A method for preparing nitrogen-containing cyclic derivatives

Abstract

The present invention relates to a method for preparing a nitrogen-containing cyclic derivative. The method of the present invention overcomes the defects existing in the prior art, greatly reduces the cost, effectively avoids the technical difficulty of unstable intermediate state, thereby reducing the generation of reaction by-products, improving the operability and yield of the process, and having high process safety. Therefore, the method is suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing nitrogen-containing cyclic derivatives. Background Art

[0002] Neurokinin (NK) includes substance P (SP), neurokinin A and neurokinin B, and the corresponding three types of receptors are neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R) and neurokinin 3 receptor (NK3R). All three types of receptors are G protein-coupled receptors, among which NK1R is the most widely distributed, distributed in both the central and peripheral nervous systems, NK2R is mainly distributed in the peripheral nervous system, and NK3R is mainly distributed in the central nervous system. At present, NK receptor inhibitors have been used to treat psychiatric diseases such as menopausal anxiety, hot flashes, depression, schizophrenia, etc., especially NK3R is closely related to symptoms such as hot flashes of menopausal syndrome, and NK3R inhibitors have been shown to have a good effect in improving menopausal hot flashes.

[0003] Menopausal hot flashes refer to the symptoms of hot flashes and sweating that often occur in menopausal people. They are the prominent manifestations of menopausal syndrome. Menopausal hot flashes are caused by vasomotor dysfunction caused by the decline of estrogen levels in the body. When estrogen levels in the body drop, the brain will mistakenly think that the body temperature is too high. Therefore, the brain will send a signal to the heart to ask the heart to pump more blood and the sweat glands to release more sweat, accompanied by sweating, palpitations, dizziness, etc. More than three-quarters of women have hot flashes during menopause, and 80% of patients can have this symptom for more than 1 year, and some can even last for about 5 years after menopause. At present, the main treatment for menopausal hot flashes is hormone replacement therapy, but this therapy is prone to cause breast cancer, stroke, coronary heart disease, dementia and other diseases, and the risk factor is relatively high. Oral medications, such as paroxetine (a SSRI drug for the treatment of depression), are the only small molecule drugs approved for the treatment of menopausal hot flashes. They also have side effects and are only approved in the United States. Therefore, there is a clinical need to develop safer and more effective drugs for the treatment of menopausal syndrome.

[0004] Patent WO2022022680 discloses a series of NK3R inhibitors, which have good effects. The present invention further studies the preparation process of NK3R inhibitor compounds to meet the needs of industrial scale-up. The prior art patent WO2013050424A1 discloses the following process route:

[0005]

[0006] This process uses triethoxylium tetrafluoroborate as an alkylating agent to construct an intermediate state with ethoxy as a leaving group, which is then cyclized with carbohydrazide to form 1,2,4-triazole. This process has many disadvantages, such as poor stability of the intermediate state, complex control during the reaction, low cyclization yield, and complex post-treatment, which is not conducive to subsequent process scale-up. Therefore, a process route that is more suitable for process scale-up is needed. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the present invention further studies the preparation method of compound (R)-(3-(3-chloro-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone.

[0008] The present invention provides a compound represented by formula (III) or a salt thereof,

[0009]

[0010] Wherein, R1 is selected from C 1-6 Alkyl, C 6-12 Aryl or 5-12 membered heteroaryl; preferably, R1 is selected from C 1-4 Alkyl, C 6-10 Aryl or 5-8 membered heteroaryl; further preferably, R1 is selected from C 1-3 Alkyl, phenyl or pyridyl;

[0011] PG is N-sp 3 Protecting group, the N-sp 3 The protecting group is a benzylic protecting group; preferably, the benzylic protecting group is selected from benzyl (Bn), 4-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB) and 2,4,6-trimethoxybenzyl (TMB), and more preferably DMB.

[0012] The present invention also provides a method for preparing a compound represented by formula (III) or a salt thereof, characterized in that: a compound represented by formula (I) or a salt thereof and a compound represented by a reaction reagent represented by formula (II) are reacted to obtain a compound represented by formula (III) or a salt thereof,

[0013]

[0014] Among them, PG and R1 are as described above.

[0015] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the reaction is carried out under the protection of an inert gas, preferably nitrogen.

[0016] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from a mixed solvent of acetonitrile and dichloromethane; further preferably, the ratio of the organic solvent is acetonitrile: dichloromethane = 1:1 to 8:1, and further preferably, the ratio of the organic solvent is acetonitrile: dichloromethane = 4:1.

[0017] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the reaction is carried out in the presence of a base; preferably, the base is selected from sodium carbonate, potassium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate, lithium hydroxide, potassium phosphate, sodium bicarbonate, cesium carbonate, sodium thiosulfate, ammonia water, ammonia methanol solution, ammonium bicarbonate, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, triethylamine, N-methylimidazole, N,N-dimethylaniline, pyridine, quinoline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium, phenyl lithium, N-methylmorpholine (NMM), morpholine, triethylenediamine (DABCO), N,N-dimethylbenzylamine, N-methylpiperidine, 1-methylpyrrolidine, N-methyldicyclohexylamine, tetrahydropyrrole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or potassium hexamethyldisilazide (KHMDS) or more; further preferably, the base is N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, 2,6-lutidine, imidazole, potassium phosphate, potassium carbonate or potassium acetate; further preferably, the base is N-methylimidazole;

[0018] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (III), the molar ratio of the compound of formula (I) to the compound of reaction reagent formula (II) is 1:1 to 1:3; preferably 1:2.

[0019] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (III), the molar ratio of the base to the compound of formula (I) is 1:0.3-1; preferably 1:0.5-0.6 (e.g. 1:0.57).

[0020] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (III), the molar ratio of the base to the compound of formula (II) is 1:0.8-1.5; preferably 1:1.1-1.2 (e.g. 1:1.1).

[0021] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the concentration of the base in the organic solvent is 0.2-0.6 mol / L; preferably 0.3-0.4 mol / L (eg 0.33 mol / L).

[0022] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the reaction time is 1-8 hours, preferably 2-5 hours (eg 3 hours).

[0023] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (III), the reaction temperature is -15 to 15 ℃, preferably -5~0℃.

[0024] The present invention also provides a method for preparing a compound of formula (V), which further comprises the following steps: further reacting a compound of formula (III) or a salt thereof with a compound of formula (IV) to obtain a compound of formula (V) or a salt thereof by cyclization,

[0025]

[0026] wherein R2 is selected from halogen; preferably chlorine; PG and R1 are as described above.

[0027] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (V), the reaction time is 1-8 hours, preferably 2-5 hours (eg 3 hours).

[0028] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (V), the reaction temperature is 5 to 70 ℃, preferably 10 to 60 ℃, more preferably 40 to 60 ℃ (for example, 50 ℃).

[0029] In a further preferred embodiment of the present invention, the present invention also provides a method for preparing a compound represented by formula (VII-2), characterized in that the compound represented by formula (VII-1) or a salt thereof and an alkaline reagent are reacted to obtain a compound represented by formula (VII-2) or a salt thereof,

[0030]

[0031] Wherein, X1 and X2 are selected from halogen, preferably, X1 is selected from F, and X2 is selected from bromine;

[0032] M is a metal ion selected from Na, K or Li. Preferably, M is selected from Li.

[0033] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII-2), the alkaline reagent is selected from LiHMDS, NaHMDS, KHMDS, NaOH, LiOH, KOH, LDA, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, TMSOK, TMSOLi; preferably LiHMDS.

[0034] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII-2), the alkaline reagent needs to be mixed with an organic solvent and added dropwise; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from tetrahydrofuran.

[0035] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-2), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from acetonitrile.

[0036] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-2), the reaction time is 1-8 hours, more preferably 2-6 hours (eg 2-3 hours).

[0037] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-2), the reaction temperature is 0 to 50 ℃, more preferably 5~20℃.

[0038] The present invention also provides a method for preparing a compound of formula (VII-3) or a salt thereof, characterized in that it further comprises the following steps: the compound of formula (VII-2) or a salt thereof is further subjected to a deuteration reaction to obtain a compound of formula (VII-3) or a salt thereof,

[0039]

[0040] Among them, X1 and X2 are as described above.

[0041] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-3), the reaction is carried out in the presence of a base; preferably, the base is selected from dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate, lithium hydroxide, potassium phosphate, sodium bicarbonate, cesium carbonate, sodium thiosulfate, ammonia water, ammonia methanol solution, ammonium bicarbonate, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylpyridine One or more of methylaminopyridine, imidazole, triethylamine, N-methylimidazole, N,N-dimethylaniline, pyridine, quinoline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium, phenyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or potassium hexamethyldisilazide (KHMDS); more preferably, the base is selected from potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide; further preferably, the base is selected from potassium phosphate.

[0042] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII-3), the reaction is carried out by adding a deuterated reagent; preferably, the deuterated reagent is deuterated water, deuterated methanol, deuterated ethanol, deuterated propanol, deuterated trifluoroacetic acid, deuterated sulfuric acid; further preferably, the deuterated reagent is deuterated water.

[0043] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-3), the reaction is carried out by adding a reducing agent; preferably, the reducing agent is zinc powder, iron powder, magnesium powder, or aluminum powder; further preferably, the reducing agent is zinc powder.

[0044] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-3), the mass ratio of the alkaline reagent to deuterated water is 1:1 to 1:20; preferably 1:1 to 1:4; more preferably 1:1.5 to 1:2.5 (e.g. 1:2.1);

[0045] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII-3), the mass ratio of the compound of formula (VII-2) to deuterated water is 1:1~1:20; preferably 1:1~1:4; more preferably 1:1.5~1:2.5 (for example 1:2).

[0046] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-3), the reaction time is 5 to 20 hours, preferably 8 to 14 hours.

[0047] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VII-3), the reaction temperature is 60-100°C, preferably 80-90°C.

[0048] The present invention also provides a method for preparing a compound represented by formula (V) or a salt thereof, characterized in that it comprises the following steps:

[0049]

[0050] Wherein, PG, R1, and R2 are as described above, and the preparation methods of the compounds represented by the formulae are the same as described above.

[0051] The present invention also provides a method for preparing the compound represented by formula (VI) or a salt thereof, characterized in that it comprises the following steps:

[0052]

[0053] Wherein, PG, R1, and R2 are as described above, and the preparation methods of the compounds represented by the formulae are the same as described above.

[0054] The present invention also provides a method for preparing a compound represented by formula (VIII) or a salt thereof, characterized in that it comprises the following steps:

[0055]

[0056] in,

[0057] PG, R1, R2, and X1 are as described above, and the preparation methods of the compounds represented by the formulae are the same as described above.

[0058] In a further preferred embodiment of the present invention, in the preparation method of the compound of formula (VIII), in the preparation of the compound of formula (III), the reaction is carried out under nitrogen protection; the reaction is carried out in a solvent, and the solvent is an organic solvent; the organic solvent is selected from a mixed solvent selected from acetonitrile and dichloromethane; the ratio of the organic solvent is acetonitrile: dichloromethane = 4:1; the reaction is carried out in the presence of a base; the base is N-methylimidazole; the molar ratio of the compound of formula (I) to the compound of reaction reagent formula (II) is 1:2; the molar ratio of the base to the compound of formula (I) is 1:0.5~0.6 (for example, 1:0.57); the molar ratio of the base to the compound of formula (II) is 1:1.1~1.2 (for example, 1:1.1); the concentration of the base in the organic solvent is 0.3~0.4 mol / L (for example, 0.33 mol / L); the reaction time is 2-5 hours (for example, 3 hours); and the reaction temperature is -5~0°C.

[0059] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (VIII) or a salt thereof, in the preparation of the compound represented by formula (V), the reaction time is 2-5 hours (e.g., 3 hours) and the reaction temperature is 40-60°C (e.g., 50°C).

[0060] The present invention also provides a method for preparing a compound represented by formula (VII-3) or a salt thereof, characterized in that it comprises the following steps:

[0061]

[0062] in,

[0063] X1, X2 and M are as defined above, and the preparation methods of the compounds represented by the formulae are the same as described above.

[0064] The present invention also provides a method for preparing a compound represented by formula (VII) or a salt thereof, characterized in that it comprises the following steps:

[0065]

[0066] in,

[0067] X1, X2 and M are as defined above, and the preparation methods of the compounds represented by the formulae are the same as described above.

[0068] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII), in the preparation of the compound of formula (VII-2), the alkaline reagent is selected from LiHMDS; the alkaline reagent needs to be mixed with an organic solvent and added dropwise; the organic solvent is selected from tetrahydrofuran; the reaction is carried out in a solvent, and the solvent is an organic solvent; the organic solvent is selected from acetonitrile; the reaction time is 2-6 hours (e.g., 2~3 hours); and the reaction temperature is 5~20°C.

[0069] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (VII), in the preparation of the compound of formula (VII-3), the reaction is carried out in the presence of a base; the base is selected from potassium phosphate; the reaction is carried out by adding a deuterated reagent, and the deuterated reagent is deuterated water; the reaction is carried out by adding a reducing reagent, and the reducing reagent is zinc powder; the mass ratio of the alkaline reagent to deuterated water is 1:2; the reaction time is 8-14 hours; and the reaction temperature is 80~90°C.

[0070] The present invention also provides a method for preparing the compound represented by formula (A) or a salt thereof, characterized in that it comprises the following steps:

[0071]

[0072] Wherein, PG is an amino protecting group, preferably, the amino protecting group is selected from 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), benzyl (Bn), 4-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB) and 2,4,6-trimethoxybenzyl (TMB), and Boc is more preferred;

[0073] R2 is halogen, preferably chlorine.

[0074] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing the compound represented by formula (A-2), the reaction is carried out in the presence of a base; preferably, the base is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate, lithium hydroxide, potassium phosphate, sodium bicarbonate, cesium carbonate, sodium thiosulfate, ammonia water, ammonia methanol solution, ammonium bicarbonate, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, triethylamine, N-methylimidazole, N,N-dimethylaniline, pyridine, quinoline, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) or potassium hexamethyldisilazide (KHMDS); more preferably, the base is selected from sodium bicarbonate.

[0075] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or its salt, in the method for preparing the compound represented by formula (A-2), the reaction is carried out in a solvent, and the solvent is an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from ethylene glycol dimethyl ether.

[0076] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (A) or its salt, wherein in the method for preparing the compound of formula (A-2), the reaction is carried out under inert gas protection, preferably nitrogen protection.

[0077] In a further preferred embodiment of the present invention, in the method for preparing the compound of formula (A) or its salt, wherein in the method for preparing the compound of formula (A-2), the reaction time is 1-8 hours, preferably 2-5 hours (e.g. 3 hours).

[0078] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing the compound represented by formula (A-2), the reaction temperature is 50 to 120 ℃, preferably 70~90℃ (for example, 80℃).

[0079] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing formula (A-2) → formula (A), the reaction is carried out in a solvent, and the solvent is an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from dichloromethane.

[0080] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing formula (A-2) → formula (A), acetic acid is added to carry out the reaction.

[0081] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing formula (A-2) → formula (A), the reaction is carried out by adding silver benzoate.

[0082] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing formula (A-2) → formula (A), the reaction time is 8-24 hours, preferably 10-15 hours (e.g. 12 hours).

[0083] In a further preferred embodiment of the present invention, in the method for preparing the compound represented by formula (A) or a salt thereof, in the method for preparing formula (A-2) → formula (A), the reaction temperature is 15-35°C, preferably 25°C.

[0084] Compared with the existing technology, this patent uses cheap raw materials and reaction reagents, and prepares 1,2,4-triazole derivatives in a one-pot method by constructing intermediate states of different leaving groups, effectively avoiding the technical difficulty of unstable intermediate states, thereby reducing the production of reaction by-products, improving the operability of the process, and ultimately increasing the yield and purity.

[0085] Detailed description of the invention

[0086] According to the present invention, the term "N-sp 3 A "protecting group" is defined as a tertiary amine (i.e., sp 3 hybrid nitrogen).

[0087] The term "benzylic protecting group" according to the present invention is defined as benzyl (Bn), 4-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB) and 2,4,6-trimethoxybenzyl (TMB), among which DMB and TMB are preferred, and DMB is particularly preferred.

[0088] "DMF" means N,N-dimethylformamide;

[0089] "THF" means tetrahydrofuran;

[0090] "EA" means ethyl acetate;

[0091] “TFA” refers to trifluoroacetic acid;

[0092] "DCM" means dichloromethane;

[0093] “K2CO3” means potassium carbonate;

[0094] “H2O” means water;

[0095] "KOAc" means potassium acetate;

[0096] "MTBE" means methyl tert-butyl ether. DETAILED DESCRIPTION

[0097] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0098] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) or deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0099] Thermo ISQ EM LC-MS was used for LC-MS. Titank C18 column (2.1×50mm, 3μm) was used for HPLC. Other information is shown in the following table:

[0100]

[0101] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0102] Example 1

[0103]

[0104] Add 2.4L acetonitrile and 0.6L dichloromethane to a 5L jacketed bottle, start stirring, add 150g of compound 1 to the jacketed bottle and stir at room temperature until dissolved, then add 305g of compound 2 diphenyl chlorophosphate, replace with nitrogen 3 times, cool to -5~0℃, add 83.9g N-methylimidazole to the jacketed bottle to control the temperature at -5~0℃, and stir for 3 hours. Take samples for control, the control mass spectrum data of compound 3 is: [M+H]+ m / z 497.10, after the first stage of the reaction is completed, heat to 10-15℃, add 111.6g of compound 4 at one time, heat to 20℃, and stir for 0.5 hours. Heat to 50℃, stir for 3 hours, and take samples for control. After the reaction is completed, cool to room temperature, add 1.5L DCM and 1.5L water to the reaction solution, stir and separate, extract the aqueous phase with 750mL DCM, and separate. The organic phases were combined, washed once with 1.5 L of saturated sodium bicarbonate aqueous solution, and then washed once with 1.5 L of semi-saturated sodium chloride aqueous solution, separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 267.7 g of crude compound 5 with a purity of 78.51%, a content of 69.12%, and a yield of 80%.

[0105] Example 2

[0106]

[0107] Add 726mL of dichloromethane and 242g of compound 5 to a 2L jacketed bottle, adjust the internal temperature to 0-10℃, slowly drop 363mL of TFA into the jacketed bottle, control the temperature to 10~15℃, and after dropping, warm to room temperature, stir for 2 hours, and take samples for control. After the reaction is completed, filter out the white solid, rinse twice with 120mL of dichloromethane, and adjust the temperature of the mother liquor to 10~20℃. Slowly add 750mL of water to the mother liquor, stir for 10 minutes and then separate the liquids. The organic phase is extracted three times with 500mL of water, the aqueous phase is combined, the aqueous phase is washed once with 250mL of dichloromethane, and the aqueous phase is separated. The aqueous phase is added to a 2L jacketed bottle, cooled to 0~10℃, 1L of dichloromethane is added, stirring is turned on, and the pre-cooled 6M sodium hydroxide aqueous solution is slowly added to adjust the pH>12. Filter through a diatomaceous earth pad, separate the liquids, and retain the dichloromethane phase. The aqueous phase was extracted twice with 500 mL of dichloromethane, the organic phases were combined, washed once with 500 mL of saturated brine, separated, the dichloromethane phase was retained, and dried over anhydrous sodium sulfate. Concentrated to obtain 200 g of an off-white solid. The solid was added to 400 ml of ethyl acetate and stirred at room temperature for 30 minutes, 800 ml of methyl tert-butyl ether was added dropwise, stirred at room temperature overnight, filtered, and dried at 50 ° C for 2 hours to obtain 69.32 g of compound 6, with a purity of 98.04%, a content of 100%, and a yield of 65.5%.

[0108] Example 3

[0109]

[0110] Add 1625 mL of dichloromethane, 65 g of compound 6, and 39.3 g of DIPEA to a 5 L jacketed bottle and adjust the temperature to -5-5 o C, stir to dissolve. Slowly add compound 7 in dichloromethane (325 mL) to the jacketed bottle, control the temperature at -5-5 o C, stirred for 1 hour. Take samples for control. After the reaction is finished, add 650 mL of pre-cooled 15% sodium chloride and 5% sodium bicarbonate aqueous solution, stir for 10 minutes, stand for separation, keep the dichloromethane phase, and dry it over anhydrous sodium sulfate. Concentrate to obtain 104 g of crude compound 8 with a purity of 96.58%, a content of 88.88%, and a yield of 96.3%.

[0111] Example 4

[0112]

[0113] Add 120 mL of DMSO to a 1 L jacketed bottle, add 15 g of the crude product, and start mechanical stirring. Heat the internal temperature to 80-85 o C until clear, then add 30 mL of DMSO to the jacketed bottle and cool the internal temperature to 55-60 o C, add 0.1% seed crystals, and continue stirring at this temperature for 1h; o C, add 450 mL of anhydrous ethanol within 1 h, and gradually reduce the temperature to 20 within 5 h. o C, keep at 20 o C and continue stirring for more than 6 h, filter, wash twice with 15 mL of ethanol, and o C and dried with forced air for 5 h to obtain 12.12 g of compound 8 (purity: 99.93%, chiral purity: 100%, assay: 100%, isolated yield: 89%)

[0114] Example 5

[0115]

[0116] Weigh the raw material compound 9 (100 g) and add it to acetonitrile (1000 ml), stir and disperse it evenly, record it as R1; control the internal temperature not higher than 10°C to add 460 ml of LiHMDS (1M in THF) to R1, and the addition time is 2-3 hours; after the addition, control the internal temperature not higher than 20°C, keep warm and stir for 2-3 hours; TLC detection shows that there is basically no raw material point; filter, rinse with 1V-2V acetonitrile each time, rinse twice in total; the filter cake is vacuum dried at 70-75°C for 18-21 hours, and sample to measure the moisture (KF<0.2%) to obtain 96 g (yield: 95%) of compound 10.

[0117] Example 6

[0118]

[0119] Add 104g of anhydrous potassium phosphate, 210g of deuterium water and 86g of zinc powder to a 1000ml three-necked flask; add 100g of compound 10 to the above reaction flask in five times; adjust the internal temperature to 80-88℃, keep warm and stir for 8h-14h, after the reaction, adjust the internal temperature to 20-35℃, add 500ml of process water, stir for 0.5h-1h, filter, collect the filtrate, transfer the filtrate water layer to R1, add 9V-11V EA to R1, control the internal temperature not exceeding 30℃, add 0.5V-0.8V concentrated hydrochloric acid to adjust the pH to 1-2, stop stirring, stand for 20-30min, transfer the water layer to R2, separate the organic layer, extract the water layer with 5V-6V ethyl acetate each time, extract twice in total, combine the organic layers, add 1.0X-1.5X anhydrous sodium sulfate to dry, The residue was concentrated under reduced pressure to obtain 56 g of compound 11 with a purity of 99.6% and a yield of 89.3% to 93%.

[0120] Example 7

[0121]

[0122] Compound 11 (42.8 g, 303.29 mmol) and 3 drops of DMF were added to DCM (200 mL), and oxalyl chloride (57.74 g, 454.94 mmol, 38.50 mL) was added dropwise. After the addition was completed, the reaction was allowed to proceed for 3 hours. After the solvent was removed by vacuum concentration, the product was distilled under reduced pressure (diaphragm pump, 115°C oil bath) to obtain the product compound 12 (45 g, 93% yield).

[0123] Example 8

[0124]

[0125] 80 mL of ethylene glycol dimethyl ether, 4 g of compound 13, 8.32 g of P2S5 and 6.28 g of NaHCO3 were added to a 250 mL three-necked flask, and N2 was replaced three times. o C for 3 hours. After the reaction, the mixture was cooled to room temperature and filtered. The filter cake was rinsed with 20 mL of ethylene glycol dimethyl ether. The filtrate was directly concentrated and passed through a column to obtain 4.03 g of compound 14 with a purity of 98%, a content of 91.1%, and a yield of 93.7%.

[0126] Example 9

[0127]

[0128] Add 80 mL of dichloromethane, 4 g of compound 14, 4 g of compound 15, 3.36 g of acetic acid, and 8.56 g of silver benzoate to a 250 mL three-necked flask and react at room temperature overnight. Take samples for control. After the reaction is completed, add 80 mL to quench the reaction, let stand and separate the liquids, extract the aqueous phase once with 50 mL of dichloromethane, combine the organic phases, wash the organic phases twice with saturated brine, dry and concentrate the organic phase, and pass it through a column to obtain 4.3 g of compound 16 with a purity of 98.25%, a content of 97.8%, and a yield of 74.6%.

[0129] Example 10

[0130]

[0131] Add 160 mL acetonitrile, 40 mL dichloromethane, 10 g compound 1 and 10.93 g compound 17 dimethyl chlorophosphate to a 500 mL jacketed bottle, replace with nitrogen three times, cool to -5~0°C, add 5.6 g N-methylimidazole dropwise at this temperature, and continue stirring for 3 hours. Sample control, compound 18 control mass spectrum data is [M+H] + m / z 373.11. After the reaction is completed, the temperature is raised to 10-15°C, 7.5g of compound 4 is added, the temperature is raised to 20°C, and the mixture is stirred for 0.5 hours. The temperature is then raised to 50°C, stirred for 3 hours, and the sample is taken for control. After the reaction is completed, the mixture is cooled to room temperature, 100 mL of DCM and 100 mL of water are added to the reaction solution, the mixture is stirred and separated, and the aqueous phase is extracted with 50 mL of DCM and separated. The organic phases are combined, washed once with 100 mL of saturated sodium bicarbonate aqueous solution, and the organic phase is washed once with 100 mL of semi-saturated sodium chloride aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1) to obtain 9.83 g of compound 5 with a purity of 97.2% and a yield of 64%.

[0132] Embodiment 11

[0133]

[0134] Add 160 mL acetonitrile, 40 mL dichloromethane, 10 g compound 1 and 13.05 g compound 19 diethyl chlorophosphate to a 500 mL jacketed bottle, replace with nitrogen three times, cool to -5~0°C, add 5.6 g N-methylimidazole dropwise at this temperature, and continue stirring for 3 hours. Sample control, compound 20 control mass spectrum data is [M+H] +m / z 401.18. After the reaction is completed, the temperature is raised to 10-15°C, 7.5g of compound 4 is added, the temperature is raised to 20°C, and the mixture is stirred for 0.5 hours. The temperature is then raised to 50°C, stirred for 3 hours, and the sample is taken for control. After the reaction is completed, the mixture is cooled to room temperature, 100 mL of DCM and 100 mL of water are added to the reaction solution, the mixture is stirred and separated, and the aqueous phase is extracted with 50 mL of DCM and separated. The organic phases are combined, washed once with 100 mL of saturated sodium bicarbonate aqueous solution, and the organic phase is washed once with 100 mL of semi-saturated sodium chloride aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1) to obtain 8.91 g of compound 5 with a purity of 95.6% and a yield of 58%.

[0135] Example 12

[0136]

[0137] Add 160 mL acetonitrile, 40 mL dichloromethane, 10 g compound 1 and 15.18 g compound 21 diisopropyl chlorophosphate to a 500 mL jacketed bottle, replace with nitrogen three times, cool to -5~0°C, add 5.6 g N-methylimidazole dropwise at this temperature, and continue stirring for 3 hours. Take a sample for central control, the mass spectrum data of compound 22 is [M+H] + m / z 429.24. After the reaction is completed, the temperature is raised to 10-15°C, 7.5g of compound 4 is added, the temperature is raised to 20°C, and the mixture is stirred for 0.5 hours. The temperature is then raised to 50°C, stirred for 3 hours, and the sample is taken for control. After the reaction is completed, the mixture is cooled to room temperature, 100 mL of DCM and 100 mL of water are added to the reaction solution, the mixture is stirred and separated, and the aqueous phase is extracted with 50 mL of DCM and separated. The organic phases are combined, washed once with 100 mL of saturated sodium bicarbonate aqueous solution, and the organic phase is washed once with 100 mL of semi-saturated sodium chloride aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1) to obtain 10.29 g of compound 5 with a purity of 98.9% and a yield of 67%.

Claims

1. A method for preparing a compound represented by formula (III) or a salt thereof, characterized in that: The compound represented by formula (I) or its salt reacts with the compound represented by reaction reagent (II) to obtain the compound represented by formula (III) or its salt, ， Wherein, R1 is selected from C 1-6 Alkyl or C 6-10 Aryl; PG is selected from benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl or 2,4,6-trimethoxybenzyl; The reaction is carried out in the presence of a base, wherein the base is N-methylimidazole, and the molar ratio of the base to the compound represented by formula (I) is 1:0.3-1.

2. The method for preparing the compound represented by formula (III) or a salt thereof according to claim 1, characterized in that: R1 is selected from C 1-4 PG is selected from benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl or 2,4,6-trimethoxybenzyl.

3. The method for preparing the compound represented by formula (III) or a salt thereof according to claim 1, characterized in that: The reaction is carried out in an organic solvent, and the organic solvent is selected from a mixed solvent of acetonitrile and dichloromethane; Alternatively, the molar ratio of the compound represented by formula (I) to the compound represented by reaction reagent formula (II) is 1:1 to 1:

3.

4. The method for preparing the compound represented by formula (III) or a salt thereof according to claim 3, characterized in that: The organic solvent ratio is acetonitrile: dichloromethane = 1:1~8:1; Alternatively, the molar ratio of the compound represented by formula (I) to the compound represented by reaction reagent formula (II) is 1:

2.

5. The method for preparing the compound represented by formula (III) or a salt thereof according to claim 3, characterized in that: The ratio of the organic solvent is acetonitrile: dichloromethane = 4:

1.

6. The method for preparing the compound represented by formula (III) or a salt thereof according to claim 1, characterized in that: The molar ratio of the base to the compound represented by formula (I) is 1: 0.5-0.

6.

7. A method for preparing a compound represented by formula (V), characterized in that: The method comprises the following steps: the compound of formula (III) or its salt is further reacted with the compound of formula (IV) to obtain the compound of formula (V) or its salt by a ring-forming reaction. ， in, The method for preparing the compound of formula (III) or its salt as claimed in claim 1; R2 is selected from halogen; PG and R1 are the same as those described in claim 1.

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