An intermediate of alectinib and a preparation method thereof

Abstract

The application discloses a preparation method of an intermediate of Axitinib and an intermediate of Axitinib as shown in formula VI. The application provides a preparation method of a compound as shown in formula VII, which comprises the following steps: performing ring formation reaction on a compound of formula VI in the presence of a base and a solvent to obtain the compound of formula VII. The Axitinib synthesis route provided by the application has the advantages of less steps, low cost, high purity of a synthesis product and no introduction of toxic substances.

Description

Technical Field

[0001] This invention relates to an intermediate of alectinib and its preparation method. Background Technology

[0002] Alectinib, also known as alectinib, is an anaplastic lymphoma kinase (ALK) inhibitor used to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC) with ALK gene mutations, or those resistant to crizotinib. Its chemical name is 9-ethyl-6,6-dimethyl-8-[4-(4-morpholino)-1-piperidinyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile, and its molecular structure is as follows:

[0003]

[0004] Alectinib

[0005] The original patents WO2010143664 and WO2012023597 reported two synthetic routes for alectinib.

[0006] Route 1: Starting with 7-methoxy-3,4-dihydro-2-naphthone, alectinib is prepared through 9 steps. This route is lengthy, cumbersome, and has high production costs, making it unsuitable for commercialization. The synthetic route is as follows:

[0007]

[0008] Route 2: Alectinib is prepared from 2-methyl-2-(4-ethyl-3-iodophenyl)-propionic acid through a 6-step reaction. This route is much simpler than Route 1, but isomers are easily generated during the synthesis process.

[0009]

[0010] Patent CN104402862A reports a six-step reaction to prepare alectinib using 3-bromo-4-ethylacetophenone and 6-cyanoindole as starting materials. The reagents used in this reaction are relatively expensive, resulting in high costs. The synthetic route is as follows:

[0011]

[0012] Patent CN106928184B reports a five-step process for preparing alectinib from 2-methyl-2-(4-ethyl-3-iodophenyl)-propionic acid. This process has fewer steps and readily available raw materials. However, 3-cyanophenylhydrazine is expensive and has genotoxicity. In the hydrolysis of tert-butyl formate at the 3-position of the indole ring, inexpensive acid-base hydrolysis cannot be used. Only relatively expensive trifluoroethanol can be used as a solvent to remove the tert-butyl group with trimethylchlorosilane, resulting in higher costs.

[0013]

[0014] In summary, the preparation of alectinib involves the key intermediate compound I, 6-cyano-2-(2-(4-ethyl-3-(4-morpholino-1-piperazinyl)phenyl-isopropyl)-3-indolecarboxylic acid:

[0015] Summary of the Invention

[0016] The technical problem this invention aims to solve is that existing technologies involve high production costs, complex production operations, and demanding equipment requirements. This invention provides a method for preparing an intermediate of iletinib, which avoids the problems of existing methods and significantly reduces production costs.

[0017] The preparation method of the present invention is shown below:

[0018]

[0019] The present invention mainly solves the above-mentioned technical problems through the following technical solutions.

[0020] This invention provides a method for preparing a compound of formula VII, comprising the following steps:

[0021] In the presence of a base and a solvent, the compound of formula VI was subjected to the following cyclization reaction to obtain the compound of formula VII.

[0022]

[0023] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0024] In some embodiments, the C1-C10 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; and the C6-C10 aryl groups are phenyl or naphthyl.

[0025] In some implementation schemes, R 2 It can be methyl, ethyl, tert-butyl, or phenyl.

[0026] In some embodiments, the reactants in the preparation method of the compound of formula VII are the compound of formula VI, the base, and the solvent.

[0027] In some embodiments, the preparation method of the compound of formula VII further includes the following specific steps: dissolving the compound of formula VI in the solvent, and then adding the base to carry out the cyclization reaction to obtain the compound of formula VII.

[0028] In some embodiments, in the preparation method of the compound of formula VII, the base can be a base conventional in this type of reaction in the art, such as an alkyl lithium reagent, such as a n-butyllithium reagent, preferably a n-butyllithium n-hexane solution (2.7M).

[0029] In some embodiments, in the preparation method of the compound of formula VII, the solvent may be a conventional solvent in this type of reaction in the art, such as a cyclic ether solvent, for example, tetrahydrofuran.

[0030] In some embodiments, in the preparation method of the compound of formula VII, the molar ratio of the compound of formula VI to the base can be 1:(2-4), preferably 1:3.

[0031] In some embodiments, the cyclization reaction is carried out at a temperature of 10–40°C, preferably 20–30°C, in the method for preparing the compound of formula VII.

[0032] In some embodiments, the progress of the reaction in the preparation method of the compound of formula VII can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound as shown in formula VI, or the cessation of the increase of the compound of formula VII. For example, the reaction time can be 15 to 20 hours.

[0033] In some embodiments, the method for preparing the compound of formula VII further includes the following post-processing step: (preferably, when R...) 2 (When tert-butyl) After the reaction is complete, the reaction solution is cooled to -10 to 10°C, and anhydrous ethanol, 10% sodium chloride aqueous solution, and isopropyl acetate are added sequentially. The aqueous phase obtained by separation is extracted with isopropyl acetate, the organic phases are combined, and 10% sodium chloride solution and 5% sodium bicarbonate solution are added sequentially. The organic phase is separated, washed with 10% sodium chloride solution until neutral, and the organic phase is concentrated to obtain compound of formula VII.

[0034] In some embodiments, the method for preparing compound VII involves directly using the compound of formula I without post-processing after the reaction.

[0035] In some embodiments, the method for preparing the compound of formula VII may further include a method for preparing the compound of formula VI, which may include the following steps:

[0036] (a) In the presence of a solvent, the compound of formula V is subjected to an acyl chloride reaction with an acyl chloride reagent to obtain a mixed solution 1.

[0037] (b) The mixed solution 1, the compound of formula A shown, and a base are reacted in the presence of a solvent to obtain the compound of formula VI.

[0038]

[0039] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0040] In some implementations, the C1-C 10 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; the C6-C 10 The aryl group is either phenyl or naphthyl.

[0041] In some implementation schemes, R 2 It can be methyl, ethyl, tert-butyl, or phenyl.

[0042] In some embodiments, the acyl chloride reaction may further include a catalyst, which may be N,N-dimethylformamide.

[0043] In some embodiments, the reaction materials in the preparation method of the compound of formula VI are the compound of formula V, the compound of formula A, the N,N-dimethylformamide, the base, the acyl chloride reagent, and the solvent.

[0044] In some embodiments, the preparation method of the compound of formula VI further includes the following steps: dissolving the compound of formula V and the N,N-dimethylformamide in the solvent, then adding the acyl chloride reagent to react; after the compound of formula V has reacted completely, concentrating the reaction solution, and then adding a solvent to obtain mixed solution 1; dissolving the compound of formula A and the base in the solvent to obtain mixed solution 2; and mixing mixed solution 1 and mixed solution 2 to react. Preferably, mixed solution 1 and mixed solution 2 are mixed at -5 to 5°C.

[0045] In some embodiments, in the preparation method of the compound of formula VI, the acyl chloride reagent can be a conventional acyl chloride reagent used in this type of reaction in the art, such as oxalyl chloride or thionyl chloride, preferably oxalyl chloride.

[0046] In some embodiments, in the preparation method of the compound of formula VI, the base can be a base conventional in this type of reaction in the art, such as an organic base, preferably triethylamine.

[0047] In some embodiments, in the preparation method of the compound of formula VI, the solvent may be a conventional solvent in this type of reaction in the art, such as a chloroalkane solvent. Preferably, the chloroalkane solvent is dichloromethane or dichloroethane, and dichloromethane is preferred.

[0048] In some embodiments, in the preparation method of the compound of formula VI, the molar ratio of the compound of formula V to the N,N-dimethylformamide is (10-20):1, preferably 16:1.

[0049] In some embodiments, in the preparation method of the compound of formula VI, the molar ratio of the compound of formula V to the oxaloyl chloride is 1:(1-3), preferably 1:1.7.

[0050] In some embodiments, in the preparation method of the compound of formula VI, the molar ratio of the compound of formula V to the compound of formula A is 1:(1-2), preferably 1:1.

[0051] In some embodiments, the reaction temperature in the preparation method of the compound of formula VI is 10–40°C, preferably 20–30°C.

[0052] In some embodiments, the progress of the reaction in the preparation method of the compound of formula VI can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound as shown in formula A, or the cessation of the increase of the compound of formula VI. For example, the reaction time can be 20 to 21 hours.

[0053] In some embodiments, the preparation method of the compound of formula VI includes the following post-processing steps: after the reaction is completed, water is added, the mixture is separated, the organic phase is washed twice with 1M hydrochloric acid, then washed twice with 5% sodium bicarbonate solution, the organic phase is partially concentrated, n-heptane is added at 20-30°C, the mixture is stirred and filtered at 0-10°C, and dried to obtain the compound of formula VI.

[0054] In some embodiments, the preparation method of the compound of formula VII further includes the following preparation method to obtain the compound of formula V, which may include the following steps:

[0055] Option 1: Hydrolyze compound III in the presence of acid or base to obtain compound V;

[0056]

[0057] In some embodiments, the acid is an acid conventional to this type of reaction in the art, such as an inorganic acid, preferably concentrated hydrochloric acid.

[0058] In some embodiments, the base is a base conventional for this type of reaction in the art. For example, an alkali metal hydroxide, preferably sodium hydroxide, potassium hydroxide, and more preferably a 30% aqueous solution of sodium hydroxide.

[0059] In some embodiments, the ratio of the compound of formula III to the acid is 1:(15-30), preferably 1:18;

[0060] In some embodiments, the molar ratio of the compound of formula III to the base is 1:(5-10), preferably 1:7.5.

[0061] In some embodiments, when the hydrolysis reaction is carried out in the presence of acid, the temperature of the hydrolysis reaction is 100-115°C.

[0062] In some embodiments, when the hydrolysis reaction is carried out in the presence of an alkali, the temperature of the hydrolysis reaction is 90–110°C, preferably 100°C.

[0063] In some embodiments, when the hydrolysis reaction is carried out under concentrated hydrochloric acid conditions, the hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with ethyl acetate, the pH is adjusted to 6-7 with 20% NaOH aqueous solution, the aqueous phase is extracted with dichloromethane, the organic phase is partially concentrated, petroleum ether is added at 20-30°C, the mixture is stirred at 0-10°C, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V.

[0064] In some embodiments, when the hydrolysis reaction is carried out under alkaline conditions, the hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with dichloromethane, the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid, the aqueous phase is extracted again with dichloromethane, the organic phase is partially concentrated, petroleum ether is added at 20-30°C, the mixture is stirred at 0-10°C, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V.

[0065] Option 2: In the presence of a base, the compound of formula IV undergoes an ester hydrolysis reaction to obtain the compound of formula V.

[0066]

[0067] In some embodiments, the base is a base conventional for this type of reaction in the art. For example, an alkali metal hydroxide, preferably sodium hydroxide, potassium hydroxide, or lithium hydroxide, more preferably 30% sodium hydroxide.

[0068] In some embodiments, the hydrolysis reaction is carried out at a temperature of 90–110°C, preferably 100°C.

[0069] In some embodiments, the hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with dichloromethane, the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid, the aqueous phase is extracted again with dichloromethane, the organic phase is partially concentrated, petroleum ether is added at 20-30°C, the mixture is stirred at 0-10°C, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V.

[0070] Option 3: In the presence of a catalyst, a bis(trimethylsilyl)amino metal reagent, and a solvent, compound II and compound B undergo a coupling reaction to obtain compound V.

[0071] In some embodiments, the catalyst is a conventional catalyst in this type of reaction in the art, such as a metal coupling catalyst, preferably allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium.

[0072] In some embodiments, the solvent is an ether solvent, preferably ethylene glycol dimethyl ether.

[0073] In some embodiments, the molar ratio of the Formula II compound to the catalyst is from 30:1 to 15:1, preferably 20:1.

[0074] In some embodiments, the molar ratio of the compound of formula II to the bis(trimethylsilyl)aminometal reagent is 1:2 to 1:3, preferably 1:2.4.

[0075] In some embodiments, the ratio of the compound of formula II to the compound of formula B is 1:1 to 1:2, preferably 1:1.1.

[0076] In some embodiments, the coupling reaction is carried out at a temperature of 25–55°C, preferably 35–45°C.

[0077] In some embodiments, the coupling reaction further includes the following post-processing steps: after the reaction is completed, water is added, and the mixture is extracted with dichloromethane. The aqueous phase is collected, and the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid. The aqueous phase is then extracted with dichloromethane again, and the organic phase is concentrated to obtain a crude product of compound V. Preferably, the crude product of compound V is purified by column chromatography to obtain compound V. Preferably, the ratio of the mobile phase for column chromatography purification is a volume ratio of dichloromethane to methanol of (100-10):1.

[0078] In some embodiments, the bis(trimethylsilyl)aminometal reagent is lithium bis(trimethyl)amino, sodium bis(trimethyl)amino, or potassium bis(trimethyl)amino, preferably sodium bis(trimethyl)amino.

[0079] In some embodiments, the preparation method of the compound of formula VII may further include a preparation method of the compound of formula III, which may include the following steps: in the presence of a base, a catalyst and a solvent, the compound of formula II-1 and the compound of formula B undergo a coupling reaction to obtain the compound of formula III.

[0080]

[0081] Among them, R 1 It can be Br, I, or OTf.

[0082] In some embodiments, the preparation method of the compound of formula III further includes the following steps: dissolving the compound of formula II-1, the compound of formula B and the catalyst in the solvent, and adding the base in batches under a nitrogen atmosphere to react and obtain the compound of formula III.

[0083] In some embodiments, the base is a base conventional in this type of reaction in the art, such as an inorganic or organic base, preferably sodium tert-butoxide.

[0084] In some embodiments, the catalyst is a conventional catalyst in this type of reaction in the art, such as a metal coupling catalyst, preferably allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium.

[0085] In some embodiments, the solvent is an ether solvent, preferably ethylene glycol dimethyl ether.

[0086] In some embodiments, the molar ratio of the compound of formula II-1 to the base is 1:0.9 to 1:1.2; for example, 1:1.1.

[0087] In some embodiments, the molar ratio of the compound of formula II-1 to the catalyst is 25:1 to 15:1, for example 20:1.

[0088] In some embodiments, the molar ratio of the compound of formula II-1 to the compound of formula B is from 1:0.9 to 1:1.2; for example, 1:1.1.

[0089] In some embodiments, when R1 is Br or I, the coupling reaction temperature is 25–55°C, preferably 35–45°C.

[0090] In some implementations, when the R 1 When the OTf is used, the coupling reaction temperature is 85–90°C.

[0091] In some embodiments, the coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled to 20-30°C, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, the organic phase is washed with 10% sodium chloride solution, concentrated, ethyl hydrochloride solution is added, filtered, and the filter cake is washed with ethyl acetate to obtain compound III.

[0092] In some embodiments, the method for preparing the compound of formula VII may further include a method for preparing the compound of formula IV, which may include the following steps: in the presence of a base, a catalyst and a solvent, the compound of formula II-2 and compound B undergo a coupling reaction to obtain the compound of formula IV.

[0093]

[0094] Among them, R 1 It can be Br, I, or OTf.

[0095] In some embodiments, the preparation method of the compound of formula IV further includes the following steps: dissolving the compound of formula II-2, the compound of formula B and the catalyst in the solvent, and adding the base under a nitrogen atmosphere to react and obtain the compound of formula IV.

[0096] In some embodiments, the base is a base conventional in this type of reaction in the art, such as an inorganic base or an organic base, wherein the organic base is sodium tert-butoxide.

[0097] In some embodiments, the catalyst is a conventional catalyst in this type of reaction in the art, such as a metal coupling catalyst, preferably allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium.

[0098] In some embodiments, the solvent is an ether solvent, preferably ethylene glycol dimethyl ether.

[0099] In some embodiments, the molar ratio of the compound of formula II-2 to the base is from 1:0.9 to 1:1.2; for example, 1:1.1.

[0100] In some embodiments, the molar ratio of the compound of formula II-2 to the catalyst is 25:1 to 15:1, for example 20:1.

[0101] In some embodiments, the molar ratio of the compound of formula II-2 to the compound of formula B is 1:0.9 to 1:1.2; for example, 1:1.1.

[0102] In some implementations, when the R 1 When the solvent is Br or I, the coupling reaction temperature is 25–55°C, preferably 35–45°C.

[0103] In some implementations, when the R 1 When the OTf is used, the coupling reaction temperature is 85–90°C.

[0104] In some embodiments, the coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled to 20-30°C, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, the organic phase is washed with 10% sodium chloride solution, concentrated, ethyl hydrochloride solution is added, filtered, and the filter cake is washed with ethyl acetate to obtain compound of formula IV.

[0105] The present invention also provides a method for preparing a compound of formula VI, comprising the following steps:

[0106] (a) In the presence of a solvent, the compound of formula V is subjected to an acyl chloride reaction with an acyl chloride reagent to obtain a mixed solution 1.

[0107] (b) The mixed solution 1, the compound of formula A shown, and a base are reacted in the presence of a solvent to obtain the compound of formula VI.

[0108]

[0109] The definition of R2 is as described above;

[0110] The operation and reaction conditions of the reaction are as described above.

[0111] The present invention also provides a method for preparing a compound of formula V, which may include scheme 1, scheme 2 or scheme 3.

[0112] Option 1 includes the following steps:

[0113] In the presence of an acid or a base, the compound of formula III is hydrolyzed to obtain the compound of formula V.

[0114]

[0115] Option 2 includes the following steps:

[0116] In the presence of a base, the compound of formula IV undergoes an ester hydrolysis reaction to obtain the compound of formula V.

[0117]

[0118] Option 3 includes the following steps:

[0119] In the presence of a catalyst, a bis(trimethylsilyl)aminometal reagent, and a solvent, compound II and compound B undergo a coupling reaction to yield compound V.

[0120]

[0121] Among them, R 1 It can be Br, I, or OTf.

[0122] The preparation method and reaction conditions of compound V are as described above.

[0123] The present invention also provides a method for preparing a compound of formula III, which may include the following steps: in the presence of a base, a catalyst and a solvent, a coupling reaction is carried out between a compound of formula II-1 and a compound of formula B to obtain the compound of formula III.

[0124]

[0125] Among them, R 1 It can be Br, I, or OTf.

[0126] The preparation method and reaction conditions of the compound of formula III are as described above.

[0127] The present invention also provides a method for preparing a compound of formula IV, which may include the following steps: in the presence of a base, a catalyst and a solvent, a coupling reaction is carried out between a compound of formula II-2 and a compound of formula B to obtain the compound of formula IV.

[0128]

[0129] Among them, R 1 It can be Br, I, or OTf.

[0130] The preparation method and reaction conditions of the compound of formula IV are as described above.

[0131] The present invention also provides a method for preparing a compound of formula I, comprising the following steps:

[0132] In the presence of a base and a solvent, the compound of formula VII is subjected to the hydrolysis reaction shown below to give the compound of formula I.

[0133]

[0134] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0135] In some embodiments, the C1-C10 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; and the C6-C10 aryl groups are phenyl or naphthyl.

[0136] In some implementation schemes, R 2 It can be methyl, ethyl, tert-butyl, or phenyl.

[0137] In some embodiments, in the method for preparing the compound of formula I, the base can be a base conventional in this type of reaction in the art, such as an alkali metal hydroxide, preferably lithium hydroxide.

[0138] In some embodiments, in the method for preparing the compound of formula I, the solvent can be a conventional solvent used in this type of reaction in the art, such as a mixture of water and a water-soluble organic solvent, preferably water:acetone = 1:1.

[0139] In some embodiments, the reactants in the preparation method of the compound of formula I are the compound of formula VII, the base, and the solvent.

[0140] In some embodiments, the preparation method of the compound of formula I includes the following specific steps: dissolving the compound of formula VII in the solvent, then adding water to carry out the reaction, thereby obtaining the compound of formula I.

[0141] The present invention also provides a compound having the following structure:

[0142]

[0143] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0144] In some schemes, R 2 Methyl group, CH2R, CHR2, C6-C 10 Aryl; R is a C1-C3 alkyl group.

[0145] In some schemes, R 2 In, the C1-C 10 The alkyl group is either methyl or ethyl.

[0146] In some schemes, R 2 In the context, the C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl.

[0147] In some embodiments, the structure of compound VI is as follows:

[0148]

[0149] The present invention also provides a compound having the following structure:

[0150]

[0151] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0152] In some schemes, R 2 Methyl group, CH2R, CHR2, C6-C 10 Aryl; R is a C1-C3 alkyl group.

[0153] In some schemes, R 2 In, the C1-C 10 The alkyl group is either methyl or ethyl.

[0154] In some schemes, R 2 In the context, the C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl.

[0155] In some embodiments, the structure of the compound of formula VII is as follows:

[0156]

[0157] The present invention also provides a compound having the following structure:

[0158]

[0159] Among them, R 2 For C1-C 10 Alkyl, C6-C 10 Aryl.

[0160] In some schemes, R 2 Methyl group, CH2R, CHR2, C6-C 10 Aryl; R is a C1-C3 alkyl group.

[0161] In some schemes, R 2 In, the C1-C 10 The alkyl group is either methyl or ethyl.

[0162] In some schemes, R 2 In the context, the C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl.

[0163] In some schemes, the structure of compound A is shown below:

[0164]

[0165] Unless otherwise specified, the terms used in this invention have the following meanings:

[0166] When listing numerical ranges, each value and subranges within that range are included. For example, "C1 to C6" includes C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl groups.

[0167] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0168] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 An aryl group is a cyclic group consisting solely of carbon atoms, which may be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). An aryl group is linked to other segments of the molecule via an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0169] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and mesylate salts. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0170] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0171] The reagents and raw materials used in this invention are all commercially available.

[0172] The positive and progressive effects of this invention are: the synthetic route provided by this invention has fewer steps, lower cost, higher yield and purity of the synthetic product, and does not introduce toxic substances. Detailed Implementation

[0173] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0174] Example 1: Synthesis of Compound V

[0175]

[0176] a. Compound IIA (25.2 g, 0.1 mol), 4-(4-piperidinyl)morpholine (18.7 g, 0.11 mol), allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (2.86 g, 5 mmol), and 126 mL of ethylene glycol dimethyl ether were added to a reaction flask. Sodium tert-butoxide (9.16 g, 0.11 mol) was added under nitrogen protection. After the addition was complete, the temperature was raised to 35-45 °C, and the reaction was maintained at this temperature for 5 h. The mixture was then cooled. At 20-30℃, add 126mL of water dropwise under controlled temperature, neutralize to pH 7-8 with 2M dilute hydrochloric acid, extract with ethyl acetate (126mL*2), wash the organic phase with 126mL of 10% sodium chloride solution, concentrate to 100-126mL, slowly add ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6g) dropwise under controlled temperature of 0-10℃, keep warm and stir for 16 hours, filter, and wash the filter cake with 50mL of ethyl acetate to obtain the wet product of compound III.

[0177] MS(M+H + ): 342.0

[0178] NMR: 1 H-NMR (400MHz, DMSO-d6) δppm: 7.08 (d, J = 8.4Hz, 1H), 6.90

[0179] (d,J=2.4Hz,1H),6.71(dd,J1=8.4Hz,J2=2.4Hz,1H),3.68-3.55(m,4H),3.30-3.19(m,2H),2.88-2.6 9(m,4H),2.41-2.30(m,2H),1.98-1.89(m,2H),1.77(s,6H),1.71-1.55(m,2H),1.31(t,J=7.2Hz,3H)

[0180] The wet product of compound III was added to a reaction flask, followed by 150 mL of concentrated hydrochloric acid. The mixture was heated to 100-115 °C and maintained at this temperature until compound III disappeared. The mixture was then cooled to 20-30 °C and extracted with 50 mL of ethyl acetate. The pH of the aqueous phase was adjusted to 6-7 with 20% NaOH aqueous solution, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL, and 200 mL of petroleum ether was added dropwise while maintaining the temperature at 20-30 °C. The mixture was stirred for 1 h, cooled to 0-10 °C, and stirred for 2-3 h. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to give 26.9 g of compound V, with a yield of 74.5%.

[0181] MS(M+H + ): 361.0,

[0182] NMR: 1 H-NMR (400MHz, DMSO-d6) δppm: 11.35 (brs, 1H), 7.04 (d, J=

[0183] 8.4Hz,1H),6.86(d,J=2.4Hz,1H),6.67(dd,J1=8.4Hz,J2=2.4Hz,1H),3.63-3.52(m,4H),3.28-3.19(m,2H),2 .88-2.69(m,4H),2.39-2.28(m,2H),1.97-1.88(m,2H),1.75(s,6H),1.69-1.53(m,2H),1.28(t,J=7.2Hz,3H).

[0184] b. Take 25.2g of compound IIA (0.1mol), 18.7g 4-(4-piperidinyl)morpholine (0.11 mol), 2.86 g allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (5 mmol), and 126 mL ethylene glycol dimethyl ether were added to a reaction flask. Under nitrogen protection, 9.16 g sodium tert-butoxide (0.11 mol) was added in portions. After the addition was complete, the temperature was raised to 34-45 °C and the reaction was maintained at this temperature for 5 h. The temperature was then cooled to 20-30 °C, and 126 mL of water was added dropwise under controlled temperature. The mixture was neutralized to pH 7-8 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (126 mL * 2). The organic phase was washed with 126 mL of 10% sodium chloride solution and concentrated to 100-126 mL. Ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) was slowly added dropwise at 0-10 °C. The mixture was stirred and maintained at this temperature for 16 h. The mixture was filtered, and the filter cake was washed with 50 mL of ethyl acetate to obtain the wet product of compound III.

[0185] The wet product of compound III was added to a reaction flask, along with 100 mL of 30% sodium hydroxide. The mixture was heated to 100°C and maintained at this temperature until compound III disappeared. The mixture was then cooled to 20-30°C and extracted with 50 mL of dichloromethane. The pH of the aqueous phase was adjusted to 6-7 with concentrated hydrochloric acid, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL. 200 mL of n-heptane was added dropwise while maintaining the temperature at 20-30°C. The mixture was stirred for 1 hour, cooled to 0-10°C, and stirred for 2-3 hours. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to obtain 30.4 g of compound V, with a yield of 84.3%.

[0186] c. Take 29.9g of compound IIB (0.1mol) and 18.7g... 4-(4-piperidinyl)morpholine (0.11 mol), 2.86 g allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (5 mmol), and 126 mL ethylene glycol dimethyl ether were added to a reaction flask. Under nitrogen protection, 9.16 g sodium tert-butoxide (0.11 mol) was added in portions. After the addition was complete, the temperature was raised to 34-45 °C and the reaction was maintained at this temperature for 5 h. The temperature was then cooled to 20-30 °C, and 126 mL of water was added dropwise under controlled temperature. The mixture was neutralized to pH 7-8 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (126 mL * 2). The organic phase was washed with 126 mL of 10% sodium chloride solution and concentrated to 100-126 mL. Ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) was slowly added dropwise at 0-10 °C. The mixture was stirred and maintained at this temperature for 16 h. The mixture was filtered, and the filter cake was washed with 50 mL of ethyl acetate to obtain the wet product of compound III.

[0187] The wet product of compound III was added to a reaction flask, along with 100 mL of 30% sodium hydroxide. The mixture was heated to 100°C and maintained at this temperature until compound III disappeared. The mixture was then cooled to 20-30°C and extracted with 50 mL of dichloromethane. The pH of the aqueous phase was adjusted to 6-7 with concentrated hydrochloric acid, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL. 200 mL of n-heptane was added dropwise while maintaining the temperature at 20-30°C. The mixture was stirred for 1 hour, cooled to 0-10°C, and stirred for 2-3 hours. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to obtain 31.0 g of compound V, with a yield of 85.9%.

[0188] d. Add 32.1 g of compound IIC (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), and 126 mL of ethylene glycol dimethyl ether to a reaction flask. Under nitrogen protection, add 9.16 g of sodium tert-butoxide (0.11 mol) in portions. After the addition is complete, heat to reflux (85-90℃) and maintain the temperature for 3 h. Cool to 20-30℃ and add 126 mL of water dropwise under controlled temperature. Neutralize with 2M dilute hydrochloric acid to pH 7-8. Extract with ethyl acetate (126 mL * 2). Wash the organic phase with 126 mL of 10% sodium chloride solution and concentrate to 100-126 mL. Slowly add ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) dropwise under controlled temperature of 0-10℃. Stir for 16 h, filter, and wash the filter cake with 50 mL of ethyl acetate to obtain compound III wet product.

[0189] The wet product of compound III was added to a reaction flask, along with 100 mL of 30% sodium hydroxide. The mixture was heated to 100°C and maintained at this temperature until compound III disappeared. The mixture was then cooled to 20-30°C and extracted with 50 mL of dichloromethane. The pH of the aqueous phase was adjusted to 6-7 with concentrated hydrochloric acid, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL. 200 mL of petroleum ether was added dropwise while maintaining the temperature at 20-30°C. The mixture was stirred for 1 hour, cooled to 0-10°C, and stirred for 2-3 hours. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to obtain 30.1 g of compound V, with a yield of 83.4%.

[0190] e. Add 27.0 g of compound IID (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), 2.86 g of allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (5 mmol), and 126 mL of ethylene glycol dimethyl ether to a reaction flask. Under nitrogen protection, slowly add sodium bis(trimethylsilylamino)amine (0.24 mol). After the addition is complete, raise the temperature to 35-45℃ and maintain the reaction temperature for 4-5 h. Cool to 20-30℃ and add 126 mL of water dropwise under controlled temperature. Extract with 50 mL of dichloromethane. Adjust the pH of the aqueous phase to 6-7 with concentrated hydrochloric acid, then extract the aqueous phase with dichloromethane (150 mL * 3). Purify by column chromatography (V). DCM :V MeOH (100:1 to 10:1) yielded 15.6 g of compound V, with a yield of 43.2%.

[0191] f. Add 27.0 g of compound IIE (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), 2.86 g of allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (5 mmol), and 126 mL of ethylene glycol dimethyl ether to a reaction flask. Under nitrogen protection, slowly add sodium bis(trimethylsilylamino)amine reagent (0.24 mol). After addition, raise the temperature to 35-45℃ and maintain the reaction for 4-5 h. Cool to 20-30℃ and add 126 mL of water dropwise under controlled temperature. Extract with 50 mL of dichloromethane. Adjust the pH of the aqueous phase to 6-7 with concentrated hydrochloric acid, then extract the aqueous phase with dichloromethane (150 mL * 3). Column chromatography purification (V DCM :V MeOH (100:1 to 10:1) yielded 18.5 g of compound V, with a yield of 51.2%.

[0192] g. Add 32.6 g of compound IIF (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), 2.86 g of allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium (5 mmol), and 126 mL of ethylene glycol dimethyl ether to a reaction flask. Under nitrogen protection, add 9.16 g of sodium tert-butoxide in portions. After the addition is complete, raise the temperature to 34-45 °C and maintain the reaction temperature for 5 h. Cool to 20-30 °C and add 126 mL of water dropwise while controlling the temperature. Neutralize with 2 M dilute hydrochloric acid to pH 7-8. Extract with ethyl acetate (126 mL * 2). Use 126 mL of ethyl acetate as the organic phase. Wash with 10% sodium chloride solution, concentrate to 100-126 mL, slowly add ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) at 0-10℃, keep warm and stir for 16 hours, filter, and wash the filter cake with 50 mL of ethyl acetate to obtain the wet product of compound IV.

[0193] MS(M+H + ): 417.1,

[0194] NMR: 1 H-NMR (400MHz, DMSO-d6) δppm: 7.02 (d, J = 8.4Hz, 1H), 6.91

[0195] (d,J=2.4Hz,1H),6.65(dd,J1=8.4Hz,J2=2.4Hz,1H),3.69-3.56(m,4H),3.31-3.20(m,2H),2.89-2.70(m,4H ),2.42-2.31(m,2H),1.99-1.90(m,2H),1.75(s,6H),1.72-1.56(m,2H),1.50(s,9H),1.31(t,J=7.2Hz,3H).

[0196] The wet product of compound IV was added to a reaction flask, along with 100 mL of 30% sodium hydroxide. The mixture was heated to 100°C and maintained at this temperature until compound IV disappeared. The mixture was then cooled to 20-30°C and extracted with 50 mL of dichloromethane. The pH of the aqueous phase was adjusted to 6-7 with concentrated hydrochloric acid, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL. 200 mL of n-heptane was added dropwise while maintaining the temperature at 20-30°C. The mixture was stirred for 1 hour, cooled to 0-10°C, and stirred for 2-3 hours. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to obtain 31.5 g of compound V, with a yield of 87.2%.

[0197] h. 37.4 g of compound IIG (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), and 126 mL of ethylene glycol dimethyl ether were added to a reaction flask. Under nitrogen protection, 9.16 g of sodium tert-butoxide (0.11 mol) was added in portions. After the addition was complete, the mixture was heated to reflux (85-90 °C) and reacted for 3 h. The mixture was then cooled to 20-30 °C, and 126 mL of water was added dropwise under controlled temperature. The mixture was neutralized to pH 7-8 with 2 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (126 mL * 2). The organic phase was washed with 126 mL of 10% sodium chloride solution and concentrated to 100-126 mL. Ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) was slowly added dropwise at 0-10 °C. The mixture was stirred and kept at this temperature for 16 h. The mixture was filtered, and the filter cake was washed with 50 mL of ethyl acetate to obtain compound IV wet product.

[0198] Add the above wet sample to a reaction flask, add 100 mL of 30% sodium hydroxide, heat to 100 °C, and maintain the temperature until compound IV disappears. Cool to 20-30 °C, extract with 50 mL of dichloromethane, adjust the pH of the aqueous phase to 6-7 with concentrated hydrochloric acid, and then extract the aqueous phase with dichloromethane (150 mL * 3). Concentrate the organic phase under reduced pressure to 50-75 mL, add 200 mL of petroleum ether dropwise while maintaining the temperature at 20-30 °C, stir for 1 h, cool to 0-10 °C, stir for 2-3 h, filter, wash the filter cake with 50 mL of n-heptane, and dry under vacuum to give 30.7 g of compound V, yield 85.0%.

[0199] j. Add 39.6 g of compound IIH (0.1 mol), 18.7 g of 4-(4-piperidinyl)morpholine (0.11 mol), and 126 mL of ethylene glycol dimethyl ether to a reaction flask. Under nitrogen protection, add 9.16 g of sodium tert-butoxide in portions. After the addition is complete, heat to reflux (85-90℃) and maintain the temperature for 3 h. Cool to 20-30℃ and add 126 mL of water dropwise under controlled temperature. Neutralize with 2M dilute hydrochloric acid to pH 7-8. Extract with ethyl acetate (126 mL * 2). Wash the organic phase with 126 mL of 10% sodium chloride solution and concentrate to 100-126 mL. Slowly add ethyl hydrogen chloride solution (total hydrogen chloride content 10.9-14.6 g) dropwise under controlled temperature of 0-10℃. Stir and maintain the temperature for 16 h. Filter and wash the filter cake with 50 mL of ethyl acetate to obtain compound IV wet product.

[0200] The above wet sample was added to a reaction flask, followed by 100 mL of 30% sodium hydroxide. The mixture was heated to 100°C and maintained at this temperature until compound IV disappeared. The mixture was then cooled to 20-30°C and extracted with 50 mL of dichloromethane. The pH of the aqueous phase was adjusted to 6-7 with concentrated hydrochloric acid, followed by extraction with dichloromethane (150 mL x 3). The organic phase was concentrated under reduced pressure to 50-75 mL. 200 mL of petroleum ether was added dropwise while maintaining the temperature at 20-30°C. The mixture was stirred for 1 hour, cooled to 0-10°C, and stirred for 2-3 hours. The mixture was filtered, and the filter cake was washed with 50 mL of n-heptane and dried under vacuum to give 30.1 g of compound V, with a yield of 83.4%.

[0201] Example 2: Synthesis of Compound VI

[0202]

[0203] Add 37.8 g of compound V (0.105 mol), 0.5 mL of N,N-dimethylformamide, and 180 mL of dichloromethane to a reaction flask. Cool to below 0°C, maintaining a temperature not exceeding 5°C. Add 15.9 g of oxaloyl chloride (0.177 mol) dropwise to the reaction flask. After the addition is complete, slowly raise the temperature to 20-30°C and stir the reaction for 4-5 hours. LC-MS indicates that compound V has reacted completely. Concentrate under reduced pressure at 30-40°C until no liquid flows out. Add 180 mL of dichloromethane and continue to concentrate under reduced pressure until no liquid flows out. Add 180 mL of dichloromethane and stir until dissolved to obtain solution 1. Add 0.1 mol of 2-amino-4-cyanophenylacetic acid ester, 20.2 g of triethylamine, and 180 mL of dichloromethane to a reaction flask. Cool to -5 to 5°C, maintaining a temperature not exceeding 5°C. Slowly add the aforementioned solution 1 dropwise to the reaction flask. After the addition is complete, slowly raise the temperature to 20-30℃ and maintain this temperature with stirring for 16 hours. Add 100 mL of water dropwise to the reaction system and stir for 5-10 minutes. Separate the liquids. Wash the organic phase twice with 1M hydrochloric acid (80 mL each time), then wash twice with 5% sodium bicarbonate solution (100 mL each time). Concentrate the organic phase to 50-60 mL dryness, add n-heptane dropwise while maintaining the temperature at 20-30℃, then cool to 0-10℃ and stir for 2-3 hours. Filter and dry under vacuum to obtain a pale yellow solid.

[0204] R2 is methyl, yielding 54.7 g, 92.6% (MS(M+H)). + 591.1; 1 H-NMR (400MHz, DMSO-d6) δppm: 11.5 (s, 1H), 8.42 (d, J = 1.2Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.88 ( dd, J1=8.0Hz, J2=1.2Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 6.66 (dd, J1=8.4Hz, J2=2.4Hz,1H),5.52(s,1H),3.90(s,6H),3.69-3.56(m,4H),3.30-3.20(m,2H),2.89-2.71(m,4 H),2.43-2.32(m,2H),1.99-1.89(m,2H),1.77(s,6H),1.72-1.56(m,2H),1.31(t,J=7.2Hz,3H).

[0205] R2 is ethyl, yielding 61.8 g, 99.8% yield, MS (M+H) + ): 619.1. 1H-NMR (400MHz, DMSO-d6) δppm: 11.0 (s, 1H), 8.40 (d, J = 1.2Hz, 1H), 8.19 (d, J = 8.0Hz, 1H), 7.86 (dd, J1 = 8 .0Hz,J2=1.2Hz,1H),7.03(d,J=8.4Hz,1H),6.91(d,J=2.4Hz,1H),6.67(dd,J1=8.4Hz,J2=2.4Hz,1H),5 .43(s,1H),4.29(q,J=9.6Hz,4H),3.68-3.55(m,4H),3.29-3.19(m,2H),2.88-2.70(m,4H),2.43-2.31( m,2H),1.98-1.89(m,2H),1.75(s,6H),1.70-1.54(m,2H),1.42(t,J=9.6Hz,3H),1.30(t,J=7.2Hz,3H).

[0206] R2 is tert-butyl, yielding 67.4 g, 99.8% yield, MS (M+H) + ): 1 H-NMR (400MHz, DMSO-d6) δppm: 11.1 (s, 1H), 8.41 (d, J = 1.2Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.88 ( dd,J1=8.0Hz,J2=1.2Hz,1H),7.04(d,J=8.4Hz,1H),6.91(d,J=2.4Hz,1H),6.68(dd,J1=8.4Hz,J 2=2.4Hz,1H),5.44(s,1H),3.68-3.55(m,4H),3.30-3.20(m,2H),2.89-2.71(m,4H),2.43-2.32 (m,2H),1.99-1.89(m,2H),1.76(s,6H),1.70-1.55(m,2H),1.49(s,18H),1.29(t,J=7.2Hz,3H).

[0207] R2 is phenyl, yielding 71.5 g, 100.0% yield, MS (M+H) + ): 715.1; 1H-NMR (400MHz, DMSO-d6) δppm: 11.2 (s, 1H), 8.40 (d, J = 1.2Hz, 1H), 8.14 (d, J = 8.0Hz, 1H), 7. 91-7.72(m,3H),7.59-7.48(m,4H),7.11-7.03(m,5H),6.93(d,J=2.4Hz,1H),6.71(dd,J1=8 .4Hz, J2=2.4Hz,1H),5.50(s,1H),3.69-3.56(m,4H),3.31-3.21(m,2H),2.90-2.72(m,4H), 2.42-2.33(m,2H),1.97-1.88(m,2H),1.75(s,6H),1.71-1.56(m,2H),1.28(t,J=7.2Hz,3H).

[0208] Example 3: Synthesis of Compound I

[0209]

[0210] a. When R 2 The radicals are easily hydrolyzed under alkaline conditions (methyl, CH2R, CHR2, Ar). 0.1 mol of compound VI and 200 mL of tetrahydrofuran were added to a reaction flask. The temperature was maintained at 20-30°C, and 110 mL of n-butyllithium hexane solution (2.7 M) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 16 h, and the reaction was monitored by HPLC until completion. The reaction solution was cooled to -10 to 0°C, and the temperature was maintained no higher than 10°C. 5 mL of anhydrous ethanol was slowly added dropwise. After the addition was complete, the temperature was raised to 20-30°C. A tetrahydrofuran solution of compound VII was obtained and kept at this temperature for later use.

[0211] A solution of compound VII was added to the reaction vessel. While maintaining the temperature at 20-30°C, 50 mL of water was slowly added dropwise, and the reaction continued until complete. The temperature was then lowered to 0-5°C, and the pH was adjusted to 6-7 with 10% phosphoric acid. 190 g of acetone was added dropwise, and the temperature was lowered to 0-10°C. The mixture was stirred for 1 hour, filtered, washed with an acetone / water solution (V:V = 1:1), and dried under vacuum to obtain compound I. Yield: R 2 When methyl is used: 45.1 g of product is obtained, yield: 90.0%; R 2 When the ethyl group is used: 46.2 g of product is obtained, yield: 92.2%, R 2 When phenyl: 43.8 g of product was obtained, yield: 87.4%. MS(M+H) + ):501.1.

[0212] b. When R 2When the group is base-stable (CR3, R is not hydrogen), taking tert-butyl as an example, 0.1 mol of compound VI (67.5 g) and 200 mL of tetrahydrofuran were added to a reaction flask. The temperature was controlled at 20-30℃, and 110 mL of n-butyllithium hexane solution (2.7 M) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 16 h, and the reaction was completed under HPLC control. The temperature of the reaction solution was cooled to -10 to 0℃, and the temperature was controlled not to exceed 10℃. 5 mL of anhydrous ethanol was slowly added dropwise. After the addition was complete, 200 mL of 10% sodium chloride aqueous solution and 300 mL of isopropyl acetate were added while maintaining the temperature at 0-10℃. The mixture was stirred for 10 minutes and then separated. The aqueous phase was extracted with 100 mL of isopropyl acetate. The organic phases were combined, and 100 mL of 10% sodium chloride solution and 100 mL of 5% sodium bicarbonate solution were added. The mixture was stirred for 10 minutes and then separated after standing. The organic phase was washed with 10% sodium chloride solution until neutral. The organic phase was concentrated under reduced pressure to give compound VII, resulting in a viscous oily solid VII. MS (M+H) + ):557.1.

[0213] Add 250 mL of trifluoroethanol to the concentrated residue. Cool to 0-5 °C, and add 0.43 mol of trimethylchlorosilane dropwise while maintaining the temperature at 0-10 °C. After the addition is complete, maintain the temperature at 0-10 °C for 5 h, add 190 g of acetone, raise the temperature to 20-25 °C, and add 190 g of 1N sodium hydroxide solution dropwise. Then adjust the pH to 6-7 with 10% K2HPO4, cool to 0-10 °C, stir for 1 h, filter, wash with acetone / water solution (V:V = 1:1), and dry under vacuum to obtain 47.6 g of compound I, yield 95.0%.

[0214] Example 4: Synthesis of Compound A:

[0215] Taking R2 as an ethyl group as an example: 3-chloro-4-nitrophenylcyanide (55 g, 0.301 mmol), diethyl malonate (51 mL, 0.331 mmol), potassium carbonate (75 g, 0.541 mmol), and 220 mL DMF were added to a reaction flask. The reaction mixture was reacted at 30-35 °C for 6-7 hours. The reaction solution was then neutralized with 1 M dilute hydrochloric acid to a pH less than 7, while maintaining the temperature below 20 °C. 550 mL of water was added, and the mixture was extracted with ethyl acetate (550 mL * 2). The organic phase was concentrated under reduced pressure to 500-600 mL. 1.1 g of Raney nickel was added to the resulting solution, and the mixture was reacted with hydrogen gas at 10-20 °C for 8-10 hours. The mixture was then filtered. The solution was concentrated under reduced pressure to 100-150 mL, and 500 mL of n-heptane was added dropwise while maintaining the temperature at 0-10 °C. The mixture was filtered, and the product was dried under vacuum at 40-50 °C to obtain 77.5 g, with a yield of 93.2%. MS(M+H) +:277.1. Other compounds shown in Formula A can be prepared by replacing the diethyl malonate in this example with other diesters of malonate using the same method. When R2 is methyl, MS(M+H)+: 249.0; when R2 is tert-butyl, MS(M+H)+: 333.2; when R2 is phenyl, MS(M+H)+: 373.2.

Claims

1. A method for preparing a compound of formula VII, characterized in that, It includes the following steps: In the presence of a base and a solvent, compound VI is subjected to the following cyclization reaction to obtain compound VII; ； Among them, R 2 It can be methyl, ethyl, tert-butyl, or phenyl; The base is an alkyl lithium reagent; The solvent is a cyclic ether solvent; The molar ratio of the compound of formula VI to the base is 1:(2-4); The cyclization reaction is carried out at a temperature of 10~40℃; The reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, and anhydrous ethanol, sodium chloride aqueous solution, and isopropyl acetate are added sequentially. The aqueous phase obtained by separation is extracted with isopropyl acetate, the organic phases are combined, and sodium chloride solution and sodium bicarbonate solution are added sequentially. The organic phase is separated, washed with sodium chloride solution, and concentrated to obtain the compound of formula VII.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The base is n-butyllithium reagent; (2) The solvent is tetrahydrofuran; (3) The reactants are the compound of formula VI, the base, and the solvent; (4) The reaction further includes the following specific steps: dissolving the compound of formula VI in the solvent, and then adding the base to carry out the cyclization reaction to obtain the compound of formula VII.

3. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The alkali is a n-butyllithium n-hexane solution; (2) The molar ratio of the compound of formula VI to the base is 1:3; (3) The cyclization reaction is carried out at a temperature of 20~30℃.

4. The preparation method according to claim 1, characterized in that, The alkali is a 2.7M n-butyllithium n-hexane solution.

5. The preparation method according to any one of claims 1-4, characterized in that, The preparation method further includes the following steps to prepare the compound of formula VI: (a) In the presence of a solvent, the compound of formula V is subjected to an acyl chloride reaction with an acyl chloride reagent to obtain a mixed solution 1; (b) In the presence of a solvent, the mixed solution 1, compound A and base are reacted to obtain compound VI; ； Among them, R 2 The definition is as described in claim 1.

6. The preparation method according to claim 5, characterized in that, It satisfies one or more of the following conditions: (1) The acyl chloride reagent is oxalyl chloride or thionyl chloride; (2) The molar ratio of the compound of formula V to the acyl chloride reagent is 1:(1-3); (3) The acyl chloride reaction also includes a catalyst; (4) The alkali is an organic alkali; (5) The solvent is a chloroalkane solvent; (6) The molar ratio of compound V to compound A is 1:(1-2); (7) In step (a), the reaction temperature is -10~10℃; (8) In step (b), the reaction temperature is 10~40℃; (9) The reaction further includes the following post-processing steps: after the reaction is completed, water is added, the liquid is separated, the organic phase is washed with hydrochloric acid and then with sodium bicarbonate solution, the organic phase is partially concentrated, n-heptane is added, the mixture is stirred and filtered, and dried to obtain compound VI. (10) The reactants are the compound of formula V, the acyl chloride reagent, the compound of formula A, the base and the solvent.

7. The preparation method according to claim 6, characterized in that, The acyl chloride reaction also includes a catalyst, which is N,N-dimethylformamide.

8. The preparation method according to claim 7, characterized in that, (1) The acyl chloride reagent is oxalyl chloride; (2) The molar ratio of the compound of formula V to the acyl chloride reagent is 1:1.7; (3) The molar ratio of the compound of formula V to the N,N-dimethylformamide is (10-20):1; (4) The base is triethylamine; (5) The solvent is dichloromethane or dichloroethane; (6) The molar ratio of compound V to compound A is 1:1; (7) In step (a), the reaction temperature is -5~5℃; (8) In step (b), the reaction temperature is 20~30℃; (9) The reaction further includes the following steps: dissolving the compound of formula V and the N,N-dimethylformamide in the solvent, then adding the acyl chloride reagent to react, after the compound of formula V has reacted completely, concentrating the reaction solution, and then adding a solvent to obtain mixed solution 1; dissolving the compound of formula A and the base in the solvent to obtain mixed solution 2, and mixing mixed solution 1 and mixed solution 2 to carry out the reaction.

9. The preparation method according to claim 7, characterized in that, (1) The molar ratio of the compound of formula V to the N,N-dimethylformamide is 16:1; (2) The solvent is dichloromethane; (3) The reaction further includes the following steps: dissolving the compound of formula V and the N,N-dimethylformamide in the solvent, then adding the acyl chloride reagent to react, after the compound of formula V has reacted completely, concentrating the reaction solution, and then adding a solvent to obtain mixed solution 1; dissolving the compound of formula A and the base in the solvent to obtain mixed solution 2, and mixing mixed solution 1 and mixed solution 2 to react, wherein mixed solution 1 and mixed solution 2 are mixed at -5~5℃.

10. The preparation method according to claim 5, characterized in that, The preparation method further includes the following preparation method to prepare the compound of formula V. Option 1 includes the following steps: In the presence of an acid or a base, the compound of formula III is hydrolyzed to obtain the compound of formula V; ； Option 2 includes the following steps: In the presence of a base, compound IV is subjected to ester hydrolysis to obtain compound V. ； Option 3, its Includes the following steps, In the presence of a catalyst, a bis(trimethylsilyl)amino metal reagent, and a solvent, compound II and compound B are coupled to obtain compound V. ； Among them, R 1 It can be Br, I, or OTf.

11. The preparation method according to claim 10, characterized in that, Option 1 satisfies one or more of the following conditions: (1) The acid is an inorganic acid; (2) The alkali is an alkali metal hydroxide; (3) The ratio of the compound of formula III to the acid is 1:(15-30). (4) The molar ratio of the compound of formula III to the base is 1:(5-10); (5) When the hydrolysis reaction is carried out in the presence of acid, the temperature of the hydrolysis reaction is 100~115℃; (6) When the hydrolysis reaction is carried out in the presence of an alkali, the temperature of the hydrolysis reaction is 90~110℃; (7) When the hydrolysis reaction is carried out under acidic conditions, the hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with ethyl acetate, the pH is adjusted to 6-7 with NaOH aqueous solution, the aqueous phase is extracted with dichloromethane, the organic phase is partially concentrated, petroleum ether is added, the mixture is stirred, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V. (8) When the hydrolysis reaction is carried out under alkaline conditions, the hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with dichloromethane, the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid, the aqueous phase is extracted with dichloromethane, the organic phase is partially concentrated, petroleum ether is added, stirred, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V. (9) The reactants are the acid or base and the compound of formula III; Option 2 satisfies one or more of the following conditions: (1) The alkali is an alkali metal hydroxide; (2) The molar ratio of the compound of formula III to the base is 1:(5-10); (3) The temperature of the hydrolysis reaction is 90~110℃; (4) The hydrolysis reaction further includes the following post-treatment steps: after the reaction is completed, the reaction solution is extracted with dichloromethane, the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid, the aqueous phase is extracted with dichloromethane, the organic phase is concentrated, petroleum ether is added, the mixture is stirred, filtered, the filter cake is washed with n-heptane, and dried to obtain compound V. Option 3 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula V further includes the following steps: dissolving the compound of formula II, the compound of formula B and the catalyst in the solvent, adding the bistrimethylsilylaminometal reagent under a nitrogen atmosphere to react and obtain the compound of formula V; (2) The catalyst is a metal coupling catalyst; (3) The solvent is an ether solvent; (4) The molar ratio of the compound of formula II to the catalyst is 30:1 to 15:1; (5) The molar ratio of the compound of formula II to the bistrimethylsilylaminometal reagent is 1:2 to 1:3; (6) The molar ratio of the compound of formula II to the compound of formula B is 1:1 to 1:2; (7) The temperature of the coupling reaction is 25~55℃; (8) The coupling reaction further includes the following post-processing steps: after the reaction is completed, water is added, and the mixture is extracted with dichloromethane. The aqueous phase is collected, and the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid. The aqueous phase is then extracted with dichloromethane, and the organic phase is concentrated to obtain the crude product of compound V. (9) The bistrimethylsilylamino metal reagent is lithium bistrimethylsilylamino, sodium bistrimethylsilylamino or potassium bistrimethylsilylamino.

12. The preparation method according to claim 10, characterized in that, Option 1 satisfies one or more of the following conditions: (1) The acid is concentrated hydrochloric acid; (2) The alkali is sodium hydroxide or potassium hydroxide; (3) The ratio of the compound of formula III to the acid is 1:18; (4) The molar ratio of the compound of formula III to the base is 1:7.5; (5) When the hydrolysis reaction is carried out in the presence of an alkali, the temperature of the hydrolysis reaction is 100°C; Option 2 satisfies one or more of the following conditions: (1) The alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide; (2) The molar ratio of the compound of formula III to the base is 1:7.5; (3) The temperature of the hydrolysis reaction is 100℃; Option 3 satisfies one or more of the following conditions: (1) The catalyst is allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium; (2) The solvent is ethylene glycol dimethyl ether; (3) The molar ratio of the compound of formula II to the catalyst is 20:1; (4) The molar ratio of the compound of formula II to the bis(trimethylsilyl)aminometal reagent is 1:2.4; (5) The molar ratio of the compound of formula II to the compound of formula B is 1:1.1; (6) The coupling reaction temperature is 35~45℃; (7) The coupling reaction further includes the following post-processing steps: after the reaction is completed, water is added, dichloromethane is extracted, the aqueous phase is collected, the pH of the aqueous phase is adjusted to 6-7 with concentrated hydrochloric acid, the aqueous phase is extracted with dichloromethane, the organic phase is concentrated to obtain crude compound V, and the crude compound V is purified by column chromatography to obtain compound V. (8) The bistrimethylsilylamino metal reagent is sodium bistrimethylsilylamino.

13. The preparation method according to claim 12, characterized in that, In Scheme 1, the alkali is a 30% sodium hydroxide aqueous solution; And / or, in Scheme 2, the base is 30% sodium hydroxide.

14. The preparation method according to claim 10, characterized in that, In Scheme 1, the preparation method further includes the following steps to prepare the compound of Formula III: In the presence of a base, a catalyst, and a solvent, the compound of formula II-1 and the compound of formula B are coupled to obtain the compound of formula III. ； Among them, R 1 For Br, I, or OTf; In Scheme 2, the preparation method further includes the following steps to prepare the compound of formula IV: In the presence of a base, a catalyst, and a solvent, compound II-2 and compound B are coupled to obtain compound IV. ； Among them, R 1 It can be Br, I, or OTf.

15. The preparation method according to claim 14, characterized in that, In the preparation method of the compound of formula III described in Scheme 1, one or more of the following conditions are satisfied: (1) The preparation method of the compound of formula III further includes the following steps: dissolving the compound of formula II-1, the compound of formula B and the catalyst in the solvent, and adding the base in batches under a nitrogen atmosphere to react and obtain the compound of formula III; (2) The alkali is an organic alkali; (3) The catalyst is a metal coupling catalyst; (4) The solvent is an ether solvent; (5) The molar ratio of the compound of formula II-1 to the base is from 1:0.9 to 1:1.2; (6) The molar ratio of the compound of formula II-1 to the catalyst is 25:1 to 15:1; (7) The molar ratio of the compound of formula II-1 to the compound of formula B is 1:0.9 to 1:1.2; (8) When the R 1 When the molecule is Br or I, the coupling reaction temperature is 25~55℃; (9) When the R 1 When the OTf is used, the coupling reaction temperature is 85~90℃; (10) The coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, sodium chloride solution is used to wash the organic phase, the concentration is carried out, ethyl hydrogen chloride solution is added, the mixture is filtered, and the filter cake is washed with ethyl acetate to obtain compound III. In the preparation method of the compound of formula IV in Scheme 2, one or more of the following conditions are satisfied: (1) The preparation method of the compound of formula IV further includes the following steps: dissolving the compound of formula II-2, the compound of formula B and the catalyst in the solvent, and adding the base under a nitrogen atmosphere to react and obtain the compound of formula IV; (2) The alkali is an organic alkali; (3) The catalyst is a metal coupling catalyst; (4) The solvent is an ether solvent; (5) The molar ratio of the compound of formula II-2 to the base is from 1:0.9 to 1:1.2; (6) The molar ratio of the compound of formula II-2 to the catalyst is 25:1 to 15:1; (7) The molar ratio of the compound of formula II-2 to the compound of formula B is from 1:0.9 to 1:1.2; (8) When the R 1 When the molecule is Br or I, the coupling reaction temperature is 25~55℃; (9) When the R 1 When the OTf is used, the coupling reaction temperature is 85~90℃; (10) The coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, the organic phase is washed with sodium chloride solution, concentrated, ethyl hydrogen chloride solution is added, filtered, and the filter cake is washed with ethyl acetate to obtain compound IV.

16. The preparation method according to claim 15, characterized in that, In the preparation method of the compound of formula III described in Scheme 1, one or more of the following conditions are satisfied: (1) The alkali is sodium tert-butoxide; (2) The catalyst is allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium; (3) The solvent is ethylene glycol dimethyl ether; (4) The molar ratio of the compound of formula II-1 to the base is 1:1.1; (5) The molar ratio of the compound of formula II-1 to the catalyst is 20:1; (6) The molar ratio of the compound of formula II-1 to the compound of formula B is 1:1.1; (7) When the R 1 When the molecule is Br or I, the coupling reaction temperature is 35~45℃; (8) The coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, sodium chloride solution is used to wash the organic phase, the concentration is carried out, ethyl hydrogen chloride solution is added, the mixture is filtered, and the filter cake is washed with ethyl acetate to obtain compound III; after the post-processing is completed, it is directly used in the next reaction. In the preparation method of the compound of formula IV described in Scheme 2, one or more of the following conditions are satisfied: (1) The alkali is sodium tert-butoxide; (2) The catalyst is allyl chloride [1,3-bis(2,6-diisopropylbenzyl)imidazol-2-yl]palladium; (3) The solvent is ethylene glycol dimethyl ether; (4) The molar ratio of the compound of formula II-2 to the base is 1:1.1; (5) The molar ratio of the compound of formula II-2 to the catalyst is 20:1; (6) The molar ratio of the compound of formula II-2 to the compound of formula B is 1:1.1; (7) When the R 1 When the molecule is Br or I, the coupling reaction temperature is 35~45℃; (8) The coupling reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, water is added, hydrochloric acid is added to adjust the pH to 7-8, ethyl acetate is used for extraction, sodium chloride solution is used to wash the organic phase, the concentration is carried out, ethyl chloride solution is added, the mixture is filtered, and the filter cake is washed with ethyl acetate to obtain compound IV; after the post-processing is completed, it is directly used for the next reaction.

17. A method for preparing a compound of formula VI, characterized in that, It includes the following steps: (a) In the presence of a solvent, the compound of formula V is subjected to an acyl chloride reaction with an acyl chloride reagent to obtain a mixed solution 1; (b) In the presence of a solvent, the mixed solution 1, compound A and base are reacted to obtain compound VI; ； Wherein, the R 2 The definition is as described in claim 1; The operation and reaction conditions of the preparation method are as described in any one of claims 5-16.

18. A compound of formula VI; ； in, R 2 It can be methyl, ethyl, or phenyl.

19. The compound of formula VI as claimed in claim 18, characterized in that, It is , or .

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