CN112479876B - Oxazepane spiro compounds, intermediates and process for their preparation - Google Patents

Oxazepane spiro compounds, intermediates and process for their preparation Download PDF

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CN112479876B
CN112479876B CN202010951640.6A CN202010951640A CN112479876B CN 112479876 B CN112479876 B CN 112479876B CN 202010951640 A CN202010951640 A CN 202010951640A CN 112479876 B CN112479876 B CN 112479876B
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CN112479876A (en
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温剑锋
冯建鹏
吴清泉
王传申
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Yasheng Pharmaceutical Group Hong Kong Co ltd
Suzhou Yasheng Pharmaceutical Co ltd
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Suzhou Yasheng Pharmaceutical Co ltd
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Abstract

The invention provides an oxazepan spiro compound, an intermediate and a preparation method thereof. The invention discloses an oxazepan spiro compound with a novel structure, an intermediate thereof and a preparation method thereof. The invention relates to a preparation method of a compound shown as a formula 7a or a formula 8a, which comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 1 The salt forming reaction shown below is carried out; wherein X is 1 Chiral resolving agents in the R configuration; the preparation method of the compound shown in the formula 8a comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 2 The salt forming reaction shown below is carried out; wherein X is 2 Chiral resolving agent with S configuration.

Description

Oxazepane spiro compounds, intermediates and process for their preparation
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to an oxazepan spiro compound, an intermediate and a preparation method thereof.
Background
The oxazepan spiro compounds are an important class of nitrogen-containing heterocyclic compounds, and have the structure as follows Many drugs and intermediates thereof contain the structural units described above, for example:
very few synthetic processes are reported for this class of compounds, for example: patent application WO2016033486A1 discloses a process for the preparation of similar compounds, the synthetic route of which is as follows:
in the above route, 6-chloro-3, 4-dihydro-1 (2H) naphthalenone is subjected to the action of boron trifluoride diethyl ether to obtain an epoxy compound in the presence of trimethylsulfonium iodide, the aldehyde compound is subjected to the action of boron trifluoride diethyl ether to obtain an aldehyde group, the aldehyde compound is subjected to the action of diethylene glycol and formaldehyde to obtain a diol compound, 4-bromobenzoyl chloride is continuously added to obtain a monosubstituted ester compound, then an alcoholic hydroxyl group is oxidized into an aldehyde group in the presence of an oxidant Dess-Martin periodinane, a ketone-based protector is formed in the presence of p-toluenesulfonic acid and trimethyl orthoformate, etherification reaction is carried out with 4-fluoro-3-nitro-benzoic acid tert-butyl ester, and then erbium triflate hydrate is added to convert the aldehyde compound, the nitro group is reduced, and the oxaazepane spiro compound is obtained through intramolecular reductive amination. The method has the defects of numerous reaction raw materials, long route, column chromatography for post-treatment, poor stereoselectivity, low yield and the like.
In view of the great demand in the current market for oxazepan spiro compounds, there is an urgent need to develop new process routes.
Disclosure of Invention
The invention provides an oxazepan spiro compound, an intermediate and a preparation method thereof.
The invention provides a preparation method of a compound shown as a formula 7a or a formula 8a,
the preparation method of the compound shown in the formula 7a comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 1 The salt forming reaction shown below is carried out; wherein X is 1 Chiral resolving agents in the R configuration;
the preparation method of the compound shown in the formula 8a comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 2 The salt forming reaction shown below is carried out; wherein X is 2 Chiral resolving agent with S configuration;
wherein R is 1 、R 2 、R 3 And R is 4 Independently hydrogen, hydroxy, cyano, amino, nitro, aldehyde, halogen, C 1 -C 4 Alkyl, R of (2) 1-1 Substituted C 1 -C 4 Alkyl, C of (2) 1 -C 4 Haloalkyl radicals R of (2) 1-2 Substituted C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, R 1-3 Substituted C 1 -C 4 or-C (=O) R 1-4 ；
R 1-1 、R 1-2 、R 1-3 And R is 1-4 Independently is hydroxy, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Alkoxy, C 3 -C 5 Cycloalkyl or NR of (C) 1-1a R 1-1b ；
R 1-1a And R is 1-1b Independently hydrogen or C 1 -C 4 Is a hydrocarbon group.
In the preparation method of the compound shown in the formula 7a or the formula 8a, R is 1-1 May be 1 or more, for example 1, 2 or 3, when there are a plurality of R 1-1 When said R is 1-1 May be the same or different.
In the preparation method of the compound shown in the formula 7a or the formula 8a, R is 1-2 May be 1 or more, for example 1, 2 or 3, when there are a plurality of R 1-2 When said R is 1-2 May be the same or different.
In the preparation method of the compound shown in the formula 7a or the formula 8a, R is 1-3 May be 1 or more, for example 1, 2 or 3, when there are a plurality of R 1-3 When said R is 1-3 May be the same or different.
In the preparation method of the compound shown in the formula 7a or the formula 8a, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In the preparation method of the compound shown in the formula 7a or the formula 8a, the C 1 -C 4 Alkyl, and R 1-1 Substituted C 1 -C 4 Said C is an alkyl group 1 -C 4 The alkyl groups of (a) may independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In the preparation method of the compound shown in the formula 7a or the formula 8a, the C 1 -C 4 Is preferably substituted by 1, 2 or3 halogen substitutions, wherein the halogen may be fluorine, chlorine, bromine or iodine, and the C 1 -C 4 preferably-CHF 2 or-CF 3 。
In the preparation method of the compound shown in the formula 7a or the formula 8a, the C 1 -C 4 Alkoxy, and R 1-3 Substituted C 1 -C 4 In the alkoxy group of (C) 1 -C 4 The alkoxy groups of (a) may independently be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
In a preferred embodiment of the present invention, certain groups of the compounds of formula 7a or 8a are defined as follows (undefined groups are as described in any of the previous embodiments): r is R 1 、R 2 、R 3 And R is 4 Independently hydrogen and halogen.
In a preferred embodiment of the present invention, certain groups of the compounds of formula 7a or 8a are defined as follows (undefined groups are as described in any of the previous embodiments): r is R 1 And R is 2 Is hydrogen, R 3 And R is 4 Independently halogen.
In a preferred embodiment of the present invention, certain groups of the compounds of formula 7a or 8a are defined as follows (undefined groups are as described in any of the previous embodiments): r is R 1 And R is 2 Is hydrogen, R 3 Is chlorine, R 4 Is fluorine.
In the preparation method of the compound shown in the formula 7a or the formula 8a, the compound shown in the formula 7a is preferably a compound shown in the formula 7a-1,
in the preparation method of the compound shown in the formula 7a or the formula 8a, the compound shown in the formula 8a is preferably a compound shown in the formula 8a-1,
In the preparation method of the compound shown in the formula 7a or the formula 8a, the chiral resolving agent with R configuration can be chiral resolving agents with R configuration, preferably amine chiral resolving agents with R configuration, such as (R) -1- (1-naphthyl) -ethylamine, (R) -phenethylamine, (R) -phenylalaninol, (R) -N-benzyl phenethylamine or (R) -quinidine, and more preferably (R) -1- (1-naphthyl) -ethylamine, which are conventional in the art.
In the preparation method of the compound shown in the formula 7a or the formula 8a, the chiral resolving agent in the S configuration can be a chiral resolving agent in the S configuration which is conventional in the art, preferably an amine chiral resolving agent in the S configuration, such as (S) -1- (1-naphthyl) -ethylamine, (S) -phenethylamine, (S) -phenylalaninol, (S) -N-benzyl phenethylamine or (S) -quinidine, and more preferably (S) -1- (1-naphthyl) -ethylamine.
In the preparation method of the compound shown as the formula 7a or the formula 8a, the organic solvent can be a solvent conventional in the art, preferably C 1 -C 4 More preferably an ester solvent. The C is 1 -C 4 Preferably one or more of methanol, ethanol and isopropyl alcohol (IPA). The ester solvent is preferably ethyl acetate.
In the preparation method of the compound shown in formula 7a or formula 8a, the molar ratio of the compound shown in formula 6 to the chiral resolving agent may be a conventional molar ratio in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:3, still more preferably 1:1 to 1:1.5, for example 1:1.
In the preparation method of the compound shown in formula 7a or formula 8a, the mass-to-volume ratio of the compound shown in formula 6 to the organic solvent may be a mass-to-volume ratio conventional in the art, preferably 1:1 to 1:10g/mL, more preferably 1:1 to 1:6g/mL, for example 1:5.2g/mL.
In the preparation method of the compound shown as the formula 7a or the formula 8a, the temperature of the salification reaction can be a temperature conventional in the art, preferably 20-30 ℃.
In the preparation of the compound of formula 7a or 8a, the progress of the salt formation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the reaction time is preferably 1 to 5 hours, e.g., 3 hours.
In the method for preparing the compound represented by formula 7a or formula 8a, preferably, after the salt formation reaction is completed and before the neutralization reaction, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: filtering the reaction solution, and recrystallizing the filtered filter cake. The filtration is preferably suction filtration. The recrystallization procedure may be conventional in the art, and the recrystallization solvent is preferably an alcoholic solvent (e.g., ethanol) and water, and the volume ratio of the alcoholic solvent to the water is preferably 5:1 to 15:1 (e.g., 10:1).
In the preparation method of the compound shown in the formula 7a or the formula 8a, the preparation method of the compound shown in the formula 6 can comprise the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown in the formula 5 to obtain the compound shown in the formula 6;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 6, the organic solvent can be organic solvent conventional in the field, preferably C 1 -C 4 One or more of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents and sulfoxide solvents, more preferably C 1 -C 4 Alcohol solvents of (2). The C is 1 -C 4 The alcohol solvent of (a) is preferably one or more of methanol, ethanol and isopropanol, and more preferably isopropanol. The ester solvent is preferably ethyl acetate. The ether solvent is preferably diethyl ether and/or Tetrahydrofuran (THF). The ketone solvent is preferably acetone and/or 2-butanone. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-Dimethylformamide (DMF). The sulfoxide is solubleThe agent is preferably dimethyl sulfoxide (DMSO).
In the preparation method of the compound shown in the formula 6, the reducing agent can be a reducing agent commonly used in the field, and alkali metal hydride is preferred. The alkali metal hydride may be lithium aluminum hydride (LiAlH) 4 ) Lithium borohydride (LiBH) 4 ) Sodium borohydride (NaBH) 4 ) Potassium borohydride (KBH) 4 ) Diisobutyl aluminum hydride [ (i-Bu) 2 AlH]Sodium cyanoborohydride (NaBH) 3 CN), sodium thioborohydride (NaBH) 2 S 3 ) And lithium tri-sec-butylborohydride [ LiBH (CH) 3 CH 2 CH(CH 3 )) 3 ]Preferably one or more of lithium borohydride, sodium borohydride and potassium borohydride, more preferably lithium borohydride.
In the preparation method of the compound shown in the formula 6, the mass-volume ratio of the compound shown in the formula 5 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:10-1:20g/mL, more preferably 1:10-1:15g/mL, for example 1:13.3g/mL.
In the preparation method of the compound shown in formula 6, the molar ratio of the compound shown in formula 5 to the reducing agent may be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:2, for example 1:2.
In the preparation method of the compound shown in formula 6, the temperature of the reduction reaction may be a temperature conventional in the art, preferably-5 to 30 ℃, more preferably 20 to 30 ℃, for example 20 ℃ or 25 ℃.
In the preparation method of the compound shown in formula 6, the progress of the reduction reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the reduction reaction is preferably carried out for 1 to 3 hours, such as 2 hours or 2.5 hours.
In the method for preparing the compound shown in formula 6, preferably, after the reduction reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: cooling the reaction solution to-10-0deg.C (e.g. -5deg.C), adjusting pH to 1-2 with acid (preferably hydrochloric acid, such as 1N hydrochloric acid), adding organic solvent (preferably ester solvent, such as ethyl acetate), adding water, separating to obtain water layer, extracting (preferably ester solvent, such as ethyl acetate) water layer, collecting organic layer, washing (preferably saline solution, such as saturated saline solution), drying, and concentrating.
In the preparation method of the compound shown in the formula 6, the preparation method of the compound shown in the formula 5 can further comprise the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on a compound shown in a formula 4 to obtain the compound shown in a formula 5;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 5, the solvent is preferably C 1 -C 4 One or more of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents or sulfoxide solvents, more preferably C 1 -C 4 Alcohol solvents of (2). The C is 1 -C 4 The alcohol solvent of (a) is preferably one or more of methanol, ethanol and isopropanol, more preferably ethanol. The ester solvent is preferably ethyl acetate. The ether solvent is preferably diethyl ether and/or tetrahydrofuran. The ketone solvent is preferably acetone and/or 2-butanone. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-dimethylformamide. The sulfoxide solvent is preferably dimethyl sulfoxide.
In the preparation method of the compound shown in the formula 5, the base can be a base conventional in the art, such as an inorganic base. The inorganic base is preferably an alkali metal carbonate and/or alkali metal hydroxide, more preferably an alkali metal hydroxide, and the alkali metal carbonate is preferably K 2 CO 3 And/or Cs 2 CO 3 The alkali metal hydroxide is preferably one or more of LiOH, naOH and KOH.
In the preparation method of the compound shown in the formula 5, the mass-volume ratio of the compound shown in the formula 4 to the solvent is preferably 1:1-1:20g/mL, more preferably 1:5-1:13g/mL, for example 1:5g/mL, 1:6g/mL or 1:13g/mL.
In the preparation method of the compound shown in the formula 5, the molar ratio of the compound shown in the formula 4 to the alkali is preferably 1:1-1:5, more preferably 1:1-1:3, for example 1:2.9.
In the preparation method of the compound shown in the formula 5, the temperature of the hydrolysis reaction can be a temperature conventional in the art, for example, -5 ℃ to 30 ℃, preferably 20 ℃ to 30 ℃.
In the preparation method of the compound shown in the formula 5, the progress of the hydrolysis reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the hydrolysis reaction time is preferably 1 to 3 hours, more preferably 2 to 3 hours.
In the method for preparing the compound shown in formula 5, preferably, after the hydrolysis reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction mixture is cooled to-10 to-0deg.C (e.g., -5deg.C), an acid (preferably hydrochloric acid, such as 1N hydrochloric acid) is added to adjust pH to 1-2, an organic solvent (preferably a halogenated hydrocarbon solvent such as dichloromethane) is used for extraction, the organic layers are combined, washed (the washed solvent is preferably a saline solution such as saturated saline solution), dried, and concentrated.
In the preparation method of the compound shown in the formula 5, the preparation method of the compound shown in the formula 4 can further comprise the following steps: in the presence of acid and oxidant under the atmosphere of protective gas, carrying out the intramolecular cyclization reaction of the compound shown in the formula 3 to obtain the compound shown in the formula 4;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the method for preparing the compound shown in formula 4, the shielding gas may be a shielding gas conventional in the art, such as nitrogen or argon.
In the preparation method of the compound shown in the formula 4, the acid can be acid conventional in the art, such as inorganic acid and/or organic acid. The mineral acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic acid is preferably formic acid and/or acetic acid.
In the preparation method of the compound shown in the formula 4, the oxidant can be a single-electron oxidant, and the single-electron oxidant can be a single-electron oxidant conventional in the art, preferably manganese salt and/or cerium salt. The manganese salt is preferably manganese acetate. The cerium salt is preferably ammonium cerium nitrate.
In the preparation method of the compound shown in the formula 4, preferably, the intramolecular cyclization reaction can be performed in the presence of copper salt. The copper salt may be a copper salt conventional in the art, such as one or more of copper acetate, copper oxide, copper chloride, copper bromide, and copper bromide, preferably copper acetate. The molar ratio of the copper salt to the compound of formula 3 may be conventional in the art, preferably 1:1 to 2:1, more preferably 1:1 to 1.5:1, for example 1:1.
In the preparation method of the compound shown in the formula 4, the mass-volume ratio of the compound shown in the formula 3 to the acid is 1:1-1:20g/mL, more preferably 1:1-1:15g/mL, for example 1:8.9g/mL.
In the preparation method of the compound shown in the formula 4, the molar ratio of the compound shown in the formula 3 to the oxidant may be a molar ratio conventional in the art, preferably 1:1 to 5:1, more preferably 1:1 to 3:1, still more preferably 1:1 to 2.5:1, for example 2.5:1.
In the preparation method of the compound shown in the formula 4, the temperature of the intramolecular cyclization reaction can be a temperature conventional in the art, preferably 90-110 ℃, for example 95 ℃.
In the preparation method of the compound shown in the formula 4, the progress of the intramolecular cyclization reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the period of the intramolecular cyclization reaction is preferably 8 to 20 hours, more preferably 8 to 12 hours, for example 12 hours.
In the method for preparing the compound shown in formula 4, preferably, after the intramolecular reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: concentrating the reaction solution, adding water and organic solvent (preferably ether solvent such as tert-butyl methyl ether), separating water layer, extracting with organic solvent (preferably ether solvent such as tert-butyl methyl ether), mixing organic layers, washing with alkali to neutrality, drying, and concentrating.
In the preparation method of the compound shown in the formula 4, the preparation method of the compound shown in the formula 3 can comprise the following steps: in an organic solvent, in the presence of a metal catalyst, carrying out the reduction reaction of a compound shown in a formula 2 and hydrogen to obtain the compound shown in a formula 3;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 3, the organic solvent can be organic solvent conventional in the field, preferably C 1 -C 4 One or more of an alcohol solvent, an ester solvent and an ether solvent, and an ester solvent is more preferable. The C is 1 -C 4 The alcohol solvent of (a) is preferably one or more of methanol, ethanol and isopropanol. The ester solvent is preferably ethyl acetate. The ether solvent is preferably diethyl ether and/or tetrahydrofuran.
In the preparation method of the compound shown in the formula 3, the metal catalyst can be a metal catalyst conventional in the art, preferably Pd/C, pd (OH) 2 Raney nickel, pt/C and PtO 2 More preferably Pd/C.
In the preparation method of the compound shown in the formula 3, the mass-to-volume ratio of the compound shown in the formula 2 to the organic solvent can be a mass-to-volume ratio conventional in the art, preferably 1:1-10:1g/mL, more preferably 1:1-8:1g/mL, still more preferably 1:1-5:1g/mL, for example 3:1g/mL.
In the preparation method of the compound shown in the formula 3, the mass ratio of the compound shown in the formula 2 to the metal catalyst is 10:1-100:1, and more preferably 20:1-100:1, for example 20:1.
In the method for preparing the compound represented by formula 3, the amount of hydrogen is not particularly limited, and the pressure of hydrogen in the reaction system may be a pressure conventional in the art, preferably 14.5 to 72.5psi, more preferably 15 to 50psi, for example 15psi, 30psi or 50psi.
In the method for producing a compound represented by formula 3, the reduction reaction is preferably carried out in the presence of an acid. The acid may be any acid conventional in the art, such as organic and/or inorganic acids. The organic acid is preferably formic acid and/or acetic acid. The mineral acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The molar ratio of the compound of formula 2 to the acid may be conventional in the art, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5, for example 1:1.5.
In the preparation method of the compound shown in formula 3, the temperature of the reduction reaction may be a temperature conventional in the art, preferably 20 to 50 ℃, more preferably 15 to 30 ℃, for example 15 ℃ or 30 ℃.
In the preparation method of the compound shown in formula 3, the reduction reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the reduction reaction time is preferably 0.5 to 8 hours, more preferably 0.5 to 5 hours, for example 0.5 hours, 1 hour or 2 hours.
In the method for preparing the compound shown in formula 3, preferably, after the reduction reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: filtering the reaction solution, and concentrating.
In the preparation method of the compound shown in the formula 3, the preparation method of the compound shown in the formula 2 can comprise the following steps: in an organic solvent in the presence of alkali and a catalyst under the atmosphere of protective gas, carrying out the coupling reaction of a compound shown in a formula 1 and a compound shown in a formula A to obtain the compound shown in a formula 2; the catalyst comprises a ligand and a palladium compound;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the method for preparing the compound shown in formula 2, the shielding gas may be a shielding gas conventional in the art, such as nitrogen and/or argon.
In the method for preparing the compound shown in the formula 2, the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, an ether solvent and a ketone solvent, and more preferably an aromatic hydrocarbon solvent. The aromatic solvent is preferably toluene and/or xylene, more preferably toluene. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-Dimethylformamide (DMF) and/or N, N-Dimethylacetamide (DMA). The sulfoxide solvent is preferably dimethyl sulfoxide (DMSO). The ether solvent is preferably Tetrahydrofuran (THF) and/or 1, 4-dioxane. The ketone solvent is preferably N-methyl pyrrolidone (DMP).
In the preparation method of the compound shown in the formula 2, the base can be a base conventional in the art, such as an organic base and/or an inorganic base. The organic base is preferably pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane (DABCO), alkali metal alkoxides andone or more of them, more preferablyFor example triethylamine (Et) 3 N) and/or N-methyldicyclohexylamine (Cy) 2 NMe); wherein R is 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). The alkali metal alkoxide may be C 1 ～C 4 Alkali metal alkoxides of alcohols, such as potassium tert-butoxide and/or sodium tert-butoxide. The inorganic base may be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide. The alkali metal carbonate may be K 2 CO 3 And/or Cs 2 CO 3 . The alkali metal hydride may be NaH. The alkali metal hydroxide may be NaOH and/or KOH.
In the preparation method of the compound shown in the formula 2, the ligand can be phosphine ligand, and the phosphine ligand can be one or more of phosphine ligands conventional in the art, such as monodentate phosphine ligand, bidentate phosphine ligand and multidentate phosphine ligand, preferably monodentate phosphine ligand. The monodentate phosphine ligand is preferably one or more of triphenylphosphine, tris (2-tolyl) phosphine, tris (3-tolyl) phosphine, tri-p-tolyl phosphine, tris (4-fluorophenyl) phosphine, tris (2-methoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine and 2- (di-t-butylphosphine) biphenyl, more preferably triphenylphosphine and/or tris (2-tolyl) phosphine. The multidentate phosphine ligand is preferably
In the preparation method of the compound shown in the formula 2, the palladium compound can be zero-valent palladium and/or divalent palladium. The zero-valent palladium can be Pd 2 (dba) 3 (dba: dibenzylideneacetone). The divalent palladium may be Pd (OAc) 2 、PdCl 2 、Pd(TFA) 2 And Pd (MeCN) 2 Cl 2 One or more of the following.
In the preparation method of the compound shown in the formula 2, the palladium compound and the ligand can be added separately, the palladium compound and the ligand can form a complex, or the palladium compound and the ligand can form a complex first and then are added separately with the ligand; the ligands may independently be phosphine ligands.
In the preparation method of the compound shown in the formula 2, when the palladium compound and the ligand can form a complex to be added, or the palladium compound and the ligand can form a complex first and then are added separately from the ligand, the complex formed by the palladium compound and the ligand can be a complex formed by zero-valent palladium and the ligand and/or a complex formed by divalent palladium and the ligand; the complex formed by the zero-valent palladium and the ligand is preferably Pd (PPh 3 ) 4 The method comprises the steps of carrying out a first treatment on the surface of the The complex formed by the bivalent palladium and the ligand is preferably Pd (PPh) 3 ) 2 Cl 2 And/or Pd (dppf) Cl 2 。
In the preparation method of the compound shown in the formula 2, the molar ratio of the compound shown in the formula 1 to the compound shown in the formula A can be a conventional molar ratio in the field, preferably 1:1-1:3, further preferably 1:1-1:2, for example 1:1.2.
In the preparation method of the compound shown in the formula 2, the mass-volume ratio of the compound shown in the formula 1 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:10g/mL, more preferably 1:1-1:5g/mL, and even more preferably 1:1-1:2g/mL.
In the preparation method of the compound shown in the formula 2, the molar ratio of the compound shown in the formula 1 to the base can be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:3, and even more preferably 1:1 to 1:2.
In the preparation method of the compound shown in the formula 2, the molar ratio of the compound shown in the formula 1 to the ligand can be a molar ratio conventional in the art, preferably 1:1 to 10:1, more preferably 1.25:1 to 10:1, and even more preferably 2:1 to 10:1.
In the preparation method of the compound shown in the formula 2, the molar ratio of the compound shown in the formula 1 to the palladium compound can be a conventional molar ratio in the field, preferably 10:1 to 1000:1, more preferably 100:1 to 1000:1, still more preferably 100:1 to 500:1, for example 124:1.
In the preparation method of the compound shown in the formula 2, the temperature of the coupling reaction can be a temperature conventional in the art, preferably 90-110 ℃.
In the preparation method of the compound shown in the formula 2, the progress of the coupling reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the coupling reaction time is preferably 8 to 20 hours, more preferably 8 to 12 hours.
In the preparation method of the compound shown in formula 2, preferably, after the coupling reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction solution is cooled (preferably to room temperature), the pH is adjusted to 3-4 with an acid (preferably hydrochloric acid, for example, 2M hydrochloric acid), an organic solvent (preferably an ether solvent, for example, t-butyl methyl ether) is extracted, the resultant organic phase is extracted by washing (a washed solvent is preferably a sodium chloride solution, for example, a saturated sodium chloride solution), dried, and separated and purified (preferably, column chromatography analysis, the developing solvent for the column chromatography separation is preferably an ether solvent and an ester solvent, for example, petroleum ether and ethyl acetate).
The invention provides a preparation method of a compound shown as a formula 7 or a formula 8, which comprises the following steps: neutralizing the compound shown in the formula 7a or 8a with acid to obtain a compound shown in the formula 7 or 8; wherein X is 1 And X 2 As described above; the preparation method of the compound shown in the formula 7a or the formula 8a is as described in any one of the previous schemes;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula 7 or the formula 8, the conditions and the operation of the neutralization reaction can be conventional conditions and operations in the field.
The invention provides a preparation method of a compound shown as a formula 6, which comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown in the formula 5 to obtain the compound shown in the formula 6;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 6, the conditions and the operation of the reduction reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula 5, which comprises the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the compound shown in the formula 4 as follows to obtain the compound shown in the formula 5;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 5, the conditions and the operation of the hydrolysis reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula 4, which comprises the following steps:
in the presence of acid and oxidant under the atmosphere of protective gas, carrying out the intramolecular cyclization reaction of the compound shown in the formula 3 to obtain the compound shown in the formula 4;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 4, the conditions and the operation of the internal cyclization reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula 3, which comprises the following steps: in an organic solvent, in the presence of a metal catalyst, carrying out the reduction reaction of a compound shown in a formula 2 and hydrogen to obtain the compound shown in a formula 3;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 3, the conditions and the operation of the reduction reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula 2, which comprises the following steps: in an organic solvent in the presence of alkali and a catalyst under the atmosphere of protective gas, carrying out the coupling reaction of a compound shown in a formula 1 and a compound shown in a formula A to obtain the compound shown in a formula 2; the catalyst comprises a ligand and a palladium compound;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown in the formula 2, the conditions and the operation of the coupling reaction are the same as those of the reaction.
The invention also provides a preparation method of the compound shown in the formula I, which is a first method or a second method:
wherein, the method one includes the following steps: in an organic solvent, in the presence of acid and silane compounds, carrying out reductive amination reaction on a compound shown as a formula B13;
the second method comprises the following steps: in an organic solvent, in the presence of alkali, carrying out ether forming reaction on a compound shown as a formula C13 as follows;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the first method, the organic solvent may be an organic solvent conventional in the art, preferably C 1 -C 4 One or more of an alcohol solvent, an aromatic hydrocarbon solvent, and an ether solvent, more preferably an ether solvent. The C is 1 -C 4 The alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol. The aromatic solvent is preferably toluene and/or xylene. The ether solvent is preferably one or more of diethyl ether, tetrahydrofuran and 1, 4-dioxane, and more preferably tetrahydrofuran.
In the first method, the acid may be an acid which is conventional in the art, and may be an inorganic acid and/or an organic acid. The mineral acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid, more preferably trifluoroacetic acid.
In the first method, the silane compound is preferably one or more of phenylsilane, diethylsilane, triethylsilane, trichlorosilane and diethoxymethylsilane, more preferably one or more of phenylsilane, diethylsilane and triethylsilane, and still more preferably phenylsilane.
In the first method, the mass-to-volume ratio of the compound shown in the formula B13 to the organic solvent may be a mass-to-volume ratio conventional in the art, preferably 1:1 to 1:20g/mL, more preferably 1:1 to 1:15g/mL, for example 1:12g/mL.
In the first method, the mass-to-volume ratio of the compound represented by the formula B13 to the acid may be a mass-to-volume ratio conventional in the art, preferably 1:1 to 1:5g/mL, more preferably 1:1 to 1:3g/mL, for example 1:2.67g/mL.
In the first method, the molar ratio of the compound shown as the formula B13 to the silane compound is preferably 1:1-1:10, more preferably 1:1-1:5, for example 1:4.6.
In the first method, the reductive amination reaction temperature may be a temperature conventional in the art, preferably 20-30 ℃.
In the first method, the progress of the reductive amination reaction can be monitored by means conventional in the art (e.g.TLC, HPLC or LC-MS), and the reductive amination reaction is preferably carried out for a period of 1 to 5 hours, more preferably 1 to 3 hours.
In the first method, preferably, after the reductive amination reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: removing solvent (preferably spin drying) to obtain residue, adding organic solvent (preferably halogenated hydrocarbon solvent such as dichloromethane), washing (preferably sodium bicarbonate solution and saline solution such as saturated sodium bicarbonate solution and saturated saline solution), and concentrating.
In the second method, the organic solvent may be one or more of an aromatic solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, an ether solvent and a ketone solvent, which are conventional in the art, preferably an amide solvent and/or a sulfoxide solvent, for example, a sulfoxide solvent. The aromatic solvent is preferably toluene and/or xylene, more preferably toluene. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The sulfoxide solvent is preferably dimethyl sulfoxide. The ether solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether. The ketone solvent is preferably N-methyl pyrrolidone.
In the second method, the base may be a base conventional in the art, such as an organic base and/or an inorganic base. The organic base is preferably pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene or 1, 4-diazabicyclo [2.2.2]Octane, alkali metal alkoxide and its preparationOne or more of the following; wherein R is 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). The alkali metal alkoxide may be C 1 ～C 4 Alkali metal alkoxides of alcohols, such as potassium tert-butoxide and/or sodium tert-butoxide. The inorganic base may be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide. The alkali metal carbonate may be K 2 CO 3 And/or Cs 2 CO 3 Preferably Cs 2 CO 3 . The alkali metal hydride may be NaH. The alkali metal hydroxide may be NaOH and/or KOH.
In the second method, the mass-to-volume ratio of the compound shown in the formula C13 to the organic solvent may be a mass-to-volume ratio conventional in the art, preferably 1:1 to 1:30g/mL, and more preferably 1:1 to 1:20g/mL, for example 1:20g/mL.
In the second method, the molar ratio of the compound represented by formula C13 to the base may be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:3, still more preferably 1:1 to 1:2, for example 1:2.
In the second process, the temperature of the ether formation reaction may be a temperature conventional in the art, preferably 50 to 100 ℃, more preferably 90 to 100 ℃, for example 90 ℃.
In the second method, the progress of the ether formation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the time of the ether formation reaction is preferably 1 to 20 hours, more preferably 1 to 15 hours, for example 15 hours.
In the second method, preferably, after the completion of the ether formation reaction, the method may further include a post-treatment operation, where the post-treatment operation includes the following steps: mixing the reaction solution with water, extracting with organic solvent (preferably ester solvent such as ethyl acetate), drying the organic layer, filtering, concentrating, and purifying. The purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
In the first method, the preparation method of the compound shown as the formula B13 can comprise the following steps: in a solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown as the formula B12 to obtain a compound shown as the formula B13;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B13, the solvent can be a solvent conventional in the art, such as C 1 -C 4 One or more of alcohols, ester solvents, and ether solvents. The C is 1 -C 4 The alcohol may be one or more of methanol, ethanol and isopropanol. The ester solvent may be ethyl acetate. The ether solvent can be tetrahydrofuran and/or 1, 4-dioxane.
In the preparation method of the compound shown in the formula B13, the reducing agent can be a reducing agent which is conventional in the field, and can be sodium hydrosulfite, lithium aluminum hydride, sodium borohydride or an active metal with reducing capability. The active metal may be one or more of iron, zinc or tin, preferably iron and/or zinc.
In the method for preparing the compound shown in the formula B13, when the reducing agent is an active metal with reducing capability, the reducing reaction is performed in the presence of an acid, preferably the acid is used as a solvent. The acid may be any acid conventional in the art, such as an inorganic acid and/or an organic acid. The inorganic acid may be hydrochloric acid, sulfuric acid and/or phosphoric acid. The organic acid may be formic acid and/or acetic acid, preferably acetic acid.
In the preparation method of the compound shown in the formula B13, a salt electrolyte can be added in the reduction reaction, and the salt electrolyte is used for activating metal and promoting the reduction reaction. The salt electrolyte may be a salt electrolyte conventional in the art, such as an ammonium salt, preferably ammonium chloride.
In the preparation method of the compound shown as the formula B13, the mass-volume ratio of the compound shown as the formula B12 to the solvent can be a mass-volume ratio conventional in the art, preferably 1:10-1:30g/mL, and more preferably 1:10-1:20g/mL.
In the preparation method of the compound shown as the formula B13, the molar ratio of the compound shown as the formula B12 to the reducing agent can be a molar ratio conventional in the art, preferably 1:1-1:8, and more preferably 1:1-1:6.
In the preparation method of the compound shown as the formula B13, the temperature of the reduction reaction can be a temperature conventional in the art, preferably 20-75 ℃, more preferably 50-75 ℃, for example 70-75 ℃.
In the preparation of the compound of formula B13, the progress of the reduction reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the reduction reaction is preferably carried out for a period of 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound represented by formula B13, preferably, after the reduction reaction is completed, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction mixture is cooled (preferably to room temperature), an organic solvent (preferably a halogenated hydrocarbon solvent such as methylene chloride) is added, filtration (preferably diatomaceous earth filtration) is performed, and the cake is washed (the washed solvent is preferably a halogenated hydrocarbon solvent such as methylene chloride) and dried.
In the second method, the preparation method of the compound shown as the formula C13 can comprise the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of a compound shown as a formula C12 to obtain the compound shown as a formula C13;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C13, the organic solvent can be an organic solvent which is conventional in the art, such as an aromatic hydrocarbon solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, an ether solvent, a ketone solvent and C 1 -C 4 One or more, preferably C, of the alcoholic solvents of (C) 1 -C 4 Alcohol solvents of (2). The aromatic solvent is preferably toluene and/or xylene. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The sulfoxide solvent is preferably dimethyl sulfoxide. The ether solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether. The ketone solvent is preferably N-methyl pyrrolidone. The C is 1 -C 4 The alcohol solvent of (a) is preferably one or more of methanol, ethanol and isopropanol, and more preferably isopropanol.
In the method for preparing the compound represented by formula C13, the reducing agent may be a reducing agent conventional in the art, such as an alkali metal hydride. The alkali metal hydride may be one or more of lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride and lithium tri-sec-butylborohydride, preferably one or more of lithium borohydride, sodium borohydride and potassium borohydride, more preferably lithium borohydride.
In the preparation method of the compound shown as the formula C13, the mass-volume ratio of the compound shown as the formula C12 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:20g/mL, further preferably 1:1-1:12g/mL, for example 10.6g/mL.
In the method for preparing the compound represented by formula C13, the molar ratio of the compound represented by formula C12 to the reducing agent may be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:2, for example 1:2.
In the preparation method of the compound shown as the formula C13, the temperature of the reduction reaction can be a temperature conventional in the art, preferably 20-90 ℃.
In the preparation of the compound of formula C13, the progress of the reduction reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the reduction reaction is preferably carried out for a period of 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound represented by formula C13, preferably, after the reduction reaction is completed, the method may further include a post-treatment operation, wherein the post-treatment operation includes the following steps: the reaction solution and water (preferably ice water) are mixed and quenched for reaction, extraction is carried out (the extracted solvent is preferably an ester solvent, preferably ethyl acetate), the organic layer is dried, filtered, concentrated to dryness and purified. The purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
In the preparation method of the compound shown as the formula B13, the preparation method of the compound shown as the formula B12 can comprise the following steps: in an organic solvent, in the presence of an oxidant, carrying out the following oxidation reaction on the compound shown as the formula B11 to obtain the compound shown as the formula B12;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B12, the organic solvent can be one or more of conventional organic solvents in the field, such as halogenated hydrocarbon solvents, amide solvents, sulfoxide solvents and ketone solvents, preferably halogenated hydrocarbon solvents. The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1, 2-dichloroethane, more preferably dichloromethane. The amide solvent is preferably N, N-dimethylformamide. The sulfoxide solvent is preferably dimethyl sulfoxide. The ketone solvent is preferably acetone and/or 2-butanone.
In the preparation method of the compound shown as the formula B12, the oxidant can be an oxidant conventional in the field, such as a metal oxidant and/or a non-metal oxide. The metal oxidant may be chromium oxide and/or manganese oxide. The chromium oxide may be pyridinium chlorochromate (PCC). The manganese oxide may be manganese dioxide. The non-metal oxide may be dess-martin reagent (DMP).
In the preparation method of the compound shown as the formula B12, the mass-volume ratio of the compound shown as the formula B11 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:20g/mL, more preferably 1:1-1:15g/mL, and even more preferably 1:1-1:12g/mL.
In the preparation method of the compound shown as the formula B12, the molar ratio of the compound shown as the formula B11 to the oxidant can be a molar ratio conventional in the art, preferably 1:1-1:3, and more preferably 1:1-1:1.5.
In the preparation method of the compound shown as the formula B12, the temperature of the oxidation reaction can be a reaction conventional in the art, preferably 20-30 ℃.
In the preparation of the compound of formula B12, the progress of the oxidation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the oxidation reaction is preferably carried out for a period of 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound shown in formula B12, preferably, after the oxidation reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction solution is filtered (preferably with celite), the filtrate is washed (the washed solvent is preferably a mixed solution of sodium sulfite and sodium bicarbonate, more preferably a saturated mixed solution of sodium sulfite and sodium bicarbonate), and the organic phase is separated and concentrated.
In the preparation method of the compound shown as the formula C13, the preparation method of the compound shown as the formula C12 can comprise the following steps: in an organic solvent, in the presence of acid and silane compounds, carrying out reductive amination reaction on a compound shown as a formula C11 and a compound shown as a formula C10 to obtain a compound shown as a formula C12;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C12, the organic solvent can be organic solvents conventional in the field, preferably C 1 -C 4 One or more of an alcohol solvent, an aromatic hydrocarbon solvent, and an ether solvent, more preferably an ether solvent. The C is 1 -C 4 The alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol. The aromatic solvent is preferably toluene and/or xylene. The ether solvent is preferably one or more of diethyl ether, THF and 1, 4-dioxane, and more preferably THF.
In the preparation method of the compound shown as the formula C12, the acid can be an acid which is conventional in the field and can be an inorganic acid and/or an organic acid. The mineral acid is preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid, more preferably trifluoroacetic acid.
In the preparation method of the compound shown in the formula C12, the silane compound is preferably one or more of phenylsilane, diethylsilane, triethylsilane, trichlorosilane and diethoxymethylsilane, more preferably one or more of phenylsilane, diethylsilane and triethylsilane, and further preferably phenylsilane.
In the preparation method of the compound shown as the formula C12, the mass-volume ratio of the compound shown as the formula C11 to the organic solvent is a mass-volume ratio which can be conventional in the art, preferably 1:1-1:20g/mL, more preferably 1:1-1:12g/mL.
In the method for preparing the compound represented by formula C12, the molar ratio of the compound represented by formula C11 to the compound represented by formula C10 may be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:2, for example 1:1.2.
In the preparation method of the compound shown as the formula C12, the mass-to-volume ratio of the compound shown as the formula C11 to the acid can be a mass-to-volume ratio conventional in the art, preferably 1:1-1:5g/mL, more preferably 1:1-1:3g/mL, for example 1:3g/mL.
In the preparation method of the compound shown in the formula C12, the molar ratio of the compound shown in the formula C11 to the silane compound is preferably 1:1-1:10, more preferably 1:1-1:6, for example 1:5.14.
In the preparation method of the compound shown as the formula C12, the temperature of the reductive amination reaction is preferably 20-30 ℃.
In the preparation of the compound of formula C12, the progress of the reductive amination reaction can be monitored by means conventional in the art (e.g.TLC, HPLC or LC-MS), and the reductive amination reaction is preferably carried out for a period of 1 to 30 hours, more preferably 1 to 20 hours.
In the method for preparing the compound shown in formula C12, preferably, after the reductive amination reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction mixture is mixed with water, quenched, extracted with an organic solvent (preferably an ester solvent, preferably ethyl acetate), dried, filtered, concentrated to dryness, and purified (preferably by column chromatography).
In the preparation method of the compound shown as the formula B12, the preparation method of the compound shown as the formula B11 can be any one of a method A, a method B, a method C and a method D,
the method A comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out hydrolysis reaction on a compound shown as a formula B10 to obtain a compound shown as a formula B11;
the method B comprises the following steps:
(b1) The compound shown as the formula B10 and a halogenating agent are subjected to the acylation reaction shown as follows to obtain acyl chloride;
(b2) Carrying out the reduction reaction of the acyl chloride obtained in the step (B1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
the method C comprises the following steps:
(c1) Carrying out esterification reaction on the compound shown as the formula B10 and alcohol to obtain ester;
(c2) Carrying out the reduction reaction of the ester obtained in the step (c 1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
the method D comprises the following steps:
(d1) In the presence of an activating agent and alkali, carrying out the following reaction on the compound shown as the formula B10 to obtain anhydride;
(d2) Carrying out the reduction reaction of the anhydride obtained in the step (d 1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes;
R 5 and R is 6 Independently C 1 -C 4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
In the preparation method of the compound shown as the formula B11, in the method A, the organic solvent can be organic solvents conventional in the field, preferably aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents, ketone solvents and C 1 -C 4 One or more of the alcohol solvents of (a) are more preferably ether solvents. The aromatic solvent may be toluene and/or xylene. The nitrile solvent may be acetonitrile. The amide solvent can be N, N-dimethylformamide and/or N, N-Dimethylacetamide (DMA). The sulfoxide solvent can be dimethyl sulfoxide. The ether solvent may be one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether (DME), preferably DME. The ketone solvent may be N-methylpyrrolidone. The C is 1 -C 4 The alcohol solvent of (a) may be one or more of methanol, ethanol and isopropanol.
In the method for preparing the compound shown as the formula B11, in the method A, the reducing agent can be a reducing agent conventional in the art, such as alkali metal hydride. The alkali metal hydride may be lithium aluminum hydride (LiAlH) 4 ) Lithium borohydride (LiBH) 4 ) Sodium borohydride (NaBH) 4 ) Potassium borohydride (KBH) 4 ) Diisobutylaluminum hydride, sodium cyanoborohydride (NaBH) 3 CN) and lithium tri-sec-butylborohydride, preferably lithium borohydride, sodium borohydride and borohydrideOne or more of potassium, more preferably sodium borohydride.
In the method for preparing the compound shown in the formula B11, in the method a, the mass-to-volume ratio of the compound shown in the formula B10 to the organic solvent may be a mass-to-volume ratio conventional in the art, preferably 1:1 to 1:20g/mL, more preferably 1:1 to 1:15g/mL, still more preferably 1:1 to 1:12g/mL, for example 1:10.26g/mL.
In the method for preparing the compound represented by formula B11, the molar ratio of the compound represented by formula B10 to the reducing agent may be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:2, for example 1:1.1.
In the preparation method of the compound shown as the formula B11, the temperature of the reduction reaction can be a temperature conventional in the art, preferably-10-10 ℃, more preferably-5-5 ℃, for example-5-0 ℃.
In the preparation method of the compound shown as the formula B11, in the method A, the progress of the reduction reaction can be monitored by means conventional in the art (such as TLC, HPLC or LC-MS), and the reduction reaction time is preferably 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound represented by formula B11, in step (B1), the halogenating agent may be one or more of halogenating agents conventional in the art, such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride and oxalyl chloride, preferably thionyl chloride and/or oxalyl chloride.
In the method for preparing the compound represented by formula B11, in step (B1), the molar ratio of the compound represented by formula B10 to the halogenating agent may be a molar ratio conventional in the art, preferably 1:1 to 1:3, more preferably 1:1 to 1:2.
In the preparation method of the compound shown as the formula B11, in the step (B1), other conditions and operations of the acylation reaction are the same as those of the conventional reaction in the field.
In the preparation method of the compound shown as the formula B11, in the step (B2), the conditions and the operation of the reduction reaction are the same as those of the conventional reaction in the field.
In the process for preparing the compound of formula B11, in step (C1), the alcohol may be an alcohol conventional in the art, preferably C 1 -C 4 For example methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol.
In the method for preparing the compound represented by formula B11, in step (c 1), the molar ratio of the compound represented by formula B10 to the alcohol may be a molar ratio conventional in the art, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5.
In the preparation method of the compound shown as the formula B11, in the step (c 1), other conditions and operations of the esterification reaction are the same as those of the conventional reaction in the field.
In the preparation method of the compound shown as the formula B11, in the step (c 2), the conditions and the operation of the reduction reaction are the same as those of the conventional reaction in the field.
In the preparation method of the compound shown as the formula B11, in the step (d 1), the activating agent can be one or more of ethyl chloroformate, isobutyl chloroformate, trichloromethyl chloroformate and benzyl chloroformate, preferably ethyl chloroformate and/or isobutyl chloroformate, which are conventional in the art.
In the process for producing the compound of formula B11, in the step (d 1), the base may be a base conventional in the art, preferably an organic base such as Et 3 N, diisopropylethylamine (i-Pr) 2 Net), DBU, DABCO, pyridine, piperidine and N-methylmorpholine.
In the method for preparing the compound represented by formula B11, in step (d 1), the molar ratio of the compound represented by formula B10 to the activator may be a molar ratio conventional in the art, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5.
In the method for preparing the compound represented by formula B11, in step (d 1), the molar ratio of the compound represented by formula B10 to the base may be a molar ratio conventional in the art, preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5.
In the preparation method of the compound shown as the formula B11, in the step (d 2), the conditions and the operation of the reduction reaction are the same as those of the conventional reaction in the field.
In the method for preparing the compound represented by formula B11, preferably, after the reduction reaction is completed, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: the reaction solution and water (preferably ice water) are mixed and quenched for reaction, extraction is carried out (the extracted solvent is preferably an ester solvent, preferably ethyl acetate), the organic layer is dried, filtered, concentrated to dryness and purified. The purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
In the preparation method of the compound shown as the formula C12, the preparation method of the compound shown as the formula C11 can comprise the following steps: in an organic solvent, in the presence of an oxidant, carrying out the following oxidation reaction on a compound shown as a formula C9 to obtain a compound shown as a formula C11;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C11, the organic solvent can be one or more of conventional organic solvents in the field, such as halogenated hydrocarbon solvents, amide solvents, sulfoxide solvents and ketone solvents, preferably halogenated hydrocarbon solvents. The halogenated hydrocarbon solvent can be one or more of dichloromethane, chloroform and 1, 2-dichloroethane, preferably dichloromethane. The amide solvent can be N, N-dimethylformamide. The sulfoxide solvent can be dimethyl sulfoxide. The ketone solvent can be acetone and/or 2-butanone.
In the preparation method of the compound shown as the formula C11, the oxidant can be an oxidant conventional in the field, such as a metal oxidant and/or a non-metal oxide. The metal oxidant may be chromium oxide and/or manganese oxide. The chromium oxide may be a pyridinium chlorochromate salt. The manganese oxide may be manganese dioxide. The non-metal oxide may be a dess-martin reagent.
In the preparation method of the compound shown as the formula C11, the mass-volume ratio of the compound shown as the formula C9 and the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:30g/mL, more preferably 1:1-1:22g/mL, for example 20.3g/mL.
In the method for preparing the compound represented by formula C11, the molar ratio of the compound represented by formula C9 to the oxidizing agent may be a molar ratio conventional in the art, preferably 1:1 to 1:3, more preferably 1:1 to 1:1.5, for example 1:1.48.
In the method for preparing the compound represented by formula C11, the temperature of the oxidation reaction may be a reaction conventional in the art, preferably 20 to 50℃and more preferably 20 to 30 ℃.
In the preparation of the compound of formula C11, the progress of the oxidation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the oxidation reaction is preferably carried out for a period of 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound represented by formula C11, preferably, after the oxidation reaction is completed, the method may further include a post-treatment operation, where the post-treatment operation includes the following steps: the reaction solution is mixed with a solvent (preferably a mixed solution of sodium sulfite and sodium bicarbonate), an organic layer is separated, an organic solvent (preferably an ester solvent such as ethyl acetate) is extracted, the organic layer is dried, filtered, concentrated, and purified (preferably column chromatography separation).
In the preparation method of the compound shown as the formula B11, the preparation method of the compound shown as the formula B10 can comprise the following steps: in an organic solvent, in the presence of alkali, carrying out the ether forming reaction of a compound shown in a formula 7 and a compound shown in a formula B9 to obtain a compound shown in a formula B10;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the method for preparing the compound represented by formula B10, the ether formation reaction is preferably performed under a protective gas atmosphere, and the protective gas may be a protective gas conventional in the art, such as nitrogen.
In the preparation method of the compound shown in the formula B10, the organic solvent can be one or more of aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents and ketone solvents, preferably amide solvents and/or sulfoxide solvents, which are conventional in the art. The aromatic solvent is preferably toluene and/or xylene, more preferably toluene. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The sulfoxide solvent is preferably dimethyl sulfoxide. The ether solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether. The ketone solvent is preferably N-methyl pyrrolidone.
In the preparation method of the compound shown as the formula B10, the alkali can be common alkali in the field, such as organic alkali and/or inorganic alkali. The organic base is preferably pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene or 1, 4-diazabicyclo [2.2.2]Octane, alkali metal alkoxide and its preparationOne or more of the following; wherein R is 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). The alkali metal alkoxide may be C 1 ～C 4 Alkali metal alkoxides of alcohols, e.g. potassium tert-butoxide and/or tert-butoxideSodium. The inorganic base may be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide. The alkali metal carbonate may be K 2 CO 3 And/or Cs 2 CO 3 . The alkali metal hydride may be NaH. The alkali metal hydroxide may be NaOH and/or KOH.
In the preparation method of the compound shown in the formula B10, the mass-volume ratio of the compound shown in the formula 7 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:20g/mL, more preferably 1:1-1:15g/mL, and even more preferably 1:1-1:12g/mL.
In the preparation method of the compound shown in the formula B10, the molar ratio of the compound shown in the formula 7 to the compound shown in the formula 9 can be a conventional molar ratio in the art, preferably 1:1-1:5, more preferably 1:1-1:3, and even more preferably 1:1-1:2.
In the preparation method of the compound shown as the formula B10, the molar ratio of the compound shown as the formula 7 to the alkali can be a molar ratio conventional in the art, preferably 1:1-1:5, and more preferably 1:1-1:4.
In the preparation method of the compound shown as the formula B10, the temperature of the ether forming reaction can be a temperature conventional in the field, preferably-10-10 ℃, further preferably-5-5 ℃, such as-2-2 ℃.
In the preparation of the compound of formula B10, the progress of the ether formation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the time of the ether formation reaction is preferably 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound shown in the formula B10, preferably, after the ether forming reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: mixing the reaction solution with water (preferably ice water), adjusting pH to 3-4 with acid (preferably hydrochloric acid such as 1N hydrochloric acid), extracting with organic solvent (preferably ester solvent such as ethyl acetate), drying the organic layer, filtering, concentrating to dryness, and purifying. The purification is preferably recrystallization or column chromatography separation, and the conditions and operations of the recrystallization and column chromatography separation are the same as those conventional in the art.
In the preparation method of the compound shown as the formula B10, the preparation method of the compound shown as the formula 7 is described in any one of the previous schemes.
In the preparation method of the compound shown as the formula C11, the preparation method of the compound shown as the formula C9 can comprise the following steps: in an organic solvent, in the presence of alkali, carrying out methylation reaction shown in the following formula 8 with a methylation reagent to obtain the compound shown in the formula C9;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C9, the organic solvent can be one or more of aromatic hydrocarbon solvents, nitrile solvents, amide solvents, sulfoxide solvents, ether solvents and ketone solvents, preferably amide solvents, which are conventional in the art. The aromatic solvent is preferably toluene and/or xylene, more preferably toluene. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide such as N, N-dimethylformamide. The sulfoxide solvent is preferably dimethyl sulfoxide. The ether solvent is preferably tetrahydrofuran and/or 1, 4-dioxane. The ketone solvent is preferably N-methyl pyrrolidone.
In the preparation method of the compound shown as the formula C9, the alkali can be a common alkali in the field, such as an organic alkali and/or an inorganic alkali. The organic base is preferably pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2]Octane (DABCO), alkali metal alkoxides andone or more of the following;wherein R is 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) or C 5 -C 6 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). The alkali metal alkoxide may be C 1 ～C 4 Alkali metal alkoxides of alcohols, such as potassium tert-butoxide and/or sodium tert-butoxide. The inorganic base may be one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide, preferably alkali metal carbonate. The alkali metal carbonate may be K 2 CO 3 And/or Cs 2 CO 3 Preferably K 2 CO 3 . The alkali metal hydride may be NaH. The alkali metal hydroxide may be NaOH and/or KOH.
In the preparation method of the compound shown as the formula C9, the methylating agent can be one or more methylating agents conventional in the field, such as halogenated methane, dimethyl sulfate and dimethyl carbonate, and halogenated methane is preferred. The methyl halide is preferably methyl iodide.
In the preparation method of the compound shown as the formula C9, the mass-volume ratio of the compound shown as the formula 8 to the organic solvent can be a mass-volume ratio conventional in the art, preferably 1:1-1:30g/mL, more preferably 1:1-1:20g/mL, for example 1:20g/mL.
In the preparation method of the compound shown as the formula C9, the molar ratio of the compound shown as the formula 8 to the base can be a molar ratio conventional in the art, preferably 1:1 to 1:5, more preferably 1:1 to 1:3, still more preferably 1:1 to 1:2, for example 1:1.7.
In the method for preparing the compound represented by formula C9, the molar ratio of the compound represented by formula 8 to the methylating agent may be a molar ratio conventional in the art, preferably 1:1 to 1:2, and more preferably 1:1 to 1:1.5, for example 1:1.2.
In the preparation method of the compound shown as the formula C9, the temperature of the methylation reaction can be a temperature conventional in the field, preferably 20-30 ℃.
In the preparation of the compound of formula C9, the progress of the methylation reaction can be monitored by means conventional in the art (e.g., TLC, HPLC or LC-MS), and the time of the methylation reaction is preferably 1 to 5 hours, more preferably 1 to 3 hours.
In the method for preparing the compound shown in formula C9, preferably, after the methylation reaction is finished, the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps: quenching the reaction by adding a solvent (preferably an acid solvent such as hydrochloric acid, and also such as 1N hydrochloric acid), extracting with an organic solvent (preferably an ester solvent such as ethyl acetate), drying the organic layer, filtering, concentrating, and purifying (preferably column chromatography).
In the preparation method of the compound shown as the formula C9, the preparation method of the compound shown as the formula 8 is described in any one of the previous schemes.
The invention provides a preparation method of a compound shown as a formula B13, which comprises the following steps: in a solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown as the formula B12 to obtain a compound shown as the formula B13;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B13, the conditions and the operation of the reduction reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula B12, which comprises the following steps: in an organic solvent, in the presence of an oxidant, carrying out the following oxidation reaction on the compound shown as the formula B11 to obtain the compound shown as the formula B12;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B12, the conditions and the operation of the oxidation reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula B11, which can be any one of a method A, a method B, a method C and a method D,
the method A comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out hydrolysis reaction on a compound shown as a formula B10 to obtain a compound shown as a formula B11;
the method B comprises the following steps:
(b1) The compound shown as the formula B10 and a halogenating agent are subjected to the acylation reaction shown as follows to obtain acyl chloride;
(b2) Carrying out the reduction reaction of the acyl chloride obtained in the step (B1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
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the method C comprises the following steps:
(c1) Carrying out esterification reaction on the compound shown as the formula B10 and alcohol to obtain ester;
(c2) Carrying out the reduction reaction of the ester obtained in the step (c 1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
The method D comprises the following steps:
(d1) In the presence of an activating agent and alkali, carrying out the following reaction on the compound shown as the formula B10 to obtain anhydride;
(d2) Carrying out the reduction reaction of the anhydride obtained in the step (d 1) and a reducing agent as shown below to obtain the compound shown in the formula B11;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 And R is 6 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B11, the conditions and the operation of each reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula B10, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out the ether forming reaction of a compound shown in a formula 7 and a compound shown in a formula B9 to obtain a compound shown in a formula B10;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula B10, the condition and the operation of the ether forming reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula C13, which comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of a compound shown as a formula C12 to obtain the compound shown as a formula C13;
Wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C13, the conditions and the operation of the reduction reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula C12, which comprises the following steps: in an organic solvent, in the presence of acid and silane compounds, carrying out reductive amination reaction on a compound shown as a formula C11 and a compound shown as a formula C10 to obtain a compound shown as a formula C12;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C12, the conditions and the operation of the reductive amination reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula C11, which comprises the following steps: in an organic solvent, in the presence of an oxidant, carrying out the following oxidation reaction on a compound shown as a formula C9 to obtain a compound shown as a formula C11;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C11, the conditions and the operation of the oxidation reaction are the same as those of the reaction.
The invention provides a preparation method of a compound shown as a formula C9, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out methylation reaction shown in the following formula 8 with a methylation reagent to obtain the compound shown in the formula C9;
wherein R is 1 、R 2 、R 3 And R is 4 As in any of the preceding schemes.
In the preparation method of the compound shown as the formula C9, the condition and the operation of the methylation reaction are the same as those of the reaction.
The invention also provides a preparation method of the compound shown in the formula I-1, and the synthetic route can be any one of the following routes 1 to 4:
route 1
Route 2
Route 3
Route 4
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The reaction conditions and operations in any of the above-mentioned schemes 1 to 4 are the same as those in the above-mentioned scheme.
The invention also provides a preparation method of the compound shown as the formula 7-1 or the formula 8-1,
wherein, the synthetic route of the compound shown in the formula 7-1 is as follows:
the synthetic route of the compound shown in the formula 8-1 is as follows:
the conditions and operations of any reaction in the synthetic route of the compound shown in the formula 7-1 or the formula 8-1 are the same as those of the reaction.
The present invention also provides a compound of the formula:
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wherein R is 1 、R 2 、R 3 、R 4 、X 1 And X 2 As in any of the preceding schemes.
The present invention also provides a compound of the formula:
the invention provides a crystal form of a compound 7a-1 or a compound 8a-1,
the space group of the crystal form of the compound 7a-1 is P21 21 21, and the unit cell parameter isα＝90°；/>β＝90°；/>γ＝90°；
Preferably, the crystal form 7a-1 belongs to an orthorhombic system, the space group is P21 21 21, and the unit cell parameters are α＝90°；/>β＝90°；/>γ=90°; unit cell volume of The number of asymmetric units in the unit cell z=4;
more preferably, the crystal form parameters of the compound 7a-1 are those in Table 1;
the space group of the crystal form of the compound 8a-1 is P21 21 21, and the unit cell parameter isα＝90°；/>β＝90°；/>γ＝90°；
Preferably, the crystal form of 8a-1 belongs to an orthorhombic system, the space group is P21 21 21, and the unit cell parameters are α＝90°；/>β＝90°；/>γ=90°; unit cell volume ofThe number of asymmetric units in the unit cell z=4;
more preferably, the crystal form parameter of 8a-1 is the parameter in Table 2;
table 1 Crystal form data of Compound 7a-1
TABLE 2 Crystal form data for Compound 8a-1
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Unless otherwise stated, the temperature is usually at room temperature, and in the present invention, room temperature is 20 to 30 ℃.
Unless specifically emphasized, "h" in the present invention refers to hours.
Unless specifically emphasized, "min" or "mins" in the present invention refers to minutes.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available unless otherwise specified.
The invention has the positive progress effects that:
the invention provides a brand-new method for preparing the oxazepan spiro compound and the intermediate thereof, which is simple and convenient to operate, and the synthesized oxazepan spiro compound and the intermediate thereof have better stereoselectivity.
Drawings
FIG. 1 is a single crystal diffraction pattern of compound 7 a-1.
FIG. 2 is a single crystal diffraction pattern of compound 8 a-1.
Detailed Description
For a better understanding of the present invention, reference will be made to the following description of specific examples. It should be understood that the following specific examples are illustrative of the present invention and are not intended to be limiting.
Example 1
Pd (ACN) was added to a toluene solution (5L) of the compound of formula 1-1 (3 kg,14.3 mol), the compound of formula A (2.7 kg,15.8 mol) under nitrogen 2 Cl 2 (29.7g,0.115mol)，Cy 2 NMe (5.6 kg,28.7 mol) and tri (o-tolyl) phosphine (236 g,1.43 mol), heating and stirring the reaction system at 110+ -5deg.C, cooling to room temperature after the reaction, adding HCl aqueous solution for washing, extracting the washing solution with tert-butyl methyl ether for 3 The organic phases were combined, washed with saturated sodium chloride, dried, column chromatographed, and eluted with a mixture of petroleum ether and ethyl acetate, the acceptable fractions were collected and concentrated to give the compound of formula 2-1 in a yield of about 2.5kg, about 58%.
Compounds of formula 2-1 1 H-NMR(400MHz,CDCl 3 )δ7.19-7.32(m,2H),6.94-7.02(t,J＝8.0Hz,1H),6.59(d,J＝16.0Hz,1H),6.18-6.32(m,1H),3.74(s,6H),3.54(t,J＝7.2Hz,1H),2.83(t,J＝7.2Hz,2H)
Example 2
Pd (ACN) in example 1 2 Cl 2 Change to Pd (pph) 3 ) 2 Cl 2 Tri (o-tolyl) phosphine is replaced by triphenylphosphine, cy 2 Nme to Et 3 N, toluene was changed to 1, 4-dioxane, and the yield of the compound of formula 2-1 was 35% under the same conditions as in example 1.
Example 3
Pd (ACN) in example 1 2 Cl 2 Change to Pd (pph) 3 ) 4 Tri (o-tolyl) phosphine is replaced by tri-o-methoxy triphenylphosphine, cy 2 Nme to Et 3 N, the other conditions were the same as in example 1, and the yield of the compound of formula 2-1 was 45%.
Example 4
To the autoclave, the compound of formula 2-1 (150 g,0.5 mol), ethyl acetate (44.9 g,0.748 mol), and 5% Pd/C (7.5 g), acetic acid (44.9 g,0.748 mol) were added in this order, and after replacing the nitrogen several times, hydrogen (50 psi) was introduced, and the reaction was carried out at 30℃for 0.5 hours, and after the completion of the reaction, filtration and concentration were carried out, to obtain about 136g of the compound of formula 3-1 in 90% yield.
Compounds of formula 3-1 1 H-NMR(400MHz,CDCl 3 )δ7.23(s,1H),7.03-7.09(m,1H),6.96-7.02(m,1H),3.73(s,6H),3.39(t,J＝7.6Hz,1H),2.69(t,J＝7.61Hz,2H),1.89-2.01(m,2H),1.58-1.70(m,2H).
Example 5
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was used in an amount of 1.5 times equivalent to the compound of formula 2-1, the mass of 5% Pd/C was 5% of the mass of the compound of formula 2-1, the reaction temperature was 50℃and the reaction was carried out for 8 hours, the other conditions being the same as in example 4. The reaction was complete and LCMS monitoring showed 1.0% dehalogenated impurities.
Example 6
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was used in an amount of 1.5 times equivalent to the compound of formula 2-1, the mass of 5% Pd/C was 5% of the mass of the compound of formula 2-1, the reaction temperature was 50℃and the reaction was carried out for 2 hours, and the other conditions were the same as in example 4. The reaction was complete and LCMS monitoring showed 1.0% dehalogenated impurities.
Example 7
The compound of formula 2-1 in example 4 was changed to 20g, acetic acid was used in an amount of 1.5 times equivalent to the compound of formula 2-1, and the mass of 5% Pd/C was 5% of the mass of the compound of formula 2-1, with the other conditions being the same as in example 4. The reaction was complete and LCMS monitoring showed 0.3% dehalogenated impurities.
Example 8
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, the mass of 5% Pd/C was 5% of the mass of the compound of formula 2-1, the reaction temperature was 50℃and the reaction was carried out for 1 hour, and the other conditions were the same as in example 4. The reaction was complete and LCMS monitoring showed 1.0% dehalogenated impurities.
Example 9
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, the mass of 5% Pd/C was 5% of the mass of the compound of formula 2-1, the hydrogen pressure was 30psi, and the reaction was carried out for 1 hour, the other conditions being the same as in example 4. The reaction was complete and LCMS monitoring showed 0.4% dehalogenated impurities.
Example 10
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, and the mass of 5% Pd/C was 2% of the mass of the compound of formula 2-1, and the reaction was carried out for 1 hour, with the other conditions being the same as in example 4. The reaction was complete and LCMS monitoring showed 2.3% dehalogenated impurities.
Example 11
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, the mass of 5% Pd/C was 2% of the mass of the compound of formula 2-1, the hydrogen pressure was 30psi, and the reaction was carried out for 2 hours under the same conditions as in example 4. The reaction was complete and LCMS monitoring showed 0.1% dehalogenated impurities.
Example 12
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, the mass of 5% Pd/C was 2% of the mass of the compound of formula 2-1, the hydrogen pressure was 15psi, and the reaction was carried out for 2 hours under the same conditions as in example 4. The reaction was complete and LCMS monitoring showed 0.17% dehalogenated impurities.
Example 13
The compound of formula 2-1 in example 4 was changed to 10g, acetic acid was not added, the mass of 5% Pd/C was 2% of the mass of the compound of formula 2-1, the hydrogen pressure was 15psi, the reaction temperature was 15℃and the reaction was carried out for 2 hours, and the other conditions were the same as in example 4. The reaction was complete and LCMS monitoring showed no dehalogenated impurities.
Example 14
Copper acetate (997 g,5.49 mol), manganese acetate (3.68 kg,13.7 mol) and acetic acid (13L) are sequentially added into a reaction kettle under the protection of nitrogen, an acetic acid solution of a compound (1.8 kg,5.49 mol) of formula 3-1 is added after nitrogen is replaced for a plurality of times, the reaction solution is stirred for 12 hours at 95 ℃, after the reaction is finished, the mixture is concentrated, tert-butyl methyl ether and water are added, layering is carried out, a water layer is extracted by the tert-butyl methyl ether, an organic layer after combination is washed by alkali, drying and concentration are carried out, and 1.7kg of the compound of formula 4-1 is obtained, and the yield is 95%.
Compounds of formula 4-1 1 H-NMR(400MHz,CDCl 3 )δ7.18-7.25(m,1H),7.10-7.16(m,1H),3.77(s,6H),2.79(t,J＝6.8Hz,2H),2.37-2.44(m,2H),1.80-1.88(m,2H).
Example 15
Sequentially adding a compound (100 g,0.33 mol) of formula 4-1, ethanol (1300 mL), mechanically stirring, controlling the temperature to be minus 10 ℃, starting to slowly dropwise add 800mL of aqueous solution of potassium hydroxide (53.4 g,0.95 mol), controlling the temperature below 0 ℃, after about 2h dropwise addition, raising the temperature to 20 ℃ for 2h-3h, after the reaction is finished, reducing the temperature to minus 5 ℃, slowly dropwise adding 1N HCl (about 1000 mL), adjusting the pH to about 1-2, adding 600mL of dichloromethane, extracting for 3 times, merging organic layers, adding saturated saline for washing, drying, concentrating, and obtaining 92.56g of the compound of formula 5-1, wherein the yield is 97%.
Compounds of formula 5-1 1 H-NMR(400MHz,DMSO-d 6 )δ13.43(s,1H),7.45–7.35(m,1H),7.23-7.15(m,1H),3.69(s,3H),2.80-2.65(m,2H),2.37–2.18(m,2H),1.86–1.63(m,2H).
Example 16
The reaction temperature in example 15 was changed to 0-5℃and the reaction was carried out for 2 hours under the same conditions as in example 15, except that the yield of the compound of formula 5-1 was 67%.
Example 17
Sequentially adding a compound (91.4 g,0.32 mol) of formula 5-1, isopropanol (900 mL), stirring thoroughly, slowly dropwise adding 320mL of THF solution of 2M lithium borohydride (320 mL,0.64 mol) at a temperature lower than-10 ℃, controlling the temperature lower than 0 ℃, keeping the temperature at 0+ -2 ℃ after the dropwise addition is finished, reacting for 0.5h, then heating to 20 ℃, continuing the reaction for 2h, reducing the temperature to-5 ℃ after the reaction is finished, slowly dropwise adding 1N HCl (about 750 mL), adjusting the pH to about 1-2, adding 1L ethyl acetate, washing with 1L water, separating the liquid, extracting the water layer with ethyl acetate continuously (500 mL×2 times), merging the organic layers, adding saturated saline for washing, drying, concentrating to obtain 74.2g of the compound of formula 6-1, and obtaining the compound with the yield of 90%.
Compounds of formula 6-1 1 H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H)
Example 18
The lithium borohydride in example 17 was replaced by BH 3 ·Me 2 S was used in an amount of 1.2 equivalents of the compound of formula 5-1, and reacted at 25℃for 7 hours, the other conditions were the same as in example 17, and the yield of the compound of formula 6-1 was 40%.
Example 19
The solvent in example 17 was changed to isopropyl alcohol and reacted at 25℃for 1 hour, and the other conditions were the same as in example 17, except that the yield of the compound of formula 6-1 was 82%.
Example 20
The solvent in example 17 was changed to isopropyl alcohol and reacted at 0℃for 6 hours, and the other conditions were the same as in example 17, except that the yield of the compound of formula 6-1 was 70%.
Example 21
The compound of formula 6-1 (86.5 g,0.335 mol), ethyl acetate (450 mL) was added sequentially, stirred at room temperature, and (R) -1- (1-naphthyl) ethylamine (57.4 g,0.335 mol) was added dropwise to the above system, stirring at room temperature was continued, a large amount of solid was instantaneously precipitated, stirring at room temperature for 3h, suction filtration, and the filter cake was dried under vacuum to obtain compound 7a-1.
Post-treatment of the compound 7a-1, recrystallizing the dried compound 7a-1 with a mixed solvent of ethanol and water (10 v:1 v), adding hydrochloric acid hydrolysis salt, and releasing to obtain the compound of formula 7-1, wherein the yield is 20% and the Ee value is 99%.
Compounds of formula 7-1 1 H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H)
According to the same manner as that described above, (S) -1- (1-naphthyl) ethylamine (57.4 g,0.335 mol) was added for resolution to give compound 8a-1, which was free to give the compound of formula 8-1 in a yield of 19% and Ee value of 100%.
Compounds of formula 8-1 1 H-NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.35-7.32(m,2H),4.98(s,1H),3.81(d,J＝10.6Hz,1H),3.66(d,J＝10.6Hz,1H),2.79–2.57(m,2H),2.15-2.05(m,1H),1.94-1.68(m,3H).
The Ee values were determined by HPLC and the test conditions are shown in table 3 below:
TABLE 3 Table 3
Example 22: single crystal diffraction experiment of Compound 7a-1 and Compound 8a-1
1. And (3) crystal form culture:
compound 7a-1: 10mg of compound 7a-1 and 10 mu L of ethanol are added into a 5ml test tube, the mixture is filtered, and the mixture is left to stand for crystallization for 4 days, single crystals are separated out, and the single crystals are collected for single crystal diffraction test.
Compound 8a-1: 10mg of Compound 8a-1 was added to a 5ml test tube, 10. Mu.L of DMSO was dissolved, and the mixture was placed in a jar with an appropriate amount of n-heptane, allowed to stand for 4 days, and single crystals were precipitated, and collected for single crystal diffraction test.
2. Crystal form parameters: see tables 1 and 2 above.
3. Experimental results: the compound 7a-1 has an R configuration (the crystal structure is shown in figure 1), the compound 8a-1 has an S configuration (the crystal structure is shown in figure 2), and thus the compound 7-1 has an R configuration and the compound 8-1 has an S configuration.
Example 23
NaH (1.9 g) and 50mL DMF were weighed and transferred into a reaction flask, N 2 Replacing three times, magnetically stirring, controlling the temperature below 0deg.C, adding compound (6 g) of formula 7-1, and stirring for 0.5h. Weighing tert-butyl 4-fluoro-3-nitrobenzoate (6.86 g), dissolving in 22mL DMF for use, dropwise adding DMF reaction solution at 0+ -2deg.C, magnetically stirring for 2 hr, detecting reaction, pouring into 50mL ice water after reaction, stirring for 5min, adjusting pH to 3-4 with 1N HCl, washing water layer with 50mL ethyl acetate×3, mixing organic layers, drying, filtering, concentrating To dryness, 14.92g of crude product was obtained, and column chromatography gave 7.84g of pure product in 70% yield.
Compounds of formula B10-1 1 H-NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.29(d,J＝2.2Hz,1H),8.10(dd,J＝8.8,2.2Hz,1H),7.52(d,J＝8.9Hz,1H),7.38(t,J＝8.1Hz,1H),7.30(d,J＝8.6Hz,1H),4.63(d,J＝9.5Hz,1H),4.49(d,J＝9.5Hz,1H),2.81-2.69(m,2H),2.30–2.16(m,1H),2.14–2.02(m,1H)，1.88-1.83(m,2H),1.55(s,9H).
Example 24
Transferring 80mL DME (7.8 g,16.3 mmol) of the compound of formula B10-1 into a reaction bottle, magnetically stirring, controlling the reaction temperature to be-5-0 ℃, dropwise adding N-methylmorpholine (1.82 g,18 mmol) into the reaction bottle, controlling the reaction temperature to be-5-0 ℃ after the dropwise adding, and controlling the isobutyl chloroformate (ClCO) 2 iBu,2.45 g) was added dropwise to the reaction system, and after the completion of the addition, the mixture was stirred thoroughly for 2 hours to obtain NaBH 4 (0.68 g) is dissolved in 2.5g of water, slowly added into a reaction system in a dropwise manner, the reaction temperature is controlled to be-5 ℃ to 0 ℃, magnetic stirring is carried out for 2 hours, detection reaction is carried out, 100ml of ice water is poured into the reaction system for quenching after the reaction is finished, 50ml of ethyl acetate multiplied by 3 is used for washing a water layer, the organic layers are combined, dried, filtered, concentrated to be dry, and column chromatography is carried out to obtain 5.38g, and the yield is 71%.
Compounds of formula B11-1 1 H-NMR(400MHz,DMSO-d6)δ8.29(d,J＝2.2Hz,1H),8.10(dd,J＝8.8,2.2Hz,1H),7.45(t,J＝8.4Hz,2H),7.30(t,J＝8.2Hz,1H),5.00(t,J＝5.3Hz,1H),4.41–4.26(m,2H),,3.64(d,J＝5.0Hz,2H),2.74-2.63(m,2H),1.94–1.83(m,4H),1.54(s,9H).
Example 25
The compound of formula B11-1 (8.9 g), 100mL DCM was transferred to a reaction flask, magnetically stirred, cooled below 0deg.C in an ice bath, DMP oxidant (12.18 g) was added, and the ice bath was removedStirring for 1 hr, filtering with diatomite, and sequentially adding saturated Na 2 S 2 O 3 And saturated NaHCO 3 The mixed solution (1:1) was washed 2 times, saturated saline was washed 1 time, and the organic phase was concentrated to give 8.70g of crude product for use in the next reaction.
Compounds of formula B12-1 1 H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.31(d,J＝2.2Hz,1H),8.12(dd,J＝8.8,2.2Hz,1H),7.53(d,J＝8.9Hz,1H),7.45(t,J＝8.1Hz,1H),7.22-7.20(m,1H),4.77(d,J＝9.6Hz,1H),4.53(d,J＝9.6Hz,1H),2.80-2.70(m,2H),2.25-2.15(m,,1H),2.03-1.95(m,1H),1.94–1.84(m,1H),1.83–1.74(m,1H),1.55(s,9H).
Example 26
The compound (8 g,0.017 mol) of the formula B12-1, 160mL of acetic acid is transferred into a reaction bottle, the mechanical stirring is carried out, iron powder (4.8 g,0.086 mol) is added, the stirring is carried out for 3 hours at the temperature of 70-75 ℃, the temperature is reduced to room temperature after the reaction is finished, DCM is added, diatomite is stirred for filtration, a filter cake is washed by DCM, 12.1g of crude product is obtained after spinning, and the crude product is directly participated in the next reaction without purification.
Example 27
Transferring the compound of formula B13-1 (7.5 g,0.017 mol) and THF (90 mL) into a reaction flask, magnetically stirring at room temperature, sequentially adding trifluoroacetic acid (20 mL) and phenylsilane (8.4 g,0.078 mol), reacting for 1h, detecting reaction, drying the solvent after reaction, dissolving the solid with 350mL DCM, sequentially adding saturated NaHCO respectively 3 Washing for 2 times, washing with saturated saline solution for 1 time, spin-drying the organic layer to obtain 9.7g of crude product, and purifying to obtain 5.29g of product (total yield of the last three steps is 73.4%).
Compounds of formula I-1 1 H-NMR(400MHz,DMSO-d6)δ7.69(dd,J＝8.6,1.2Hz,1H),7.42(t,J＝8.3Hz,1H),7.33(d,J＝2.1Hz,1H),7.15(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.06(s,1H),4.16–4.06(m,2H),3.35–3.18(m,2H),2.78-2.58(m,2H),1.86–1.71(m,3H),1.60-1.54(m,1H),1.51(s,9H).
Example 28
The compound of formula 8-1 (7 g,0.027 mol), 140mL of DMF was transferred into a reaction flask, stirred at room temperature, potassium carbonate (6.4 g,0.046 mol) was added, stirred at room temperature for 0.5h, methyl iodide (4.62 g,0.033 mol) was added dropwise to the reaction flask, stirred at room temperature for 3h, the reaction was checked, and after completion of the reaction, 1N HCl was added to quench the reaction, 50mL of EA×3 extract aqueous layer was added, the organic layers were combined, dried, filtered, and the filtrate was concentrated to give 7.62g of crude product, which was directly used for the next reaction without purification.
Compounds of formula C9-1 1 H-NMR(400MHz,DMSO-d6)δ7.40-7.20(m,2H),3.90-3.70(m,1H),3.70-3.64(m,1H),3.60(s,3H),2.82-2.57(m,2H),2.20-2.00(m,1H),1.92–1.60(m,3H).
Example 29
The compound of formula C9-1 (7.4 g,0.027 mol), 150mL DCM was transferred into a reaction flask, stirred at room temperature, DMP (17.2 g,0.04 mol) was added, stirred at room temperature, and after completion of the reaction (Na 2 S 2 O 3 ：NaHCO 3 ) The solution was mixed, stirred for 20min, separated, 50ml of EA×3 extract water layer was added, the organic layers were combined, dried, filtered, and the filtrate was concentrated to give 7.0g of crude product, and column chromatography gave 5.45g of pure product, with a total yield of 74% in two steps, based on the compound of formula 8-1.
Compounds of formula C11-1 1 H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),7.51–7.42(m,1H),7.10-7.03(m,1H),3.71(s,3H),2.80-2.63(m,2H),2.35-2.25(m,1H),2.23-2.10(m,1H),1.86-1.74(m,1H),1.65-1.55(m,1H).
Example 30
The compound of formula C11-1 (5 g,0.018 mol), 30mL of THF was transferred into a reaction flask, stirred at room temperature, 3-amino-4 fluorobenzoic acid tert-butyl ester (4.7 g,0.022 mol), 30mL of THF, 15mL of trifluoroacetic acid, phenylsilane (10 g,0.0926 mol) were sequentially added, stirred at room temperature overnight (about 18 h), the reaction was detected, 100mL of water was added to quench after the reaction was completed, 100mL of EA×3 extract water layer was added, the organic layers were combined, dried, filtered, and the filtrate was concentrated, and the pure product of 8.62g was obtained by column chromatography in 100% yield.
Compounds of formula C12-1 1 H-NMR(400MHz,DMSO-d6)δ7.35-7.25(m,1H),7.23–7.04(m,4H),5.45-5.30(m,1H),3.82-3.73(m,2H),3.60(s,3H),2.82-2.74(m,2H),2.25-2.15(m,1H),2.04–1.92(m,1H),1.90-1.75(m,2H),1.51(s,9H).
Example 31
The compound of formula C12-1 (8.5 g,18.3 mmol), 90mL of IPA was transferred to a reaction flask, stirred at room temperature and LiBH was added dropwise 4 Tetrahydrofuran solution (36.4 mmol,18.2 mL), heating and refluxing for 3h, detecting reaction, and after the reaction is finished, 150ml of water is added for quenching, stirring is carried out for 10min, 100ml of EA×3 extraction water layer is added, the organic layers are combined, dried, filtered, and filtrate is concentrated to obtain crude product 10.8g, and column chromatography is carried out to obtain pure product 6.6g with yield of 84%.
Compounds of formula C13-1 1 H-NMR(400MHz,DMSO-d 6 )δ7.33-7.20(m,2H),7.16–7.04(m,3H),5.37-5.30(m,1H),5.12-5.03(m,1H),3.65–3.50(m,2H),3.45-3.35(m,2H),2.80-2.60(m,2H),2.05-1.95(m,1H),1.90-1.70(m,5H),1.50(s,9H).
Example 32
The compound of formula C13-1 (6.5 g,0.015 mol), 130mL DMSO was transferred to a reaction flask, stirred at room temperature, and Cs was added 2 CO 3 (9.7 g,0.03 mol), stirring overnight (15 h) at 90 ℃, detecting reaction, adding 100ml H2O,100ml EA extract liquid after the reaction is finished, adding 100ml of EA×3 extract water layer, merging organic layers, drying, filtering, concentrating filtrate to obtain crude product 5.90g, and obtaining pure product 3.72g by column chromatography with the yield of 60%.
Compounds of formula I-1 1 H-NMR(400MHz,DMSO-d6)δ7.69(dd,J＝8.6,1.2Hz,1H),7.42(t,J＝8.3Hz,1H),7.33(d,J＝2.1Hz,1H),7.15(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.06(s,1H),4.16–4.06(m,2H),3.35–3.18(m,2H),2.78-2.58(m,2H),1.86–1.71(m,3H),1.60-1.54(m,1H),1.51(s,9H).
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (44)

1. A method for preparing a compound shown as a formula 7a or a formula 8a is characterized in that,
the preparation method of the compound shown in the formula 7a comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 1 The salt forming reaction shown below is carried out; wherein X is 1 Chiral resolving agents in the R configuration;
the preparation method of the compound shown in the formula 8a comprises the following steps: in an organic solvent, a compound shown as a formula 6 and a chiral resolving agent X 2 The salt forming reaction shown below is carried out; wherein X is 2 Chiral resolving agent with S configuration;
wherein R is 1 、R 2 、R 3 And R is 4 Independently hydrogen, hydroxy, cyano, amino, nitro, aldehyde, halogen, C 1 -C 4 Alkyl, R of (2) 1-1 Substituted C 1 -C 4 Alkyl, C of (2) 1 -C 4 Haloalkyl radicals R of (2) 1-2 Substituted C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, R 1-3 Substituted C 1 -C 4 or-C (=O) R 1-4 ；
R 1-1 、R 1-2 、R 1-3 And R is 1-4 Independently is hydroxy, C 1 -C 4 Alkyl, C of (2) 1 -C 4 Alkoxy, C 3 -C 5 Cycloalkyl or NR of (C) 1- 1a R 1-1b ；
R 1-1a And R is 1-1b Independently hydrogen or C 1 -C 4 Is a hydrocarbon group.
2. The process for producing a compound of formula 7a or 8a according to claim 1, wherein R 1 、R 2 、R 3 And R is 4 Independently hydrogen and halogen;
and/or the chiral resolving agent with R configuration is an amine chiral resolving agent with R configuration;
and/or the chiral resolving agent with S configuration is an amine chiral resolving agent with S configuration;
and/or the organic solvent is C 1 -C 4 Alcohol solvents and/or ester solvents;
and/or the mol ratio of the compound shown in the formula 6 to the chiral resolving agent is 1:1-1:5;
and/or the mass-to-volume ratio of the compound shown in the formula 6 to the organic solvent is 1:1-1:10 g/mL;
and/or, the temperature of the salification reaction is 20-30 ℃;
And/or the salification reaction time is 1-5h.
3. The method for preparing the compound shown in the formula 7a or the formula 8a according to claim 2, wherein the chiral resolving agent with R configuration is (R) -1- (1-naphthyl) -ethylamine, (R) -phenethylamine, (R) -phenylalaninol, (R) -N-benzyl phenethylamine or (R) -quinidine;
and/or the chiral resolving agent with S configuration is (S) -1- (1-naphthyl) -ethylamine, (S) -phenethylamine, (S) -phenylalaninol, (S) -N-benzyl phenethylamine or (S) -quinidine;
and/or the organic solvent is an ester solvent;
and/or the mol ratio of the compound shown in the formula 6 to the chiral resolving agent is 1:1-1:3;
and/or the mass-volume ratio of the compound shown in the formula 6 to the organic solvent is 1:1-1:6 g/mL.
4. The method for preparing the compound shown in the formula 7a or the formula 8a according to claim 2, wherein the chiral resolving agent with R configuration is (R) -1-naphthyl) -ethylamine;
and/or the chiral resolving agent with S configuration is (S) -1- (1-naphthyl) -ethylamine;
and/or, the C 1 -C 4 The alcohol solvent is one or more of methanol, ethanol and isopropanol;
and/or the ester solvent is ethyl acetate;
And/or the mol ratio of the compound shown in the formula 6 to the chiral resolving agent is 1:1-1:1.5.
5. The method for preparing the compound shown in formula 7a or formula 8a according to claim 1, wherein the method for preparing the compound shown in formula 6 comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown in the formula 5;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
6. The method for producing a compound of formula 7a or 8a according to claim 5, wherein the organic solvent is C 1 -C 4 One or more of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents and sulfoxide solvents;
and/or the reducing agent is an alkali metal hydride;
and/or the mass-to-volume ratio of the compound shown in the formula 5 to the organic solvent is 1:10-1:20 g/mL;
and/or the mol ratio of the compound shown in the formula 5 to the reducing agent is 1:1-1:5;
and/or, the temperature of the reduction reaction is-5-30 ℃;
and/or the time of the reduction reaction is 1-3h.
7. The method for producing a compound of formula 7a or 8a according to claim 6, wherein the organic solvent is C 1 -C 4 Alcohol solvents of (2);
and/or the reducing agent is one or more of lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride, sodium thioborohydride and lithium tri-sec-butylborohydride; and/or the mass-to-volume ratio of the compound shown in the formula 5 to the organic solvent is 1:10-1:15 g/mL;
and/or the mol ratio of the compound shown in the formula 5 to the reducing agent is 1:1-1:2;
and/or the temperature of the reduction reaction is 20-30 ℃.
8. The method for producing a compound of formula 7a or 8a according to claim 6, wherein C 1 -C 4 The alcohol solvent is one or more of methanol, ethanol and isopropanol;
and/or the ester solvent is ethyl acetate;
and/or the ether solvent is diethyl ether and/or tetrahydrofuran;
and/or the ketone solvent is acetone and/or 2-butanone;
and/or the nitrile solvent is acetonitrile;
and/or the amide solvent is N, N-dimethylformamide;
And/or the sulfoxide solvent is dimethyl sulfoxide;
and/or the reducing agent is one or more of lithium borohydride, sodium borohydride and potassium borohydride.
9. The method for producing a compound of formula 7a or 8a according to claim 8, wherein C 1 -C 4 The alcohol solvent of (2) is isopropanol;
and/or the reducing agent is lithium borohydride.
10. The method for preparing the compound shown in formula 7a or formula 8a according to claim 5, wherein the method for preparing the compound shown in formula 5 comprises the following steps: in a solvent, in the presence of alkali, carrying out hydrolysis reaction of the compound shown in the formula 4;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
11. The method of claim 10, wherein the compound is represented by formula 7a or formula 8aThe preparation method of the compound is characterized in that the solvent is C 1 -C 4 One or more of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, or sulfoxide solvents;
and/or, the alkali is inorganic alkali;
and/or the mass-to-volume ratio of the compound shown in the formula 4 to the solvent is 1:1-1:20 g/mL;
And/or the molar ratio of the compound shown as the formula 4 to the alkali is 1:1-1:5;
and/or, the temperature of the hydrolysis reaction is-5-30 ℃;
and/or the hydrolysis reaction time is 1-3h.
12. The method for producing a compound of formula 7a or 8a according to claim 11, wherein the solvent is C 1 -C 4 Alcohol solvents of (2);
and/or the inorganic base is alkali metal carbonate and/or alkali metal hydroxide;
and/or the mass-to-volume ratio of the compound shown in the formula 4 to the solvent is 1:5-1:13 g/mL;
and/or the molar ratio of the compound shown as the formula 4 to the alkali is 1:1-1:3;
and/or the temperature of the hydrolysis reaction is 20-30 ℃;
and/or the hydrolysis reaction time is 2-3h.
13. The method for producing a compound of formula 7a or 8a according to claim 11, wherein C 1 -C 4 The alcohol solvent is one or more of methanol, ethanol and isopropanol;
and/or the ester solvent is ethyl acetate;
and/or the ether solvent is diethyl ether and/or tetrahydrofuran;
and/or the ketone solvent is acetone and/or 2-butanone;
And/or the nitrile solvent is acetonitrile;
and/or the amide solvent is N, N-dimethylformamide;
and/or the sulfoxide solvent is dimethyl sulfoxide;
and/or the inorganic base is an alkali metal hydroxide.
14. The method for producing a compound of formula 7a or 8a according to claim 12, wherein C 1 -C 4 The alcohol solvent of (2) is ethanol;
and/or, the alkali metal carbonate is K 2 CO 3 And/or Cs 2 CO 3 ；
And/or the alkali metal hydroxide is one or more of LiOH, naOH and KOH.
15. The method for preparing the compound represented by formula 7a or formula 8a according to claim 10, wherein the method for preparing the compound represented by formula 4 comprises the steps of: in the presence of acid and oxidant under the atmosphere of protective gas, carrying out intramolecular cyclization reaction on the compound shown in the formula 3;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
16. The method for preparing the compound of formula 7a or formula 8a according to claim 15, wherein the method for preparing the compound of formula 3 comprises the steps of: in an organic solvent, in the presence of a metal catalyst, carrying out the reduction reaction of the compound shown in the formula 2 and hydrogen as shown below;
Wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
17. The method for preparing a compound of formula 7a or 8a as claimed in claim 16, wherein the organic solvent is C 1 -C 4 One or more of an alcohol solvent, an ester solvent and an ether solvent;
and/or the metal catalyst is Pd/C, pd (OH) 2 Raney nickel, pt/C and PtO 2 One or more of the following;
and/or the mass-to-volume ratio of the compound shown as the formula 2 to the organic solvent is 1:1-10:1 g/mL;
and/or the mass ratio of the compound shown as the formula 2 to the metal catalyst is 10:1-100:1;
and/or, the hydrogen gas pressure is 14.5-72.5psi;
and/or the temperature of the reduction reaction is 20-50 ℃;
and/or the time of the reduction reaction is 0.5-8h;
and/or the reduction reaction is carried out in the presence of an acid, wherein the acid is an organic acid and/or an inorganic acid.
18. The method for preparing a compound represented by formula 7a or formula 8a according to claim 17, wherein the organic solvent is an ester solvent;
and/or the metal catalyst is Pd/C;
and/or the mass-to-volume ratio of the compound shown as the formula 2 to the organic solvent is 1:1-8:1 g/mL;
And/or the mass ratio of the compound shown as the formula 2 to the metal catalyst is 20:1-100:1;
and/or, the hydrogen gas pressure is 15-50psi;
and/or, the temperature of the reduction reaction is 15-30 ℃;
and/or the time of the reduction reaction is 0.5-5h;
and/or the organic acid is formic acid and/or acetic acid;
and/or the inorganic acid is one or more of hydrochloric acid, sulfuric acid and phosphoric acid;
and/or the molar ratio of the compound shown as the formula 2 to the acid is 1:1-1:2.
19. The method for producing a compound of formula 7a or 8a according to claim 17, wherein C 1 -C 4 The alcohol solvent is one or more of methanol, ethanol and isopropanol;
and/or the ester solvent is ethyl acetate;
and/or the ether solvent is diethyl ether and/or tetrahydrofuran;
and/or the mass-to-volume ratio of the compound shown as the formula 2 to the organic solvent is 1:1-5:1 g/mL;
and/or the molar ratio of the compound shown as the formula 2 to the acid is 1:1-1:1.5.
20. The method for preparing the compound of formula 7a or formula 8a according to claim 16, wherein the method for preparing the compound of formula 2 comprises the steps of: in the presence of alkali and a catalyst in an organic solvent under the atmosphere of protective gas, performing the coupling reaction of a compound shown in a formula 1 and a compound shown in a formula A as follows; the catalyst comprises a ligand and a palladium compound;
Wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
21. The method for preparing a compound represented by formula 7a or formula 8a according to claim 20, wherein the shielding gas is nitrogen and/or argon;
and/or the organic solvent is one or more of an aromatic hydrocarbon solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, an ether solvent and a ketone solvent;
and/or, the alkali is organic alkali and/or inorganic alkali;
and/or the ligand is phosphine ligand; the phosphine ligand is one or more of a monodentate phosphine ligand, a bidentate phosphine ligand and a multidentate phosphine ligand;
and/or the palladium compound is zero-valent palladium and/or divalent palladium;
and/or the palladium compound and the ligand are added separately, the palladium compound and the ligand form a complex, or the palladium compound and the ligand form a complex first and then are added separately from the ligand; the ligands are independently phosphine ligands;
and/or the mol ratio of the compound shown in the formula 1 to the compound shown in the formula A is 1:1-1:3;
and/or the mass-to-volume ratio of the compound shown in the formula 1 to the organic solvent is 1:1-1:10 g/mL;
And/or the molar ratio of the compound shown as the formula 1 to the alkali is 1:1-1:5;
and/or the molar ratio of the compound shown as the formula 1 to the ligand is 1:1-10:1;
and/or, in the preparation method of the compound shown in the formula 2, the molar ratio of the compound shown in the formula 1 to the palladium compound is 10:1-1000:1;
and/or, the temperature of the coupling reaction is 90-110 ℃;
and/or the coupling reaction time is 8-20h.
22. The method for preparing a compound represented by formula 7a or 8a according to claim 21, wherein the organic solvent is an aromatic hydrocarbon solvent;
and/or the organic base is pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene, 1, 4-diazabicyclo [2.2.2]Octane, alkali metal alkoxide and its preparationOne or more of the following; r is R 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl or C of (2) 5 -C 6 Cycloalkyl of (c);
and/or the inorganic alkali is one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide;
and/or, the phosphine ligand is a monodentate phosphine ligand;
and/or the zero-valent palladium is Pd 2 (dba) 3 ；
And/or the divalent palladium is Pd (OAc) 2 、PdCl 2 、Pd(TFA) 2 And Pd (MeCN) 2 Cl 2 One or more of the following;
and/or the mol ratio of the compound shown in the formula 1 to the compound shown in the formula A is 1:1-1:2;
and/or the mass-to-volume ratio of the compound shown in the formula 1 to the organic solvent is 1:1-1:5 g/mL;
and/or the molar ratio of the compound shown as the formula 1 to the alkali is 1:1-1:3;
and/or the molar ratio of the compound shown as the formula 1 to the ligand is 1.25:1-10:1;
and/or the molar ratio of the compound shown as the formula 1 to the palladium compound is 100:1-1000:1;
and/or the coupling reaction time is 8-12h.
23. The method for preparing a compound represented by formula 7a or 8a according to claim 21, wherein the aromatic solvent is toluene and/or xylene;
and/or the nitrile solvent is acetonitrile;
and/or the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
and/or the sulfoxide solvent is dimethyl sulfoxide;
and/or the ether solvent is tetrahydrofuran and/or 1, 4-dioxane;
and/or, the ketone solvent is N-methyl pyrrolidone;
And/or the organic base isR 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl or C of (2) 5 -C 6 Cycloalkyl of (c);
and/or the monodentate phosphine ligand is one or more of triphenylphosphine, tris (2-tolyl) phosphine, tris (3-tolyl) phosphine, tri-p-tolyl phosphine, tris (4-fluorophenyl) phosphine, tris (2-methoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine and 2- (di-t-butylphosphine) biphenyl;
and/or the multidentate phosphine ligand is
And/or the molar ratio of the compound shown as the formula 1 to the alkali is 1:1-1:2;
and/or the molar ratio of the compound shown as the formula 1 to the ligand is 2:1-10:1;
and/or the mol ratio of the compound shown in the formula 1 to the palladium compound is 100:1-500:1.
24. The method for preparing a compound of formula 7a or 8a according to claim 22, wherein the aromatic solvent is toluene;
and/or, the alkali metal alkoxideIs C 1 ～C 4 Alkali metal alkoxides of alcohols;
and/or, saidIs triethylamine and/or N-methyl dicyclohexylamine;
and/or, the alkali metal carbonate is K 2 CO 3 And/or Cs 2 CO 3 ；
And/or, the alkali metal hydride is NaH;
and/or the alkali metal hydroxide is NaOH and/or KOH;
And/or, the monodentate phosphine ligand is triphenylphosphine and/or tri (2-tolyl) phosphine.
25. The method for preparing a compound of formula 7a or 8a according to claim 24, wherein the alkali metal alkoxide is potassium butoxide and/or sodium tert-butoxide.
26. The method according to claim 21, wherein when the palladium compound and the ligand form a complex or the palladium compound and the ligand form a complex first and then are added separately from the ligand, the complex is a complex of zero-valent palladium and ligand and/or a complex of divalent palladium and ligand.
27. The method for preparing a compound of formula 7a or 8a according to claim 26, wherein when the palladium compound and the ligand form a complex, or the palladium compound and the ligand form a complex first and then are added separately from the ligand, the complex is Pd (PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 And/or Pd (dppf) Cl 2 。
28. A compound shown in formula 7 or formula 8The preparation method of (2) comprises the following steps: the compound shown in the formula 7a or 8a and acid are subjected to neutralization reaction shown below; wherein X is 1 Chiral resolving agents in the R configuration; x is X 2 Chiral resolving agent with S configuration; the preparation method of the compound shown in the formula 7a or the formula 8a is as defined in any one of claims 1 to 27;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
29. A preparation method of a compound shown as a formula I, which is a method I or a method II:
the method one comprises the following steps: in an organic solvent, in the presence of acid and silane compounds, carrying out reductive amination reaction on a compound shown as a formula B13;
the second method comprises the following steps: in an organic solvent, in the presence of alkali, carrying out ether forming reaction on a compound shown as a formula C13 as follows;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
30. The method of claim 29, wherein in method one, the organic solvent is C 1 -C 4 One or more of an alcohol solvent, an aromatic hydrocarbon solvent and an ether solventSeed;
and/or, in method one, the acid is an inorganic acid and/or an organic acid;
and/or in the first method, the silane compound is one or more of phenylsilane, diethylsilane, triethylsilane, trichlorosilane and diethoxymethylsilane;
And/or, in the first method, the mass-volume ratio of the compound shown as the formula B13 to the organic solvent is 1:1-1:20 g/mL;
and/or, in the first method, the mass-to-volume ratio of the compound shown as the formula B13 to the acid is 1:1-1:5 g/mL;
and/or, in the first method, the mol ratio of the compound shown as the formula B13 to the silane compound is 1:1-1:10;
and/or, in the first method, the temperature of the reductive amination reaction is 20-30 ℃;
and/or, in the first method, the reductive amination reaction time is 1-5h;
and/or in the second method, the organic solvent is one or more of an aromatic hydrocarbon solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, an ether solvent and a ketone solvent;
and/or, in the second method, the alkali is organic alkali and/or inorganic alkali;
and/or in the second method, the mass-volume ratio of the compound shown as the formula C13 to the organic solvent is 1:1-1:30 g/mL;
and/or, in the second method, the molar ratio of the compound shown as the formula C13 to the alkali is 1:1-1:5;
and/or, in the second method, the temperature of the ether forming reaction is 50-100 ℃;
And/or, in the second method, the time of the ether forming reaction is 1-20h.
31. The method of claim 30, wherein in method one, the compound of formula I is C 1 -C 4 The alcohol solvent is methanol, ethanol, n-propanol or isopropanolOne or more of propanol;
and/or, in the first method, the aromatic solvent is toluene and/or xylene;
and/or in the first method, the ether solvent is one or more of diethyl ether, tetrahydrofuran and 1, 4-dioxane;
and/or in the first method, the inorganic acid is one or more of hydrochloric acid, sulfuric acid and phosphoric acid;
and/or in the first method, the organic acid is one or more of formic acid, acetic acid and trifluoroacetic acid;
and/or in the first method, the silane compound is one or more of phenylsilane, diethylsilane and triethylsilane;
and/or, in the first method, the mass-volume ratio of the compound shown as the formula B13 to the organic solvent is 1:1-1:15 g/mL;
and/or, in the first method, the mass-to-volume ratio of the compound shown as the formula B13 to the acid is 1:1-1:3 g/mL;
and/or, in the first method, the mol ratio of the compound shown as the formula B13 to the silane compound is 1:1-1:5;
And/or, in the first method, the reductive amination reaction time is 1-3h;
and/or, in the second method, the aromatic solvent is toluene and/or xylene;
and/or, in the second method, the nitrile solvent is acetonitrile;
and/or in the second method, the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide;
and/or in the second method, the sulfoxide solvent is dimethyl sulfoxide;
and/or in the second method, the ether solvent is one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether;
and/or, in the second method, the ketone solvent is N-methyl pyrrolidone;
and/or, in method two, whereThe organic base is pyridine, piperidine, 1, 8-diazabicyclo undec-7-ene, 1, 4-diazabicyclo [2.2.2]Octane, alkali metal alkoxide and its preparationOne or more of the following; wherein R is 1a 、R 2a And R is 3a Independently hydrogen, C 1 ～C 4 Alkyl or C of (2) 5 -C 6 Cycloalkyl of (c);
and/or in the second method, the inorganic alkali is one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide;
and/or in the second method, the mass-volume ratio of the compound shown as the formula C13 to the organic solvent is 1:1-1:20 g/mL;
And/or, in the second method, the molar ratio of the compound shown as the formula C13 to the alkali is 1:1-1:3;
and/or, in the second method, the temperature of the ether forming reaction is 90-100 ℃;
and/or, in the second method, the time of the ether forming reaction is 1-15h.
32. The method for preparing a compound of formula I according to claim 30, wherein in method one, the organic solvent is an ether solvent;
and/or in the second method, the organic solvent is an amide solvent and/or a sulfoxide solvent.
33. The method of claim 31, wherein in the first method, the organic acid is trifluoroacetic acid;
and/or, in the first method, the silane compound is phenylsilane;
and/or, in method two, the alkali metal alkoxide is C 1 ～C 4 Alkali metal alkoxides of alcohols;
and/or, in method two, the alkali metal carbonate is K 2 CO 3 And/or Cs 2 CO 3 ；
And/or, in the second method, the alkali metal hydride is NaH;
and/or, in the second method, the alkali metal hydroxide is NaOH and/or KOH;
and/or, in the second method, the molar ratio of the compound shown as the formula C13 to the alkali is 1:1-1:2.
34. The method for preparing a compound of formula I as claimed in claim 31, wherein in method one, the ether solvent is tetrahydrofuran;
and/or, in the second method, the aromatic solvent is toluene;
and/or, in the second method, the alkali metal alkoxide is potassium tert-butoxide and/or sodium tert-butoxide;
and/or, in method two, the alkali metal carbonate is Cs 2 CO 3 。
35. The process for preparing a compound of formula I as claimed in claim 29,
the preparation method of the compound shown as the formula B13 comprises the following steps: in a solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown as the formula B12;
alternatively, the preparation method of the compound shown as the formula C13 comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of a compound shown as a formula C12;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
36. The process for preparing a compound of formula I as claimed in claim 35,
in the preparation method of the compound shown as the formula B13, the preparation method of the compound shown as the formula B12 comprises the following steps: in an organic solvent, in the presence of an oxidant, carrying out the oxidation reaction of the compound shown as the formula B11;
Alternatively, in the preparation method of the compound shown as the formula C13, the preparation method of the compound shown as the formula C12 comprises the following steps: in an organic solvent, in the presence of acid and silane compounds, carrying out reductive amination reaction on a compound shown as a formula C11 and a compound shown as a formula C10;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
37. The process for preparing a compound of formula I as defined in claim 36,
in the preparation method of the compound shown in the formula B12, the preparation method of the compound shown in the formula B11 is any one of a method A, a method B, a method C and a method D,
the method A comprises the following steps: in an organic solvent, in the presence of a reducing agent, carrying out the reduction reaction of the compound shown as the formula B10;
the method B comprises the following steps:
(b1) The compound shown as the formula B10 and a halogenating agent are subjected to the acylation reaction shown as follows to obtain acyl chloride;
(b2) The acyl chloride obtained in the step (b 1) and a reducing agent are subjected to the reduction reaction shown below;
the method C comprises the following steps:
(c1) Carrying out esterification reaction on the compound shown as the formula B10 and alcohol to obtain ester;
(c2) The ester obtained in the step (c 1) and the reducing agent are subjected to the reduction reaction shown below;
the method D comprises the following steps:
(d1) In the presence of an activating agent and alkali, carrying out the following reaction on the compound shown as the formula B10 to obtain anhydride;
(d2) The anhydride obtained in the step (d 1) and a reducing agent are subjected to the reduction reaction shown below;
alternatively, in the preparation method of the compound shown as the formula C12, the preparation method of the compound shown as the formula C11 comprises the following steps: in an organic solvent, in the presence of an oxidant, carrying out the oxidation reaction of a compound shown as a formula C9;
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2;
R 5 and R is 6 Independently C 1 -C 4 Is a hydrocarbon group.
38. The process for preparing a compound of formula I as claimed in claim 37,
in the preparation method of the compound shown as the formula B11, the preparation method of the compound shown as the formula B10 comprises the following steps: in an organic solvent, in the presence of alkali, carrying out ether forming reaction on a compound shown in a formula 7 and a compound shown in a formula B9;
alternatively, in the preparation method of the compound shown as the formula C11, the preparation method of the compound shown as the formula C9 further comprises the following steps: in an organic solvent, in the presence of alkali, carrying out methylation reaction shown in the following on a compound shown in a formula 8 and a methylation reagent;
Wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
39. The method of claim 38, wherein the method of preparing the compound of formula 7 or formula 8 is as defined in claim 28.
40. A preparation method of a compound shown as a formula I-1 comprises the following synthetic route of a route 1 or a route 2:
route 1
Route 2
The preparation method of the compound shown as the formula I-1 is as claimed in any one of claims 35-39.
41. The process for preparing a compound of formula I-1 as claimed in claim 40, wherein the synthetic route is either scheme 3 or scheme 4:
route 3
Route 4
/>
42. A method for preparing a compound represented by formula 7-1 or formula 8-1,
wherein, the synthetic route of the compound shown in the formula 7-1 is as follows:
the synthetic route of the compound shown in the formula 8-1 is as follows:
wherein the preparation method of the compound shown as the formula 7-1 or the formula 8-1 is as claimed in claim 28.
43. A compound of the formula:
wherein R is 1 、R 2 、R 3 And R is 4 The method of claim 1 or 2.
44. The compound of claim 43, which is
/>
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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN107001387A (en) * 2014-08-29 2017-08-01 美国安进公司 Suppress the compound of the albumen of MCL 1

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WO2018107060A1 (en) * 2016-12-09 2018-06-14 Denali Therapeutics Inc. Compounds, compositions and methods
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LASA Marta等.Synthesis of the four stereoisomers of cyclobutane analogues of phenylalanine in enantiomerically pure form. Tetrahedron: Asymmetry.2005,第16卷(第24期),第4022-4033页. *
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