CN116514813A - Preparation method of tyrosine kinase inhibitor and intermediate thereof - Google Patents

Preparation method of tyrosine kinase inhibitor and intermediate thereof Download PDF

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Publication number
CN116514813A
CN116514813A CN202211718989.0A CN202211718989A CN116514813A CN 116514813 A CN116514813 A CN 116514813A CN 202211718989 A CN202211718989 A CN 202211718989A CN 116514813 A CN116514813 A CN 116514813A
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compound
solvent
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朱鹏
王海波
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Xuanzhu Pharma Co Ltd
Xuanzhu Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the field of medicinal chemistry, and in particular discloses a tyrosine kinase inhibitor shown in a formula (I), an intermediate thereof and a preparation method of a stereoisomer thereof. The method has mild and controllable reaction conditions, simple and convenient operation, and the obtained final product has high purity and high yield, and is more suitable for large-scale industrial production.

Description

Preparation method of tyrosine kinase inhibitor and intermediate thereof
Technical Field
The invention relates to the field of pharmaceutical organic synthesis, in particular to a preparation method of a compound capable of being used as a tyrosine kinase inhibitor and an intermediate compound thereof. Wherein the tyrosine kinase is one or more of TRK, ALK and/or ROS 1.
Background
Molecular targeted therapy is a major breakthrough in cancer therapy in recent years. Compared with the traditional treatment means such as surgery, radiotherapy, chemotherapy and the like, the molecular targeting treatment opens up a new day for the treatment of cancer with high specificity and relatively low toxic and side effects, and has gradually become a standard treatment scheme for patients with advanced cancer. Protein kinases, a major area of targeted therapies, are key regulators of cell growth, proliferation and survival, and both genetic and epigenetic changes may lead to the development of cancer.
Anaplastic lymphoma kinase (ALK, anaplastic Lymphoma Kinase) belongs to the insulin receptor superfamily of receptor tyrosine kinases and plays an important role in brain development and in specific neurons. ALK mutations have been found in a variety of cancers, including Anaplastic Large Cell Lymphoma (ALCL), non-small cell lung cancer, inflammatory myofibroblast tumors, colorectal cancer, breast cancer, and several others.
Tropomyosin-related receptor tyrosine kinase (TRK) is a high affinity receptor for Neurotrophins (NTs). Members of the TRK family are highly expressed in cells of neural origin. Since TRK plays an important role in pain perception as well as tumor cell growth and survival signaling, inhibitors of TRK receptor kinase may provide benefits as therapeutic agents for pain and cancer.
ROS1 kinase is also a currently of interest as a tyrosine kinase receptor. ROS1 kinase has been reported to undergo gene rearrangement to produce constitutively active fusion proteins in many human cancers including glioblastoma, non-small cell lung cancer, colorectal cancer, breast cancer, and the like.
The three tyrosine kinases have stronger homology. The ROS1 gene and the ALK gene have 49% homology in a tyrosine kinase region sequence, the homology of the ROS1 gene and the ALK gene is as high as 77% in an ATP binding site of a kinase catalytic region, the kinase region sequence of TRK A/B/C has more than 80% homology, and the TRK A gene, the ROS1 gene and the ALK gene have about 40% homology in the tyrosine kinase region sequence. The ALK inhibitor Crizotinib (Crizotinib) on the market has the inhibition activity of ROS1 and TRK at the same time, and the TRK inhibitor Entrictinib (Entrectrinib) also has the inhibition activity of ALK and ROS 1.
Patent application CN113166155A discloses a compound with good tyrosine kinase receptor inhibition effect, the compound can effectively inhibit one or more tyrosine kinase receptors in TRK, ALK and ROS1, and meanwhile, the application document also discloses a preparation method of the compound, for example, an example compound 3', the specific synthetic route is as follows:
the method has a large number of reaction steps, and the post-treatment process is performed for multiple times, so that the application of the method in industrial production is greatly limited. Therefore, it is necessary to develop a preparation process which is simple in reaction steps, convenient to operate and easy to perform large-scale industrial production.
Disclosure of Invention
In view of the above problems, the present invention provides a preparation method of an intermediate useful for preparing a tyrosine kinase inhibitor represented by the general formula (I) and stereoisomers thereof, and further provides a method of preparing a tyrosine kinase inhibitor and stereoisomers thereof using the intermediate obtained by the method.
Scheme 1: the invention provides a preparation method of a compound shown in a formula (I) or a stereoisomer intermediate of the compound shown in a formula (VII) or a stereoisomer of the compound, which comprises the following steps:
Step 3: the compound of the formula (VI) is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII);
wherein,,
M 2 is N;
M 5 、M 6 each independently selected from CH or N;
ring C is selected from 3-6 membered saturated mono-heterocyclyl and 5-6 membered nitrogen containing mono-heterogenidesAryl, preferably a 5-6 membered saturated mono-heterocyclyl; the 3-6 membered saturated mono-heterocyclyl and 5-6 membered nitrogen containing mono-heteroaryl are each independently optionally substituted with: halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 An alkoxy group;
ring a is selected from phenyl and 5-6 membered mono-heteroaryl, preferably 5-6 membered nitrogen containing heteroaryl;
-(X 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, the left-hand bond of which is attached to ring A and the right-hand bond of which is attached to X 3 Are connected;
-(X 3 ) q -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, its left-side chemical bond and X 2 Is connected, and the right side chemical bond is connected with R;
R 2 each occurrence is independently selected from hydrogen, halogen, and the following groups optionally substituted with 1-3Q 1: c (C) 1-4 Alkyl, -OR a and-NR a R b The method comprises the steps of carrying out a first treatment on the surface of the Q1 is independently at each occurrence selected from hydroxy, amino, halogen, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 An alkoxy group;
R a and R is b Each at each occurrence is independently selected from hydrogen and C 1-4 An alkyl group;
R 5 and R is 6 Each at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, C 1-4 Alkyl and C 1-4 An alkoxy group;
R 4 independently at each occurrence selected from hydrogen and C optionally substituted with 1-2Q 2 1-4 An alkyl group; q2 is independently at each occurrence selected from the group consisting of hydroxy, amino, halogen, and C 1-4 An alkoxy group;
n is 0, 1 or 2;
r is selected from H or a protecting group.
Scheme 2: the preparation method of the foregoing scheme 1 further comprises the following steps:
step 2: the compound of formula (IV) and the compound of formula (V) are subjected to Mitsunobu reaction to obtain the compound of formula (VI);
wherein- (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) - (X) in the formula (VI) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected; ring a, ring C, R 2 、M 2 、M 5 、M 6 、-(X 3 ) q -、R a 、R b 、R 4 、R 5 、R 6 N, Q1, Q2, R are as described in scheme 1.
Scheme 3: the preparation method of the foregoing scheme 1 or scheme 2 further includes the following steps:
step 1: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound (IV);
wherein X is halogen, ring A, ring C, R 2 、M 2 、M 5 、M 6 、R a 、R b N, Q1, R are as described in scheme 1.
Scheme 4: the production process according to any one of the aforementioned schemes 1 to 3, wherein,
ring C is selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, diethylamino, trifluoromethyl and trifluoromethoxy; preferably, ring C is substituted with M and N atoms in its ring 5 、M 6 The C atoms attached are connected;
ring a is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, 1,3, 5-triazinyl and tetrazinyl;
R 2 Independently at each occurrence, selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl and trifluoromethoxy;
R 5 and R is 6 Each independently at each occurrence is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, and isopropoxy;
R 4 independently at each occurrence selected from hydrogen, methyl, ethyl, propylIsopropyl, butyl, isobutyl, and sec-butyl.
Scheme 5: the production process according to any one of the aforementioned schemes 1 to 4, wherein,
ring C is selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl; each of which is optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, diethylamino, trifluoromethyl and trifluoromethoxy; preferably, ring C is substituted with M and N atoms in its ring 5 、M 6 The C atoms attached are connected;
ring a is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, 1,3, 5-triazinyl and tetrazinyl;
R 2 independently at each occurrence, selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;
R 5 and R is 6 Each independently at each occurrence is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, or isopropyl;
R 4 independently at each occurrence selected from hydrogen, methyl, ethyl, propyl or isopropyl.
Scheme 6: a process for the preparation of a compound of formula (VII) or a stereoisomer thereof, comprising the steps of:
step 1: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);
step 2: the compound of formula (IV) and the compound of formula (V) are subjected to Mitsunobu reaction to obtain the compound of formula (VI);
step 3: the compound of the formula (VI) is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII);
wherein- (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) - (X) in the formulae (VI) and (VII) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected; ring a, ring C, R 2 、M 2 、M 5 、M 6 、-(X 2 ) p -、-(X 3 ) q -、R a 、R b 、R 4 、R 5 、R 6 N, Q1, Q2, R are as described in any one of schemes 1-5.
Scheme 7: the production process according to any one of the preceding schemes 1 to 6, wherein,
the compound of formula (I) has a structure as shown in formula (I-1):
the compound of formula (II) has a structure as shown in formula (II-1):
the compound of formula (III) has a structure as shown in formula (III-1):
the compound of formula (IV) has a structure as shown in formula (IV-1):
the compound of formula (VI) has a structure as shown in formula (VI-1):
the compound of formula (VII) has a structure as shown in formula (VII-1):
M 5 、M 6 each independently selected from CH or N;
ring C is selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, or hexahydropyrimidinyl; each of which is optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy;
ring A is selected fromPreferably, the wavy line labeled 1 indicates the point of attachment of ring A to ring C, and the wavy line labeled 2 indicates rings A and X 2 Is a connection point of (2);
-(X 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) Preferably with the left-hand bond attached to ring A and the right-hand bond attached to X 3 Are connected; preferably, - (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) -, the left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; - (X) 3 ) q -is selected from-C (R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, preferably its left-hand bond with X 2 Is connected, and the right side chemical bond is connected with R;
R 2 independently at each occurrence, selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;
R 5 and R is 6 Each independently at each occurrence is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, or isopropyl;
R 4 independently at each occurrence selected from hydrogen, methyl, ethyl, propyl, or isopropyl;
r is selected from H or a protecting group.
Scheme 8: the production process according to any one of the preceding schemes 1 to 7, wherein,
-(X 2 ) p -is selected from-CH 2 -、-CH 2 -CH 2 -、-CH(CH 3 )CH 2 -、-NH-CH 2 -、-CH 2 CH(CH 3 )-、-O-CH 2 -、-O-CH(CH 3 ) -, or-NH-CH (CH) 3 ) - (X) in the formulae (I), (VI), (VII), formula (I-1), (VI-1) and (VII-1) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected;
preferably, - (X) 2 ) p -selected from-NH-CH 2 -、-O-CH 2 -、-O-CH(CH 3 ) -or-NH-CH (CH) 3 ) - (X) in the formulae (I), (VI), (VII), formula (I-1), (VI-1) and (VII-1) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected; - (X) 3 ) q -is selected from-CH 2 -、-CH 2 -NH-、-CH(CH 3 )-NH-、-CH 2 -N(CH 3 )-、-CH(CH 3 )-O-、-CH 2 -O-or-CH (CH) 3 )-N(CH 3 ) -, preferably the left-hand bond thereof is bonded to X 2 The right side chemical bond is connected with R;
r is selected from H, an amino protecting group or a hydroxy protecting group, preferably acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl protecting groups.
Scheme 9: the production process according to any one of the preceding schemes 1 to 8, wherein the compound of formula (I) may be selected from the following compound structures or stereoisomers thereof:
scheme 10: the production process according to any one of the preceding schemes 1 to 9, wherein,
the specific process of the step 1 is as follows: mixing a compound of a formula (II), alkali and a solvent A, adding a compound of a formula (III), heating to a first temperature for reaction, and after the reaction is finished, carrying out aftertreatment to obtain a compound of a formula (IV);
the specific process of the step 2 is as follows: mixing a compound of a formula (V), a compound of a formula (IV), a solvent B and an azo reagent, adding a trisubstituted phosphine reagent at a certain temperature, heating to a second temperature for reaction, and after the reaction is finished, carrying out aftertreatment to obtain a compound of a formula (VI);
The specific process of the step 3 is as follows: mixing a solvent C, a compound of a formula (VI), trialkyl orthoformate, lewis acid and a catalyst, heating to a third temperature in a hydrogen environment for reaction, and performing aftertreatment after the reaction is finished to obtain the compound of the formula (VII).
Scheme 11: the production method according to any one of the foregoing schemes 1 to 10, wherein, in step 1,
the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, N-diisopropylethylamine, N-diisopropylmethylamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, sodium methoxide, potassium ethoxide, potassium acetate, potassium tert-butoxide, sodium hydride, potassium phosphate or sodium phosphate; preferably, the base is selected from triethylamine, N-diisopropylethylamine, N-diisopropylmethylamine or 4-dimethylaminopyridine; more preferably, the base is N, N-diisopropylethylamine;
the solvent A is an aprotic polar solvent, and the aprotic polar solvent is selected from an amide solvent, a ketone solvent, a nitrile solvent, a sulfoxide solvent or pyridine; preferably, the solvent a is selected from acetonitrile, N dimethylformamide, 1, 3-dimethyl-2-imidazolidinone or dimethylsulfoxide, more preferably, the solvent a is acetonitrile.
Scheme 12: the production method according to any one of the foregoing schemes 1 to 11, wherein, in step 2,
the azo reagent is selected from azo dicarboxylic acid di-lower alkyl ester and azo diamide reagent; the azo dicarboxylic acid di-lower alkyl ester reagent comprises azo dicarboxylic acid diethyl ester, azo dicarboxylic acid diisopropyl ester and di-tert-butyl azo dicarboxylic acid ester; the azodicarbonamide reagent comprises azodicarbonyl dipiperidine, N, N, N ', N' -tetraisopropyl azodicarbonamide and N, N, N ', N' -tetramethyl azodicarbonamide; preferably, the azo reagent is selected from diisopropyl azodicarboxylate and azodicarboxdipiperidine; more preferably, the azo reagent is azodicarbonyl dipiperidine;
the trisubstituted phosphine reagent is selected from triphenylphosphine, tri-n-butylphosphine and trimethylphosphine; preferably, the trisubstituted phosphine reagent is tri-n-butyl phosphine;
the solvent B is selected from halogenated hydrocarbon solvents, ether solvents, amide solvents, aromatic hydrocarbon solvents and nitrile solvents; the halogenated hydrocarbon solvent is selected from dichloromethane and chloroform; the ether solvent is selected from diethyl ether, diisopropyl ether, 1, 4-dioxane, tetrahydrofuran or methyl tertiary butyl ether; the amide solvent is selected from N, N-dimethylformamide and N, N-dimethylacetamide; the aromatic solvent is selected from toluene and benzene; the nitrile solvent is selected from acetonitrile; preferably, the solvent B is selected from dichloromethane or tetrahydrofuran.
Scheme 13: the process of any one of the preceding schemes 1 to 12, wherein, in step 3,
the solvent C is selected from alcohol solvents, and the alcohol solvents are selected from methanol, ethanol, isopropanol, tertiary butanol, tertiary amyl alcohol, tertiary hexanol, benzyl alcohol, glycol or glycerol;
the trialkyl orthoformate is selected from trimethyl orthoformate and triethyl orthoformate;
the lewis acid is selected from boron trifluoride, aluminum trichloride, ferric trichloride, indium tribromide, copper triflate, ytterbium triflate, yttrium triflate, scandium triflate, zinc triflate, iron triflate, lutetium triflate, lanthanum triflate, erbium triflate, samarium triflate, holmium triflate, dysprosium triflate, preferably the preferred lewis acid is selected from samarium triflate or ytterbium triflate;
the catalyst is selected from Raney nickel or Pd/C.
Scheme 14: the production process according to any one of the preceding schemes 1 to 13, wherein, in step 1,
the post-treatment comprises the following steps: cooling, adding water, regulating the pH of the reaction solution to 3.0-7.5 by using an acid solution, stirring to precipitate solid, filtering, washing and drying to obtain a compound shown in a formula (IV); optionally, the acidic solution is a saturated aqueous solution of citric acid.
Scheme 15: the production process according to any one of the schemes 1 to 14, wherein, in step 2,
the post-treatment comprises the following steps: cooling, adding an ester solvent, stirring to precipitate a solid, filtering, washing a filter cake, washing a filtrate with water, concentrating, adding an alcohol solvent, heating, stirring for crystallization, cooling, filtering, washing, and drying to obtain a compound shown in a formula (V); optionally, the ester solvent is selected from one or more of methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate, and the alcohol solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol and glycerol; preferably, the ester solvent is ethyl acetate, and the alcohol solvent is ethanol.
Scheme 15-1: the production process according to any one of the schemes 1 to 14, wherein, in step 2,
the post-treatment comprises the following steps: cooling, filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an alcohol solvent, pulping under heating, cooling, filtering, washing, and drying to obtain a compound shown in a formula (VI); optionally, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol; preferably, the alcoholic solvent is ethanol.
Scheme 16: the production process according to any one of the schemes 1 to 15 to 1, wherein in step 3,
the post-treatment comprises the following steps: filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an aliphatic hydrocarbon solvent, stirring for crystallization, filtering, washing and drying to obtain a compound shown in a formula (VII); optionally, the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane.
Scheme 17: the production process according to any one of the schemes 1 to 16, wherein, in step 1,
the molar ratio of the compound of formula (II) to the compound of formula (III) is from 1:0.8 to 1:1.2, preferably from 1:0.9 to 1:1.05;
the molar ratio of the compound of formula (II) to the base is from 1:1 to 1:10, preferably from 1:1 to 1:5, preferably from 1:2 to 1:4, preferably from 1:2 to 1:3;
the first reaction temperature is 25 to 80 ℃, preferably 50 to 80 ℃, more preferably 60 to 80 ℃.
Scheme 18: the production process according to any one of the schemes 1 to 17, wherein, in step 2,
the molar ratio of the compound of formula (IV) to the compound of formula (V) is from 1:1 to 1:2, preferably from 1:1 to 1:1.5;
the molar ratio of the compound of formula (IV) to azo reagent is from 1:1 to 1:5, preferably from 1:1 to 1:3, preferably from 1:1.2 to 1:2.2;
the molar ratio of the compound of formula (IV) to trisubstituted phosphine reagent is 1:1 to 1:5, preferably 1:1 to 1:3, preferably 1:1.2 to 1:2.2;
The addition temperature of the trisubstituted phosphine reagent is 5-50 ℃, preferably 20-40 ℃, preferably 25-45 ℃;
the second reaction temperature is 20 to 60 ℃, preferably 20 to 50 ℃, more preferably 35 to 45 ℃.
Scheme 19: the production process according to any one of the schemes 1 to 18, wherein, in step 3,
the molar ratio of the compound of formula (VI) to the trialkylorthoformate is from 1:1 to 1:20, preferably from 1:5 to 1:15;
the molar ratio of the compound of formula (VI) to Lewis acid is from 1:0.1 to 1:2, preferably from 1:0.1 to 1:1, more preferably from 1:0.1 to 1:0.5;
the third reaction temperature is 20 to 70 ℃, preferably 20 to 60 ℃, more preferably 30 to 60 ℃.
Scheme 20: the production process according to any one of the preceding schemes 1 to 19, wherein,
the compound represented by formula (I) has a structure represented by formula (I'):
the compound represented by formula (II) has a structure represented by formula (II'):
the compound represented by formula (III) has a structure represented by formula (III'):
the compound represented by formula (IV) has a structure represented by formula (IV'):
the compound represented by formula (V) has a structure represented by formula (V):
the compound represented by formula (VI) has a structure represented by formula (VI'):
the compound represented by formula (VII) has a structure represented by formula (VII'):
Scheme 21: a process for producing a compound represented by the formula (VII') or a stereoisomer thereof, which comprises the steps of,
step 1: mixing a compound of a formula (II '), a nitrile solvent and alkali, adding the compound of a formula (III'), and heating to 60-80 ℃ for reaction; after the reaction is finished, obtaining a compound of a formula (IV') through post-treatment;
step 2: mixing a compound of a formula (IV '), a compound of a formula (V'), an ether reagent and an azo reagent, controlling the temperature to be 25-45 ℃, dropwise adding a trisubstituted phosphine reagent, and controlling the temperature to be 35-45 ℃ for reaction after the dropwise adding is finished; after the reaction is finished, obtaining a compound of a formula (VI') through post-treatment;
step 3: mixing alcohol reagent, compound of formula (VI'), trialkyl orthoformate, lewis acid and catalyst, H 2 Heating to 50-60 ℃ for reaction under the environment; after the reaction is finished, the compound of formula (VII') is obtained through post-treatment.
Scheme 21-1: a process for producing a compound represented by the formula (VII') or a stereoisomer thereof, which comprises the steps of,
step 1: mixing a compound of a formula (II '), a nitrile solvent and alkali, adding the compound of a formula (III') under stirring, and heating to 60-80 ℃ for reaction; after the reaction is finished, cooling to 20-30 ℃, regulating the pH of the reaction solution to 6.0-7.5 through an acid solution, stirring to separate out solid, filtering, washing and drying to obtain a compound of a formula (IV');
Step 2: mixing a compound of a formula (IV '), a compound of a formula (V'), an ether reagent and an azo reagent, controlling the temperature to be 25-45 ℃ under stirring, dropwise adding a trisubstituted phosphine reagent, and controlling the temperature to be 35-45 ℃ for reaction after the dropwise adding is finished; after the reaction is finished, cooling to 10-15 ℃, adding an ester reagent, stirring to separate out solid, filtering, washing filtrate with water, concentrating, adding an alcohol solvent, heating to 60-70 ℃, stirring for crystallization, cooling, filtering, washing and drying to obtain a compound of the formula (VI');
step 3: mixing alcohol reagent, compound of formula (VI'), trialkyl orthoformate, lewis acid and catalyst, H 2 Heating to 50-60 ℃ for reaction under the environment; after the reaction is finished, filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an aliphatic hydrocarbon solvent, stirring for crystallization, filtering, washing and drying to obtain the compound shown in the formula (VII').
Scheme 21-2: a process for producing a compound represented by the formula (VII') or a stereoisomer thereof, which comprises the steps of,
step 1: mixing a compound of a formula (II '), a nitrile solvent and alkali, adding the compound of a formula (III') under stirring, and heating to 60-80 ℃ for reaction; after the reaction is finished, cooling to 20-30 ℃, regulating the pH of the reaction solution to 6.0-7.5 through an acid solution, stirring to separate out solid, filtering, washing and drying to obtain a compound of a formula (IV');
Step 2: mixing a compound of a formula (IV '), a compound of a formula (V'), an ether reagent and an azo reagent, controlling the temperature to be 20-40 ℃ under stirring, dropwise adding a trisubstituted phosphine reagent, and controlling the temperature to be 30-40 ℃ for reaction after the dropwise adding is finished; after the reaction is finished, cooling to 10-15 ℃, filtering, washing, merging filtrate, concentrating, adding an alcohol solvent, heating to 60-80 ℃, stirring for crystallization, cooling, filtering, washing and drying to obtain a compound shown in a formula (VI');
step 3: mixing alcohol reagent, compound of formula (VI'), trialkyl orthoformate, lewis acid and catalyst, H 2 Heating to 50-60 ℃ for reaction under the environment; after the reaction is finished, filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an aliphatic hydrocarbon solvent, stirring and crystallizingThe compound of formula (VII') is obtained by filtration, washing and drying.
Scheme 22: the production method according to the aforementioned scheme 21, 21-1 or 21-2, wherein,
the nitrile solvent is acetonitrile;
the base is selected from triethylamine, N-diisopropylethylamine or N, N-diisopropylethylamine;
the acid solution is saturated citric acid aqueous solution;
the ether reagent is selected from methyl tertiary butyl ether or tetrahydrofuran;
the azo reagent is selected from diisopropyl azodicarboxylate or azodicarbonyl dipiperidine;
The trisubstituted phosphine reagent is tri-n-butyl phosphine;
the ester reagent is ethyl acetate;
the alcohol solvent is selected from methanol, ethanol, isopropanol, n-butanol or glycol; the alcohol reagent is selected from methanol, ethanol, isopropanol, n-butanol or ethylene glycol;
the trialkyl orthoformate is selected from trimethyl orthoformate or triethyl orthoformate;
the Lewis acid is ytterbium triflate;
the catalyst is selected from Raney nickel or Pd/C;
the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane.
Scheme 23: a process for the preparation of a compound of formula (I) or a stereoisomer thereof, comprising the steps of:
1) A process for the preparation of a compound of formula (VII) or a stereoisomer thereof according to any one of schemes 1-22;
2) Step 4: when R is a protecting group, the compound of the formula (VII) is subjected to deprotection reaction to obtain the compound of the formula (VIII), and then the compound of the formula (VIII) is subjected to acylation reaction to obtain the compound of the formula (I); when R is H, the compound of the formula (I) is directly obtained through an acylation reaction of the compound of the formula (VII);
wherein- (X) 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, the left-hand bond of which is attached to ring A and the right-hand bond of which is attached to X 3 Are connected; preferably, - (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -or-O-C (R) 5 )(R 6 ) -, the left bond is attached to ring A and the right bond is attached to X 3 Are connected; m is M 2 、M 5 、M 6 Ring C, ring A, R 2 、-(X 3 ) q -、R、n、R 4 、R 5 、R 6 、R a 、R b Q1, Q2 are as described in any one of schemes 1-8.
Scheme 24: a process for the preparation of a compound of formula (I) or a stereoisomer thereof, comprising the steps of:
step 1: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);
step 2: the compound of formula (IV) and the compound of formula (V) are subjected to Mitsunobu reaction to obtain the compound of formula (VI);
step 3: the compound of the formula (VI) is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII);
step 4: when R is a protecting group, the compound of the formula (VII) is subjected to deprotection reaction to obtain the compound of the formula (VIII), and then the compound of the formula (VIII) is subjected to acylation reaction to obtain the compound of the formula (I); when R is H, the compound of the formula (I) is directly obtained through an acylation reaction of the compound of the formula (VII);
wherein- (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) -, in the formula (VI), the formula (VII), the formula (V)III) and- (X) in formula (I) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected; m is M 2 、M 5 、M 6 Ring C, ring A, R 2 、-(X 3 ) q -、R、n、R 4 、R 5 、R 6 、R a 、R b Q1, Q2 are as described in any one of schemes 1-8; the preparation method of step 1-step 3 is as described in any one of schemes 1-22.
Scheme 25: the production method according to the aforementioned scheme 23 or scheme 24, wherein,
the compound of formula (VII) further has a structure as shown in formula (VII-1):
the compound of formula (VIII) further has a structure as shown in formula (VIII-1):
the compound of formula (I) further has a structure as shown in formula (I-1):
wherein- (X) 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, the left-hand bond of which is attached to ring A and the right-hand bond of which is attached to X 3 Are connected; preferably, - (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -or-O-C (R) 5 )(R 6 ) -, the left bond is attached to ring A and the right bond is attached to X 3 Are connected; m is M 5 、M 6 Ring C, ring A, R 2 、-(X 3 ) q -、R、n、R 4 、R 5 、R 6 、R a 、R b Q1, Q2 are as described in any one of schemes 1-8.
Scheme 26: the production process according to any one of the preceding schemes 23 to 25, wherein,
the compound of formula (VII) further has a structure as shown in formula (VII'):
the compound of formula (VII) further has a structure as shown in formula (VIII):
the compound of formula (I) further has a structure as shown in formula (I'):
scheme 27: a process for the preparation of a compound of formula (I') or a stereoisomer thereof, comprising the steps of:
step 1: reacting a compound of formula (II ') with a compound of formula (III ') to obtain a compound of formula (IV ');
step 2: the compound of formula (IV ') and the compound of formula (V ') are subjected to Mitsunobu reaction to obtain the compound of formula (VI ');
Step 3: the compound of the formula (VI ') is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII');
step 4: deprotection of a compound of formula (VII ') to give a compound of formula (VIII');
step 5: the compound of formula (VIII ') is acylated to obtain a compound of formula (I');
wherein, the preparation method of the step 1 to the step 3 is as described in any one of the schemes 10 to 22.
The options of any of the embodiments described in the present invention may be combined with each other, and the combined technical solutions are still included in the protection scope of the present invention.
In the description and claims of the present invention, compounds are named according to chemical structural formulas, and if the same compounds are represented, the named and chemical structural formulas of the compounds are not identical, the chemical structural formulas are used as references.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is in control.
"halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
"C" as described in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, for example," C 1-5 Alkyl "," C 1-4 Alkyl "," C 1-3 Alkyl "," C 1-2 Alkyl "," C 2-6 Alkyl "," C 2-5 Alkyl "," C 2-4 Alkyl "," C 2-3 Alkyl "," C 3-6 Alkyl "," C 3-5 Alkyl "," C 3-4 Alkyl "," C 4-6 Alkyl "," C 4-5 Alkyl "," C 5-6 Alkyl ", and the like. Examples thereof include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" as described in the present invention 1-4 Alkyl "means C 1-6 Having 1-4 carbon atoms in the alkyl radicalIs a specific example of (a).
"C" as described in the present invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" as described in the present invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
The invention relates to a hydroxy C 1-6 Alkyl "," amino C 1-6 Alkyl "and" halo C 1-6 Alkyl "refers to C respectively 1-6 A group obtained by substituting hydrogen in an alkyl group with one or more hydroxyl groups, amino groups or halogens, wherein the C 1-6 Alkyl is as defined above.
"halogenated C" according to the invention 1-6 Alkoxy "means" C 1-6 The hydrogen in the alkoxy "is substituted with one or more halogens.
"C" as described in the present invention 1-6 Alkylamino groups and di (C) 1-6 Alkyl) amino "means" C ", respectively 1-6 alkyl-NH- "and its preparation
The "3-to 10-membered cycloalkyl" as used herein includes "3-to 8-membered cycloalkyl" and "8-to 10-membered fused ring alkyl".
The "3-8-membered cycloalkyl" as used herein means a saturated or partially saturated and non-aromatic monocyclic alkyl group having 3 to 8 ring carbon atoms, and includes "3-8-membered saturated cycloalkyl" and "3-8-membered partially saturated cycloalkyl", preferably "3-4-membered cycloalkyl", "3-5-membered cycloalkyl", "3-6-membered cycloalkyl", "3-7-membered cycloalkyl", "4-5-membered cycloalkyl", "4-6-membered cycloalkyl", "4-7-membered cycloalkyl", "4-8-membered cycloalkyl", "5-6-membered cycloalkyl", "5-7-membered cycloalkyl", "5-8-membered cycloalkyl", "6-7-membered cycloalkyl", "6-8-membered cycloalkyl", "3-6-membered saturated cycloalkyl", "5-8-membered saturated cycloalkyl", "5-7-membered saturated cycloalkyl", "5-6-membered saturated cycloalkyl", and the like. Specific examples of the "3-8 membered saturated cycloalkyl group" include, but are not limited to, cyclopropane group (cyclopropyl group), cyclobutane group (cyclobutyl group), cyclopentane group (cyclopentyl group), cyclohexane group (cyclohexyl group), cycloheptane group (cycloheptyl group), cyclooctyl group (cyclooctyl group) and the like; and specific examples of the "3-8 membered partially saturated cycloalkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-dienyl, cyclohex-1, 4-dienyl, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl, and the like.
The term "8-to 10-membered fused ring alkyl" as used herein refers to a saturated or partially saturated cyclic alkyl group having 8 to 10 ring carbon atoms and having no aromaticity, which is formed by sharing two or more cyclic structures with each other by two or more adjacent carbon atoms (one ring of the fused ring alkyl groups may be an aromatic ring but the fused ring alkyl group as a whole does not have aromaticity), and includes "8-to 9-membered fused ring alkyl", "9-to 10-membered fused ring alkyl", and the like, and the manner of the fusion thereof may be 5-to 6-membered cycloalkyl and 5-to 6-membered cycloalkyl, benzo 5-to 6-membered cycloalkyl, and the like. Examples include, but are not limited to, bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, decatetrahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3 a-tetrahydropenta-dienyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3, 4a,5,6,8 a-octahydro-naphthyl, 1,2,4a,5,6,8 a-hexahydro-naphthyl, 1,2,3,4,5,6,7,8,9, 10-decahydro-phenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.
The "3-10 membered heterocyclic group" as used herein includes "3-8 membered heterocyclic group" and "8-10 membered condensed heterocyclic group".
As used herein, "3-8 membered heterocyclyl" means a ring having at least one (e.g., 1,2, 3,4 or 5) ring heteroatomAnd a saturated or partially saturated monocyclic group having 3 to 8 ring atoms and having no aromaticity, and the hetero atom is a nitrogen atom, an oxygen atom and/or a sulfur atom. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) may be substituted with oxo (oxo) groups (forming, e.g., c= O, N = O, S =o or SO 2 Ring members). "3-8 membered heterocyclic group" includes "3-8 membered saturated heterocyclic group" and "3-8 membered partially saturated heterocyclic group". Preferably, a "3-8 membered heterocyclic group" contains 1-3 heteroatoms, for example, contains one or two heteroatoms selected from nitrogen atoms and oxygen atoms, or contains one nitrogen atom. Preferably, the "3-8 membered heterocyclic group" is "3-7 membered heterocyclic group", "3-6 membered heterocyclic group", "4-7 membered heterocyclic group", "4-6 membered heterocyclic group", "6-8 membered heterocyclic group", "5-7 membered heterocyclic group", "5-6 membered heterocyclic group", "3-6 membered saturated heterocyclic group", "5-6 membered saturated heterocyclic group", "3-6 membered nitrogen-containing heterocyclic group", "3-6 membered saturated nitrogen-containing heterocyclic group", "5-6 membered saturated nitrogen-containing heterocyclic group", or the like. It may for example contain only one or two nitrogen atoms, or one nitrogen atom and one or two other heteroatoms (e.g. oxygen atoms and/or sulphur atoms). Specific examples of "3-8 membered heterocyclic group" include, but are not limited to, aziridinyl, 2H-aziridinyl, diazacyclyl, 3H-diazacyclyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, oxazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 2, 6-oxazinyl, 4, 3-oxazinyl, 4-1, 3-dihydropyrazinyl, 4H-3-oxazinyl, 4H-1, 3-oxazinyl, 4H-3H-oxazinyl, 4-H-1, 3-H-oxazinyl, etc.
The "8-to 10-membered fused heterocyclic group" as described in the present invention means a saturated or partially saturated and non-aromatic cyclic group containing 8 to 10 ring atoms and at least one of which is a heteroatom (one ring in the fused heterocyclic group may be an aromatic ring but the fused heterocyclic group as a whole does not have aromatic properties) formed by sharing two adjacent atoms with each other by two or more cyclic structures, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) may be substituted with oxo groups (forming, for example, c= O, N = O, S =o or SO 2 Ring members). "8-10 membered fused heterocyclic group" includes "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group" and the like, and the manner of the fusion may be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered cycloalkyl group, benzo 5-6 membered heterocyclic group, 5-6 membered heteroaryl group and 5-6 membered heterocyclic group, wherein 5-6 membered heteroaryl group is defined as below. Examples of "8-to 10-membered fused heterocyclyl" include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinyl-morpholinyl, benzopyrrolidinyl, tetrahydroimidazo [4,5-c ] ]Pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl and benzo [ d ]][1,3]Dioxolanyl, 1, 3-dihydroisobenzofuranyl, 2H-chromene-2-keto, 4H-chromene, 4H-chromen-4-keto, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d]Imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ]]Imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ]]Imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ]]Imidazolyl, benzimidazolyl, and octahydrobenzo [ d ]]Imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ]]Imidazolyl, octahydrocyclopenta [ c ]]Pyrrolyl, indolinyl, isoindolinyl, benzoxazolidinyl, benzothiazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 4H-1, 3-benzoxazinyl, and the like.
The "6-10 membered aryl" described herein includes "6-8 membered monocyclic aryl" and "8-10 membered condensed ring aryl".
"6-8 membered monocyclic aryl" as used herein refers to monocyclic aryl groups containing 6-8 ring carbon atoms, examples of which include, but are not limited to, phenyl, cyclooctatetraenyl, and the like, and phenyl is preferred.
The "8-to 10-membered condensed ring aryl" as used herein refers to an aromatic cyclic group containing 8 to 10 ring carbon atoms formed by sharing two or more adjacent carbon atoms with each other by two or more cyclic structures, and preferably "9-to 10-membered condensed ring aryl" such as naphthyl and the like.
The "5-to 10-membered heteroaryl" as used herein includes "5-to 8-membered single heteroaryl" and "8-to 10-membered fused heteroaryl".
"5-8 membered mono-heteroaryl" as used herein refers to an aromatic monocyclic ring group containing 5-8 ring atoms, at least one of which is a heteroatom, such as nitrogen, oxygen or sulfur. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) may be substituted with oxo groups (forming, for example, c= O, N = O, S =o or SO 2 Ring members). "5-8 membered mono-heteroaryl" includes "5-7 membered mono-heteroaryl", "5-6 membered nitrogen containing mono-heteroaryl", "6 membered nitrogen containing mono-heteroaryl", etc., at least one of the ring heteroatoms in the "nitrogen containing mono-heteroaryl" being a nitrogen atom, e.g. it may contain only one or two nitrogen atoms, or one nitrogen atom and one or two other heteroatoms (e.g. oxygen atom and/or sulfur atom), or two nitrogen atoms and one or two other heteroatoms (e.g. oxygen atom and/or sulfur atom). Specific examples of "5-8 membered mono-heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazinohepttrienyl, azocyclotetraenyl and the like. Specific examples of "5-6 membered single heteroaryl" include, but are not limited to, those containing 5-6 ring atoms in the specific examples of "5-8 membered single heteroaryl" described above.
The "8-to 10-membered fused heteroaryl group" as used herein refers to a cyclic structure having an aromatic nature, which is formed by sharing two adjacent atoms with each other by two or more cyclic structures, wherein at least one ring atom is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom. Optionally, the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) may be substituted with oxo groups (forming, for example, c= O, N = O, S =o or SO 2 Ring members). "8-10 membered fused heteroaryl" includes "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl" and the like, and the manner of fusion may be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and the like. Specific examples of "8-to 10-membered fused heteroaryl" include, but are not limited to, pyrrolopyrrolyl, pyrrolofuranyl, pyrazolopyrrolyl, pyrazolothienyl, furanothioyl, pyrazolooxazolyl, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The term "optionally substituted with … …" as used herein includes both "substituted with … …" and "unsubstituted with … …".
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound through which an acidic functional group (e.g., -COOH, -OH, -SO) is present 3 H, etc.) with suitable inorganic or organic bases (including alkali metal salts, alkaline earth metal salts, ammonium salts, and salts with nitrogen-containing organic bases), or by basic functional groups present therein (e.g., -NH) 2 Etc.) with a suitable inorganic or organic acid (e.g., carboxylic acid, etc.).
"stereoisomers" as used herein refers to compounds of the present invention which may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers when they contain one or more asymmetric centers. The compounds of the invention may have asymmetric centers and thus result in the presence of two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compounds of the present invention contain olefinic double bonds, the scope of the present invention includes cis-isomers and trans-isomers unless specified otherwise. The compounds described herein may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.
The organic solvent is selected from at least one of aromatic hydrocarbon, aliphatic hydrocarbon, alicyclic hydrocarbon, halohydrocarbon, alcohols, ethers, esters, ketones, glycol derivatives, phenols, nitriles, amides, sulfones, sulfoxides, heteroaromatics and mixtures thereof, wherein the aromatic hydrocarbon solvent is selected from at least one of benzene, toluene and xylene, the aliphatic hydrocarbon solvent is selected from at least one of N-pentane, N-hexane, N-heptane and N-octane, the alicyclic hydrocarbon solvent is selected from at least one of cyclopentane and cyclohexane, the halohydrocarbon solvent is selected from at least one of dichloromethane, chloroform, chlorobenzene and dichlorobenzene, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, tert-hexyl alcohol, benzyl alcohol, ethylene glycol and glycerol, the ether solvent is at least one selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether and 1, 4-dioxane, the ester solvent is at least one selected from methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate, the ketone solvent is at least one selected from acetone, methyl butyl ketone, 1, 3-dimethyl-2-imidazolidinone and methyl isobutyl ketone, the glycol derivative solvent is at least one selected from ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, the phenolic solvent is at least one selected from phenol and p-cresol, the nitrile solvent is at least one selected from acetonitrile and propionitrile, the amide solvent is at least one selected from N, N-dimethylformamide and N, N-dimethylacetamide, the sulfone solvent is at least one selected from dimethyl sulfone, phenyl sulfone, diethyl sulfone, diphenyl sulfone and sulfolane, the sulfoxide solvent is selected from at least one of dimethyl sulfoxide, diethyl sulfoxide and benzyl sulfoxide, and the heteroaromatic solvent is selected from pyridine.
The 'alkali' is at least one of organic alkali and inorganic alkali respectively and independently.
The "inorganic base" as used herein refers to an inorganic substance capable of giving a lone pair of electrons and generally not containing a carbon element, and specific examples thereof include, but are not limited to: sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, ammonium hydroxide, lithium hydroxide as an alkali metal hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide as an alkaline earth metal hydroxide, magnesium hydroxide, barium hydroxide, and the like.
The "organic base" refers to an organic compound having basicity. The organic base is classified into alkali metal salts of alcohols selected from at least one of lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, alkyl metal lithium compounds selected from at least one of butyl lithium and phenyl lithium, amino metal lithium compounds selected from at least one of lithium diisopropylamide and lithium hexamethyldisilazide, and amine compounds selected from fatty amines such as at least one of N, N-diisopropylethylamine, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzylamine, tert-butylamine and hexamethylenediamine; an alcohol amine such as at least one of monoethanolamine, diisopropanolamine and N, N-diethylethanolamine, an amide such as at least one of formamide, acetamide, acrylamide, colchicine, camptothecine, N-dimethylformamide and dimethylacetamide, an alicyclic amine such as at least one of cyclohexylamine, diethylenetriamine, hexamethylenetetramine, morpholine and piperazine, an aromatic amine such as at least one of aniline, diphenylamine, benzidine, o-phenylenediamine, p-methylaniline, p-chloroaniline, m-ethoxyaniline and m-nitroaniline, a naphthalene amine such as at least one of 1-naphthylamine, 2-naphthylamine, clavulanic acid, tobias acid, R acid, K acid and naphthalene diamine, polyethylenimine, hydroxylamine; fatty amines, such as at least one of N, N-diisopropylethylamine, dimethylamine, diethylamine, triethylamine and hexamethylenediamine, are preferred.
The "acid" as used herein includes organic acids and inorganic acids, the organic acids including, but not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, citric acid, and the like; inorganic acids include, but are not limited to, hydrochloric acid, concentrated sulfuric acid, hydrobromic acid, hydrofluoric acid, nitric acid, nitrous acid, boric acid, and the like.
The term "protecting group" as used herein refers to a class of substituents that are used to react with other functional groups on a compound to block or protect a particular functional group. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects an amino function on a compound. "hydroxy protecting group" refers to a class of hydroxy substituents that effectively block or protect the function of a hydroxy group. Suitable protecting groups include, but are not limited to, acetyl and silyl. "carboxy protecting group" refers to a class of carboxy substituents that effectively block or protect a carboxy group.
"amino protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzoyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucinyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, trityl, 2-nitrobenzylthio, methanesulfonyl, p-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxyphenylmethylene, 2-hydroxy-5-chlorobenzenemethylene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3-dimethyl-5-oxycyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l, 3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.
"carboxy" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-methylsulfonylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, isopropylsilyl, di-t-butylsilyl, di-butylsilyl, and di-t-butylsilyl.
"hydroxy or mercapto" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropyloxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2-trichloroethoxycarbonyl, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphine) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl methylate, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, t-butyl, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methylsulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl and t-butylmethoxyphenylsilyl.
In the preparation method of the invention, the drying includes but is not limited to the following drying methods: normal pressure drying, reduced pressure drying, spray drying, boiling drying, freeze drying, infrared drying, microwave drying, moisture absorption drying, etc. One skilled in the art can select one or more drying modes depending on the nature of the product obtained, and perform one or more drying modes depending on the humidity of the product.
The raw materials or reagents described in the present invention are commercially available unless otherwise specified.
The beneficial technical effects of the invention are as follows:
(1) The synthetic route of the compound of the formula (VII ') disclosed in the prior art comprises a plurality of reaction steps such as substitution reaction, reduction reaction, cyclization reaction, demethylation reaction, upper protection reaction and the like, and the compound of the formula (VII') disclosed in the invention can be obtained only through three steps of substitution reaction, mitsunobu reaction and reductive cyclization reaction, so that the total yield of the whole route reaction is improved by at least 10% while the reaction steps are reduced, and the cost is reduced by 45%.
(2) In the preparation method disclosed by the invention, the reaction raw materials are easy to obtain, the reaction selectivity is high, the byproducts are few, and in the reaction process of each step, no hazardous reagent is used, so that the reaction process is environment-friendly.
(3) The reaction conditions of each step are mild and controllable, the post-treatment process is simple and convenient, the operations such as column chromatography and the like are avoided, and the method is more suitable for industrial production.
Detailed Description
Preferred embodiments of the present invention will be described in detail below with reference to examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention may be made by those skilled in the art without departing from the spirit and scope of this invention.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1: preparation of tert-butyl ((R) -1- ((3- ((R) -1- (3H-imidazo [4,5-b ] pyridin-5-yl) pyrrolidin-2-yl) -5-fluoropyridin-2-yl) oxy) propan-2-yl) carbamate (Compound of formula (VII')
1. Preparation of (R) -3- [1- (6-amino-5-nitropyridin-2-yl) pyrrolidin-2-yl ] -5-fluoropyridin-2-ol (preparation of Compound of formula (IV'))
Acetonitrile (300 mL) and (R) -5-fluoro-3- (pyrrolidin-2-yl) pyridin-2-ol hydrochloride (90.25 g,0.38mol, 91.60% content) and N, N-diisopropylethylamine (147.52 g,1.14 mol) were added to a 3L three-necked flask with stirring. After stirring at 25℃for 0.5h, 2-amino-3-nitro-6-chloropyridine (65.95 g,0.38 mol) was added, followed by acetonitrile (60 mL). Heating to 70 ℃, and treating the reaction until the reaction is completed when the raw material is less than 1.0%. Cooling to 20-30 ℃, adding water (2.2L), and then adjusting the pH to about 7 by using saturated citric acid aqueous solution. Cooling to 5-15 ℃, stirring for 1 hour, filtering, washing a filter cake with water (200 mL), transferring to a vacuum drying oven, drying under reduced pressure for 20-24 hours at 50 ℃ to obtain 114.81g of a target compound, and obtaining the yield: 94.7%, degree: 99.1%
The molecular formula: c (C) 14 H 14 FN 5 O 3 Molecular weight 319.3LC-MS (M/e): 320.1 (M+H) + )
1 H-NMR(400MHz,DMSO-d6)δ:11.64(s,1H),8.11(d,J＝9.2Hz,0.5H),7.98(d,J＝9.2Hz,1H),7.65-7.85(m,1H),7.46-7.54(m,1.5H),7.12(d,J＝5.2Hz,0.5H),7.02(d,J＝6.0Hz,0.5H),6.14(d,J＝9.4Hz,0.5H),5.54(d,J＝9.3Hz,0.5H),5.27(d,J＝7.4Hz,0.5H),4.94(d,J＝7.7Hz,0.5H),3.87～3.96(m,1H),3.61～3.64(m,0.5H),3.45～3.48(m,0.5H),2.20-2.50(m,0.5H),2.05-2.0(m,0.5H),1.75-2.00(m,3H).
The inventors examined some of the influencing factors in the above step 1, and the results thereof are as follows:
1) By varying the amount of N, N-diisopropylethylamine, the compound of formula (IV') was obtained when the amount of N, N-diisopropylethylamine to be fed was 2.0eq, 2.2eq, 2.4eq, 2.6eq, 2.8eq, 3.0eq, 3.2eq and 3.4eq, respectively, relative to (R) -5-fluoro-3- (pyrrolidin-2-yl) pyridin-2-ol hydrochloride, and the purity of the product was highest when N, N-diisopropylethylamine was 3.0 eq.
2) The compound of formula (IV') can be obtained by changing the first reaction temperature to 25 ℃, 50 ℃, 60 ℃ and 80 ℃ respectively.
3) The compound of formula (IV') can be obtained by changing the amount of 2-amino-3-nitro-6-chloropyridine when the amount of the 2-chloropyridine to be added is 0.8eq, 0.9eq, 0.95eq, 1.0eq, 1.05eq, respectively, relative to the amount of the (R) -5-fluoro-3- (pyrrolidin-2-yl) pyridine-2-ol hydrochloride.
4) The compound of formula (IV') can be obtained when the pH is 3.2, 4.5, 6.0, or 7.5, by changing the pH adjusted with saturated aqueous citric acid during the post-treatment.
2. Preparation of tert-butyl ((R) -1- ((3- ((R) -1- (6-amino-5-nitropyridin-2-yl) pyrrolidin-2-yl) -5-fluoropyridin-2-yl) oxy) propan-2-yl) carbamate (preparation of Compound of formula (VI'))
Tetrahydrofuran (1.5L) was added to a 3L three-necked flask, and tert-butyl (R) - (1-hydroxypropan-2-yl) carbamate (59.95 g,0.34 mol), (R) -3- [1- (6-amino-5-nitropyridin-2-yl) pyrrolidin-2-yl) was added sequentially with stirring]5-Fluoropyridin-2-ol (100.51 g,0.31 mol) and azodicarbonyl dipiperidine (160.40 g,0.63 mol) were added to tetrahydrofuran (0.5L). N (N) 2 Stirring at 25℃for 0.5h under protection. Trin (130.55 g,0.64 mol) was added dropwise at a controlled temperature of 25℃to 45 ℃. After the addition, the mixture is reacted at the temperature of between 35 and 45 ℃ until the raw materials remain<1.0%. After the reaction was completed, the temperature was lowered to 10℃and ethyl acetate (1L) was added thereto and stirred for 0.5h. The mixture was filtered, and the filter cake was washed with ethyl acetate (1L), and the filtrates were combined. The filtrate was washed with water (2 L.times.3), the organic phase was concentrated under reduced pressure, then, anhydrous ethanol (500 mL) was added, the mixture was heated to 65℃and stirred for crystallization for 1 hour, the temperature was lowered to 25℃and stirred for 0.5 hour, the mixture was filtered, washed with ethanol (100 mL) and n-heptane (200 mL) in this order, and dried to give 100.68g of the target compound in 67.1% yield. Purity 99.6%.
The molecular formula: c (C) 22 H 29 FN 6 O 5 Molecular weight 476.5LC-MS (M/e): 477.2 (M+H) + )
1 H-NMR(400MHz,DMSO-d 6 )δ:7.70-8.25(m,4H),6.90-7.01(m,1H),6.14(d,J＝8.4Hz,0.5H),5.54(d,J＝9.2Hz,0.5H),5.38(s,0.5H),5.13(s,0.5H),4.05～4.30(m,2H),3.80～3.95(m,2H),3.45～3.78(m,1H),2.20-2.50(m,1H),1.90-2.05(m,2H),1.38(s,9H),1.15(d,J＝6.8Hz,3H).
The inventors examined some of the influencing factors in the above step 2, and the results thereof are as follows:
(1) Changing the feeding amount of the azodicarbonyl dipiperidine, and obtaining the compound of the formula (IV ') after reaction when the feeding amount is 1.2eq, 1.4eq, 1.6eq, 1.8eq, 2.0eq and 2.2eq relative to the compound of the formula (IV'). And when the charging amount of the azodicarbonyl dipiperidine is 1.4 to 1.6eq, the product has higher purity.
(2) Changing the feeding amount of tri-n-butyl phosphine, and obtaining the compound of the formula (IV ') through reaction when the feeding amount is 1.2eq, 1.4eq, 1.6eq, 1.8eq, 2.0eq and 2.2eq relative to the compound of the formula (IV'). And when the feeding amount of tri-n-butyl phosphine is 1.4 eq-1.6 eq, the product has higher purity.
(3) The temperature of the tri-n-butyl phosphine is changed, and when the temperature of the tri-n-butyl phosphine is 5-10 ℃, 15-20 ℃, 25-35 ℃ and 35-43 ℃ respectively, the compound of the formula (VI') can be obtained.
(4) The compound of formula (VI') can be obtained by changing the second reaction temperature at 30.+ -. 3 ℃, 40.+ -. 3 ℃, 50.+ -. 3 ℃ and 60.+ -. 3 ℃ respectively.
(5) Changing the post-treatment mode, cooling to 10-15 ℃ after the reaction is finished, filtering, washing a filter cake by tetrahydrofuran, merging filtrate, concentrating filtrate, adding ethanol, stirring for 2 hours at 60-80 ℃, cooling to 10-30 ℃, filtering, washing and drying to obtain the compound shown in the formula (VI').
3. Preparation of tert-butyl ((R) -1- ((3- ((R) -1- (3H-imidazo [4,5-b ] pyridin-5-yl) pyrrolidin-2-yl) -5-fluoropyridin-2-yl) oxy) propan-2-yl) carbamate (preparation of Compound of formula (VII')
To a 3L three-necked flask was added absolute ethanol (1L), followed by stirring by tert-butyl ((R) -1- ((3- ((R) -1- (6-amino-5-nitropyridin-2-yl) pyrrolidin-2-yl) -5-fluoropyridin-2-yl) oxy) propan-2-yl) carbamate (200 g,0.42 mol), trimethyl orthoformate (4476 g,4.2 mol), ytterbium triflate (2.6 g,42 mmol) and Pd/C (20 g) and then ethanol (1L) was added. H 2 The reaction is carried out for three times, and stirring reaction is carried out at 40-50 ℃ under the hydrogen environment until the residual amount of the raw materials is less than or equal to 0.5 percent. Filtering, filteringThe cake was rinsed with absolute ethanol (600 mL) and the filtrates combined. After the filtrate was concentrated under reduced pressure, n-heptane (320 mL) was added thereto, and the mixture was stirred and crystallized at 25℃for 1 hour. The mixture was filtered, and the cake was washed with n-heptane (190 mL), then transferred to a vacuum oven and dried under reduced pressure at 50℃for 15 hours to give 169.68g of the objective compound in 88.5% yield.
The molecular formula: c (C) 23 H 29 FN 6 O 3 Molecular weight 456.5LC-MS (M/e): 457.3 (M+H+)
1 H-NMR(400MHz,DMSO-d 6 )δ:12.5(s,1H),7.97(d,J＝2.8Hz,1H),7.90(s,1H),7.75(d,J＝8.2Hz,1H),7.12(dd,J＝2.8Hz,J＝8.8Hz,1H),6.97(d,J＝8.0Hz,1H),6.30(d,J＝4.8Hz,1H),5.20(d,J＝8.0Hz,1H),4.24～4.29(m,1H),4.13～4.18(m,1H),3.95～3.98(m,1H),3.87(t,J＝8.0Hz,1H),3.46-3.54(m,1H),2.31-2.38(m,1H),1.89-2.05(m,2H),1.70-1.89(m,1H),1.40(s,9H),1.19(d,J＝7.2Hz,3H).
Example 2: (2 2 R,6R)-3 5 -fluoro-6-methyl-1 3 H-4-oxa-7-aza-1 (5, 3) -imidazo [4,5-b]Preparation of pyridin-3 (3, 2) -pyridin-2 (1, 2) -pyrrolidin-cyclooctan-8-one (Compound of formula (I'))
A process for preparing a compound of formula (VIII ') from a compound of formula (VII'), and a process for preparing a compound of formula (I ') from a compound of formula (VIII') are described in example 5 of PCT/CN 2019/116459.

Claims (10)

1. A process for producing a compound represented by the formula (VII) or a stereoisomer thereof, characterized by comprising the steps of:
step 3: the compound of the formula (VI) is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII);
wherein,,
M 2 is N;
M 5 、M 6 each independently selected from CH or N;
ring C is selected from 3-6 membered saturated mono-heterocyclyl and 5-6 membered nitrogen containing mono-heteroaryl, preferably 5-6 membered saturated mono-heterocyclyl; the 3-6 membered saturated mono-heterocyclyl and 5-6 membered nitrogen containing mono-heteroaryl are each independently optionally substituted with: halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 An alkoxy group;
ring a is selected from phenyl and 5-6 membered mono-heteroaryl, preferably 5-6 membered nitrogen containing heteroaryl;
-(X 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、
-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, the left-hand bond of which is attached to ring A and the right-hand bond of which is attached to X 3 Are connected;
-(X 3 ) q -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、
-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, its left-side chemical bond and X 2 Is connected, and the right side chemical bond is connected with R;
R 2 each occurrence is independently selected from hydrogen, halogen, and the following groups optionally substituted with 1-3Q 1: c (C) 1-4 Alkyl, -OR a and-NR a R b The method comprises the steps of carrying out a first treatment on the surface of the Q1 is independently at each occurrence selected from hydroxy, amino, halogen, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino group,Di (C) 1-4 Alkyl) amino, halo C 1-4 Alkyl, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 An alkoxy group;
R a and R is b Each at each occurrence is independently selected from hydrogen and C 1-4 An alkyl group;
R 5 and R is 6 Each at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, C 1-4 Alkyl and C 1-4 An alkoxy group;
R 4 independently at each occurrence selected from hydrogen and C optionally substituted with 1-2Q 2 1-4 An alkyl group; q2 is independently at each occurrence selected from the group consisting of hydroxy, amino, halogen, and C 1-4 An alkoxy group;
n is 0, 1 or 2;
r is H or a protecting group.
2. A process for the preparation of a compound of formula (VII) or a stereoisomer thereof as claimed in claim 1, further comprising the steps of:
step 2: the compound of formula (IV) and the compound of formula (V) are subjected to Mitsunobu reaction to obtain the compound of formula (VI);
wherein- (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -and-O-C (R 5 )(R 6 ) - (X) in the formula (VI) 2 ) p The left-hand bond is attached to ring A and the right-hand bond is attached to X 3 Are connected; in the formula (V) - (X) 2 ) p The left-hand bond is attached to a hydrogen atom and the right-hand bond is attached to X 3 Are connected; ring a, ring C, R 2 、M 2 、M 5 、M 6 、-(X 3 ) q -、R a 、R b 、R 4 、R 5 、R 6 N, Q1, Q2, R are as defined in claim 1.
3. A process for the preparation of a compound of formula (VII) or a stereoisomer thereof as claimed in claim 1 or 2, further comprising the steps of:
step 1: reacting a compound of formula (II) with a compound of formula (III) to obtain a compound (IV);
wherein X is halogen, ring A, ring C, R 2 、M 2 、M 5 、M 6 、R a 、R b N, Q1, R are as defined in claim 1.
4. A process for the preparation of a compound of formula (VII) or a stereoisomer thereof according to claim 1 to 3,
the specific process of the step 1 is as follows: mixing a compound of a formula (II), alkali and a solvent A, adding a compound of a formula (III), heating to a first temperature for reaction, and after the reaction is finished, carrying out aftertreatment to obtain a compound of a formula (IV);
The specific process of the step 2 is as follows: mixing a compound of a formula (V), a compound of a formula (IV), a solvent B and an azo reagent, adding a trisubstituted phosphine reagent at a certain temperature, heating to a second temperature for reaction, and after the reaction is finished, carrying out aftertreatment to obtain a compound of a formula (VI);
the specific process of the step 3 is as follows: mixing a solvent C, a compound of a formula (VI), trialkyl orthoformate, lewis acid and a catalyst, heating to a third temperature in a hydrogen environment for reaction, and performing aftertreatment after the reaction is finished to obtain the compound of the formula (VII).
5. A process for the preparation of a compound of formula (VII) as claimed in any of claims 1 to 4,
in step 1, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, N-diisopropylethylamine, N-diisopropylmethylamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, sodium methoxide, potassium ethoxide, potassium acetate, potassium t-butoxide, sodium hydride, potassium phosphate, or sodium phosphate; preferably, the base is selected from triethylamine, N-diisopropylethylamine, N-diisopropylmethylamine or 4-dimethylaminopyridine; more preferably, the base is N, N-diisopropylethylamine;
The solvent A is an aprotic polar solvent, and the aprotic polar solvent is selected from amide solvents, ketone solvents, nitrile solvents, sulfoxide solvents or pyridine; preferably, the solvent a is selected from acetonitrile, N dimethylformamide, 1, 3-dimethyl-2-imidazolidinone or dimethyl sulfoxide, more preferably, the solvent a is acetonitrile;
in the step 2, the azo reagent is selected from azo dicarboxylic acid di-lower alkyl ester and azo diamide reagent; the azo dicarboxylic acid di-lower alkyl ester reagent comprises azo dicarboxylic acid diethyl ester, azo dicarboxylic acid diisopropyl ester and di-tert-butyl azo dicarboxylic acid ester; the azodicarbonamide reagent comprises azodicarbonyl dipiperidine, N, N, N ', N' -tetraisopropyl azodicarbonamide and N, N, N ', N' -tetramethyl azodicarbonamide; preferably, the azo reagent is selected from diisopropyl azodicarboxylate and azodicarboxdipiperidine; more preferably, the azo reagent is azodicarbonyl dipiperidine;
the trisubstituted phosphine reagent is selected from triphenylphosphine, tri-n-butylphosphine and trimethylphosphine; preferably, the trisubstituted phosphine reagent is tri-n-butyl phosphine;
the solvent B is selected from halogenated hydrocarbon solvents, ether solvents, amide solvents, aromatic hydrocarbon solvents and nitrile solvents; the halogenated hydrocarbon solvent is selected from dichloromethane and chloroform; the ether solvent is selected from diethyl ether, diisopropyl ether, 1, 4-dioxane, tetrahydrofuran or methyl tertiary butyl ether; the amide solvent is selected from N, N-dimethylformamide and N, N-dimethylacetamide; the aromatic solvent is selected from toluene and benzene; the nitrile solvent is selected from acetonitrile; preferably, the solvent B is selected from dichloromethane or tetrahydrofuran;
In the step 3, the solvent C is selected from alcohol solvents, wherein the alcohol solvents are selected from methanol, ethanol, isopropanol, tertiary butanol, tertiary amyl alcohol, tertiary hexanol, benzyl alcohol, ethylene glycol and glycerol;
the trialkyl orthoformate is selected from trimethyl orthoformate and triethyl orthoformate;
the lewis acid is selected from boron trifluoride, aluminum trichloride, ferric trichloride, indium tribromide, copper triflate, ytterbium triflate, yttrium triflate, scandium triflate, zinc triflate, iron triflate, lutetium triflate, lanthanum triflate, erbium triflate, samarium triflate, holmium triflate, dysprosium triflate, preferably the preferred lewis acid is selected from samarium triflate or ytterbium triflate;
the catalyst is selected from Raney nickel or Pd/C.
6. A process for the preparation of a compound of formula (VII) or a stereoisomer thereof according to any one of claims 1 to 5,
in step 1, the post-treatment comprises the following steps: cooling, adding water, regulating the pH of the reaction solution to 3.0-7.5 with an acidic solution, stirring to precipitate a solid, filtering, washing, and drying to obtain a compound shown in a formula (IV); optionally, the acidic solution is a saturated aqueous solution of citric acid;
In step 2, the post-processing includes the following steps: cooling, adding an ester solvent, stirring to precipitate a solid, filtering, washing a filter cake, washing a filtrate with water, concentrating, adding an alcohol solvent, heating, stirring for crystallization, cooling, filtering, washing, and drying to obtain a compound shown in a formula (VI); optionally, the ester solvent is selected from one or more of methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate, and the alcohol solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol and glycerol; preferably, the ester solvent is ethyl acetate, and the alcohol solvent is ethanol;
or in step 2, the post-treatment comprises the following steps: cooling, filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an alcohol solvent, pulping under heating, cooling, filtering, washing, and drying to obtain a compound shown in a formula (VI); optionally, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol; preferably, the alcohol solvent is ethanol;
In step 3, the post-processing includes the following steps: filtering, washing a filter cake, concentrating the filtrate under reduced pressure, adding an aliphatic hydrocarbon solvent, stirring for crystallization, filtering, washing and drying to obtain a compound shown in a formula (VII); optionally, the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane.
7. A process for the preparation of a compound of formula (VII) or a stereoisomer thereof according to any one of claims 1 to 6,
in step 1, the molar ratio of the compound of formula (II) to the compound of formula (III) is from 1:0.8 to 1:1.2, preferably from 1:0.9 to 1:1.05;
the molar ratio of the compound of formula (II) to the base is from 1:1 to 1:10, preferably from 1:1 to 1:5, preferably from 1:2 to 1:4, preferably from 1:2 to 1:3;
the first reaction temperature is 25 to 80 ℃, preferably 50 to 80 ℃, more preferably 60 to 80 ℃;
in step 2, the molar ratio of the compound of formula (IV) to the compound of formula (V) is from 1:1 to 1:2, preferably from 1:1 to 1:1.5;
the molar ratio of the compound of formula (IV) to azo reagent is from 1:1 to 1:5, preferably from 1:1 to 1:3, preferably from 1:1.2 to 1:2.2;
the molar ratio of the compound of formula (IV) to trisubstituted phosphine reagent is 1:1 to 1:5, preferably 1:1 to 1:3, preferably 1:1.2 to 1:2.2;
the addition temperature of the trisubstituted phosphine reagent is 5-50 ℃, preferably 20-40 ℃, preferably 25-45 ℃;
The second reaction temperature is 20 to 60 ℃, preferably 20 to 50 ℃, more preferably 35 to 45 ℃;
in step 3, the molar ratio of the compound of formula (VI) to the trialkylorthoformate is from 1:1 to 1:20, preferably from 1:5 to 1:15;
the molar ratio of the compound of formula (VI) to Lewis acid is from 1:0.1 to 1:2, preferably from 1:0.1 to 1:1, more preferably from 1:0.1 to 1:0.5;
the third reaction temperature is 20 to 70 ℃, preferably 20 to 60 ℃, more preferably 30 to 60 ℃.
8. A process for the preparation of a compound of formula (I) or a stereoisomer thereof, comprising the steps of:
1) A process for the preparation of a compound of formula (VII) or a stereoisomer thereof as defined in any one of claims 1 to 7;
2) Step 4: when R is a protecting group, the compound of the formula (VII) is subjected to deprotection reaction to obtain the compound of the formula (VIII), and then the compound of the formula (VIII) is subjected to acylation reaction to obtain the compound of the formula (I); when R is H, the compound of the formula (I) is directly obtained through an acylation reaction of the compound of the formula (VII);
wherein- (X) 2 ) p -is selected from-C (R 5 )(R 6 )-、-C(R 5 )(R 6 )-C(R 5 )(R 6 )-、-N(R 4 )-C(R 5 )(R 6 )-、-O-C(R 5 )(R 6 )-、-C(R 5 )(R 6 )-N(R 4 ) -and-C (R) 5 )(R 6 ) O-, the left-hand bond of which is attached to ring A and the right-hand bond of which is attached to X 3 Are connected; preferably, - (X) 2 ) p -is selected from-N (R) 4 )-C(R 5 )(R 6 ) -or-O-C (R) 5 )(R 6 ) -, the left bond is attached to ring A and the right bond is attached to X 3 Are connected; m is M 2 、M 5 、M 6 Ring C, ring A, R 2 、-(X 3 ) q -、R、n、R 4 、R 5 、R 6 、R a 、R b Q1, Q2 are as defined in claim 1.
9. A process for producing a compound of formula (I) or a stereoisomer thereof according to claim 8,
the formula (VII) beingThe compound further has a structure as shown in formula (VII'):
the compound of formula (VIII) further has a structure as shown in formula (VIII'):
the compound of formula (I) further has a structure as shown in formula (I'):
10. a process for the preparation of a compound of formula (I') or a stereoisomer thereof, comprising the steps of:
step 1: reacting a compound of formula (II ') with a compound of formula (III ') to obtain a compound of formula (IV ');
step 2: the compound of formula (IV ') and the compound of formula (V ') are subjected to Mitsunobu reaction to obtain the compound of formula (VI ');
step 3: the compound of the formula (VI ') is subjected to reduction and ring closure reaction to obtain a compound of the formula (VII');
step 4: deprotection of a compound of formula (VII ') to give a compound of formula (VIII');
step 5: the compound of formula (VIII ') is acylated to give the compound of formula (I').
CN202211718989.0A 2021-12-31 2022-12-30 Preparation method of tyrosine kinase inhibitor and intermediate thereof Pending CN116514813A (en)

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