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

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 present invention relates to the field of pharmaceutical organic synthesis, and in particular, to a method for preparing a compound that can be used as a tyrosine kinase inhibitor and an intermediate compound thereof, wherein the tyrosine kinase is one or more of TRK, ALK and/or ROS1.

Background Art

Molecular targeted therapy is a major breakthrough in cancer treatment in recent years. Compared with traditional treatments such as surgery, radiotherapy and chemotherapy, molecular targeted therapy has opened up a new world for cancer treatment with its high specificity and relatively low toxicity and side effects, and has gradually become a standard treatment for patients with advanced cancer. Protein kinase, as a major area of targeted therapy, is a key regulator of cell growth, proliferation and survival, and its genetic and epigenetic changes may lead to the occurrence of cancer.

Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor superfamily of receptor tyrosine kinases and plays an important role in brain development and specific neurons. ALK mutations have been found in a variety of cancers, including anaplastic large cell lymphoma (ALCL), non-small cell lung cancer, inflammatory myofibroblastic tumors, colorectal cancer, breast cancer and several other cancers.

Tropomyosin-related receptor tyrosine kinase (TRK) is a high affinity receptor for neurotrophin (NT). Members of the TRK family are highly expressed in cells of neural origin. Since TRK plays an important role in pain perception and tumor cell growth and survival signaling, inhibitors of TRK receptor kinases may provide benefits as therapeutic agents for pain and cancer.

ROS1 kinase is also a tyrosine kinase receptor that has attracted much attention. 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, etc.

The above three tyrosine kinases have strong homology. The ROS1 gene and the ALK gene have 49% homology in the tyrosine kinase region sequence, and the homology between the two in the ATP binding site of the kinase catalytic region is as high as 77%. The kinase region sequence of TRK A/B/C has more than 80% homology, and the TRK A gene, ROS1 gene and ALK gene have about 40% homology in the tyrosine kinase region sequence. The ALK inhibitor Crizotinib, which has been marketed, has inhibitory activity against both ROS1 and TRK, and the TRK inhibitor Entrectinib also has inhibitory activity against ALK and ROS1.

Patent application CN113166155A discloses a class of compounds with good tyrosine kinase receptor inhibitory effects, which can effectively inhibit one or more tyrosine kinase receptors in TRK, ALK and ROS1. The application document also discloses a method for preparing such compounds, such as Example Compound 3', whose specific synthesis route is as follows:

The method has a large number of reaction steps and multiple column chromatography operations are performed during the post-treatment process, which greatly limits its application in industrial production. Therefore, it is necessary to develop a preparation process with simple reaction steps, convenient operation, and easy large-scale industrial production.

Summary of the invention

In view of the above problems, the present invention provides a method for preparing an intermediate of a tyrosine kinase inhibitor as shown in the general formula (I) and its stereoisomers, and further provides a method for preparing a tyrosine kinase inhibitor and its stereoisomers using the intermediate obtained by the method.

Scheme 1: The present invention provides a method for preparing a compound represented by formula (I) or an intermediate of a stereoisomer thereof represented by formula (VII) or a stereoisomer thereof, which comprises the following steps:

Step 3: The compound of formula (VI) is subjected to a reduction ring-closing reaction to obtain the compound of formula (VII);

in,

M ² is N;

M ⁵ and M ⁶ are independently selected from CH or N;

Ring C is selected from 3-6 membered saturated monoheterocyclic group and 5-6 membered nitrogen-containing monoheteroaryl group, preferably 5-6 membered saturated monoheterocyclic group; the 3-6 membered saturated monoheterocyclic group and the 5-6 membered nitrogen-containing monoheteroaryl group are each independently and optionally substituted by the following substituents: halogen, amino, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di(C _1-4 alkyl)amino, halogenated C _1-4 alkyl, hydroxyl C _1-4 alkyl, aminoC _1-4 alkyl and halogenated C _1-4 alkoxy;

Ring A is selected from phenyl and 5-6 membered monoheteroaryl, 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 )-, -OC(R ⁵ )(R ⁶ )-, -C(R ⁵ )(R ⁶ )-N(R ⁴ )- and -C(R ⁵ )(R ⁶ )-O-, the left side chemical bond of which is connected to ring A, and the right side chemical bond of which is connected to X ³ ;

-(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 )-, -OC(R ⁵ )(R ⁶ )-, -C(R ⁵ )(R ⁶ )-N(R ⁴ )- and -C(R ⁵ )(R ⁶ )-O-, the left side chemical bond of which is connected to X ² , and the right side chemical bond of which is connected to R;

^R2 is independently selected at each occurrence from hydrogen, halogen, and the following groups optionally substituted with 1-3 Q1: _C1-4 alkyl, ^-ORa and ^-NRaRb ; Q1 is independently selected at each occurrence from hydroxyl, amino, halogen, nitro, cyano, _C1-4 ^alkyl , _C1-4 alkoxy, _C1-4 alkylamino, di( _C1-4 alkyl)amino, _haloC1-4 alkyl, _hydroxyC1-4 alkyl, _aminoC1-4 alkyl and _haloC1-4 alkoxy;

^Ra and ^Rb, at each occurrence, are independently selected from hydrogen and _C1-4 alkyl;

R ⁵ and R ⁶ are each independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C _1-4 alkyl and C _1-4 alkoxy;

^R4 is independently selected at each occurrence from hydrogen and _C1-4 alkyl optionally substituted with 1-2 Q2; Q2 is independently selected at each occurrence from hydroxy, amino, halogen and _C1-4 alkoxy;

n is 0, 1 or 2;

R is selected from H or a protecting group.

Scheme 2: The preparation method described in Scheme 1 above 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 -OC(R ⁵ )(R ⁶ )-; in formula (VI), the left chemical bond of -(X ² ) _p - is connected to ring A, and the right chemical bond is connected to X ³ ; in formula (V), the left chemical bond of -(X ² ) _p - is connected to a hydrogen atom, and the right chemical bond is connected to X ³ ; ring A, ring C, R ² , M ² , M ⁵ , M ⁶ , -(X ³ ) _q -, ^Ra , R ^b , R ⁴ , R ⁵ , R ⁶ , n, Q1, Q2, and R are as described in Scheme 1.

Scheme 3: The preparation method described in Scheme 1 or Scheme 2 above further comprises 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, and ring A, ring C, R ² , M ² , M ⁵ , M ⁶ , ^Ra , R ^b , n, Q1, and R are as described in Scheme 1.

Scheme 4: The preparation method according to any one of Schemes 1 to 3, wherein:

Ring C is selected from aziridine, 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 following: 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 connected to the C atom to which M ⁵ and M ⁶ are connected via the N atom on its ring;

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, pyridinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl and tetrazinyl;

^R2, at each occurrence, is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methylamino, dimethylamino, ethylamino, diethylamino, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;

R ⁵ and R ⁶ are each independently selected at each occurrence from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy and isopropoxy;

^R4 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl.

Scheme 5: The preparation method according to any one of Schemes 1 to 4, wherein:

Ring C is selected from aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl; each of which is optionally substituted by a substituent selected from the following: 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 connected to the C atom to which M ⁵ and M ⁶ are connected via the N atom on its ring;

Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl and tetrazinyl;

^R2, at each occurrence, is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;

R ⁵ and R ⁶ are each independently selected at each occurrence from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl or isopropyl;

^R4 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

Scheme 6: A method for preparing a compound represented by intermediate formula (VII) or a stereoisomer thereof, comprising the following steps:

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 formula (VI) is subjected to a reduction ring-closing reaction to obtain the compound of formula (VII);

Wherein, -(X ² ) _p - is selected from -N(R ⁴ )-C(R ⁵ )(R ⁶ )- and -OC(R ⁵ )(R ⁶ )-; in formula (VI) and formula (VII), the left chemical bond of -(X ² ) _p - is connected to ring A, and the right chemical bond is connected to X ³ ; in formula (V), the left chemical bond of -(X ² ) _p - is connected to a hydrogen atom, and the right chemical bond is connected to X ³ ; ring A, ring C, R ² , M ² , M ⁵ , M ⁶ , -(X ² ) _p -, -(X ³ ) _q -, ^Ra , R ^b , R ⁴ , R ⁵ , R ⁶ , n, Q1, Q2, and R are as described in any one of Schemes 1 to 5.

Scheme 7: The preparation method described in any one of 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 and M ⁶ are independently selected from CH or N;

Ring C is selected from aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl or hexahydropyrimidinyl; each of which is optionally substituted with a substituent selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy;

Ring A is selected from Preferably, the wavy line marked with 1 represents the connection point between ring A and ring C, and the wavy line marked with 2 represents the connection point between ring A and ^X2 ;

-(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 -OC(R ⁵ )(R ⁶ )-, preferably the left chemical bond thereof is connected to ring A, and the right chemical bond thereof is connected to X ³ ; preferably, -(X ² ) _p - is selected from -N(R ⁴ )-C(R ⁵ )(R ⁶ )- and -OC(R ⁵ )(R ⁶ )-, preferably the left chemical bond thereof is connected to ring A, and the right chemical bond thereof is connected to X ³ ; -(X ³ ) _q - is selected from -C(R ⁵ )(R ⁶ )-N(R ⁴ )- and -C(R ⁵ )(R ⁶ )-O-, preferably the left chemical bond thereof is connected to X ² , and the right side chemical bond is connected to R;

^R2, at each occurrence, is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;

R ⁵ and R ⁶ are each independently selected at each occurrence from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, methyl, ethyl, propyl or isopropyl;

R ⁴ at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;

R is selected from H or a protecting group.

Scheme 8: The preparation method according to any one of 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 )-, and in Formula (I), Formula (VI), Formula (VII), Formula (I-1), Formula (VI-1) and Formula (VII-1), the left chemical bond of -(X ² ) _p - is connected to Ring A, and the right chemical bond is connected to X ³ ; in Formula (V), the left chemical bond of -(X ² ) _p - is connected to a hydrogen atom, and the right chemical bond is connected to X ³ ;

Preferably, -(X ² ) _p - is selected from -NH-CH ₂ -, -O-CH ₂ -, -O-CH(CH ₃ )- or -NH-CH(CH ₃ )-, and in Formula (I), Formula (VI), Formula (VII), Formula (I-1), Formula (VI-1) and Formula (VII-1), the left chemical bond of -(X ² ) _p - is connected to Ring A, and the right chemical bond is connected to X ³ ; in Formula (V), the left chemical bond of -(X ² ) _p - is connected to a hydrogen atom, and the right chemical bond is connected to X ³ ; -(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 )-, and preferably the left chemical bond thereof is connected to X ² , and the right side chemical bond is connected to R;

R is selected from H, an amino protecting group or a hydroxy protecting group, preferably an acetyl group, a trifluoroacetyl group, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group and a 9-fluorenylmethoxycarbonyl protecting group.

Scheme 9: The preparation method according to any one of Schemes 1 to 8, wherein the compound of formula (I) can be selected from the following compound structures or stereoisomers thereof:

Scheme 10: The preparation method according to any one of Schemes 1 to 9, wherein:

The specific process of step 1 is: mixing the compound of formula (II), a base and a solvent A, adding the compound of formula (III), heating to a first temperature for reaction, and after the reaction is completed, post-treating to obtain the compound of formula (IV);

The specific process of step 2 is: mixing the compound of formula (V), the compound of formula (IV), solvent B and the azo reagent, adding a trisubstituted phosphine reagent at a certain temperature, heating to a second temperature for reaction, and after the reaction is completed, post-treating to obtain the compound of formula (VI);

The specific process of step 3 is: mixing solvent C, compound of formula (VI), trialkyl orthoformate and Lewis acid, and catalyst, heating to a third temperature for reaction under a hydrogen environment, and after the reaction, post-treating to obtain compound of formula (VII).

Scheme 11: The preparation method according to any one of 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,N-diisopropylethylamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, sodium methoxide, potassium ethoxide, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium phosphate or sodium phosphate; preferably, the base is selected from triethylamine, N,N-diisopropylethylamine, N,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,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone or dimethyl sulfoxide, and more preferably, the solvent A is acetonitrile.

Scheme 12: The preparation method described in any one of Schemes 1 to 11, wherein in step 2,

The azo reagent is selected from di-lower alkyl azodicarboxylate and azodicarbonamide reagents; di-lower alkyl azodicarboxylate reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate; azodicarbonamide reagents include dipiperidine azodicarbonyl, N,N,N',N'-tetraisopropyl azodicarbonamide and N,N,N',N'-tetramethyl azodicarbonamide; preferably, the azo reagent is selected from diisopropyl azodicarboxylate and dipiperidine azodicarbonyl; more preferably, the azo reagent is dipiperidine azodicarbonyl;

The trisubstituted phosphine reagent is selected from triphenylphosphine, tri-n-butylphosphine and trimethylphosphine; preferably, the trisubstituted phosphine reagent is tri-n-butylphosphine;

The solvent B is selected from halogenated hydrocarbon solvents, ether solvents, amide solvents, aromatic hydrocarbons and nitrile solvents; the halogenated hydrocarbon solvents are selected from dichloromethane and chloroform; the ether solvents are selected from diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran or methyl tert-butyl ether; the amide solvents are selected from N,N-dimethylformamide and N,N-dimethylacetamide; the aromatic hydrocarbon solvents are selected from toluene and benzene; the nitrile solvents are selected from acetonitrile; preferably, the solvent B is selected from dichloromethane or tetrahydrofuran.

Scheme 13: The preparation method according to any one of Schemes 1 to 12, wherein in step 3,

The solvent C is selected from an alcohol solvent, and the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butyl alcohol, tert-amyl alcohol, tert-hexyl alcohol, benzyl alcohol, ethylene glycol or glycerol;

The trialkyl orthoformate is selected from trimethyl orthoformate and triethyl orthoformate;

The Lewis acid is selected from boron trifluoride, aluminum trichloride, iron trichloride, indium trichloride, indium tribromide, copper trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, iron trifluoromethanesulfonate, lutetium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, erbium trifluoromethanesulfonate, samarium trifluoromethanesulfonate, holmium trifluoromethanesulfonate, dysprosium trifluoromethanesulfonate, preferably, the preferred Lewis acid is selected from samarium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate;

The catalyst is selected from Raney nickel or Pd/C.

Scheme 14: The preparation method according to any one of Schemes 1 to 13, wherein in step 1,

The post-treatment comprises the following steps: cooling, adding water, adjusting the pH of the reaction solution to 3.0-7.5 with an acidic solution, stirring to precipitate solids, filtering, washing, and drying to obtain a compound represented by formula (IV); optionally, the acidic solution is a saturated citric acid aqueous solution.

Scheme 15: The preparation method according to any one of 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 the filter cake, washing the filtrate with water, concentrating, adding an alcohol solvent, heating and stirring to crystallize, cooling, filtering, washing, and drying to obtain a compound represented by 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, tert-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 preparation method according to any one of Schemes 1 to 14, wherein in step 2,

The post-treatment comprises the following steps: cooling, filtering, washing the filter cake, concentrating the filtrate under reduced pressure, adding an alcohol solvent for hot pulping, cooling, filtering, washing and drying to obtain a compound represented by 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.

Scheme 16: The preparation method according to any one of Schemes 1 to 15-1, wherein in step 3,

The post-treatment comprises the following steps: filtering, washing the filter cake, concentrating the filtrate under reduced pressure, adding an aliphatic hydrocarbon solvent for stirring and crystallization, filtering, washing and drying to obtain a compound represented by formula (VII); optionally, the aliphatic hydrocarbon solvent is selected from n-hexane or n-heptane.

Scheme 17: The preparation method according to any one of Schemes 1 to 16, wherein in step 1,

The molar ratio of the compound of formula (II) to the compound of formula (III) is 1:0.8 to 1:1.2, preferably 1:0.9 to 1:1.05;

The molar ratio of the compound of formula (II) to the base is 1:1 to 1:10, preferably 1:1 to 1:5, preferably 1:2 to 1:4, preferably 1:2 to 1:3;

The first reaction temperature is 25 to 80°C, preferably 50 to 80°C, more preferably 60 to 80°C.

Scheme 18: The preparation method according to any one of Schemes 1 to 17, wherein in step 2,

The molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:1 to 1:2, preferably 1:1 to 1:1.5;

The molar ratio of the compound of formula (IV) to the azo reagent is 1:1 to 1:5, preferably 1:1 to 1:3, preferably 1:1.2 to 1:2.2;

The molar ratio of the compound of formula (IV) to the 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 to 50°C, preferably 20 to 40°C, preferably 25 to 45°C;

The second reaction temperature is 20 to 60°C, preferably 20 to 50°C, more preferably 35 to 45°C.

Scheme 19: The preparation method according to any one of Schemes 1 to 18, wherein in step 3,

The molar ratio of the compound of formula (VI) to the trialkyl orthoformate is 1:1 to 1:20, preferably 1:5 to 1:15;

The molar ratio of the compound of formula (VI) to the Lewis acid is 1:0.1 to 1:2, preferably 1:0.1 to 1:1, more preferably 1:0.1 to 1:0.5;

The third reaction temperature is 20 to 70°C, preferably 20 to 60°C, and more preferably 30 to 60°C.

Scheme 20: The preparation method according to any one of 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 the 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 method for preparing a compound represented by formula (VII') or a stereoisomer thereof, comprising the following steps:

Step 1: Mix the compound of formula (II'), a nitrile solvent and a base, add the compound of formula (III'), and heat to 60-80°C for reaction; after the reaction, post-treat to obtain the compound of formula (IV');

Step 2: Mix the compound of formula (IV'), the compound of formula (V'), an ether reagent and an azo reagent, control the temperature at 25-45°C, dropwise add a trisubstituted phosphine reagent, and after the dropwise addition is completed, control the temperature at 35-45°C for reaction; after the reaction is completed, post-treat to obtain a compound of formula (VI');

Step 3: Mix an alcohol reagent, a compound of formula (VI'), a trialkyl orthoformate, a Lewis acid and a catalyst, and react at 50-60°C in a _H2 environment; after the reaction, post-treat to obtain a compound of formula (VII').

Scheme 21-1: A method for preparing a compound represented by formula (VII') or a stereoisomer thereof, comprising the following steps:

Step 1: Mix the compound of formula (II'), a nitrile solvent and a base, add the compound of formula (III') under stirring, and heat to 60-80°C for reaction; after the reaction, cool to 20-30°C, adjust the pH of the reaction solution to 6.0-7.5 with an acidic solution, stir to precipitate a solid, filter, wash and dry to obtain a compound of formula (IV');

Step 2: Mix the compound of formula (IV'), the compound of formula (V'), an ether reagent and an azo reagent, add a trisubstituted phosphine reagent dropwise under stirring at a temperature of 25-45°C, and after the addition is complete, control the temperature to 35-45°C for reaction; after the reaction is complete, cool to 10-15°C, add an ester reagent, stir to precipitate a solid, filter, wash the filtrate with water, concentrate, add an alcohol solvent, heat to 60-70°C, stir to crystallize, cool, filter, wash and dry to obtain a compound of formula (VI');

Step 3: Mix an alcohol reagent, a compound of formula (VI'), a trialkyl orthoformate, a Lewis acid and a catalyst, and react at a temperature of 50-60°C under a _H2 environment; after the reaction is completed, filter and wash the filter cake, concentrate the filtrate under reduced pressure, add an aliphatic hydrocarbon solvent, stir and crystallize, and obtain a compound of formula (VII') by filtering, washing and drying.

Scheme 21-2: A method for preparing a compound represented by formula (VII') or a stereoisomer thereof, comprising the following steps:

Step 1: Mix the compound of formula (II'), a nitrile solvent and a base, add the compound of formula (III') under stirring, and heat to 60-80°C for reaction; after the reaction, cool to 20-30°C, adjust the pH of the reaction solution to 6.0-7.5 with an acidic solution, stir to precipitate a solid, filter, wash and dry to obtain a compound of formula (IV');

Step 2: Mix the compound of formula (IV'), the compound of formula (V'), an ether reagent and an azo reagent, add a trisubstituted phosphine reagent dropwise under stirring at a temperature of 20-40°C, and after the addition is complete, control the temperature to 30-40°C for reaction; after the reaction is complete, cool to 10-15°C, filter, wash, combine the filtrate, concentrate, add an alcohol solvent, heat to 60-80°C, stir for crystallization, cool, filter, wash and dry to obtain a compound of formula (VI');

Step 3: Mix an alcohol reagent, a compound of formula (VI'), a trialkyl orthoformate, a Lewis acid and a catalyst, and react at a temperature of 50-60°C under a _H2 environment; after the reaction is completed, filter and wash the filter cake, concentrate the filtrate under reduced pressure, add an aliphatic hydrocarbon solvent, stir and crystallize, and obtain a compound of formula (VII') by filtering, washing and drying.

Scheme 22: The preparation method described in Scheme 21, 21-1 or 21-2, wherein:

The nitrile solvent is acetonitrile;

The base is selected from triethylamine, N,N-diisopropylmethylamine or N,N-diisopropylethylamine;

The acidic solution is a saturated citric acid aqueous solution;

The ether reagent is selected from methyl tert-butyl ether or tetrahydrofuran;

The azo reagent is selected from diisopropyl azodicarboxylate or dipiperidine azodicarbonyl;

The trisubstituted phosphine reagent is tri-n-butylphosphine;

The ester reagent is ethyl acetate;

The alcohol solvent is selected from methanol, ethanol, isopropanol, n-butanol or ethylene 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 trifluoromethanesulfonate;

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 method for preparing a compound of formula (I) or a stereoisomer thereof, comprising the following steps:

1) A method for preparing a compound of formula (VII) or a stereoisomer thereof according to any one of Schemes 1 to 22;

2) Step 4: When R is a protecting group, the compound of formula (VII) is subjected to a deprotection reaction to obtain a compound of formula (VIII), and then the compound of formula (VIII) is subjected to an acylation reaction to obtain a compound of formula (I); when R is H, the compound of formula (VII) is directly subjected to an acylation reaction to obtain a compound of formula (I);

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 )-, -OC(R ⁵ )(R ⁶ )-, -C(R ⁵ )(R ⁶ )-N(R ⁴ )- and -C(R ⁵ )(R ⁶ )-O-, the left chemical bond of which is connected to ring A, and the right chemical bond of which is connected to X ³ ; preferably, -(X ² ) _p - is selected from -N(R ⁴ )-C(R ⁵ )(R ⁶ )- or -OC(R ⁵ )(R ⁶ )-, the left chemical bond of which is connected to ring A, and the right chemical bond of which is connected to X ³ ; M ² , M ⁵ , M ⁶ , ring C, ring A, R ² , -(X ³ ) _q -, R, n, R ⁴ , R ⁵ , R ⁶ , ^Ra , R ^b , Q1 and Q2 are as described in any one of Schemes 1 to 8.

Scheme 24: A method for preparing a compound of formula (I) or a stereoisomer thereof, comprising the following steps:

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 formula (VI) is subjected to a reduction ring-closing reaction to obtain the compound of formula (VII);

Step 4: When R is a protecting group, the compound of formula (VII) is subjected to a deprotection reaction to obtain a compound of formula (VIII), and then the compound of formula (VIII) is subjected to an acylation reaction to obtain a compound of formula (I); when R is H, the compound of formula (VII) is directly subjected to an acylation reaction to obtain a compound of formula (I);

Wherein, -(X ² ) _p - is selected from -N(R ⁴ )-C(R ⁵ )(R ⁶ )- and -OC(R ⁵ )(R ⁶ )-; in Formula (VI), Formula (VII), Formula (VIII) and Formula (I), the left chemical bond of -(X ² ) _p - is connected to Ring A, and the right chemical bond is connected to X ³ ; in Formula (V), the left chemical bond of -(X ² ) _p - is connected to a hydrogen atom, and the right chemical bond is connected to X ³ ; M ² , M ⁵ , M ⁶ , Ring C, Ring A, R ² , -(X ³ ) _q -, R, n, R ⁴ , R ⁵ , R ⁶ , ^Ra , R ^b , Q1, Q2 are as described in any one of Schemes 1 to 8; the preparation method of Step 1 to Step 3 is as described in any one of Schemes 1 to 22.

Scheme 25: The preparation method described in 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 )-, -OC(R ⁵ )(R ⁶ )-, -C(R ⁵ )(R ⁶ )-N(R ⁴ )- and -C(R ⁵ )(R 6 )-O-, the left chemical bond of which is connected to ring A, and the right chemical bond of which is connected to X ^{3; preferably, -(X 2 ) p - is selected from -N(R 4 )-C(R 5 )(R 6 )- or -OC(R 5 )(R 6 )-, the left chemical bond of which is connected to ring A, and the right chemical bond of which is connected to X 3} _{; M 5 , M 6 , ring C, ring A, R 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 )- and -C(R ⁵ )(R 6 ⁾ -O-, the left chemical bond of which is connected to ring A, and the right chemical bond of which is connected to X ³ ; ³ ) _q- , R, n, ^R4 , ^R5 , ^R6 , ^Ra , ^Rb , Q1 and Q2 are as described in any one of Schemes 1 to 8.

Scheme 26: The preparation method according to any one of 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 method for preparing a compound represented by formula (I') or a stereoisomer thereof, comprising the following steps:

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 formula (VI') is subjected to a reduction ring-closing reaction to obtain a compound of formula (VII');

Step 4: The compound of formula (VII') is subjected to a deprotection reaction to obtain a compound of formula (VIII');

Step 5: The compound of formula (VIII') is subjected to acylation reaction to obtain the compound of formula (I');

Wherein, the preparation method of step 1 to step 3 is as described in any one of schemes 10 to 22.

Any of the options in any of the embodiments described in the present invention can be combined with each other, and the combined technical solutions are still included in the protection scope of the present invention.

In the specification and claims of the present invention, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structure shall prevail.

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided by the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided by the present invention shall prevail.

The "halogen" described in the present invention refers to fluorine, chlorine, bromine or iodine.

The “C _1-6 alkyl” described in the present invention refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, including, 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, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C _1-4 alkyl" described in the present invention refers to a specific example of a C _1-6 alkyl group containing 1 to 4 carbon atoms.

The "C _1-6 alkoxy" of the present invention refers to "C _1-6 alkyl-O-", and the "C _1-6 alkyl" is as defined above. The "C _1-4 alkoxy" of the present invention refers to "C _1-4 alkyl-O-", and the "C _1-4 alkyl" is as defined above.

The "hydroxy C _1-6 alkyl", "amino C _1-6 alkyl" and "halogenated C _1-6 alkyl" mentioned in the present invention refer to groups obtained by replacing the hydrogen in a C _1-6 alkyl with one or more hydroxyl groups, amino groups or halogen groups, respectively, wherein the C _1-6 alkyl is as defined above.

The "halogenated C _1-6 alkoxy group" of the present invention refers to a group obtained by replacing the hydrogen in the "C _1-6 alkoxy group" with one or more halogens.

The "C _1-6 alkylamino" and "di(C _1-6 alkyl)amino" of the present invention refer to "C _1-6 alkyl-NH-" and

The "3-10 membered cycloalkyl" mentioned in the present invention includes "3-8 membered cycloalkyl" and "8-10 membered condensed cycloalkyl".

The “3-8 membered cycloalkyl” described in the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 ring carbon atoms and not aromatic, including “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”, “7-8 membered cycloalkyl”, “3-6 membered saturated cycloalkyl”, “5-8 membered saturated cycloalkyl”, “5-7 membered saturated cycloalkyl”, “5-6 membered saturated cycloalkyl”, etc. Specific examples of the “3-8 membered saturated cycloalkyl” include, but are not limited to, cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentanyl (cyclopentyl), cyclohexanyl (cyclohexyl), cycloheptanyl (cycloheptyl), cyclooctyl (cyclooctyl) and the like; and specific examples of the “3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclohex-1,4-dienyl, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl and the like.

The "8-10 membered fused cycloalkyl" mentioned in the present invention refers to a saturated or partially saturated non-aromatic cyclic alkyl group containing 8-10 ring carbon atoms formed by two or more cyclic structures sharing two adjacent carbon atoms (one ring in the fused cycloalkyl group may be an aromatic ring, but the fused cycloalkyl group as a whole does not have aromaticity), including "8-9 membered fused cycloalkyl", "9-10 membered fused cycloalkyl", etc., and the fusion mode thereof may be 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, etc. 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, tetradecahydrophenanthrenyl, 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]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, 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]octanyl, Cyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

The "3-10 membered heterocyclic group" described in the present invention includes "3-8 membered heterocyclic group" and "8-10 membered fused heterocyclic group".

The "3-8 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic ring group containing at least one (e.g., 1, 2, 3, 4, or 5) ring heteroatom and 3-8 ring atoms, and having no aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom, and/or a sulfur atom. Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) may be substituted by an oxo group (forming, for example, C=O, N=O, S=O, or SO2 _ring members). The "3-8 membered heterocyclic group" includes a "3-8 membered saturated heterocyclic group" and a "3-8 membered partially saturated heterocyclic group". Preferably, the "3-8 membered heterocyclic group" contains 1-3 heteroatoms, for example, one or two heteroatoms selected from nitrogen atoms and oxygen atoms, or one nitrogen atom. Preferably, "3-8 membered heterocyclyl" is "3-7 membered heterocyclyl", "3-6 membered heterocyclyl", "4-7 membered heterocyclyl", "4-6 membered heterocyclyl", "6-8 membered heterocyclyl", "5-7 membered heterocyclyl", "5-6 membered heterocyclyl", "3-6 membered saturated heterocyclyl", "5-6 membered saturated heterocyclyl", "3-6 membered nitrogen-containing heterocyclyl", "3-6 membered saturated nitrogen-containing heterocyclyl", "5-6 membered nitrogen-containing heterocyclyl", "5-6 membered saturated nitrogen-containing heterocyclyl", etc. It may, for example, contain only one or two nitrogen atoms, or contain one nitrogen atom and one or two other heteroatoms (e.g., oxygen atoms and/or sulfur atoms). Specific examples of “3- to 8-membered heterocyclic group” include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidine oxazolyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, etc.

The "8-10 membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated cyclic group containing 8-10 ring atoms and at least one ring atom being a heteroatom formed by two or more cyclic structures sharing two adjacent atoms, and not having aromaticity (one ring in the fused heterocyclic group may be an aromatic ring, but the fused heterocyclic group as a whole does not have aromaticity), and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom. Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) may be substituted by oxo groups (forming, for example, C=O, N=O, S=O or SO2 _ring members). “8-10 membered fused heterocyclic group” includes “8-9 membered fused heterocyclic group”, “9-10 membered fused heterocyclic group”, etc., and the fusion mode can 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 and 5-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl group is defined as follows. Examples of “8-10 membered fused heterocyclic group” include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylaziridinyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 1,3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, chromanyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furanyl, [3,4-d]imidazolyl, 3a,4,6,6a-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, benzimidazolidinyl, octahydrobenzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, dihydroisoindolyl, benzoxazolidinyl, benzothiazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 4H-1,3-benzoxazinyl, and the like.

The “6-10 membered aryl group” described in the present invention includes “6-8 membered monocyclic aryl group” and “8-10 membered condensed ring aryl group”.

The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to phenyl, cyclooctatetraenyl, etc., and preferably phenyl.

The "8-10 membered fused ring aromatic group" described in the present invention refers to an aromatic cyclic group containing 8-10 ring carbon atoms formed by two or more cyclic structures sharing two adjacent carbon atoms, preferably a "9-10 membered fused ring aromatic group", such as naphthyl.

The “5-10 membered heteroaryl group” described in the present invention includes “5-8 membered single heteroaryl group” and “8-10 membered fused heteroaryl group”.

The "5-8-membered single heteroaryl" of the present invention refers to a monocyclic cyclic group with aromaticity containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) may be substituted by oxo groups (forming, for example, C=O, N=O, S=O or SO2 _ring members). "5-8-membered single heteroaryl" includes "5-7-membered single heteroaryl", "5-6-membered single heteroaryl", "5-6-membered nitrogen-containing single heteroaryl", "6-membered nitrogen-containing single heteroaryl", etc. At least one of the ring heteroatoms in the "nitrogen-containing single heteroaryl" is a nitrogen atom, for example, it may contain only one or two nitrogen atoms, or contain one nitrogen atom and one or two other heteroatoms (such as oxygen atoms and/or sulfur atoms), or contain two nitrogen atoms and one or two other heteroatoms (such as oxygen atoms and/or sulfur atoms). Specific examples of “5- to 8-membered monoheteroaryl” include, but are not limited to, furanyl, 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, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. Specific examples of "5- to 6-membered monoheteroaryl" include, but are not limited to, those containing 5 to 6 ring atoms among the specific examples of "5- to 8-membered monoheteroaryl" mentioned above.

The "8-10 membered fused heteroaryl" of the present invention refers to an aromatic cyclic structure containing 8-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) may be substituted by oxo groups (forming, for example, C=O, N=O, S=O or SO2 _ring members). "8-10 membered fused heteroaryl" includes "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode thereof may be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc. Specific examples of “8-10 membered fused heteroaryl” include, but are not limited to, pyrrolopyrrolyl, pyrrolofuranyl, pyrazolopyrrolyl, pyrazolothienyl, furathiophenyl, pyrazolooxazolyl, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl and the like.

The "optionally (or optionally) substituted by..." mentioned in the present invention includes two situations: "substituted by..." and "not substituted by...".

The "pharmaceutically acceptable salt" of the present invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO ₃ H, etc.) present in the compound and a suitable inorganic or organic base (including alkali metal salts, alkaline earth metal salts, ammonium salts, and salts formed with nitrogen-containing organic bases), or a salt formed by a basic functional group (e.g., -NH ₂ , etc.) present in the compound and a suitable inorganic or organic acid (e.g., carboxylic acid, etc.).

The "stereoisomer" of the present invention means that when the compound of the present invention contains one or more asymmetric centers, it can exist as a racemate and a racemic mixture, a single enantiomer, a diastereomeric mixture and a single diastereomer. The compound of the present invention may have an asymmetric center, which results in the existence of two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compound of the present invention contains an olefin double bond, unless otherwise specified, the scope of the present invention includes cis isomers and trans isomers. The compound of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen connection points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included in the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds are included in the scope of the present invention.

The "organic solvent" described in the present invention is independently selected from at least one of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, phenols, nitriles, amides, sulfones, sulfoxides, heteroaromatic hydrocarbons 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 halogenated hydrocarbon 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-butyl alcohol, tert-amyl alcohol, tert-hexanol, benzyl alcohol, ethylene glycol and glycerol, and the ether solvent is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and 1,4-dioxane. One, the ester solvent is selected from at least one of methyl acetate, ethyl acetate, dimethyl phthalate and propyl acetate, the ketone solvent is selected from at least one of acetone, methyl butyl ketone, 1,3-dimethyl-2-imidazolidinone and methyl isobutyl ketone, the glycol derivative solvent is selected from at least one of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether and ethylene glycol diethyl ether, the phenol solvent is selected from at least one of phenol and p-cresol, the nitrile solvent is selected from at least one of acetonitrile and propionitrile, the amide solvent is selected from at least one of N,N-dimethylformamide and N,N-dimethylacetamide, the sulfone solvent is selected from at least one of dimethyl sulfone, phenethyl sulfone, diethyl sulfone, diphenyl sulfone and cyclopentane sulfone, the sulfoxide solvent is selected from at least one of dimethyl sulfoxide, diethyl sulfoxide and benzyl sulfoxide, and the heteroaromatic hydrocarbon solvent is selected from pyridine.

The "base" mentioned in the present invention is independently selected from at least one of an organic base and an inorganic base.

The "inorganic base" mentioned in the present invention refers to an inorganic substance that can donate a lone pair of electrons and usually does not contain carbon elements. It is generally a compound generated by metal ions or ammonium ions and hydroxide ions. Specific examples include but are not limited to: sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, calcium hydride, ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide as alkali metal hydroxides, calcium hydroxide, magnesium hydroxide, barium hydroxide, etc. as alkaline earth metal hydroxides.

The "organic base" refers to an organic compound with alkalinity. The organic base is divided into alkali metal salts of alcohols, alkyl metal lithium compounds, amide metal lithium compounds and amine compounds. The alkali metal salts of alcohols are selected from at least one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide. The alkyl metal lithium compound is selected from at least one of butyl lithium and phenyl lithium. The amide metal lithium compound is selected from at least one of lithium diisopropylamide and lithium hexamethyldisilazide. The amine compound is selected from aliphatic amines, such as at least one of N,N-diisopropylethylamine, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, ethylenediamine, isopropylamine, dibenzylamine, tert-butylamine and hexamethylenediamine; alcoholamines, such as monoethanolamine, diisopropanolamine and N,N-diethylethanolamine. At least one of amines, amides, such as formamide, acetamide, acrylamide, colchicine, camptothecin, N, N-dimethylformamide and dimethylacetamide, alicyclic amines, such as cyclohexylamine, diethylenetriamine, hexamethylenetetramine, morpholine and piperazine, aromatic amines, such as aniline, diphenylamine, benzidine, o-phenylenediamine, p-phenylenediamine, p-methylaniline, p-chloroaniline, m-ethoxyaniline and m-nitroaniline, naphthylamines, such as 1-naphthylamine, 2-naphthylamine, Krafci acid, Tobias acid, R acid, K acid and naphthalene diamine, polyethylene imine, hydroxylamine; preferably aliphatic amines, such as N, N-diisopropylethylamine, dimethylamine, diethylamine, triethylamine and hexamethylenediamine.

The "acid" described in the present invention includes organic acids and inorganic acids. Organic acids include but are not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, citric acid, etc.; inorganic acids include but are not limited to hydrochloric acid, concentrated sulfuric acid, hydrobromic acid, hydrofluoric acid, nitric acid, nitrous acid, boric acid, etc.

The "protecting group" of the present invention refers to a substituent used to block or protect a specific functional group by reacting with other functional groups on a compound. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the amino functional group on the compound. A "hydroxy protecting group" refers to a hydroxy substituent that can effectively block or protect the hydroxyl function. Suitable protecting groups include, but are not limited to, acetyl and silyl. A "carboxyl protecting group" refers to a carboxyl substituent that can effectively block or protect the function of the carboxyl group.

The "amino protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylformyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl , trityl, 2-nitrobenzenesulfonyl, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylethylene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxy-2H-1,3-dioxocyclopenten-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

The protecting group for the carboxyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, phenacyl, p-nitrophenacyl, p-bromophenacyl, p-methylsulfonylphenacyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthaloyloxymethyl, carboximidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

The "hydroxy or mercapto" protecting group includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(Trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formic acid, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, Phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-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, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

In the preparation method of the present 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. Those skilled in the art can select one or more drying methods according to the properties of the obtained product, and perform drying once or multiple times according to the humidity of the product.

Unless otherwise specified, the raw materials or reagents described in the present invention are commercially available.

The beneficial technical effects of the present invention are embodied in:

(1) The synthesis route of the compound of formula (VII') disclosed in the prior art includes multiple reaction steps such as substitution reaction, reduction reaction, cyclization reaction, demethylation reaction, and protection reaction, while the compound of formula (VII') disclosed in the present invention can be obtained by only three steps of substitution reaction, Mitsunobu reaction, and reduction cyclization reaction. While reducing the number of reaction steps, the total yield of the entire route is increased by at least 10%, and the cost is reduced by 45%.

(2) In the preparation method disclosed in the present invention, the reaction raw materials are easily available, the reaction selectivity is high, the by-products are few, and no hazardous reagents are used in each step of the reaction, so the reaction process is green and environmentally friendly.

(3) The reaction conditions of each step of the present invention are mild and controllable, the post-treatment process is simple, and operations such as column chromatography are avoided, which is more suitable for industrial production.

DETAILED DESCRIPTION

The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

Example 1: Preparation of tert-butyl ((R)-1-((3-((R)-1-(3H-imidazole [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-nitropyridine-2-yl)pyrrolidin-2-yl]-5-fluoropyridine-2-ol (preparation of the compound of formula (IV'))

Add acetonitrile (300mL) to a 3L three-necked flask, and add (R)-5-fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol hydrochloride (90.25g, 0.38mol, content 91.60%) and N,N-diisopropylethylamine (147.52g, 1.14mol) under stirring. After stirring at 25℃ for 0.5h, add 2-amino-3-nitro-6-chloropyridine (65.95g, 0.38mol), and then add acetonitrile (60mL). Heat to 70℃, and react until the raw material is <1.0%, which is considered to be complete. Cool to 20-30℃, add water (2.2L), and then adjust the pH to about 7 with saturated citric acid aqueous solution. Cool to 5-15°C, stir for 1 hour and filter, wash the filter cake with water (200 mL), then transfer to a vacuum drying oven, dry under reduced pressure at 50°C for 20-24 hours to obtain 114.81 g of the target compound, yield: 94.7%, purity: 99.1%

Molecular formula: C ₁₄ H ₁₄ FN ₅ O _3Molecular 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,0.5 H),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 investigated some of the influencing factors in the above step 1, and the results are as follows:

1) Changing the amount of N,N-diisopropylethylamine, when the amount of N,N-diisopropylethylamine relative to (R)-5-fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol hydrochloride was 2.0eq, 2.2eq, 2.4eq, 2.6eq, 2.8eq, 3.0eq, 3.2eq and 3.4eq, the compound of formula (IV') was obtained, and when the amount of N,N-diisopropylethylamine was 3.0eq, the product purity was the highest.

2) Changing the first reaction temperature to 25°C, 50°C, 60°C, and 80°C, respectively, can yield compounds of formula (IV').

3) Changing the amount of 2-amino-3-nitro-6-chloropyridine, when the amount thereof relative to the feed amount of (R)-5-fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol hydrochloride is 0.8 eq, 0.9 eq, 0.95 eq, 1.0 eq, and 1.05 eq, respectively, the compound of formula (IV') can be obtained.

4) Changing the pH value adjusted by saturated citric acid aqueous solution during post-treatment, when the pH value is 3.2, 4.5, 6.0, or 7.5, the compound of formula (IV') can be obtained.

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 the compound of formula (VI'))

Add tetrahydrofuran (1.5L) to a 3L three-necked flask, and add (R)-(1-hydroxypropane-2-yl)carbamic acid tert-butyl ester (59.95g, 0.34mol), (R)-3-[1-(6-amino-5-nitropyridine-2-yl)pyrrolidin-2-yl]-5-fluoropyridin-2-ol (100.51g, 0.31mol) and dipiperidine diazonium dicarbonate (160.40g, 0.63mol) in sequence under stirring, and then add tetrahydrofuran (0.5L). Stir at 25℃ for 0.5h under _N2 protection. Add tri-n-butylphosphine (130.55g, 0.64mol) dropwise at a temperature of 25℃～45℃. After addition, react at 35℃～45℃ until the remaining raw material is less than 1.0%. After the reaction is completed, cool to 10℃, add ethyl acetate (1L) and stir for 0.5h. Filter, wash the filter cake with ethyl acetate (1L), and combine the filtrate. Wash the filtrate with water (2L×3), add anhydrous ethanol (500mL) after the organic phase is concentrated under reduced pressure, heat to 65°C, stir and crystallize for 1 hour, cool to 25°C and stir for 0.5h, filter, wash with ethanol (100mL), n-heptane (200mL) in turn, and dry to obtain 100.68g of the target compound, with a yield of 67.1%. , purity 99.6%.

Molecular formula: C ₂₂ H ₂₉ FN _{6 O} 5Molecular 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 investigated some of the influencing factors in the above step 2, and the results are as follows:

(1) Changing the feed amount of azodicarbonyl dipiperidine, when the feed amount is 1.2eq, 1.4eq, 1.6eq, 1.8eq, 2.0eq and 2.2eq relative to the compound of formula (IV'), the compound of formula (IV') can be obtained after the reaction; and when the feed amount of azodicarbonyl dipiperidine is 1.4eq to 1.6eq, the product has a higher purity.

(2) Changing the feeding amount of tri-n-butylphosphine, when the feeding amount thereof is 1.2eq, 1.4eq, 1.6eq, 1.8eq, 2.0eq and 2.2eq relative to the compound of formula (IV'), the compound of formula (IV') can be obtained after the reaction; and when the feeding amount of tri-n-butylphosphine is 1.4eq to 1.6eq, the product has a higher purity.

(3) Changing the temperature of the addition of tri-n-butylphosphine. When the temperature of the addition of tri-n-butylphosphine is 5-10°C, 15-20°C, 25-35°C, or 35-43°C, the reaction can be carried out to obtain the compound of formula (VI').

(4) Changing the second reaction temperature. When the second reaction temperature is 30±3°C, 40±3°C, 50±3°C, and 60±3°C, respectively, the compound of formula (VI') can be obtained.

(5) Changing the post-treatment method, after the reaction is completed, cooling to 10-15°C, filtering, washing the filter cake with tetrahydrofuran, combining the filtrates, concentrating the filtrates, adding ethanol, stirring at 60-80°C for 2h, cooling to 10-30°C, filtering, washing, and drying to obtain the compound of formula (VI').

3. Preparation of tert-butyl ((R)-1-((3-((R)-1-(3H-imidazole [4,5-b] pyridin-5-yl) pyrrolidin-2-yl)-5-fluoropyridin-2-yl) oxy) propan-2-yl) carbamate (preparation of the compound of formula (VII'))

Add anhydrous ethanol (1L) to a 3L three-necked flask, and add tert-butyl ((R)-1-((3-((R)-1-(6-amino-5-nitropyridin-2-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxy)propane-2-yl)carbamate (200g, 0.42mol), trimethyl orthoformate (446g, 4.2mol), ytterbium trifluoromethanesulfonate (2.6g, 42mmol) and Pd/C (20g) in sequence under stirring, and then add ethanol (1L). _H2 is replaced three times, and the reaction is stirred at 40-50℃ under a hydrogen environment until the remaining raw material is ≤0.5%. Filter, rinse the filter cake with anhydrous ethanol (600mL), and combine the filtrate. After the filtrate is concentrated under reduced pressure, n-heptane (320mL) is added and stirred at 25℃ for crystallization for 1 hour. After filtration, the filter cake was washed with n-heptane (190 mL), and then transferred to a vacuum drying oven and dried under reduced pressure at 50° C. for 15 hours to obtain 169.68 g of the target compound with a yield of 88.5%.

Molecular formula: C ₂₃ H ₂₉ FN _{6 O} 3Molecular 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＝8.0 Hz,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: Preparation of (2 ² R, 6R)-3 ⁵ -fluoro-6-methyl-1 ³ H-4-oxa-7-aza-1(5,3)-imidazo[4,5-b]pyridine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclooctane-8-one (compound of formula (I'))

The method for preparing a compound of formula (VIII’) from a compound of formula (VII’) and the method for preparing a compound of formula (I’) from a compound of formula (VIII’) refer to Example 5 of patent PCT/CN2019/116459.

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').