A process for the preparation of a lumerogan intermediate compound

Abstract

The application belongs to the field of medicine and provides a new method for preparing a lumerabenzine intermediate compound shown in formula II. The method is that a compound of formula I is reacted with a methylating agent in the presence of an acid binding agent, an organic solvent and water to prepare a compound of formula II. The reaction can be carried out at a lower temperature, high-pressure reaction containers and flammable and explosive materials are avoided, energy consumption is lower, post-reaction treatment is simple, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a preparation method of a lumateperone intermediate compound. BACKGROUND

[0002] Lumateperone is a new antipsychotic drug developed by Intra-Cellular Therapies, a biopharmaceutical company in the United States, with the trade name Caplyta. It was approved for marketing by the US Food and Drug Administration (FDA) in December 2019 and is used for the treatment of adult schizophrenia. It is the first innovative drug in the field of schizophrenia treatment and can synergistically act on the 5-hydroxytryptamine, dopamine and glutamatergic systems. Its unique mechanism of action enables it to not only improve the positive symptoms of schizophrenia patients, but also effectively treat negative symptoms and depressive symptoms. Its chemical name is 4-[(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl]-1-(4-fluorophenyl)-1-butanone, and its CAS number is 313368-91-1. Its structural formula is as follows:

[0003]

[0004] Lumateperone and its related compounds can be used as 5-HT2 receptor agonists and antagonists for the treatment of central nervous system disorders, including disorders associated with 5HT 2C or 5HT 2A receptor modulation. For the preparation method of lumateperone, the synthetic routes thereof are reported in patent documents WO00 / 77002A1, WO2008 / 112280A1, WO2019 / 102240A1 and non-patent document (J. Med. Chem. 2014, 57, 2670-2682), mainly including the following two routes.

[0005] Route 1: 3,4-dihydro-1H-2-quinoxalinone is used as the raw material, and a six-hydrogen-γ-carbazole four-ring structure is constructed through nitrosation, reduction, Fischer indole reaction, then sodium cyanoborohydride reduction, amide methylation, amide reduction, amide hydrolysis to obtain a racemic cis four-ring mother nucleus, then N-alkylation with halogenated ketone to obtain racemic lumateperone, and finally chiral HPLC separation to obtain the target product lumateperone.

[0006] The specific reaction formula is as follows:

[0007]

[0008] Route two: using o-bromobenzenehydrazine hydrochloride as raw material, through Fisher indole reaction, reduction, N-acylation reaction, palladium-catalyzed C-N coupling reaction, N-alkylation reaction, imine hydrolysis and amidation reaction, amide alkylation, amide reduction, alkoxy amide hydrolysis to obtain the four-membered ring mother nucleus, then chiral HPLC preparation to obtain the chiral four-membered ring mother nucleus, and finally N-alkylation reaction with alkyl ketone to obtain the target product lumefanuron.

[0009] The specific reaction formula is as follows:

[0010]

[0011] The above route one and route two both include an amide methylation step, that is, the step of methylation of compound (cis)-9 or compound (cis)-21, which uses iodomethane as a methylation reagent, potassium carbonate / acetone is used to react at 109 DEG C in a pressure bottle, or NaH / DMF is used to react at room temperature. The former needs to use a pressure container, and the reaction is carried out under high temperature and high pressure conditions, so that the safety risk is high, and the production energy consumption is high; the latter uses NaH, and NaH decomposes to generate hydrogen gas when meeting water, the explosion limit of hydrogen gas is 4%-75%, which has high combustion and explosion risk characteristics, is not suitable for industrial scale-up, and both of them have complex post-treatment, which involves steps such as extraction, brine washing and solvent evaporation, and a large amount of industrial wastewater is generated.

[0012] In order to overcome the defects existing in the prior art, it is necessary to develop more alternative processes suitable for industrial production of lumefanuron intermediate compounds prepared by amide methylation. SUMMARY

[0013] The purpose of the present application is to provide an improved process suitable for industrial production of lumefanuron intermediate compounds. The method reacts the compound of formula I with a methylation reagent in the presence of an acid binding agent, an organic solvent and water to prepare the compound of formula II, so that the reaction can be carried out at a lower temperature, the use of high-pressure reaction containers and flammable and explosive materials (such as NaH) is avoided, the energy consumption is lower, the post-treatment after reaction is simple, and it is more suitable for industrial production.

[0014] The present application provides a preparation method of a compound of formula II, comprising: reacting a compound of formula I with a methylation reagent in the presence of an acid binding agent, an organic solvent and water to prepare a compound of formula II,

[0015]

[0016] Preferably, the compounds of general formula I and II are compounds of general formula (cis)-I and (cis)-II respectively:

[0017]

[0018] Further, the compounds represented by general formula (cis)-I, (cis)-II are compounds represented by general formula Ia, IIa respectively:

[0019]

[0020] wherein R1, R3are independently selected from H, alkyl, alkenyl or alkynyl, said alkyl, alkenyl, alkynyl are substituted or unsubstituted, and said substituent is selected from one or more of halogen, OH, SH, NH2, NO2, CN, alkoxy, alkenyl, alkynyl, cycloalkyl; R2is selected from an amino protecting group.

[0021] In some embodiments, R1, R3are independently selected from H, C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl, said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl are substituted or unsubstituted, and said substituent is selected from one or more of halogen, OH, SH, NH2, NO2, CN, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl.

[0022] In some embodiments, R1, R3are independently selected from H, C 1-10 alkyl, trifluoromethyl, ethenyl, propenyl, allyl, ethynyl or propynyl;

[0023] In some embodiments, R1, R3are independently selected from H, methyl, ethyl, propyl, butyl, t-butyl, trifluoromethyl, ethenyl, propenyl, allyl, ethynyl or propynyl.

[0024] In some embodiments, R1, R3are independently selected from H or C 1-10 alkyl.

[0025] In some embodiments, R1is selected from H or C 1-10 alkyl, and R3is selected from H.

[0026] In some embodiments, R1is selected from H or methyl, and R3is selected from H.

[0027] In some embodiments, R2is selected from COOR4, COR4, or SO2R4, R4is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, saturated or unsaturated heterocyclyl, one or more carbon atoms of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl can be replaced with a heteroatom, said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl can be substituted or unsubstituted, and the substituents thereof are selected from one or more of halo, OH, SH, NH2, NO2, CN, alkyl, alkoxy, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl.

[0028] In some embodiments, R4is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-30 aryl, C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl, C 6-30 heteroaryl-C 1-10 alkyl, or 3- to 30-membered saturated or unsaturated heterocyclyl, one or more carbon atoms of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl can be replaced with a heteroatom, said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl can be substituted or unsubstituted, and the substituents thereof are selected from one or more of halo, OH, SH, NH2, NO2, CN, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-30 aryl, C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl, C 6-30 heteroaryl-C 1-10 alkyl, 3- to 30-membered saturated or unsaturated heterocyclyl.

[0029] In some embodiments, R4is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 6-30 aryl, C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl, or C 6-30 heteroaryl-C 1-10 alkyl, the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl can be substituted or unsubstituted, with substituents selected from the group consisting of halogen, OH, SH, NH2, NO2, CN, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-20 cycloalkyl, C 6-30 aryl, C 6-30 heteroaryl.

[0030] In some embodiments, R4is independently selected from methyl, ethyl, propyl, butyl, t-butyl, trifluoromethyl, ethenyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclopentyl, phenyl, fluorenyl, trityl, pyridyl, benzyl, or pyridylmethyl.

[0031] In some embodiments, R2is selected from COOC 1-10 alkyl.

[0032] In some embodiments, R4is selected from ethyl or trifluoromethyl.

[0033] In some embodiments, R2is selected from COOEt or COCF3.

[0034] In some embodiments, R1is selected from C 1-10 alkyl, R2is selected from COCF3, and R3is selected from H.

[0035] In some embodiments, R1is selected from methyl, R2is selected from COCF3, and R3is selected from H.

[0036] In some embodiments, R1, R3are selected from H, and R2is selected from COOC 1-10 alkyl.

[0037] In some embodiments, R1, R3are selected from H, and R2is selected from COOEt.

[0038] In some embodiments, the compound of formula (cis)-I is (cis)-2-oxo-2,3,6b,9,10,10a- hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H)-carboxylic acid ethyl ester and the compound of formula (cis)-II is (cis)-3-methyl-2-oxo-2,3,6b,9,10,10a- hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H)-carboxylic acid ethyl ester.

[0039] In some embodiments, the compound of formula Ia is (6bR,10aS)-2-oxo-2,3,6b,9,10,10a- hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H)-carboxylic acid ethyl ester and the compound of formula IIa is (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a- hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H)-carboxylic acid ethyl ester.

[0040] In some embodiments, the methylating agent is selected from one or more of methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, methyl-p-toluenesulfonate, methyl triflate, methyl fluorosulfonate.

[0041] In some embodiments, the acid binding agent is selected from an organic base and / or an inorganic base. The organic base can be one or more of amines, alkoxides (such as alkali or alkaline earth metal alkoxides, including sodium alkoxide, potassium alkoxide, and the like), for example dimethylamine, diethylamine, triethylamine, triethylenediamine, N,N-diisopropylethylamine, sodium amide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium ethoxide, potassium tert-butoxide, morpholine, N-methylmorpholine, pyridine, picoline, trimethylpyridine, dimethylaniline, 4-(dimethylamino)pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO). The inorganic base can be one or more of carbonates, bicarbonates, phosphates, or hydroxides of alkali or alkaline earth metals (such as lithium, sodium, potassium, cesium, calcium, magnesium, barium), including one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide. The acid binding agent is preferably one or more of alkali or alkaline earth metal alkoxides, hydroxides, preferably potassium hydroxide, sodium hydroxide, and / or sodium ethoxide.

[0042] In some embodiments, the organic solvent is selected from one or more of alcohols, ethers, ketones, amides, sulfone solvents, preferably one or more of diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetone, butanone, pentanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide.

[0043] In some embodiments, the reaction is optionally carried out in the presence of a phase transfer catalyst.

[0044] In some embodiments, the phase transfer catalyst is a quaternary ammonium salt compound, preferably at least one of benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate.

[0045] In some embodiments, the molar ratio of the methylation reagent to Compound I is 1-5: 1, preferably 1-3: 1, more preferably 1.5-2: 1.

[0046] In some embodiments, the molar ratio of the acid binding agent to Compound I is 1-10: 1, preferably 1-5: 1, more preferably 2-2.5: 1.

[0047] In some embodiments, the mass to volume ratio (g / ml) of Compound I to the organic solvent is 0.01-1, preferably 0.05-0.7, more preferably 0.08-0.5.

[0048] In some embodiments, the volume ratio of the organic solvent to water is 2-100: 1, preferably 10-50: 1, more preferably 20-40: 1.

[0049] In some embodiments, the mass ratio of the phase transfer catalyst to Compound I is 0.01-5: 1, preferably 0.02-3: 1, more preferably 0.03-2: 1, more preferably 0.05-1: 1.

[0050] In some embodiments, the reaction temperature is not higher than 40°C, preferably -20 to 40°C, more preferably 10 to 40°C, particularly preferably 20 to 40°C, further preferably room temperature (i.e. 20 to 30°C).

[0051] In some embodiments, the compound of Formula I, the organic solvent, the acid binding agent, water and the methylation reagent are mixed, optionally with the phase transfer catalyst, the temperature is controlled not to be higher than 40°C, and the reaction is carried out.

[0052] In some embodiments, after the reaction is completed, a post-treatment step is carried out: after the reaction is completed, the reaction solution is mixed with an appropriate amount of water, stirred, the solid is precipitated, separated, dried, and the compound of Formula II is obtained.

[0053] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, an organic solvent, an acid-binding agent, water, and a methylation reagent, optionally adding a phase transfer catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0054] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, tetrahydrofuran, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0055] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, dimethyl sulfoxide, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0056] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, N,N-dimethylformamide, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0057] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, acetone, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0058] In some embodiments, a method for preparing a compound of formula II comprises: mixing a compound of formula I, tetrahydrofuran, sodium ethoxide, water, a methylation reagent, and an optional catalyst, controlling the temperature to be no higher than 40 DEG C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating the solid, separating, drying, and obtaining the compound of formula II.

[0059] Compared with the prior art, the present application has the following beneficial effects:

[0060] The method of the present application reacts the compound of formula I with a methylating agent in the presence of an acid-binding agent, an organic solvent and water to prepare the compound of formula II. The reaction can be carried out at a lower temperature, such as room temperature, thereby reducing energy consumption, and further improving the yield and purity of the product. The method solves the technical drawbacks of high temperature and high pressure production and the use of flammable and explosive materials (such as NaH) in the prior art production process, and further simplifies the post-reaction treatment and the production process, which is more suitable for large-scale industrial production.

[0061] DETAILED DESCRIPTION

[0062] The following terms, as used herein, have the following meanings unless otherwise indicated.

[0063] The term "room temperature" means 25°C ± 5°C.

[0064] The term "halogen" means fluorine, chlorine, bromine, iodine.

[0065] The term "alkyl" means a straight or branched chain alkyl group having the number of carbon atoms indicated. The alkyl group can be C 1-10 alkyl, preferably C 1-6 alkyl. "C 1-10 alkyl", "C 1-6 alkyl" means a straight or branched chain alkyl group having 1 to 10 or 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

[0066] The term "alkoxy" means "alkyl-O-", wherein alkyl is as defined above. The alkoxy group can be C 1-10 alkoxy, preferably C 1-6 alkoxy.

[0067] The term "alkenyl" means a straight or branched chain alkenyl group having the number of carbon atoms indicated. The alkenyl group can be C 2-10 alkenyl, preferably C 2-6 alkenyl. "C 2-10 alkenyl", "C 2-6"Alkenyl" refers to a straight-chain or branched alkenyl group having 2-10 or 2-6 carbon atoms, including vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylallyl, 1-methyl-1-propenyl, 1-methylallyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl alkenyl, 1,1-dimethylallyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1-dimethyl-1-butenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl, and 4-methyl-3-pentenyl.

[0068] The term "alkynyl" refers to a straight-chain or branched alkynyl group having a specified number of carbon atoms. The alkynyl group can be C16-3 ... 2-10 Alkyne group, preferably C 2-6 Alkynyl group. "C" 2-10 "Alkyne", "C" 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-10 or 2-6 carbon atoms, including ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0069] One or more carbon atoms in the "alkyl", "alkenyl", or "alkynyl" group can be replaced by heteroatoms (such as O, S, N, etc.). For example, it can be "heteroalkyl", "heteroalkenyl", or "heteroalkynyl".

[0070] The terms "heteroalkyl", "heteroalkenyl", and "heteroynyl" refer to alkyl, alkenyl, or ynyl groups as defined above, in which one or more (preferably 1, 2, or 3) carbon atoms are replaced by heteroatoms (such as O, S, N, etc.), and can be C14, C24, C24, C25 ... 1-10 Heteroalkyl, C 2-10 Heterene, C2-10 Heterynyl group, preferably C 1-6 Heteroalkyl, C 2-6 Heterene, C 2-6 Zeyne group.

[0071] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon, which can be monocyclic, spirocyclic, bridged, fused, or fused, and can be C1-C2 ... 3-20 Cycloalkyl, preferably C 3-10 Cycloalkyl, more preferably C 3-7 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and decahydronaphthalene.

[0072] The term "cycloalkenyl" refers to a cycloalkyl group as defined above that contains at least one double bond, which can be C10 or C20. 3-20 Cycloalkenyl, preferably C 3-10 Cycloalkenyl, more preferably C 3-7 Cycloalkenyl groups, such as cyclopentenyl and cyclohexenyl.

[0073] The term "cycloalkynyl" refers to a cycloalkyl group as defined above that contains at least one triple bond, which can be C1-C2-C3 ... 3-20 Cycloacetylenic, preferably C 3-10 Cycloalkynyl, more preferably C 3-7 Cycloynyl groups, such as cyclopentynyl and cyclohexynyl.

[0074] The term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be monosubstituted, disubstituted, or polysubstituted; it can be monovalent, divalent, or polyvalent; and it can be monocyclic or polycyclic (e.g., 1 to 3 rings), fused together or covalently linked. The aryl group can be C16-36. 6-30 Aryl, preferably C 6-10 Aryl groups, including, in non-limiting examples, phenyl, naphthyl, biphenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, fluorenyl, phenanthryl, benzo[a]phenanthryl, phenylphenanthryl, anthracene, benzo[a]anthryl, indene, triphenylene, pyrene, etc.

[0075] The term "heteroaryl" refers to an aryl group in which one or more (preferably 1, 2, or 3) carbon atoms are replaced by heteroatoms (such as O, S, N, etc.). The heteroaryl group can be C 6-30 heteroaryl, preferably C 6-10 Heteroaryl compounds, including, in non-limiting examples, furan, thiophene, pyrrole, thiazole, pyridyl, imidazolyl, pyrazolyl, and isoquinolinyl.

[0076] The term "saturated or unsaturated heterocyclic group" refers to a saturated or unsaturated monocyclic or polycyclic system containing at least one heteroatom (such as O, S, N, etc.). Examples include "heterocyclic alkyl", "heterocyclic alkenyl", "heterocyclic alkynyl", and "heteroaryl".

[0077] The term "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl" means a cycloalkyl, cycloalkenyl, cycloalkynyl as defined above, wherein one or more (preferably 1, 2 or 3) carbon atoms are replaced by a heteroatom (e.g. O, S, N, etc.), and can be C 3-20 heterocycloalkyl, C 3-20 heterocycloalkenyl, C 3-20 heterocycloalkynyl, preferably C 3-10 heterocycloalkyl, C 3-10 heterocycloalkenyl, C 3-10 heterocycloalkynyl, more preferably C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, C 3-7 heterocycloalkynyl, e.g. tetrahydrofuran, piperidinyl, morpholinyl, piperazinyl.

[0078] The term "aralkyl" (i.e. "aryl-alkyl"), the term "heteroaralkyl" (i.e. "heteroaryl-alkyl" or "heteroaryl-heteroalkyl") can be C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl-C 1-10 alkyl, C 6-30 heteroaryl-C 1-10 heteroalkyl, respectively, preferably C 6-10 aryl-C 1-6 alkyl, C 6-10 heteroaryl-C 1-6 alkyl, C 6-10 heteroaryl-C 1-6 heteroalkyl, wherein aryl, heteroaryl, alkyl, heteroalkyl are as defined above, e.g. benzyl, 2- or 3-ethyl-indolyl or 4-methylpyridyl, etc.

[0079] The alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl groups can be substituted or unsubstituted, and the substituents include halogen, OH, SH, NH2, NO2, CN, alkyl, alkoxy, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, etc. DETAILED DESCRIPTION

[0080] The application will be explained in more detail below with reference to specific examples, which are only intended to illustrate the technical solutions of the present application, and the spirit and scope of the present application are not limited thereto.

[0081] Comparative Example 1

[0082]

[0083] Compound 1 (cis-2-oxo-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxaline-8(7H)-carboxylate ethyl ester) (1.0 g, 3.32 mmol), DMF (15 ml) were added into a reaction flask and stirred until dissolved. Sodium ethoxide (0.47 g, 6.91 mmol) was added, and iodomethane (0.3 g, 2.11 mmol) was added under temperature control of 20-30 °C. The reaction was stirred at 20-30 °C for 4 hours. The oil bath was heated to 40 °C, and iodomethane (0.3 g, 2.11 mmol) was added. The reaction was allowed to proceed overnight. The solvent was evaporated under reduced pressure, and 50 ml of water and 30 ml of ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and washed once with 30 ml of brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 0.84 g of a foamy solid, which was Compound 2 (cis-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxaline-8(7H)-carboxylate ethyl ester), with a yield of 80.2%.

[0084] Comparative Example 2

[0085]

[0086] Compound 1 (5.0 g, 16.6 mmol), acetone (50 ml), potassium carbonate (5.73 g, 41.5 mmol) were added into a reaction flask and stirred until dissolved. Iodomethane (4.7 g, 33.1 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 24 hours. The reaction solution was analyzed by HPLC, which showed that the content of the target compound was 44.24%, and the remaining starting material was 52.77%.

[0087] Comparative Example 3

[0088]

[0089] Compound 1 (1.0 g, 3.32 mmol), DMF (10 ml) were added into a reaction flask, then sodium hydroxide (0.27 g, 6.75 mmol) was added and 0.1 g of benzyl triethyl ammonium chloride (TEBAC) was dissolved by stirring. The reaction was cooled in an ice bath and the temperature was controlled below 20 °C. Iodomethane (0.71 g, 5.00 mmol) was added dropwise. The reaction was carried out at room temperature for 1 hour. 100 ml of water was added to the reaction solution and a large amount of solid was precipitated. 50 ml of ethyl acetate was added and the solution was extracted. The aqueous phase was extracted twice with ethyl acetate and the organic phases were combined. The combined organic phase was washed three times with water and once with brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.82 g of a white solid. Then 5 ml of methyl tert-butyl ether was added and the mixture was stirred in an ice bath for about 1.5 hours. The mixture was filtered and dried to obtain 0.79 g of a white solid, with a yield of 75.5%.

[0090] Comparative Example 4

[0091]

[0092] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml) were added into a reaction flask, then sodium hydroxide (1.66 g, 41.5 mmol) was added and dissolved by stirring. Iodomethane (4.7 g, 33.1 mmol) was added dropwise and the reaction was carried out at room temperature for 5 hours. Water was added to the reaction solution and a large amount of solid was precipitated. The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed twice with purified water. The wet product was dried at 65 ± 5 °C under vacuum to a constant weight to obtain 3.90 g of a white solid, with a yield of 74.5% and a purity of 98.7%.

[0093] Example 1

[0094]

[0095] Compound 1 (5.0 g, 16.6 mmol), DMSO (50 ml) were added into a reaction flask, then sodium hydroxide (1.66 g, 41.5 mmol), 2.5 ml of water were added and the mixture was stirred until uniform. Iodomethane (4.7 g, 33.1 mmol) was added dropwise and the reaction was carried out at room temperature for about 5 hours. Water was added to the reaction solution and a large amount of solid was precipitated. The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed twice with purified water. The wet product was dried at 65 ± 5 °C under vacuum to a constant weight to obtain 4.87 g of a white solid, with a yield of 93.0% and a purity of 97.8%.

[0096] Example 2

[0097]

[0098] Compound 1 (90 g, 298.66 mmol), tetrahydrofuran (900 ml), purified water (45 ml), sodium hydroxide (23.9 g, 597.50 mmol) were added into the reaction flask, and stirred until completely dissolved. The temperature of the liquid was controlled at 20-30 °C, and iodomethane (63.6 g, 448.08 mmol) was added dropwise. After the addition of iodomethane was completed, the temperature of the liquid was controlled at 20-30 °C, and stirred for 4 hours. The reaction progress was monitored by TLC. After the reaction was completed, purified water (3150 ml) was added, and a large amount of white solid was precipitated. The temperature was controlled at 20-30 °C, and stirred overnight. Filtration was performed, and the filter cake was washed twice with purified water. The wet filter cake was placed on a tray and dried at 50 ± 5 °C under vacuum to a constant weight to obtain 89.95 g of a white solid, with a yield of 95.5% and a purity of 99.89%.

[0099] Example 3

[0100]

[0101] Compound 1 (5.0 g, 16.6 mmol), tetrahydrofuran (50 ml), sodium hydroxide (1.66 g, 41.5 mmol), 0.25 g of benzyltriethylammonium chloride, and 2.5 ml of water were added into a reaction flask and stirred until completely dissolved. Iodomethane (4.7 g, 33.1 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for about 5 hours. Water was added to the reaction liquid, and a large amount of solid was precipitated. The mixture was stirred at room temperature for 2 hours. Filtration was performed, and the filter cake was washed twice with purified water. The wet product was dried at 65 ± 5 °C under vacuum to a constant weight to obtain 5.0 g of a white solid, with a yield of 95.5% and a purity of 99.37%.

[0102] Example 4

[0103]

[0104] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml), and 2.5 ml of water were added into a reaction flask, followed by the addition of sodium hydroxide (1.66 g, 41.5 mmol) and stirring until completely dissolved. Iodomethane (4.7 g, 33.1 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 5 hours. Water was added to the reaction liquid, and a large amount of solid was precipitated. The mixture was stirred at room temperature for 2 hours. Filtration was performed, and the filter cake was washed twice with purified water. The wet product was dried at 65 ± 5 °C under vacuum to a constant weight to obtain 4.74 g of a white solid, with a yield of 90.5% and a purity of 99.37%.

[0105] Example 5

[0106]

[0107] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml), 2.5 ml water, 0.25 g benzyltriethylammonium chloride were added into a reaction flask, then sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred to dissolve. Dimethyl sulfate (4.19 g, 33.2 mmol) was added dropwise and reacted at room temperature for 3 hours. Water was added to the reaction solution, and a large amount of solid was precipitated, which was stirred at room temperature for 2 hours. Filtration was performed, and the filter cake was washed twice with purified water. The wet product was vacuum dried at 65±5°C to a constant weight to obtain 4.81 g of a white solid, with a yield of 91.9% and a purity of 99%.

[0108] Example 6

[0109]

[0110] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml), 2.5 ml water, 0.25 g benzyltriethylammonium chloride were added into a reaction flask, then sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred to dissolve. Dimethyl sulfate (4.19 g, 33.2 mmol) was added dropwise and reacted at room temperature for 3 hours. Water was added to the reaction solution, and a large amount of solid was precipitated, which was stirred at room temperature for 2 hours. Filtration was performed, and the filter cake was washed twice with purified water. The wet product was vacuum dried at 65±5°C to a constant weight to obtain 4.81 g of a white solid, with a yield of 91.9% and a purity of 99%.

[0111] Example 7

[0112]

[0113] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml), 2.5 ml water, 0.25 g benzyltriethylammonium chloride were added into a reaction flask, then sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred to dissolve. Dimethyl sulfate (4.19 g, 33.2 mmol) was added dropwise and reacted at room temperature for 3 hours. Water was added to the reaction solution, and a large amount of solid was precipitated, which was stirred at room temperature for 2 hours. Filtration was performed, and the filter cake was washed twice with purified water. The wet product was vacuum dried at 65±5°C to a constant weight to obtain 4.81 g of a white solid, with a yield of 91.9% and a purity of 99%.

[0114] Example 8

[0115]

[0116] Compound 1 (5.0 g, 16.6 mmol), sodium ethoxide (2.82 g, 41.4 mmol), tetrahydrofuran (50 ml), 2.5 ml water were added into a reaction flask and stirred uniformly. Iodomethane (4.7 g, 33.1 mmol) was added dropwise and reacted at room temperature for about 5 hours. The reaction solution was added into water and a large amount of solid was precipitated, which was stirred at room temperature for 2 hours. Filtration was performed and the filter cake was washed with purified water for 2 times. The wet product was dried at 65±5 °C under vacuum to constant weight to obtain a solid 4.83 g with a yield of 92.3% and a purity of 96.3%.

[0117] Although the present application has been described in detail, those skilled in the art understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application, and these modifications and changes should also be considered as the protection scope of the present application.

Claims

1. A process for the preparation of a compound of formula II, comprising: The compound of formula I is reacted with a methylating agent in the presence of an acid-binding agent, an organic solvent and water to prepare a compound of formula II, wherein R1is H, C 1-10 alkyl, R3is H, and R2is an amino protecting group; The acid-binding agent is potassium hydroxide and / or sodium hydroxide. The organic solvent is selected from one or more of tetrahydrofuran, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide.

2. The production method according to claim 1, wherein The compound of formula I is a compound of formula (cis)-I, and the compound of formula II is a compound of formula (cis)-II. R1, R2 and R3 are the same as defined in claim 1.

3. The production method according to claim 2, wherein The compound of formula (cis)-I is a compound of formula Ia, and the compound of formula (cis)-II is a compound of formula IIa. R1, R2 and R3 are the same as defined in claim 2.

4. The production method according to any one of claims 1 to 3, characterized by: R1 is H.

5. The production method according to any one of claims 1 to 3, characterized by: R1 is methyl.

6. The production method according to any one of claims 1 to 3, characterized by: R2 is COOR4, COR4 or SO2R4. wherein R4is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-30 aryl, C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl-C 1-10 alkyl, or a 3- to 30-membered saturated or unsaturated heterocyclyl, which alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl is substituted or unsubstituted, with substituents selected from the group consisting of halogen, OH, SH, NH2, NO2, CN, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-20 cycloalkyl, C 6-30 aryl, C 6-30 aryl-C 1-10 alkyl, C 6-30 heteroaryl-C 1-10 alkyl, one or more of 3- to 30-membered saturated or unsaturated heterocyclyl.

7. The production method according to any one of claims 1 to 3, characterized by: R2is COOC 1-10 alkyl.

8. The production method according to any one of claims 1 to 3, characterized by: R2 is COOEt.

9. The production method according to any one of claims 1 to 3, characterized by: R2 is COCF3.

10. The production method according to any one of claims 1 to 3, characterized by: R1 is H, R3 is H, and R2 is COOEt.

11. The production method according to any one of claims 1 to 3, characterized by: R1 is methyl, R3 is H, and R2 is COCF3.

12. The production method according to any one of claims 1 to 3, characterized by: The methylating agent is selected from one or more of methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl triflate, methyl fluorosulfonate.

13. The production method according to any one of claims 1 to 3, characterized by: The molar ratio of the methylating agent to compound I is 1-5:

1.

14. The production method according to any one of claims 1 to 3, characterized by: The molar ratio of the methylating agent to compound I is 1-3:

1.

15. The method of any one of claims 1-3, wherein: The molar ratio of the methylating agent to compound I is 1.5-2:

1.

16. The production method according to any one of claims 1 to 3, characterized by: The molar ratio of the acid-binding agent to compound I is 1-10:

1.

17. The method of any one of claims 1-3, wherein: The molar ratio of the acid-binding agent to compound I is 1-5:

1.

18. The method of any one of claims 1-3, wherein: The molar ratio of the acid-binding agent to compound I is 2-2.5:

1.

19. The method of any one of claims 1-3, wherein: The reaction is carried out in the presence of a phase transfer catalyst.

20. The method of claim 19, wherein: The phase transfer catalyst is a quaternary ammonium salt compound.

21. The method of claim 19, wherein: The phase transfer catalyst is at least one of benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate.

22. The method of any one of claims 1-3, wherein: The reaction temperature is not higher than 40°C.

23. The method of any one of claims 1-3, wherein: The reaction temperature is -20-40°C.

24. The method of any one of claims 1-3, wherein: The compound of formula I, an organic solvent, water, an acid-binding agent and a methylating agent are mixed, and the reaction is carried out at a temperature not higher than 40°C to prepare a compound of formula II.

25. The method of any one of claims 1-3, wherein: After the reaction is completed, the reaction solution is mixed with an appropriate amount of water, stirred, and the solid is separated, dried to obtain a compound of formula II. After the reaction is completed, the reaction solution is mixed with an appropriate amount of water, stirred, and the solid is separated, dried to obtain a compound of formula II.

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