Preparation method of lumepirone intermediate compound

Abstract

The invention belongs to the field of medicines, and provides a novel method for preparing a lumepirone intermediate compound as shown in a formula II, which comprises the following steps: reacting a compound as shown in a formula I with a methylation reagent in the presence of an acid-binding agent, an organic solvent and water to prepare the compound as shown in the formula II, so that the reaction can be carried out at a lower temperature; high-pressure reaction containers and flammable and explosive materials are not used, the energy consumption is low, the reaction post-treatment is simple, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

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

[0002] Lumateperone is a novel antipsychotic drug developed by the American biopharmaceutical company Intra-Cellular Therapies, with the trade name Caplyta. It was approved by the US Food and Drug Administration (FDA) for marketing in December 2019 for the treatment of adult schizophrenia. It is a first-in-class drug in the field of schizophrenia treatment and can act synergistically on the serotonin, dopamine, and glutamatergic systems. Its unique mechanism of action enables the drug to not only improve the positive symptoms of schizophrenia patients but also be effective against 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, with the CAS number 313368-91-1, and the 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 related to 5HT 2C or 5HT 2A receptor regulation. Regarding the preparation method of lumateperone, its synthetic routes have been reported in the patent documents WO00 / 77002A1, WO2008 / 112280A1, WO2019 / 102240A1, and the non-patent literature (J. Med. Chem. 2014, 57, 2670-2682), and there are mainly the following two.

[0005] Route 1: Using 3,4-dihydro-1H-2-quinoxalinone as the raw material, through nitrosation, reduction, and Fischer indole reaction to construct a hexahydro-γ-carboline tetracyclic structure, then through reduction with sodium cyanoborohydride, amide methylation, amide reduction, and amide hydrolysis to obtain a racemic cis-tetracyclic parent nucleus, and then through N-alkylation reaction with a halogenated ketone to obtain racemic lumateperone, and finally through chiral HPLC resolution to obtain the target product lumateperone.

[0006] The specific reaction formula is as follows:

[0007]

[0008] Route 2: Using o-bromophenylhydrazine hydrochloride as the raw material, through Fisher indole reaction, reduction, N-acylation reaction, palladium-catalyzed C-N bond coupling reaction, N-alkylation reaction, imine hydrolysis and amidation reaction, amide alkylation, amide reduction, and alkoxyamide hydrolysis to obtain the four-membered ring mother nucleus, then preparing the chiral four-membered ring mother nucleus by chiral HPLC, and finally obtaining the target product lomepirlone through N-alkylation reaction with alkyl ketone.

[0009] The specific reaction formulas are as follows:

[0010]

[0011] Both Route 1 and Route 2 described above include an amide methylation step, that is, the step of methylating compound (cis)-9 or compound (cis)-21. In this step, methyl iodide is used as the methylation reagent, and the reaction is carried out in a pressure bottle with potassium carbonate / acetone at 109 °C, or with NaH / DMF at room temperature. The former requires the use of a pressure vessel and reacts under high temperature and high pressure conditions, with relatively high safety risks and high production energy consumption; the latter uses NaH, and NaH decomposes when encountering water to produce hydrogen. The explosion limit of hydrogen is 4% - 75%, with high flammability and explosion hazard characteristics, which is not suitable for industrial scale-up. Moreover, the post-treatment of both methods is relatively complex, involving steps such as extraction, brine washing, and solvent evaporation, which will generate a large amount of industrial wastewater.

[0012] In order to overcome the defects existing in the prior art, it is necessary to develop more alternative processes suitable for industrial production for preparing lomepirlone intermediate compounds through amide methylation. Summary of the Invention

[0013] The purpose of the present invention is to provide an improved process suitable for industrial production for preparing lomepirlone intermediate compounds. This method reacts 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, enabling the reaction to be carried out at a relatively low temperature, avoiding the use of high-pressure reaction vessels and flammable and explosive materials (such as NaH), with lower energy consumption and simple post-treatment of the reaction, being more suitable for industrial production.

[0014] The present invention provides a method for preparing a compound of Formula II, including: 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 represented by General Formulas I and II are the compounds represented by General Formulas (cis)-I and (cis)-II respectively:

[0017]

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

[0019]

[0020] Among them, R1 and R3 are independently selected from H, alkyl, alkenyl or alkynyl, and the alkyl, alkenyl and alkynyl are either substituted or unsubstituted, and the substituents are selected from one or more of halogen, OH, SH, NH2, NO2, CN, alkoxy, alkenyl, alkynyl, cycloalkyl; R2 is selected from amino protecting groups.

[0021] In some embodiments, R1 and R3 are independently selected from H, C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl, and the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl are either substituted or unsubstituted, and the substituents are 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 and R3 are independently selected from H, C 1-10 alkyl, trifluoromethyl, vinyl, propenyl, allyl, ethynyl or propargyl;

[0023] In some embodiments, R1 and R3 are independently selected from H, methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, vinyl, propenyl, allyl, ethynyl or propargyl.

[0024] In some embodiments, R1 and R3 are independently selected from H or C 1-10 alkyl.

[0025] In some embodiments, R1 is selected from H or C 1-10 alkyl, and R3 is selected from H.

[0026] In some embodiments, R1 is selected from H or methyl, and R3 is selected from H.

[0027] In some embodiments, R2 is selected from COOR4, COR4, or SO2R4, and R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, saturated or unsaturated heterocyclic group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl may be replaced by heteroatoms, and the alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclic group may be substituted or unsubstituted, and the substituents are selected from one or more of halogen, OH, SH, NH2, NO2, CN, alkyl, alkoxy, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclic group.

[0028] In some embodiments, R4 is 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 a saturated or unsaturated heterocyclic group having 3 to 30 members, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl may be replaced by heteroatoms, and the alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclic group may be substituted or unsubstituted, and the substituents are selected from 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 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, a saturated or unsaturated heterocyclic group having 3 to 30 members, one or more of which.

[0029] In some embodiments, R4 is 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, and the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl may be substituted or unsubstituted, and the substituents are selected from one or more 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, R4 is independently selected from methyl, ethyl, propyl, butyl, tert-butyl, trifluoromethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclopentyl, phenyl, fluorenyl, trityl, pyridyl, benzyl or pyridylmethyl.

[0031] In some embodiments, R2 is selected from COOC 1-10 alkyl.

[0032] In some embodiments, R4 is selected from ethyl or trifluoromethyl.

[0033] In some embodiments, R2 is selected from COOEt or COCF3.

[0034] In some embodiments, R1 is selected from C 1-10 alkyl, R2 is selected from COCF3, and R3 is selected from H.

[0035] In some embodiments, R1 is selected from methyl, R2 is selected from COCF3, and R3 is selected from H.

[0036] In some embodiments, R1 and R3 are selected from H, and R2 is selected from COOC 1-10 alkyl.

[0037] In some embodiments, R1 and R3 are selected from H, and R2 is selected from COOEt.

[0038] In some embodiments, the (cis)-I compound is ethyl (cis)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate, and the (cis)-II compound is ethyl (cis)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.

[0039] In some embodiments, the compound of formula Ia is ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate, and the compound of formula IIa is ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.

[0040] In some embodiments, the methylation reagent is selected from one or more of methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, and methyl fluorosulfonate.

[0041] In some embodiments, the acid-binding agent is selected from organic bases and / or inorganic bases. The organic base can be a compound such as an amine, an alcoholate (such as an alkali metal or alkaline earth metal alcoholate, including sodium alcoholate, potassium alcoholate, etc.), for example, one or more of 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, methylpyridine, 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 a carbonate, bicarbonate, phosphate, or hydroxide of an alkali metal or alkaline earth metal (such as lithium, sodium, potassium, cesium, calcium, magnesium, barium), including one or several of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. The acid-binding agent is preferably one or more of alkali metal or alkaline earth metal alcoholates and 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, and sulfone solvents, preferably one or more of diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, pentanone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0043] In some embodiments, optionally, the reaction is 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, and tetrabutylammonium hydrogensulfate.

[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-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, even 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, and further preferably room temperature (i.e., 20 to 30 °C).

[0051] In some embodiments, Compound I, the organic solvent, the acid-binding agent, water, and the methylation reagent are mixed, optionally adding a phase transfer catalyst, and the temperature is controlled not to be higher than 40 °C to carry out the reaction.

[0052] In some embodiments, after-treatment steps are carried out after the reaction: after the reaction is completed, the reaction solution is mixed with an appropriate amount of water, stirred, a solid is precipitated, separated, and dried to obtain Compound II.

[0053] In some embodiments, a method for preparing a compound of Formula II includes: 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 not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0054] In some embodiments, a method for preparing a compound of Formula II includes: mixing a compound of Formula I, tetrahydrofuran, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0055] In some embodiments, a method for preparing a compound of Formula II includes: mixing a compound of Formula I, dimethyl sulfoxide, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0056] In some embodiments, a method for preparing a compound of Formula II includes: mixing a compound of Formula I, N,N-dimethylformamide, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0057] In some embodiments, a method for preparing a compound of Formula II includes: mixing a compound of Formula I, acetone, sodium hydroxide, water, a methylation reagent, and an optional catalyst, controlling the temperature not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0058] In some embodiments, a method for preparing a compound of Formula II includes: mixing a compound of Formula I, tetrahydrofuran, sodium ethoxide, water, a methylation reagent, and an optional catalyst, controlling the temperature not higher than 40 °C, carrying out the reaction, after the reaction is completed, mixing the reaction solution with an appropriate amount of water, stirring, precipitating a solid, separating, and drying to obtain the compound of Formula II.

[0059] The present invention has the following beneficial effects compared with the prior art:

[0060] The method of the present invention reacts 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. This not only allows the reaction to proceed at a lower temperature, such as room temperature, reducing energy consumption, but also further improves the yield and purity of the product. It not only solves the technical drawbacks of high-temperature and high-pressure production and the use of flammable and explosive materials (such as NaH) in the existing production process, but also has simple post-treatment of the reaction, further simplifies the production process, and is more suitable for industrial scale-up production.

[0061]

Detailed description

[0062] Unless otherwise specified, the following terms used herein have the following meanings.

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

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

[0065] The term "alkyl" refers to a straight-chain or branched-chain alkyl having the specified number of carbon atoms. The alkyl can be C 1-10 alkyl, preferably C 1-6 alkyl. "C 1-10 alkyl", "C 1-6 alkyl" respectively refer to a straight-chain or branched-chain alkyl having 1-10 or 1-6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-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" refers to "alkyl-O-", where alkyl is defined as above. The alkoxy can be C 1-10 alkoxy, preferably C 1-6 alkoxy.

[0067] The term "alkenyl" refers to a straight-chain or branched-chain alkenyl having the specified number of carbon atoms. The alkenyl 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-chain alkenyl group having 2 to 10 or 2 to 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, 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-chain alkynyl group having a specified number of carbon atoms. The alkynyl group can be C 2-10 alkynyl, preferably C 2-6 alkynyl. "C 2-10 alkynyl", "C 2-6 alkynyl" refers to a straight-chain or branched-chain alkynyl group having 2 to 10 or 2 to 6 carbon atoms, and includes 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", and "alkynyl" groups can be replaced by heteroatoms (such as O, S, N, etc.). For example, it can be "heteroalkyl", "heteroalkenyl", "heteroalkynyl".

[0070] The terms "heteroalkyl", "heteroalkenyl", and "heteroalkynyl" refer to the alkyl, alkenyl, and alkynyl 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 C 1-10 heteroalkyl, C 2-10 heteroalkenyl, C2-10 Heteroalkynyl, preferably C 1-6 Heteroalkyl, C 2-6 Heteroalkenyl, C 2-6 Heteroalkynyl.

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

[0072] The term "cycloalkenyl" refers to a cycloalkyl as defined above containing at least one double bond, and can be C 3-20 Cycloalkenyl, preferably C 3-10 Cycloalkenyl, more preferably C 3-7 Cycloalkenyl, such as cyclopentenyl, cyclohexenyl, etc.

[0073] The term "cycloalkynyl" refers to a cycloalkyl as defined above containing at least one triple bond, and can be C 3-20 Cycloalkynyl, preferably C 3-10 Cycloalkynyl, more preferably C 3-7 Cycloalkynyl, such as cyclopentynyl, cyclohexynyl, etc.

[0074] The term "aryl" represents a polyunsaturated aromatic hydrocarbon substituent, which can be mono-substituted, di-substituted or multi-substituted, and can be monovalent, divalent or polyvalent. It can be monocyclic or polycyclic (such as 1 to 3 rings), which are fused together or covalently linked. The aryl can be C 6-30 Aryl, preferably C 6-10 Aryl, non-limiting examples of which include phenyl, naphthyl, biphenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, fluorenyl, phenanthryl, benzophenanthryl, phenylphenanthryl, anthryl, benzoanthryl, indenyl, triphenylenyl, pyrenyl, etc.

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

[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.). For example, it can be "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "heteroaryl".

[0077] The terms "heterocycloalkyl", "heterocycloalkenyl", and "heterocycloalkynyl" refer to cycloalkyl, cycloalkenyl, and cycloalkynyl 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 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, for example, can be tetrahydrofuran, piperidinyl, morpholinyl, piperazinyl.

[0078] The term "arylalkyl" means "aryl-alkyl", and the term "heteroarylalkyl" means "heteroaryl-alkyl" or "heteroaryl-heteroalkyl", and 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, where aryl, heteroaryl, alkyl, and heteroalkyl conform to the above definitions, such as 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, arylalkyl, heteroarylalkyl, or heterocyclic group 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, arylalkyl, heteroarylalkyl, heterocyclic group, etc. Detailed implementation mode

[0080] The present invention will be explained in more detail below in combination with specific embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the essence and scope of the present invention are not limited thereto.

[0081] Comparative Example 1

[0082]

[0083] Compound 1 (ethyl cis-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate) (1.0 g, 3.32 mmol) and DMF (15 ml) were added to a reaction flask and stirred until completely dissolved. Sodium ethoxide (0.47 g, 6.91 mmol) was added, and methyl iodide (0.3 g, 2.11 mmol) was added while controlling the temperature at 20 - 30°C. The mixture was stirred at 20 - 30°C for 4 hours. The oil bath was heated to 40°C, and methyl iodide (0.3 g, 2.11 mmol) was added additionally, and the reaction was carried out overnight; the solvent was distilled off under reduced pressure, 50 ml of water and 30 ml of ethyl acetate were added, and liquid separation extraction was performed. The aqueous phase was extracted with ethyl acetate two more times. The organic phases were combined, washed once with 30 ml of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.84 g of a foamy solid, namely Compound 2 (ethyl cis-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate), and the yield was 80.2%.

[0084] Comparative Example 2

[0085]

[0086] Compound 1 (5.0 g, 16.6 mmol), acetone (50 ml), and potassium carbonate (5.73 g, 41.5 mmol) were added to a reaction flask and stirred evenly. Methyl iodide (4.7 g, 33.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 24 hours. The reaction solution was detected by HPLC, and the results showed that the content of the target compound was 44.24% and the remaining raw material was 52.77%.

[0087] Comparative Example 3

[0088]

[0089] Compound 1 (1.0 g, 3.32 mmol) and DMF (10 ml) were added to a reaction flask. Then, sodium hydroxide (0.27 g, 6.75 mmol) and 0.1 g of benzyltriethylammonium chloride (TEBAC) were added and stirred until dissolved. The temperature was lowered using an ice bath to below 20 °C, and methyl iodide (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 precipitated. 50 ml of ethyl acetate was added, and the mixture was separated by liquid extraction. The aqueous phase was extracted with ethyl acetate two more times. The organic phases were combined, washed with water three times and with brine once. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.82 g of an off-white solid. Then, 5 ml of methyl tert-butyl ether was added, and the mixture was slurried in an ice bath for about 1.5 hours, filtered, and dried to obtain 0.79 g of an off-white solid with a yield of 75.5%.

[0090] Comparative Example 4

[0091]

[0092] Compound 1 (5.0 g, 16.6 mmol) and DMF (50 ml) were added to a reaction flask. Then, sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred until dissolved. Methyl iodide (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 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 in vacuo at 65 ± 5 °C to a constant weight to obtain 3.90 g of an off-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) and DMSO (50 ml) were added to a reaction flask. Then, sodium hydroxide (1.66 g, 41.5 mmol) and 2.5 ml of water were added and stirred evenly. Methyl iodide (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 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 in vacuo at 65 ± 5 °C to a constant weight to obtain 4.87 g of an off-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), and sodium hydroxide (23.9 g, 597.50 mmol) were added to a reaction flask and stirred until completely dissolved. The temperature of the feed solution was controlled at 20 - 30°C, and methyl iodide (63.6 g, 448.08 mmol) was added dropwise. After the addition of methyl iodide was complete, the temperature of the feed solution was controlled at 20 - 30°C and stirred for 4 hours. The reaction progress was monitored by TLC. After the reaction ended, purified water (3150 ml) was added, and a large amount of white solid precipitated. The temperature was controlled at 20 - 30°C and stirred overnight. Filtration was carried out, and the filter cake was washed twice with purified water. The wet filter cake was spread on a tray and vacuum dried at 50 ± 5°C to constant weight, obtaining 89.95 g of an off-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 to a reaction flask and stirred evenly. Methyl iodide (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 precipitated. Stirring was carried out at room temperature for 2 hours. Filtration was carried out, and the filter cake was washed twice with purified water. The wet product was vacuum dried at 65 ± 5°C to constant weight, obtaining 5.0 g of an off-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 to a reaction flask, and then sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred until dissolved. Methyl iodide (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 precipitated. Stirring was carried out at room temperature for 2 hours. Filtration was carried out, and the filter cake was washed twice with purified water. The wet product was vacuum dried at 65 ± 5°C to constant weight, obtaining 4.74 g of an off-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 of water, and 0.25 g of benzyltriethylammonium chloride were added to a reaction flask. Then, sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred until dissolved. Methyl iodide (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 precipitated. The mixture was stirred at room temperature for 2 hours. The solid was filtered and the filter cake was washed twice with purified water. The wet product was dried in vacuo at 65 ± 5 °C to a constant weight, obtaining 4.78 g of an off-white solid with a yield of 91.3% and a purity of 99.48%.

[0108] Example 6

[0109]

[0110] Compound 1 (5.0 g, 16.6 mmol), acetone (50 ml), 2.5 ml of water were added to a reaction flask. Then, sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred until dissolved. Methyl iodide (4.7 g, 33.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. Water was added to the reaction solution, and a large amount of solid precipitated. The mixture was stirred at room temperature for 2 hours. The solid was filtered and the filter cake was washed twice with purified water. The wet product was dried in vacuo at 65 ± 5 °C to a constant weight, obtaining 4.91 g of an off-white solid with a yield of 93.8% and a purity of 99.50%.

[0111] Example 7

[0112]

[0113] Compound 1 (5.0 g, 16.6 mmol), DMF (50 ml), 2.5 ml of water were added to a reaction flask. Then, sodium hydroxide (1.66 g, 41.5 mmol) was added and stirred until dissolved. Dimethyl sulfate (4.19 g, 33.2 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. Water was added to the reaction solution, and a large amount of solid precipitated. The mixture was stirred at room temperature for 2 hours. The solid was filtered and the filter cake was washed twice with purified water. The wet product was dried in vacuo at 65 ± 5 °C to a constant weight, obtaining 4.81 g of an off-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), and 2.5 ml of water were added to a reaction flask and stirred evenly. Methyl iodide (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 under vacuum at 65 ± 5 °C to constant weight, and 4.83 g of solid was obtained with a yield of 92.3% and a purity of 96.3%.

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

Claims

1. A method for preparing 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, R1 and R3 are independently selected from H, alkyl, alkenyl or alkynyl, and the alkyl, alkenyl or alkynyl may be substituted or unsubstituted, and the substituents thereof are selected from one or more of halogen, OH, SH, NH2, NO2, CN, alkoxy, alkenyl, alkynyl and cycloalkyl, and R2 is selected from an amino protecting group; Preferably, the compounds represented by general formula I and II are compounds represented by general formula (cis)-I and (cis)-II, respectively: Furthermore, the compounds represented by the general formula (cis)-I and (cis)-II are the compounds represented by the general formula Ia and IIa respectively:

2. The preparation method according to claim 1, characterized in that: R1, R3 are independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl or C 2-10 Alkynyl, the alkyl, alkenyl, alkynyl may be substituted or unsubstituted, and the substituents are selected from halogen, OH, SH, NH2, NO2, CN, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-20 One or more of cycloalkyl; R2 is selected from COOR4, COR4 or SO2R4; R4 is 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 a 3-30 membered saturated or unsaturated heterocyclic group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl may be replaced by a heteroatom, and the alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclic group may be substituted or unsubstituted, and the substituents are selected from 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 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 One or more of an alkyl group, a 3- to 30-membered saturated or unsaturated heterocyclic group; Preferably, R1 and R3 are independently selected from H, C1-10 alkyl, trifluoromethyl, vinyl, propenyl, allyl, ethynyl or propynyl; R2 is selected from COOR4, COR4 or SO2R4; R4 is 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 The alkyl, alkenyl, cycloalkyl, aryl, heteroaryl may be substituted or unsubstituted, and the substituents are selected from 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 one or more of heteroaryl groups; Preferably, R1 is selected from C 1-10 Alkyl, R2 is selected from COCF3, R3 is selected from H; or R1, R3 is selected from H, R2 is selected from COOC 1-10 alkyl; Further preferably, R1 is selected from methyl, R2 is selected from COCF3, and R3 is selected from H; or R1 and R3 are selected from H, and R2 is selected from COOEt.

3. The preparation method according to claim 1 or 2, characterized in that: The methylating agent is selected from one or more of methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, and methyl fluorosulfonate.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The acid binding agent is selected from organic bases and / or inorganic bases; preferably one or more of amines, alkali metal or alkaline earth metal alkoxides, carbonates, bicarbonates, phosphates or hydroxides; more preferably potassium hydroxide, sodium hydroxide and / or sodium ethoxide.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The organic solvent is selected from one or more of ether, ketone, amide, and sulfone solvents, preferably one or more of diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetone, butanone, pentanone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar ratio of the methylating agent to the compound I is 1-5:1, preferably 1-3:1, more preferably 1.5-2:1; the molar ratio of the acid binding agent to the compound I is 1-10:1, preferably 1-5:1, more preferably 2-2.5:

1.

7. The preparation method according to any one of claims 1 to 6, characterized in that: Optionally the reaction is carried out in the presence of a phase transfer catalyst.

8. The preparation method according to claim 7, characterized in that: The phase transfer catalyst is a quaternary ammonium salt compound, preferably at least one of benzyltriethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium hydrogen sulfate.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The reaction temperature is not higher than 40°C, preferably -20 to 40°C.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The compound of formula I, an organic solvent, water, an acid-binding agent and a methylating agent are mixed and the temperature is controlled not higher than 40° C. to react to prepare a compound of formula II.

11. The preparation method according to any one of claims 1 to 10, characterized in that: After the reaction is completed, the reaction solution is mixed with an appropriate amount of water, stirred, and solids are precipitated, separated, and dried to obtain a compound of formula II.

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