3.27(s,3H),3.03-2.82(m,2H),1.74(d,J=1.8Hz,6H).

[0152] In Example 10, di-bis-tert-butylphenylphosphine palladium dichloride can be replaced by palladium acetate, palladium chloride, palladium pivalate, Pd(dppf)Cl2, bis(triphenylphosphine)palladium dichloride or tetrakistriphenylphosphine palladium or Pd2(dba)3; N,N-diisopropylethylamine can be replaced by triethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate or cesium carbonate; the reaction solvent toluene can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them. L-di-p-toluoyltartaric acid may be replaced by hydrobromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

[0153] Embodiment 11

[0154]

[0155] Compound 5e (45.73 g, 100 mmol), compound 6 (41.31 g, 110 mmol), sodium carbonate (31.80 g, 300 mmol), n-butyl acetate (229 mL) and water (52 mL) were added to a three-necked flask. After stirring, the mixture was switched to nitrogen three times under vacuum. Pd(dppf)Cl2 (365 mg, 0.5 mmol) was added under nitrogen protection. After the addition, the temperature was raised to 75-80°C for reaction for 4-6 hours. After the reaction was completed, the mixture was cooled to room temperature and 457 mL of water was added to quench the reaction. The aqueous phase was extracted three times with n-butyl acetate (229 mL). The organic phases were combined, washed once with water (229 mL), concentrated to dryness, heated to 55-60°C, n-heptane (457 mL) was added, and the mixture was slowly cooled to 0-5°C for crystallization. The mixture was filtered and the solid was collected and dried under vacuum to obtain intermediate 7e (55.22 g, 88.2%).

[0156] In Example 11, Pd(dppf)Cl2 can be replaced by palladium acetate, palladium chloride, palladium pivalate, ditriphenylphosphine palladium dichloride, tetratriphenylphosphine palladium or Pd2(dba)3, di-bis-tert-butylphenylphosphine palladium dichloride; no ligand is added or the ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine or di-tert-butylphenylphosphine; sodium carbonate can be replaced by triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate or cesium carbonate; the reaction solvent n-butyl acetate can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them. Compound 5e can also be replaced by its hydrochloride, bromate, phosphate, sulfate, p-toluenesulfonate, toluenesulfonate, methanesulfonate, acetate, trifluoroacetate, trifluoromethanesulfonate, oxalate, succinate, maleate, fumarate, citrate, L-tartrate, D-tartrate, L-dibenzoyltartrate, D-dibenzoyltartrate, L-di-p-toluoyltartrate, D-di-p-toluoyltartrate, L-malate, D-malate, L-camphorsulfonate or L-mandelate.

[0157] Example 12

[0158]

[0159] Add compound 8 (13.41 g, 100 mmol) and dichloromethane (67 mL) to a three-necked flask, stir and dissolve, add 67 mL of 5% sodium bicarbonate aqueous solution, add TEMPO (156 mg, 1 mmol), cool to 0-10°C in an ice-salt bath, slowly drop 10% sodium hypochlorite solution (148.9 g, 200 mmol), keep at 0-10°C for 3-4 hours, separate the liquid after the reaction, wash the organic phase with water once, concentrate until no fraction flows out, and obtain intermediate 9, which is directly used in the next step.

[0160] In Example 12, TEMPO reaction may not be added; the oxidant sodium hypochlorite may be replaced by Dess-Martin reagent, iodobenzene acetate, TCCA, NBS, NCS, DBDMH, liquid bromine or sodium hypobromite; sodium bicarbonate may not be added, or may be replaced by one or a mixture of two of sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bromide, TBAB; the reaction solvent dichloromethane may be replaced by tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, ethyl acetate or isopropyl acetate, or a mixed solvent system formed by any one of these solvents and water.

[0161] Embodiment 13

[0162]

[0163] Add compound 9 (~100mmol, obtained in Example 11) and tetrahydrofuran (106mL) into a three-necked flask, stir to dissolve, cool to 0-10°C in an ice-salt bath, drop 2.0M lithium diisopropylamide tetrahydrofuran solution (130mmol, 65mL) under nitrogen protection, keep at 0-10°C for 2-3 hours, slowly drop ethyl trifluoroacetate (17.05g, 120mmol), slowly warm to room temperature for 4-5 hours. After the reaction is completed, concentrate directly and feed to the next step.

[0164] In Example 13, lithium diisopropylamide can be replaced by lithium tert-butoxide, n-butyl lithium or LiHMDS; the reaction solvent tetrahydrofuran can be replaced by 2-methyltetrahydrofuran, toluene, NMP, DMPU or a mixed solvent formed by any two of these solvents.

[0165] Embodiment 14

[0166]

[0167] Add compound 10 (~100 mmol, obtained in Example 12) to a three-necked flask, add ethanol (187 mL), add ethyl hydrazinoacetate hydrochloride (15.46 g, 100 mmol), add 30% hydrochloric acid ethanol solution (36.46 mL, 300 mmol), heat to 45-50°C and react for 4-6 hours. After the reaction is completed, remove part of the ethanol by vacuum distillation, slowly add water (351 mL) at 50-55°C, slowly cool to 0-5°C, filter to obtain a solid, and dry in vacuum at room temperature to obtain intermediate 11 (25.59 g, total yield of three steps 82.5%)

[0168] In Example 14, hydrochloric acid can be replaced by sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, boron trifluoride etherate or pyridinium p-toluenesulfonate; the reaction solvent ethanol can be replaced by methanol, isopropanol, n-butanol, tert-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or a mixed solvent formed by any two of these solvents.

[0169] Embodiment 15

[0170]

[0171] Add compound 11 (31.02 g, 100 mmol) to a three-necked flask, add acetonitrile (155 mL), add anhydrous lithium bromide (26.05 g, 300 mmol), slowly add N, N-diisopropylethylamine (38.77 g, 300 mmol), heat to 55-60°C and react for 6-8 hours. After the reaction is completed, slowly cool to 0-5°C, filter to obtain a solid, add water to dissolve the solid, slowly drop dilute hydrochloric acid, cool to 0-5°C for crystallization, filter to collect the solid, and vacuum dry to obtain intermediate 12 (26.61 g, 94.3%)

[0172] In Example 15, lithium bromide can be replaced by lithium chloride, N,N-diisopropylethylamine can be replaced by triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent acetonitrile can be replaced by methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran or 2-methyltetrahydrofuran; hydrochloric acid can be replaced by sulfuric acid, phosphoric acid, citric acid or tartaric acid.

[0173] Example 16

[0174]

[0175] Compound 5a (55.34 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) were added to a three-necked flask, 277 mL of acetonitrile was added and stirred to dissolve, and triethylamine (25.30 g, 250 mmol) was added. 50% T4P ethyl acetate solution (68.72 g, 120 mmol) was added, and the mixture was reacted at room temperature of 20-30°C for 4-6 hours. After the reaction was completed, 277 mL of 0.5N dilute hydrochloric acid was added, and ethyl acetate (277 mL) was added to separate the liquids. The aqueous phase was extracted once with 277 mL of ethyl acetate, and the organic phases were combined and washed with 139 mL of 2% sodium bicarbonate and 139 mL of water, respectively, and concentrated to remove part of the ethyl acetate, heated to 50-55°C, 553 mL of n-heptane was slowly added, and the mixture was slowly cooled to 0-5°C for crystallization, filtered, and the filter cake was collected and dried under vacuum to obtain the target compound 13 (64.79 g, yield 89.8%).

[0176] In Example 16, the condensing agent T4P can be carbonyldiimidazole (CDI), isobutyl chloroformate (ICBF), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), The reaction solvent acetonitrile can be replaced by dimethylformamide, dimethylacetamide, NMP, toluene, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane or a mixed solution formed by any two of them.

[0177] Embodiment 17

[0178]

[0179] Add compound 5e (45.73 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) into a three-necked flask, add acetonitrile 229 mL and stir to dissolve, add EDCI (230.00 g, 120 mmol), add 2-hydroxypyridine-N-oxide HOPO (12.22 g, 110 mmol), add triethylamine (25.30 g, 250 mmol), and react at room temperature 20-30°C for 4-6 hours. After the reaction, 229 mL of 0.5 N dilute hydrochloric acid was added to ethyl acetate (229 mL) for separation. The aqueous phase was extracted once with 229 mL of ethyl acetate. The combined organic phases were washed with 115 mL of 2% sodium bicarbonate and 115 mL of water, respectively. The ethyl acetate was concentrated to remove part of the ethyl acetate, heated to 50-55° C., 457 mL of n-heptane was slowly added, and the mixture was slowly cooled to 0-5° C. for crystallization. The mixture was filtered and the filter cake was collected and dried under vacuum to obtain the target compound 13 (66.02 g, yield 91.5%).

[0180] In Example 17, the 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination can be carbonyldiimidazole (CDI), isobutyl chloroformate (ICBF), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC), T3P, T4P, BOP or PyBOP; triethylamine can be replaced by diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine or N-methylmorpholine; acetonitrile can be replaced by dimethylformamide, dimethylacetamide, NMP, toluene, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, 1,4-dioxane or a mixed solution formed by any two of them.

[0181] Embodiment 18

[0182]

[0183] Compound 13 (72.15 g, 100 mmol), compound 6 (41.31 g, 110 mmol) and 1,4-dioxane (360 mL) were added to a three-necked flask. After stirring, the mixture was switched to nitrogen three times under vacuum. Pd(PPh3)Cl2 (220 mg, 0.5 mmol) was added under nitrogen protection. Aqueous potassium carbonate solution (20%, 207 g, 300 mmol) was added. After the addition, the temperature was raised to 80-85°C and the mixture was reacted for 6-8 hours. After the reaction was completed, the mixture was cooled to room temperature and 360 mL of water was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (360 mL). The combined organic phases were washed once with water (260 mL), dried with anhydrous sodium sulfate, filtered, concentrated to a small volume, heated to 55-60°C, 576 mL of ether was added, the mixture was slowly cooled to 0-10°C for crystallization, filtered, the solid was collected and dried under vacuum to obtain intermediate 14a (86.31 g, 89.5%).

[0184] MS (ESI) m / z = 890.2 [M + H] +

[0185] 1H NMR (500MHz, DMSO) δ9.19(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.83-7.72*(m),7.74(d,J=2.1Hz,2H),7.10(d,J=7.6Hz,1H),7.04-6.94*(m ),7.05(s,1H),6.81(d,J=7.7Hz,1H),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.59(s,2H),4.90(d,J=16.4Hz,1H),4.74-4.59(m,1H ),4.74(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz,1H),3.38(m,4H),3.26(s,3H), 2.98-2.87(m,2H),2.60-2.58(m,2H)1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),1.09(t,J=12.1,6.1Hz,6H),0.92(t,J=8.6Hz,1H).

[0186] The X-ray powder diffraction data of the ether solvent compound obtained in this example are shown in Table 1. Figure 1a As shown, DSC Figure 1b As shown;

[0187] Table 1 X-ray powder diffraction data of ether solvent compounds

[0188] 2THETA d interval strength% 4.93 17.91 80.4 8.36 10.57 30.1 8.77 10.08 6.3 9.48 9.33 11.6 9.91 8.92 6.2 10.26 8.61 17.8 14.50 6.10 100.0 14.98 5.91 11.0 15.83 5.59 15.8 16.93 5.23 29.4 17.30 5.12 29.3 17.98 4.93 22.0 18.29 4.85 16.8 18.90 4.69 62.0 21.04 4.22 59.9 21.55 4.12 17.2 22.68 3.92 19.1 23.18 3.83 43.9 24.01 3.70 10.4 24.53 3.63 5.2 24.95 3.57 13.5 25.50 3.49 11.3 26.35 3.38 5.0 27.78 3.21 20.9 28.13 3.17 18.8 28.50 3.13 13.7 29.24 3.05 8.4 39.77 2.26 3.5

[0189] Embodiment 19

[0190]

[0191] Compound 13 (72.15 g, 100 mmol), compound 6 (41.31 g, 110 mmol) and DMF (360 mL) were added to a three-necked flask. After stirring, the mixture was switched to nitrogen three times under vacuum. Pd(PPh3)Cl2 (220 mg, 0.5 mmol) was added under nitrogen protection. Aqueous potassium carbonate solution (20%, 207 g, 300 mmol) was added. After the addition, the temperature was raised to 80-85°C and the mixture was reacted for 6-8 hours. After the reaction was completed, the mixture was cooled to room temperature and 360 mL of water was added to quench the reaction. The aqueous phase was extracted three times with dichloromethane (360 mL). The combined organic phases were washed once with water (260 mL), dried with anhydrous sodium sulfate, filtered, concentrated to a small volume, heated to 38-42°C, 576 mL of n-propyl ether was added, the mixture was slowly cooled to 0-10°C for crystallization, filtered, the solid was collected and dried under vacuum to obtain intermediate 14b (86.04 g, 86.7%).

[0192] MS (ESI) m / z = 890.2 [M + H] +

[0193] 1 H NMR (500MHz, DMSO) δ9.21(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.82-7.72*(m),7.74(d,J=2.1Hz,2H),7.10(d,J=7.6Hz,1H),7.04-6.94*(m ),7.03(s,1H),6.81(d,J=7.7Hz,1H),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.65(s,2H),4.90(d,J=16.4Hz,1H),4.78-4.59(m,1H ),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz,1H),3.64-3.53(m,2H),3.26(s, 3H),2.98-2.87(m,2H),2.60-2.58(m,2H)1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),1.03(d,J=6.1Hz,12H),0.92(t,J=8.6Hz,1H).

[0194] The X-ray powder diffraction data of the n-propyl ether solvent compound obtained in this example are shown in Table 2. Figure 2a As shown, DSC Figure 2b As shown;

[0195] Table 2 X-ray powder diffraction data of n-propyl ether solvent compound

[0196]

[0197]

[0198] Embodiment 20

[0199]

[0200] Compound 13 (72.15 g, 100 mmol), compound 6 (41.31 g, 110 mmol) and n-butyl acetate (360 mL) were added to a three-necked flask. After stirring evenly, the mixture was switched to nitrogen three times under vacuum. Pd(dppf)Cl2 (366 mg, 0.5 mmol) was added under nitrogen protection. Aqueous sodium carbonate solution (20%, 159 g, 300 mmol) was added. After the addition was complete, the temperature was raised to 80-85°C for reaction. After 8 hours, the reaction was completed and cooled to room temperature. 360 mL of water was added to quench the reaction. The liquids were separated, and the aqueous phase was extracted twice with n-butyl acetate (360 mL). The combined organic phases were washed once with water (260 mL), added with anhydrous sodium sulfate, dried, filtered, concentrated to a small volume, heated to 55-60°C, added with 576 mL of isopropyl ether, slowly cooled to 0-10°C for crystallization, filtered, and the solid was collected and dried in vacuo to obtain intermediate 14c (84.15 g, 84.8%).

[0201] MS (ESI) m / z = 890.2 [M + H] +

[0202] 1H NMR (500MHz, DMSO) δ9.21(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.82-7.72*(m),7.74(d,J=2.1Hz,2H),7.10(d,J=7.6Hz,1H),7.04-6.94*(m ),7.03(s,1H),6.81(d,J=7.7Hz,1H),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.65(s,2H),4.90(d,J=16.4Hz,1H),4.78-4.59(m,1H ),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz,1H),3.64-3.53(m,2H),3.26(s, 3H),2.98-2.87(m,2H),2.60-2.58(m,2H)1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),1.03(d,J=6.1Hz,12H),0.92(t,J=8.6Hz,1H).

[0203] The X-ray powder diffraction data of the isopropyl ether solvent compound obtained in this example are shown in Table 3. Figure 3a As shown, DSC Figure 3b As shown, the schematic diagram of the single crystal analytical structure is as follows Figure 3c As shown;

[0204] Table 3 X-ray powder diffraction data of isopropyl ether solvent compound

[0205]

[0206]

[0207] Embodiment 21

[0208]

[0209] Compound 13 (72.15 g, 100 mmol), compound 6 (41.31 g, 110 mmol) and tert-amyl alcohol (360 mL) were added to a three-necked flask. After stirring, the mixture was switched to nitrogen three times under vacuum. Pd(dppf)Cl2 (366 mg, 0.5 mmol) was added under nitrogen protection. A sodium carbonate aqueous solution (20%, 159 g, 300 mmol) was added. After the addition, the temperature was raised to 80-85°C and the mixture was reacted for 6-8 hours. After the reaction was completed, the mixture was cooled to room temperature. 360 mL of water was added to quench the reaction. The mixture was separated. The aqueous phase was extracted twice with isopropyl acetate (360 mL). The combined organic phases were washed once with water (260 mL), dried with anhydrous sodium sulfate, filtered, concentrated to a small volume, heated to 55-60°C, 576 mL of n-butyl ether was added, the mixture was slowly cooled to 0-10°C for crystallization, filtered, and the solid was collected and dried under vacuum to obtain intermediate 14d (92.14 g, 90.3%).

[0210] MS (ESI) m / z = 890.2 [M + H] +

[0211] 1 H NMR (500MHz, DMSO) δ9.21(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.82-7.72*(m),7.74(d,J=2.1Hz,2H),7.10(d,J=7.6Hz,1H),7.04-6.94*(m ),7.03(s,1H),6.81(d,J=7.7Hz,1H),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.65(s,2H),4.90(d,J=16.4Hz,1H),4.78-4.59(m,1H ),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz,1H),3.64-3.53(m,2H),3.26(s, 3H),2.98-2.87(m,2H),2.60-2.58(m,2H)1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),1.03(d,J=6.1Hz,12H),0.92(t,J=8.6Hz,1H).

[0212] The X-ray powder diffraction data of the n-butyl ether solvent compound obtained in this example are shown in Table 4. Figure 4a As shown, DSC Figure 4b As shown;

[0213] Table 4 X-ray powder diffraction data of n-butyl ether solvent compound

[0214]

[0215]

[0216] Embodiment 22

[0217]

[0218] Compound 13 (72.15 g, 100 mmol), compound 6 (41.31 g, 110 mmol) and 2-methyltetrahydrofuran (360 mL) were added to a three-necked flask. After stirring evenly, the mixture was switched to nitrogen three times under vacuum. Pd(tBu2PPh)2Cl2 (311 mg, 0.5 mmol) was added under nitrogen protection. Aqueous potassium phosphate solution (20%, 319 g, 300 mmol) was added. After the addition was complete, the mixture was heated to 90-95°C and reacted for 6-8 hours. When the reaction was finished, the mixture was cooled to room temperature, 360 mL of water was added to quench the reaction, the liquid was separated, the aqueous phase was extracted twice with ethyl acetate (360 mL), the combined organic phases were washed once with water (260 mL), anhydrous sodium sulfate was added to dry, filtered, concentrated to a small volume, heated to 55-60°C, 180 mL of isopropanol and 360 mL of methyl tert-butyl ether were added, slowly cooled to 0-10°C for crystallization, filtered, the solid was collected and dried in vacuo to obtain intermediate 14e (84.04 g, 85.9%).

[0219] MS (ESI) m / z = 890.2 [M + H] +

[0220] 1H NMR (500MHz, DMSO) δ9.22(d,J=8.3Hz,1H),8.92*(d,J=8.5Hz),7.80-7.70*(m),7.73(d,J=2.1Hz,2H),7.11(d,J=7.6Hz,1H),7.04-6.94 *(m),7.03(s,1H),6.81(d,J=7.7Hz,1H),6.53-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.60(s,2H),4.90(d,J=16.4Hz,1H),4.78-4. 59(m,1H),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.15(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz,1H),3.26(s,3H),3 .08(s,3H),2.98-2.87(m,2H),2.60-2.58(m,2H)1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),1.11(s,9H),0.92(t,J=8.6Hz,1H).

[0221] The X-ray powder diffraction data of the methyl tert-butyl ether solvent compound obtained in this example are shown in Table 5. Figure 5a As shown, DSC Figure 5b As shown;

[0222] Table 5 X-ray powder diffraction data of methyl tert-butyl ether solvent compound

[0223] 2THETA d interval strength% 6.97 12.68 23.4 8.57 10.31 18.4 10.01 8.83 20.5 12.67 6.98 27.6 13.14 6.73 11.7 14.39 6.15 41.6 14.79 5.98 100.0 15.37 5.76 38.4 16.23 5.46 16.8 17.22 5.15 66.0 17.30 5.12 33.7 17.68 5.01 19.8 17.89 4.95 38.9 18.25 4.86 37.1 19.22 4.61 24.5 19.86 4.47 31.0 20.05 4.43 29.6 20.32 4.37 52.1 20.51 4.33 66.3 21.55 4.12 47.2 21.70 4.09 9.5 22.87 3.89 17.3 23.23 3.83 43.5 23.87 3.72 9.1 24.45 3.64 29.2 25.36 3.51 10.1 25.90 3.44 8.5 26.34 3.38 9.3 26.81 3.32 18.0 28.70 3.11 8.7 29.08 3.07 9.8 29.61 3.01 14.5

[0224] Embodiment 23

[0225]

[0226] Add compound 7a (81.83 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) to a three-necked flask, add 409 mL of N,N-dimethylformamide, stir and dissolve, cool to 0-10°C, add condensation reagents EDCI (23.0 g, 120 mmol) and HOBt (16.22 g, 120 mmol), slowly drop N-methylmorpholine (30.34 g, 300 mmol), raise the temperature to 0-10°C and react for 4-6 hours. After the reaction, 409 mL of ethyl acetate and 818 mL of 0.5 N dilute hydrochloric acid were added, the liquids were separated, the aqueous phase was extracted twice with 409 mL of ethyl acetate, the combined organic phases were washed with 200 mL of 3% sodium bicarbonate and 200 mL of water, concentrated to remove part of the ethyl acetate, heated to 50-55° C., isopropyl ether (200 mL) was slowly added, slowly cooled to 0-5° C. for crystallization, filtered, and the filter cake was collected and dried under vacuum to obtain the target compound 14c (82.27 g, yield 82.9%).

[0227] In Example 23, the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination can be carbonyldiimidazole (CDI), isobutyl chloroformate (ICBF), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl The reaction solvent N,N-dimethylformamide can be replaced by dimethylacetamide, NMP, tetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane or a mixed solvent of any two of them. Compound 7a can also be replaced by its hydrochloride, bromate, phosphate, sulfate, p-toluenesulfonate, toluenesulfonate, acetate, trifluoroacetate, trifluoromethanesulfonate, oxalate, succinate, maleate, fumarate, citrate, L-tartrate, D-tartrate, L-dibenzoyltartrate, D-dibenzoyltartrate, L-di-p-toluoyltartrate, D-di-p-toluoyltartrate, L-malate, D-malate, L-camphorsulfonate or L-mandelate.

[0228] Embodiment 24

[0229]

[0230] Add compound 7e (62.60 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) into a three-necked flask, add 313 mL of N,N-dimethylformamide, stir and dissolve, cool to 0-10°C, add condensation reagent EDCI (23.0 g, 120 mmol) and 2-hydroxypyridine-N-oxide HOPO (13.33 g, 120 mmol), slowly drop N-methylmorpholine (30.34 g, 300 mmol), raise the temperature to 0-10°C and react for 4-6 hours. After the reaction, 313 mL of ethyl acetate and 626 mL of 0.5 N dilute hydrochloric acid were added, the liquids were separated, the aqueous phase was extracted twice with 313 mL of ethyl acetate, the combined organic phases were washed with 200 mL of 3% sodium bicarbonate and 200 mL of water, concentrated to dryness, heated to 50-55° C., methyl cyclopentane (200 mL) was slowly added, n-heptane (626 mL) was added, slowly cooled to 0-5° C. for crystallization, filtered, and the filter cake was collected and dried under vacuum to obtain the target compound 14f (87.65 g, yield 88.5%).

[0231] MS (ESI) m / z = 890.2 [M + H] +

[0232] 1 H NMR (500MHz, DMSO) δ9.23(d,J=8.3Hz,1H),8.94*(d,J=8.5Hz),7.82-7.72*(m),7.73(d,J=2.1Hz,2H),7.13(d,J=7.6Hz,1H),7.04-6.9 4*(m),7.04(s,1H),6.81(d,J=7.7Hz,1H),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.55(s,2H),4.90(d,J=16.4Hz,1H),4.78- 4.59(m,1H),4.73(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.76-3.71(m,2H),3.26(s,3H),3.16(s, 3H),2.30-2.87(m,2H),2.60-2.56(m,2H)1.73(d,J=2.5Hz,6H),1.67-1.41(m,8H),1.41(dd,J=13.5,7.0Hz,1H),0.92(t,J=8.6Hz,1H).

[0233] The X-ray powder diffraction data of the methyl cyclopentyl ether solvent compound obtained in this example are shown in Table 6. Figure 6a As shown, DSC Figure 6b As shown;

[0234] Table 6 X-ray powder diffraction data of methyl cyclopentyl ether solvent compound

[0235] 2THETA d interval strength% 6.89 12.82 3.6 9.69 9.12 100 13.02 6.80 34 14.03 6.31 0.3 14.58 6.07 23.6 14.94 5.93 2.7 17.44 5.08 2.7 17.95 4.94 3.7 18.51 4.79 0.4 19.27 4.60 17.4 20.46 4.34 0.3 21.35 4.16 2.7 22.13 4.01 5.8 22.50 3.95 3.2 23.89 3.72 7.2 24.22 3.67 22.5 24.55 3.62 0.6 25.26 3.52 1 25.63 3.47 0.5 26.54 3.36 5.9 26.71 3.34 1.1 27.37 3.26 0.9 28.19 3.16 3.8 29.36 3.04 1.8 30.12 2.96 1.9 31.18 2.87 0.4 32.49 2.75 4.4 33.50 2.67 0.4

[0236] In Example 24, the condensing agent 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 2-hydroxypyridine-N-oxide (HOPO) combination can be 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBT) combination, carbonyldiimidazole (CDI), isobutyl chloroformate (ICBF), O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC), T3 P, T4P, BOP or PyBOP can be used instead; N-methylmorpholine can be replaced by diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylenediamine; the reaction solvent N,N-dimethylformamide can be replaced by dimethylacetamide, NMP, tetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane or a mixed solvent formed by any two of them; the n-heptane mixed solvent can be replaced by ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isopropyl acetate, n-propyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, acetonitrile, acetone, water or a mixed solvent formed by any two of them. Compound 7e can also be replaced by its hydrochloride, bromate, phosphate, sulfate, p-toluenesulfonate, toluenesulfonate, methanesulfonate, acetate, trifluoroacetate, trifluoromethanesulfonate, oxalate, succinate, maleate, fumarate, citrate, L-tartrate, D-tartrate, L-dibenzoyltartrate, D-dibenzoyltartrate, L-di-p-toluoyltartrate, D-di-p-toluoyltartrate, L-malate, D-malate, L-camphorsulfonate or L-mandelate.

[0237] Embodiment 25

[0238]

[0239] Add compound 7e (62.60 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) into a three-necked flask, add 313 mL of N,N-dimethylformamide, stir and dissolve, cool to 0-10°C, add condensation reagent EDCI (23.0 g, 120 mmol) and 2-hydroxypyridine-N-oxide HOPO (13.33 g, 120 mmol), slowly drop N-methylmorpholine (30.34 g, 300 mmol), raise the temperature to 0-10°C and react for 4-6 hours. After the reaction, 313 mL of ethyl acetate and 626 mL of 0.5 N dilute hydrochloric acid were added, the liquids were separated, the aqueous phase was extracted twice with 313 mL of ethyl acetate, the organic phases were combined and washed with 200 mL of 3% sodium bicarbonate and 200 mL of water, concentrated to dryness, heated to 50-55° C., 2,2-dimethoxypropane (200 mL) was slowly added, n-heptane (626 mL) was added, slowly cooled to 0-5° C. for crystallization, filtered, and the filter cake was collected and dried under vacuum to obtain 14 g (89.29 g, yield 89.8%) of the target compound.

[0240] MS (ESI) m / z = 890.2 [M + H] +

[0241] 1 H NMR (500MHz, DMSO) δ9.21(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.83-7.76*(m),7.74(d,J=2.1Hz,2H),7.10(d,J=7.6Hz,1H),7.04-6.94 *(m),7.03(s,1H),6.81(d,J=7.7Hz,1H),6.53-6.50*(d,J=6.4Hz),6.43(d,J=6.3Hz,2H),5.62(s,2H),4.92(d,J=16.4Hz,1H),4.78-4.5 9(m,1H),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.74(dq,J=17.3,8.7Hz,1H),3.26(s,3H),3. 17(s,6H),2.98-2.87(m,2H),2.60-2.58(m,2H),2.09(s,6H),1.73(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),0.92(t,J=8.6Hz,1H).

[0242] The X-ray powder diffraction data of the 2,2-dimethoxypropane solvent compound obtained in this example are shown in Table 7. Figure 7a , DSC Figure 7b As shown;

[0243] Table 7 X-ray powder diffraction data of 2,2-dimethoxypropane solvent compound

[0244]

[0245]

[0246] Embodiment 26

[0247]

[0248] Add compound 7e (62.60 g, 100 mmol) and compound 12 (29.63 g, 105 mmol) into a three-necked flask, add 313 mL of N,N-dimethylformamide, stir and dissolve, cool to 0-10°C, add condensation reagent EDCI (23.0 g, 120 mmol) and 2-hydroxypyridine-N-oxide HOPO (13.33 g, 120 mmol), slowly drop N-methylmorpholine (30.34 g, 300 mmol), raise the temperature to 0-10°C and react for 4-6 hours. After the reaction, 313 mL of ethyl acetate and 626 mL of 0.5 N dilute hydrochloric acid were added, the liquids were separated, the aqueous phase was extracted twice with 313 mL of ethyl acetate, the combined organic phases were washed with 200 mL of 3% sodium bicarbonate and 200 mL of water, concentrated to dryness, heated to 50-55°C, toluene (200 mL) was slowly added, isopropanol (626 mL) was added, slowly cooled to 0-5°C for crystallization, filtered, the filter cake was collected and dried under vacuum to obtain the target compound 14h (81.34 g, yield 82.8%).

[0249] MS (ESI) m / z = 890.2 [M + H] +

[0250] 1H NMR (500MHz, DMSO) δ9.24(d,J=8.3Hz,1H),8.93*(d,J=8.5Hz),7.82-7.72*(m),7.74(d,J=2.1Hz,2H),7.27-7.23(m,2H),7.19-7.13(m,3H),7 .10(d,J=7.6Hz,1H),7.04-6.94*(m),7.03(s,1H),6.81(d,J=7.7Hz,1H ),6.51-6.50*(d,J=6.4Hz),6.44(d,J=6.3Hz,2H),5.65(s,2H),4.90(d ,J=16.4Hz,1H),4.78-4.59(m,1H),4.71(d,J=16.4Hz,1H),4.35*(dd,J=16.1,8.2Hz),4.14(dq,J=16.5,8.2Hz,1H),3.73(dq,J=17.3,8.7Hz, 1H),3.26(s,3H),2.98-2.87(m,2H),2.60-2.58(m,2H),2.30(s,3H)1.7 3(d,J=2.5Hz,6H),1.41(dd,J=13.5,7.0Hz,1H),0.92(t,J=8.6Hz,1H).

[0251] The X-ray powder diffraction data of the toluene solvent compound obtained in this example are shown in Table 8. Figure 8a , DSC Figure 8b As shown;

[0252] Table 8 X-ray powder diffraction data of toluene solvent compounds

[0253]

[0254]

[0255] Embodiment 27

[0256]

[0257] Add compound 14 (99.24 g, 100 mmol) to a three-necked flask, add 496 mL of dichloromethane and stir to dissolve, add 15% potassium carbonate aqueous solution (138.20 g, 150 mmol), cool to 0-5°C, slowly drop compound 15a (14.89 g, 130 mmol), and heat to room temperature (20-30°C) to react for 4-6 hours. After the reaction, 496 mL of dichloromethane and 595 mL of water were added, and the liquids were separated. The aqueous phase was extracted three times with 298 mL of dichloromethane, and the organic phases were combined and washed with 398 mL of 3% dilute hydrochloric acid and 298 mL of water, respectively, and concentrated to dryness. 779 mL of ethanol was added, and the mixture was heated to 50-55°C. 10% sodium ethanol ethanol solution (68.05 g, 100 mmol) was added, and the mixture was slowly cooled to 0-5°C for crystallization. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the target compound 16 (90.81 g, purity 99.92%, yield 91.7%).

[0258] In Example 27, potassium carbonate can be replaced by triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine or N-methylmorpholine; the reaction solvent dichloromethane can be replaced by N,N-dimethylformamide, toluene, acetonitrile, acetone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran , dimethylacetamide, NMP, 1,4-dioxane or a mixed solvent formed by any two of them; sodium ethoxide can be replaced by sodium hydroxide, sodium methoxide, sodium tert-butoxide, or sodium carbonate; the crystallization solvent dichloromethane can be replaced by isopropanol, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isopropyl acetate, n-propyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile, acetone, n-heptane, water or a mixed solvent formed by any two of them; compound 15a can also be replaced by

[0259] replace.

[0260] Embodiment 28

[0261]

[0262] Add compound 14 (99.24 g, 100 mmol) to a three-necked flask, add 496 mL of N,N-dimethylformamide, stir and dissolve, add triethylamine (15.18 g, 150 mmol), cool to 0-5°C, and add compound 15b (16.07 g, 110 mmol). After the addition is complete, heat to room temperature 20-30°C and react for 4-6 hours. After the reaction is completed, add 496 mL of ethyl acetate and 595 mL of water, extract the aqueous phase with 298 mL of ethyl acetate 3 times, combine the organic phases, wash with 298 mL of 3% dilute hydrochloric acid, wash with 298 mL of water, concentrate to dryness, add 779 mL of isopropanol, heat to 50-55°C, add 10% sodium hydroxide solution (40 mL, 100 mmol), slowly cool to 0-5°C for crystallization, filter, collect the filter cake and vacuum dry to obtain the target compound 16 (91.30 g, purity 99.90%, yield 92.2%).

[0263] In Example 28, triethylamine can be replaced by sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, diisopropylethylamine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine or N-methylmorpholine; the reaction solvent N,N-dimethylformamide can be replaced by dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, Furan, dimethylacetamide, NMP, 1,4-dioxane or a mixed solvent formed by any two of them; sodium hydroxide can be replaced by sodium methoxide, sodium ethoxide, sodium tert-butoxide, or sodium carbonate; the crystallization solvent isopropanol can be replaced by ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, isopropyl acetate, n-propyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, toluene, acetonitrile, acetone, n-heptane, water or a mixed solvent formed by any two of them; compound 15b can also be replaced by replace.

Claims

1. Lenacapvir N2 intermediate solvent compound 14, whose structural formula is as follows: in, The complexing solvent s°lvate is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, cyclopentyl methyl ether (CPME), 2,2-dimethoxypropane or toluene.

2. The lenacapvir N2 intermediate solvent compound 14 according to claim 1, characterized in that: Its ether solvent compound 14a has characteristic peaks at 4.93±0.2°, 8.36±0.2°, 14.50±0.2°, 18.90±0.2°, 21.04±0.2° and 23.18±0.2° in the X-ray powder diffraction pattern 2Theta value measured by Cu-Kα ray; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-115°C, the melting point peak is 110.4±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 309.9±3.0°C; Its n-propyl ether solvent compound 14b has characteristic peaks at 7.36±0.2°, 8.39±0.2°, 14.18±0.2°, 14.55±0.2°, 14.89±0.2°, 21.40±0.2° and 23.40±0.2° in the X-ray powder diffraction pattern 2Theta values ​​measured using Cu-Kα rays; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-120°C, the melting point peak is at 108.4±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 310.3±3.0°C; The single crystal structure of its isopropyl ether solvent compound 14c was confirmed by single crystal analysis, and the single crystal unit cell parameters are: α=γ=90°, β=98.558(2)°, Monoclinic system, space group is P21; Its isopropyl ether solvent compound 14c has characteristic peaks at 6.57±0.2°, 14.07±0.2°, 14.79±0.2°, 17.71±0.2°, 21.13±0.2° and 22.17±0.2° in the X-ray powder diffraction pattern 2Theta values ​​measured using Cu-Kα rays; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 95.0-125°C, the melting point peak is at 116.5°C±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 314.4°C±3.0°C; Its n-butyl ether solvent compound 14d has characteristic peaks at 12.87°, 17.27°, 17.95°, 20.21°, 20.38° and 20.92° in the X-ray powder diffraction pattern 2Theta value measured using Cu-Kα ray; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 100.0-125°C, the melting point peak is 120.6±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 310.2±3.0°C; Its methyl tert-butyl ether solvent compound 14e has characteristic peaks at Theta values ​​of 14.79°, 17.22°, 20.32°, 20.51°, 21.55° and 23.23° in the X-ray powder diffraction diagram 2 measured using Cu-Kα rays; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 90.0-120°C, the melting point peak is 111.5±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 309.5±3.0°C. Its methyl cyclopentyl ether solvent compound 14f has characteristic peaks at 6.82±0.2°, 14.09±0.2°, 14.53±0.2°, 14.87±0.2°, 18.25±0.2° and 20.30±0.2° in the X-ray powder diffraction pattern 2Theta values ​​measured using Cu-Kα rays; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 96.0-133°C, the melting point peak is at 120.3±3.0°C, and it exothermically decomposes when heated to 270-340°C, with a peak at 309.3±3.0°C; The X-ray powder diffraction pattern 2Theta value of the 2,2-dimethoxypropane solvent compound 14g thereof measured by Cu-Kα ray has characteristic peaks at 17.85°, 20.32°, 21.16°, 21.91°, 22.63° and 24.66°; the differential scanning calorimetry analysis curve (DSC) thereof shows that an endothermic peak begins to appear when heated to 90.0-115°C, the melting point peak is 109.0±3.0°C, and the exothermic decomposition is heated to 240-340°C, with a peak at 310.7±3.0°C; The toluene solvent compound 14h has characteristic peaks at 7.35°, 14.50°, 15.28°, 15.70°, 18.53° and 20.37 in the X-ray powder diffraction pattern 2Theta values ​​measured using Cu-Kα rays; its differential scanning calorimetry analysis curve (DSC) shows that an endothermic peak begins to appear when heated to 95.0-120°C, the melting point peak is 106.5±3.0°C, and it exothermically decomposes when heated to 240-340°C, with a peak at 309.6±3.0°C.

3. A method for synthesizing the lenacapvir N2 intermediate solvent compound 14 as claimed in claim 1, characterized in that: The method comprises the following steps: subjecting the free base or salt form of compound 7 to a condensation reaction with compound 12 under the action of a base and a condensing agent to obtain a free base, and then reacting with a complexing solvent to obtain a solvent compound 14; Wherein, the complexing solvent s°lvate is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene.

4. A method for synthesizing the lenacapvir N2 intermediate solvent compound 14 as claimed in claim 1, characterized in that: The steps include: (1) Compound 5 salt form is reacted with compound 12 in the presence of a base and a condensing agent to obtain compound 13; (2) Compound 13 and borate intermediate compound 6 are coupled under the action of palladium catalyst, and then reacted with a complexing solvent to obtain solvent compound 14; Wherein, the complexing solvent s°lvate is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene.

5. A method for synthesizing a lenacapvir N2 intermediate solvent compound 14 according to claim 3 or 4, characterized in that: The synthesis method of the key chiral acid intermediate compound 12 of Nacapavir comprises the following steps: (1) Compound 8 is reacted with an oxidant to obtain compound 9; (2) Compound 9 is condensed with ethyl trifluoroacetate in the presence of lithium salt to obtain intermediate compound 10; (3) Compound 10 and ethyl hydrazinoacetate complete a cyclization reaction under the action of an acid to obtain an intermediate compound 11; (4) Compound 11 is subjected to alkaline hydrolysis and acidification to obtain the key chiral acid intermediate compound 12; 6. A method for synthesizing lenacapvir sodium, characterized in that: The process comprises reacting a lenacapvir N2 solvent compound 14 with a compound 15 under the action of a base to complete a sulfonylation reaction, and finally forming a sodium salt to obtain a target product lenacapvir sodium compound 16; Among them, the complexing solvent solvate in compound 14 is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene, and M in compound 15 is chlorine, methanesulfonyloxy or N-heterocyclic compound, wherein Z is C, N, O or S.

7. The key chiral amine intermediate compound 5 salt form and intermediate compound 7 salt form of Nacapavir have the following structural formulas: in, The ratio of free base to acid in compound 5 is 1:1 or 1:2; the ratio of free base to acid in compound 7 is 1:1 or 1:2; wherein HX acid and HY acid are respectively selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

8. A method for synthesizing the key chiral amine intermediate compound 5 of lenacapvir, characterized in that: The steps include: (1) Compound 2 is exchanged with a Grignard reagent and condensed with 3,6-dibromopyridine-2-carboxylic acid methyl ester compound 1 to obtain an intermediate compound 3; (2) Compound 3 is coupled with 3-methyl-3-(methylsulfonyl)-1-butyne in the presence of a catalyst to obtain an intermediate compound 4; (3) Compound 4 reacts with an aminating agent under the catalysis of transaminase and coenzyme to obtain a free base of Compound 5 or forms a salt with HX acid to obtain a salt of Compound 5; Wherein, the HX acid is selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

9. A method for synthesizing the key chiral amine intermediate compound 7 of lenacapvir, characterized in that: The method comprises coupling a free base or salt form of compound 5 with a borate intermediate compound 6 under the action of a palladium catalyst to obtain a free base of compound 7 or forming a salt with HY acid to obtain a salt form of compound 7; Wherein, HY acid is selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

10. A method for synthesizing lenacapvir sodium, comprising: using 3,6-dibromopyridine-2-carboxylic acid methyl ester compound 1 and 3,5-difluorobenzyl bromide compound 2 as starting materials, obtaining compound 3 through Grignard addition reaction, docking with 3-methyl-3-(methylsulfonyl)-1-butyne compound 4 through coupling reaction, and then using transaminase amination reaction to obtain lenacapvir key chiral amine intermediate compound 5, and then coupling with lenacapvir key boric ester compound 6 to obtain compound 7; compound 8 is first oxidized by hydroxyl group to obtain carbonyl compound 9, and then reacted with trifluoroethyl under the action of strong base lithium reagent to obtain compound 7; Compound 10 is obtained by reacting with ethyl hydrazinoacetate to obtain compound 11, which is then hydrolyzed to obtain compound 12, a key chiral acid intermediate of lenacapvir; compound 7 and compound 12 are directly condensed, and a solvate is formed with a complexing solvent to obtain lenacapvir N2 intermediate compound 14, which is finally sulfonylated with 15 to form a sodium salt to obtain the target product lenacapvir sodium; compound 12 is first condensed with compound 5 to generate compound 13, which is then coupled with compound 6 to obtain lenacapvir N2 intermediate solvent compound 14; the reaction route is: in, In compound 14, the complexing solvent solvate is selected from diethyl ether, n-propyl ether, isopropyl ether, methyl tert-butyl ether, n-butyl ether, methyl cyclopentyl ether (CPME), 2,2-dimethoxypropane or toluene. In compound 15, M is chlorine, methanesulfonyloxy or N-heterocyclic compound, wherein Z is C, N, O or S; HX acid and HY acid are respectively selected from hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, L-tartaric acid, D-tartaric acid, L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-di-p-toluoyltartaric acid, D-di-p-toluoyltartaric acid, L-malic acid, D-malic acid, L-camphorsulfonic acid or L-mandelic acid.

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