CN115894463A - Preparation method of ROCK inhibitor, intermediate thereof and preparation method of intermediate - Google Patents

Preparation method of ROCK inhibitor, intermediate thereof and preparation method of intermediate Download PDF

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CN115894463A
CN115894463A CN202211231620.7A CN202211231620A CN115894463A CN 115894463 A CN115894463 A CN 115894463A CN 202211231620 A CN202211231620 A CN 202211231620A CN 115894463 A CN115894463 A CN 115894463A
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袁意
娄军
王亮
张轶涵
陈永凯
王朝东
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Wuhan LL Science and Technology Development Co Ltd
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract

The invention provides an intermediate for preparing a ROCK inhibitor, a preparation method thereof and a novel ROCK inhibitor preparation method. The intermediate has stable property and high yield and purity; and the preparation method is simple, the reaction raw materials are common and easy to obtain, and each intermediate product can be purified by a conventional method, so that the industrial production is facilitated, and the industrialization of the ROCK inhibitor is promoted. In the preparation method of the ROCK inhibitor, a new intermediate compound is used as an initial material, and the ROCK inhibitor is synthesized through substitution reaction, hydrogenation reaction and deprotection reaction, so that compared with other routes, the ROCK inhibitor is high in raw material conversion rate in each step, simple in reaction and not easy to generate by-products; the preparation method can control the impurities within a certain range, and effectively reduce or avoid the generation of impurities with genotoxicity; the preparation route has moderate length, the production process has strong stability and reproducibility, the obtained product can be optimized to obtain a target product through conventional pulping or recrystallization, the product quality is controllable, the safety is good, and the method is suitable for industrial amplification production.

Description

Preparation method of ROCK inhibitor, intermediate thereof and preparation method of intermediate
The present invention claims priority to a prior application entitled "a method for preparing a ROCK inhibitor, intermediates thereof and a method for preparing intermediates thereof" filed from 2021, 9, 30.9.6 by the intellectual property office of the chinese patent application No. 202111169183.6. The entire disclosure of this prior application is incorporated herein by reference.
Technical Field
The invention belongs to the field of preparation methods of pharmaceutical compounds, and particularly relates to a preparation method of a ROCK inhibitor, an intermediate thereof and a preparation method of the intermediate.
Background
Idiopathic Interstitial Pulmonary Fibrosis (IPF) is a chronic, diffuse interstitial pulmonary disease with unknown cause that changes in common interstitial pneumonia, and is characterized by common interstitial pneumonia in lung histology and/or high-resolution CT (HRCT) in the chest. IPF patients have latent disease, and the main clinical manifestations are dry cough, progressive dyspnea and obvious after-exercise. The disease condition progresses irreversibly due to the complex pathogenesis of the disease, and the early diagnosis is difficult; the survival rate of patients after diagnosis is remarkably reduced with the time, the 3-year survival rate is 50 percent, the 5-year survival rate is only 20 percent, the survival rate is lower than that of most cancers (such as leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer and the like), and the cancer is called cancer which is not cancer. At present, there is no certain significant effective therapeutic drug and method for IPF. According to the 'Chinese expert consensus on idiopathic pulmonary fibrosis diagnosis and treatment' published in 2016, only 3 kinds of drugs which are 'conditionally recommended' are pirfenidone, nintedanib and antacid drugs. However, there is currently insufficient evidence that antacid therapy can delay the decline in IPF lung function. Currently, the only drugs on the market for global IPF indications are pirfenidone and nintedanib; however, pirfenidone and nintedanib still have certain drug effect and safety deficiencies, and treatment options are limited, so that the development of other target mechanism drugs to meet the urgent needs of clinical patients and the later possible combination medication appeal is urgently needed.
ROCK (Rho-associated protein kinase) also called Rho kinase belongs to serine/threonine protein kinase, has a molecular mass of about 160kD, and is the Rho downstream target effector molecule with the most detailed functional research at present. ROCK is distributed in the tissues of the whole body, comprises ROCK1 (ROK beta, p 160-ROCK) subtypes and ROCK2 (ROK alpha) subtypes, regulates actin filament assembly and excitant contraction, regulates the injury response of various cells, particularly epithelial cells, endothelial cells and fibroblasts, and mediates the fibrosis process in an IPF pathogenesis; ROCK also plays a role in many signaling pathways involved in autoimmunity and inflammation. ROCK signals can interfere with a variety of fibrosis initiation conditions, reduce fibroblast activation and collagen deposition, and improve organ function. There are preclinical studies that show that ROCK1 and ROCK2 both play a role in pulmonary fibrosis. ROCK1 +/ And ROCK2 +/ Mouse pulmonary fibrosis study both subtypes show protective effects on vascular leakage, myofibroblast differentiation and fibrosis, ROCK1 +/ Mice showed greater attenuation of epithelial apoptosis. ROCK kinase activation in the lungs of IPF patients and disease-related animal models, and ROCK kinase inhibitors prevent the tissue fibrosis process in the model and induce regression of established fibrosis. With respect to the safety aspects of inhibiting ROCK1 and ROCK2, there is evidence that ROCK inhibitors, while vasodilating, do not necessarily induce systemic hypotension. Therefore, ROCK kinase inhibitors have great potential for the treatment of idiopathic pulmonary interstitial fibrosis.
Currently, 3 ROCK inhibitors are on the market globally, including fasudil, hydroxysulidil and neratidil, and the indications of the 3 drugs are cerebral vasospasm, glaucoma and ocular hypertension. ROCK inhibitors that were temporarily free of IPF indications were marketed. Patent application WO2021093795A1 discloses a ROCK inhibitor, which has a good inhibition effect on both ROCK1 and ROCK2, has good safety and metabolic stability and low potential hepatotoxicity risk, and can be used for preventing or treating diseases caused by high expression of one or more ROCKs or over activation of ROCK. The patent application also discloses a preparation method of the compound.
In the industrial process of the synthesis process of the pharmaceutical compound, the selection of the correct reaction sequence for large-scale synthesis and then the stepwise optimization are problems which chemical technologists are continuously seeking the root cause of the problems and trying to solve. The resolution of these problems is rarely as simple as they look after the fact, as they are derived from the interplay between experience and insight. The efficient process development process is a comprehensive process focusing on safe production, product quality, repeatability, durability and cost effectiveness, and comprises various aspects of organic synthesis methods, physicochemical properties, purification technologies, chemical engineering principles, actual mechanical operations and the like. As for the disclosures of the above prior arts, the preparation method of the compound has complicated steps, many intermediates and low yield, the yield and purity of the final product are also low, many impurities are present, and genotoxic impurities may be present, and the purification method is not suitable for industrial production, and the like, and cannot meet the needs of industrial scale production.
Disclosure of Invention
The invention aims to solve the technical problem of finding a novel preparation method of ROCK inhibitor, an intermediate thereof and a preparation method of the intermediate.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides an intermediate compound shown as a formula M01 or a pharmaceutically acceptable salt thereof:
Figure BDA0003876559350000031
wherein Q is an amino protecting group 1, such as SEM, THP, boc or trityl; q is preferably SEM or THP.
According to an embodiment of the invention, the pharmaceutically acceptable salt is for example a hydrochloride, formate, acetate, trifluoroacetate, sulfate, methanesulfonate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cypionate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate, pectate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, camphorate, undecanoate and succinate.
According to an embodiment of the invention, when the compound of formula M01 forms the pharmaceutically acceptable salt with an acid, the molar ratio of the compound of formula M01 to acid may be 5; preferably, the molar ratio of the compound of formula M01 to acid is 1.
In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt of the compound of formula M01.
The invention also provides a preparation method of the intermediate compound shown as the formula M01, which comprises the following steps:
Figure BDA0003876559350000032
a1 Compound M01-3 and compound M01-2 to obtain compound M01-1;
a2 Removing the protecting group R from the compound M01-1 to obtain a compound shown as a formula M01;
wherein Q has the definition described above; r is an amino protecting group 2, for example acetyl, benzyloxycarbonyl or trifluoroacetyl; r is preferably acetyl or benzyloxycarbonyl; g is selected from the group consisting of being able to react with X 1 Groups which undergo a coupling reaction, e.g. X when G is a boronic acid group or pinacolboronic acid ester group 1 Is Cl, br or I; when G is Cl, br or I, X 1 Is a boronic acid group or a pinacol boronic acid ester group;
according to an embodiment of the invention, when G is preferably a boronic acid group or a pinacol boronic acid ester group, X 1 Preferably Cl, br or I;
according to an embodiment of the invention, in step A1), the reaction may be carried out under the action of a catalyst, which may be a palladium catalyst, for example Pd (dppf) Cl 2 、PdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 、Pd 2 (dba) 3 At least one of (a);
according to an embodiment of the invention, in step A1), the reaction may be carried out under the action of a base, which may be an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate;
according to an embodiment of the present invention, in the step A1), the reaction is performed in the presence of an organic solvent or a mixed solvent of an organic solvent and water, and the organic solvent may be at least one of THF, ethyl acetate, methanol, ethanol, 1, 4-dioxane.
According to an embodiment of the present invention, in step A2), when Q is an SEM protecting group and R is an acetyl group, removing the acetyl group using an acid; at temperatures below 60 ℃, SEM is more resistant to acids than acetyl; the acid may be an inorganic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; the reaction is carried out in the presence of a solvent A, wherein the solvent A is one or a mixture of water, methanol, ethanol, ethyl acetate, 1, 4-dioxane and THF, and can be a mixed solvent selected from water/methanol, water/ethanol, water/ethyl acetate, water/1, 4-dioxane and water/THF; in the reaction, the molar ratio of the acid to M01-1 is (0.5-5): 1, for example (2.5-5): 1; in the reaction, the volume-to-mass ratio of the solvent A to the M01-1 is (3-6) mL/g; in some embodiments, the acid is selected from hydrochloric acid; the reaction temperature of the reaction is 50-60 ℃; preferably 55 ℃; the reaction time is 16-35h; preferably 18h and 21.5h;
when Q is a THP protecting group and R is acetyl, removing acetyl by using alkali; THP is better tolerated by bases than acetyl; the alkali can be lithium hydroxide, lithium hydroxide hydrate and piperidine, and lithium hydroxide monohydrate is preferred; the reaction is carried out in the presence of a solvent B, wherein the solvent B is one or a mixture of water, methanol, ethanol, tetrahydrofuran and 1, 4-dioxane, and can be THF/MeOH/H 2 A mixed solvent of O; in the reaction, the molar ratio of the alkali to M01-1 is (10-25): 1; preferably (15-20): 1; in the reaction, the volume-to-mass ratio of the solvent B to the solvent M01-1 is (10-30) mL/g, preferably (5-15) mL/g;
when R is benzyloxycarbonyl, the reaction is carried out in the presence of Pd/C and hydrogen.
The invention also provides a preparation method of the compound M01-2, which comprises the following steps:
Figure BDA0003876559350000041
b1 Compound 6-fluoroindole (M01-2-3) is reacted with a reducing agent and a compound providing an R group to give compound M01-2-2;
b2 Compound M01-2-2 reacts with a halogenating agent to obtain compound M01-2-1;
b3 Compound M01-2-1 with a compound providing a G group to give compound M01-2;
wherein R has the definition as described above; g is selected from boric acid group or pinacol borate group; x 2 Is Cl, br or I;
according to an embodiment of the present invention, in step B1), the reducing agent may be at least one of sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride, and potassium borohydride;
according to an embodiment of the invention, in step B1), the compound providing an R group may be RX 3 Or an acid anhydride compound containing R, X 3 Is halogen, RX 3 For example chloroacetyl, bromoacetyl or benzyl chloroformate, and the anhydride compound containing R is for example trifluoroacetic anhydride;
according to an embodiment of the invention, in step B1), the temperature of the reaction may be between 0 and 10 ℃, for example between 0 and 5 ℃;
according to an embodiment of the present invention, step B1) further comprises a step of purifying the product after the reaction is completed: pulping the product with at least one of methyl tert-butyl ether, isopropyl acetate, n-heptane, petroleum ether and isopropanol; the pulping time is 1-8h, such as 6h; the pulping temperature is room temperature.
According to an embodiment of the present invention, in the step B2), the halogenating agent may be at least one of NCS, NBS, NIS.
According to an embodiment of the present invention, in step B3), the compound providing a G group may be at least one of a bis-pinacol borate, a triisopropyl borate, a trimethyl borate, a triethyl borate, or a pinacol borane.
The invention also provides a preparation method of the compound M01-3, which comprises the following steps:
Figure BDA0003876559350000051
c) Reacting the compound M01-3-1 with a compound for providing Q to obtain a compound M01-3;
wherein, Q and X 1 Having the definitions described above;
according to an embodiment of the invention, in step C), the compound providing Q is 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), 3, 4-dihydro-2H-pyran (DHP), di-tert-butyl dicarbonate (Boc anhydride) or trityl chloride;
according to an embodiment of the present invention, after the reaction of step C), the method may further comprise a step of purifying the product: the purification is a beating of the product with at least one solvent system of n-heptane/methyl tert-butyl ether (v/v = 10/1), n-heptane/isopropyl acetate (v/v = 8/1), petroleum ether/ethyl acetate (v/v = 12/1) or methyl tert-butyl ether/isopropanol = (v/v = 20/1); the pulping temperature is room temperature; the beating time is 3-18h, such as 3h and 16h.
According to an exemplary embodiment of the present invention, the method for preparing the intermediate compound represented by the formula M01 comprises the steps of:
s1: dissolving 6-fluoroindole in a solvent 1, and adding sodium cyanoborohydride to react to obtain colorless oily liquid; dissolving the colorless oily liquid IN a solvent 2, and adding acetyl chloride IN the presence of a base 1 to react to prepare a compound shown IN a formula IN-01;
Figure BDA0003876559350000061
according to an embodiment of the present invention, the molar ratio of sodium cyanoborohydride to 6-fluoroindole is (2-3): 1, preferably 2.5:1;
according to an embodiment of the invention, the molar ratio of acetyl chloride to 6-fluoroindole is (2.5-3): 1;
according to the embodiment of the invention, the solvent 1 is acetic acid, and the volume mass ratio of the solvent 1 to the 6-fluoroindole is (5-10) mL/g; the solvent 2 is dichloromethane, and the volume-to-mass ratio of the solvent 2 to the 6-fluoroindole is (10-15) mL/g;
according to an embodiment of the invention, the base 1 is sodium bicarbonate, the molar ratio of base 1 to acetyl chloride is 1:1;
according to an embodiment of the invention, the sodium cyanoborohydride is added in portions at 0-5 ℃; the acetyl chloride is added at 0-5 ℃;
according to an embodiment of the present invention, in the reaction, the reaction time of the 6-fluoroindole and the sodium cyanoborohydride is 2-4h; the reaction time of the colorless oily liquid and acetyl chloride is 16-18h.
S2: dissolving the compound of the formula IN-01 IN a solvent 3, and adding N-bromosuccinimide to react to prepare the compound of the formula IN-02;
Figure BDA0003876559350000062
according to an embodiment of the invention, the molar ratio of IN-01 to NBS is 1: (1-2), preferably 1 (1.1-1.2);
according to an embodiment of the invention, the solvent 3 is DCM; the volume-mass ratio of the solvent 3 to the IN-01 is (8-12) mL/g;
according to the embodiment of the invention, the reaction temperature of the reaction is room temperature, and the reaction time is 2-4h;
according to an embodiment of the invention, the NBS is added in 2-4 portions at room temperature.
S3: dissolving a compound of formula IN-02 IN a solvent 4 IN the presence of a base 2 and a catalyst with (BPin) 2 Reacting to prepare a compound shown as a formula IN-03;
Figure BDA0003876559350000063
according to an embodiment of the invention, the IN-02 compound, (BPin) 2 The molar ratio of the alkali 2 to the catalyst is 1: (1-2.5): (2-3.5): 0.005-0.01; preferably 1:2:3:0.005;
according to an embodiment of the present invention, the solvent 4 is 1, 4-dioxane, and the volume-to-mass ratio of the solvent 4 to the IN-02 compound is (10-12) mL/g;
according to an embodiment of the invention, the base 2 is potassium acetate (KOAc); the catalyst is a palladium catalyst, preferably Pd (dppf) Cl 2 ；
According to an embodiment of the invention, the reaction temperature is between 100 and 120 ℃ and the reaction time is between 1.5 and 3 hours.
S4: dissolving 4-bromo-3-nitro-1H-pyrazole IN a solvent 5, and reacting with IN-SM1 under an alkaline condition to prepare a compound shown IN a formula M02;
Figure BDA0003876559350000071
according to an embodiment of the invention, Q is SEM or THP;
according to an embodiment of the invention, the IN-SM1 is SEM-Cl or 3, 4-dihydro-2H-pyran (DHP);
according to an embodiment of the present invention, when IN-SM1 is SEM-Cl, IN step S4: the molar ratio of 4-bromo-3-nitro-1H-pyrazole to SEM-Cl was 1: (1-1.5), preferably 1; the alkaline condition is obtained by adding NaH, and the molar ratio of 4-bromo-3-nitro-1H-pyrazole to NaH is 1: (2-3), preferably 1; the solvent 5 is THF, and the volume-mass ratio of the solvent 5 to the 4-bromo-3-nitro-1H-pyrazole is (8-12) mL/g, preferably 10mL/g; the NaH is added in 2-4 batches, after the NaH is added, the heating is severe, a large amount of bubbles are generated, and then the heat is preserved for 0.5-1h; the reaction temperature of the step S4 is room temperature, and the reaction time is 1.5-3h;
according to an embodiment of the invention, when IN-SM1 is 3, 4-dihydro-2H-pyran (DHP), IN step S4: the molar ratio of the 4-bromo-3-nitro-1H-pyrazole to the DHP is 1: (4.5-5.5), preferably 1:5; the alkaline condition is obtained by adding TsOH, and the molar ratio of 4-bromo-3-nitro-1H-pyrazole to TsOH is 1: (0.8-1.2), preferably 1:1; the solvent 5 is THF, and the volume-mass ratio of the solvent 5 to the 4-bromo-3-nitro-1H-pyrazole is (8-12) mL/g, preferably 8mL/g; the reaction temperature of the step S4 is 75 ℃, and the reaction time is 15-18h.
S5: dissolving a compound shown IN a formula M02 and a compound shown IN a formula IN-03 IN a solvent 6, and reacting IN the presence of a base 4 and a catalyst to obtain a compound shown IN a formula M03;
Figure BDA0003876559350000081
according to an embodiment of the present invention, the volume to mass ratio of the solvent 6 to the compound of formula M02 is (5-10) mL/g; the solvent 6 is a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water in the mixed solvent is (4-5): 1;
according to an embodiment of the present invention, the base 4 is preferably K 2 CO 3 Of bases 4 with formula M02The molar ratio of the compounds is (2-3): 1, preferably 2:1;
according to an embodiment of the invention, in step S5, the catalyst is a palladium catalyst, preferably Pd (dppf) Cl 2 ；
According to an embodiment of the present invention, IN step S5, when Q is SEM, the molar ratio of the compound of formula M02, the compound of formula IN-03, the catalyst is 1: (0.8-1.2): (0.01-0.1), preferably 1:1:0.05; the reaction temperature of the step S5 is 75-85 ℃, and the reaction time is 1.5-3h;
according to an embodiment of the invention, IN step S5, when Q is THP, the molar ratio of the compound of formula M02, the compound of formula IN-03, the catalyst is 1: (1-1.5): (0.005-0.2), preferably 1:1.3:0.1; the reaction temperature of the step S5 is 75-85 ℃, and the reaction time is 14-20h;
s6: deacetylating the compound of formula M03 to give a compound of formula M01;
Figure BDA0003876559350000082
according to an embodiment of the invention, Q is SEM or THP;
according to an embodiment of the present invention, in the step S6, when Q is SEM, the deacetylation is performed in a mixed solution of hydrochloric acid and tetrahydrofuran; the molar ratio of the hydrochloric acid to the M03 is (0.5-5): 1, e.g. (2-4): 1, preferably (2.5-3.5): 1; preferably, the hydrochloric acid is present at a concentration of 1-6M, for example 2-5M, such as 3M, 4M; the volume ratio of the hydrochloric acid to the tetrahydrofuran is 1:1; the volume-mass ratio of the mixed solution to the M03 compound is (4-6) mL/g; the reaction temperature of deacetylation is 50-60 ℃, and the reaction time is 10-35h, such as 16-22h;
according to an embodiment of the invention, when Q is THP in step S6, said deacetylation comprises: adding a compound of formula M03 into a solvent 7, and reacting in the presence of a base 5 and a phase transfer catalyst to prepare a compound of formula M01; the molar ratio of the compound of the formula M03, the base 5 and the phase transfer catalyst is 1: (15-20): (0.005-0.05); preferably 1; the phase transfer catalyst is tetrabutyl bromideAmmonium (TBAB); the base 5 is lithium hydroxide monohydrate; the solvent 7 is preferably an aqueous solution of THF and MeOH in a volume ratio of THF to MeOH to H 2 O is 1; the volume-mass ratio of the solvent 7 to the compound of the formula M03 is (10-30) mL/g; preferably 10.5mL/g; the reaction temperature is 60-65 ℃, and the reaction time is 8-12h.
The invention also provides a preparation method of the hydrochloride of the intermediate compound shown as the formula M01: reacting an intermediate compound represented by formula M01 with HCl solution to prepare S01:
Figure BDA0003876559350000091
according to an embodiment of the present invention, the HCl solution may be hydrochloric acid, HCl methanol solution, HCl ethanol solution, HCl ethyl acetate solution, HCl 1, 4-dioxane solution, HCl tetrahydrofuran solution;
the molar ratio of HCl to M01 in the reaction is (1-3): 1; when Q is THP, it is preferably 1.2.
The invention also provides application of the compound of the formula M01 in preparation of the compound shown in the formula I.
Figure BDA0003876559350000092
The invention provides a preparation method of a compound shown in a formula I, which comprises the following steps:
Figure BDA0003876559350000093
wherein Y is unsubstituted or optionally substituted by one or two R y Substituted sub-C 1-20 An alkyl group;
ring C is unsubstituted or optionally substituted with one, two, three or four R c Substituted with the following groups: c 1-20 Alkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl;
q is an amino protecting group 1, such as SEM, THP, boc or trityl, Q is preferably SEM or THP;
each R y ，R c Identical or different, independently of one another, H, halogen, nitro, nitroso, CN, OH, SH, oxo (= O), or unsubstituted or optionally substituted by one, two or three R 1 Substituted with the following groups: c 1-12 Alkyl, C optionally containing one, two or more heteroatoms 1-12 An alkyl group;
R 1 is oxo (= O), halogen, CN, OH, SH, NH 2 Or COOH.
According to an embodiment of the invention, Y is sub-C 1-6 Alkyl or OH-substituted alkylene 1-6 An alkyl group;
ring C may be unsubstituted or optionally substituted with one, two, three or four R c Substituted C 6-14 An aryl group; each R c Identical or different, independently of one another, H, halogen, CN, OH or C 1-6 An alkoxy group.
According to an embodiment of the present invention, Y is preferably a methylene, ethylene, propylene or OH substituted ethylene;
ring C is preferably unsubstituted or optionally substituted with one, two or three R c A substituted phenyl group; each R c Identical or different, independently of one another, are H, F, CN or methoxy. Preferably, ring C is
Figure BDA0003876559350000101
Step 1), reacting a compound M01 with a compound A to obtain a compound I-2;
step 2) reducing the nitro group of the compound I-2 into amino group to obtain a compound I-3;
and 3) obtaining the compound I by the compound I-3 deamination protecting group Q.
According to an embodiment of the invention, in step 1), said compound M01 may be in free form or in the form of a salt thereof; for example in the form of its hydrochloride salt;
according to an embodiment of the invention, in step 1), the molar ratio of compound M01 to compound a may be 1 (0.8-5), such as 1 (1.2-3), exemplary 1.5;
according to an embodiment of the present invention, in step 1), the reaction may be performed in the presence of an acylating agent which can react the secondary amine in the compound M01 and NH in the compound a in the reaction system 2 The compound of the formula I-2 is generated by connecting carbonyl, and the acylating reagent can be at least one of chloroformic acid p-nitrophenyl ester, triphosgene or N, N-carbonyl diimidazole; preferably, p-nitrophenyl chloroformate forms active ester with the compound M01, and then carries out nucleophilic substitution with the compound A to generate a compound I-2; triphosgene and a compound A are firstly synthesized into an isocyanate reactive intermediate, and then nucleophilic addition is carried out on the isocyanate reactive intermediate and a compound M01 to generate a compound I-2; n, N-carbonyl diimidazole forms active amide with a compound M01, and then carries out nucleophilic substitution with a compound A to generate a compound I-2;
according to an embodiment of the invention, in step 1), the molar ratio of compound M01 to acylating agent may be 1 (0.2-5), e.g. 1 (0.5-3), exemplarily 1.5, 1.15;
according to an embodiment of the present invention, in step 1), the reaction may be performed in the presence of a base, which may be at least one of Triethylamine (TEA), potassium carbonate, isopropylamine, N-methylmorpholine, diisopropylethylamine (DIEA), pyridine, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, 1, 8-diazabicycloundecen-7-ene, sodium methoxide, sodium ethoxide, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen carbonate, or potassium hydrogen carbonate; preferably DIEA, cesium carbonate or triethylamine;
according to an embodiment of the invention, in step 1), the molar ratio of compound M01 to base may be 1 (1-8), such as 1 (2-8), exemplified by 1;
according to an embodiment of the present invention, in step 1), the reaction may be carried out in the presence of a solvent, which may be an organic solvent, water, or a mixed solvent thereof; the organic solvent is preferably an aprotic organic solvent, such as one or more of tetrahydrofuran, acetonitrile, DMF, dichloromethane, n-hexane, ethyl acetate, diethyl ether, methyl tert-butyl ether, toluene, chloroform, cyclohexane, 1, 4-dioxane or acetone; the solvent is preferably a mixed solvent of acetonitrile, dichloromethane, tetrahydrofuran and water;
according to an embodiment of the invention, in step 1), the volumetric mass ratio of the solvent to compound M01 is (5-20) mL/g, such as (9-14) mL/g;
according to an embodiment of the present invention, in step 1), compound M01 may be added in 2 to 5 portions; for example, the temperature may be controlled to be-5 to 10 ℃ in portions, the compound M01 may generate heat after being added and neutralized with alkali, and the addition may be continued after the temperature does not rise any more in each addition, so that the addition is preferably performed in 3 portions with an interval of about 5 to 10min.
According to an embodiment of the present invention, in step 2), the reduction reaction of the nitro group to amino group may be performed under the action of a catalyst, and the catalyst may be at least one of iron powder, zinc powder, palladium carbon, and palladium hydroxide; ammonium chloride, hydrochloric acid or acetic acid can also be added in the reaction of reducing the nitro group into amino;
according to the embodiment of the invention, in the step 2), when the catalyst is iron powder or zinc powder and ammonium chloride is added to participate in the reaction, the molar ratio of the ammonium chloride to the reduced iron powder to the compound I-2 is 4 (3.5-4) to 1;
according to an embodiment of the present invention, in step 2), when the catalyst is palladium carbon, the mass fraction of the palladium carbon in the compound I-2 is 5 to 12%, for example 5%, 8%, 10%;
according to an embodiment of the present invention, in step 2), the reaction may be performed in the presence of a solvent, which may be one or more of water, methanol, ethanol, isopropanol, t-butanol, toluene, chloroform, cyclohexane, tetrahydrofuran (THF), dichloromethane, acetonitrile, DMF, n-hexane, ethyl acetate, diethyl ether, methyl t-butyl ether, 1, 4-dioxane, or acetone; preferably one or two of ethanol, tetrahydrofuran (THF) and water;
according to an embodiment of the present invention, in step 2), the volume-to-mass ratio of the solvent to the compound I-2 in the reaction is (5 to 24) mL/g.
According to an embodiment of the present invention, the reaction of removing the amino protecting group Q in step 3) may be carried out in the presence of an acid; the acid may be an organic acid or an inorganic acid; the acid is selected from at least one of HCl, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid; in some embodiments, the HCl can be hydrochloric acid (aqueous HCl), methanolic HCl, ethanolic HCl, ethyl acetate HCl, 1, 4-dioxane HCl; the molar ratio of the acid to the I-3 is (2-25): 1, for example (2-20): 1, more preferably (8-20): 1, exemplarily 8;
according to an embodiment of the present invention, in step 3), when Q is SEM, the reaction temperature for removing the amino protecting group Q is 70 to 90 ℃, preferably 80 ℃; the reaction time is 1.5-3h; when Q is THP, the reaction temperature for removing the amino protecting group Q is 30-60 ℃, and preferably 40-50 ℃; the reaction time is 2-10h, such as 2-3h and 4-8h;
according to an embodiment of the present invention, in step 3), the reaction may be performed in the presence of a solvent, which may be one or more of water, methanol, ethanol, isopropanol, t-butanol, toluene, chloroform, cyclohexane, tetrahydrofuran (THF), dichloromethane, acetonitrile, DMF, n-hexane, ethyl acetate, diethyl ether, methyl t-butyl ether, 1, 4-dioxane, or acetone; preferably one or two of methyl tert-butyl ether, methanol and ethanol; the ratio of the total volume of the acid and the solvent to the volume of compound I-3 by mass is (5-60) mL/g, for example (9-50) mL/g, illustratively 9mL/g, 20mL/g, 28mL/g, 35mL/g, 42mL/g, 50mL/g.
Advantageous effects
The invention protects an intermediate for preparing the ROCK inhibitor and a preparation method thereof, the intermediate has stable property, high yield and purity, simple preparation method and common and easily obtained reaction raw materials, and each intermediate product can be purified by a conventional method, so that the industrial production of the ROCK inhibitor is facilitated, and the industrialization of the ROCK inhibitor is further promoted.
The invention also provides a novel preparation method of the ROCK inhibitor, which takes a novel intermediate compound as an initial material and synthesizes the ROCK inhibitor through substitution reaction, hydrogenation reaction and deprotection reaction, compared with other routes, the route has high raw material conversion rate in each step, is not easy to generate byproducts and has simple operation; the preparation method can control the impurities within a certain range, and effectively reduce or avoid the generation of impurities with genotoxicity; the preparation route has moderate length, the production process has strong stability and reproducibility, the obtained product can be optimized to obtain the target product through conventional pulping or recrystallization, the product quality is controllable, the safety is good, and the method is suitable for industrial amplification production.
Drawings
FIG. 1 is an HPLC chromatogram of Compound S02 prepared in example 3.
FIG. 2 is a drawing of compound S02 prepared in example 3 1 H NMR spectrum.
Fig. 3 is an HPLC spectrum of compound S03 prepared in example 5.
FIG. 4 is a photograph of Compound S03 prepared in example 5 1 H NMR spectrum.
Fig. 5 is an HPLC profile of compound T345 prepared in example 6.
Fig. 6 is an HPLC profile of compound T345 prepared in example 7.
Definition and description of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety, unless otherwise indicated.
The term "room temperature" as used herein is understood to mean the temperature of the environment in which the experiment is conducted, and is, for example, 10 to 35 ℃ and preferably 25 ℃. + -. 5 ℃.
Where numerical ranges are recited in the specification and claims of this application, and where the numerical ranges are understood to be "integers," they are understood to recite both the endpoints of the ranges and each integer within the range. For example, "an integer of 0 to 10" should be understood to describe each integer of 0, 1,2, 3,4, 5,6, 7, 8, 9, and 10. When a range of values is understood to be "a number," it is understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to recite not only each integer of 0, 1,2, 3,4, 5,6, 7, 8, 9, and 10, but also at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
The term "halogen" refers to F, cl, br and I. In other words, F, cl, br, and I may be described as "halogen" in the present specification.
The term "C 1-20 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 20 carbon atoms. For example, "C 1-12 Alkyl "denotes straight or branched chain alkyl having 1,2, 3,4, 5,6, 7, 8, 9, 10, 11 or 12 carbon atoms," C 1-6 Alkyl "denotes straight or branched chain alkyl having 1,2, 3,4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc., or isomers thereof.
The term "3-20 membered heterocyclyl" means a saturated or partially unsaturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring containing 3-20 ring atoms, bicyclic and polycyclic ring systems including bridged or spiro rings, the ring atoms of which contain 1-5 heteroatoms independently selected from N, O, B, P, si, and S. The "3-to 20-membered heterocyclic group" may be, for example, "3-to 12-membered heterocyclic group", "3-to 7-membered heterocyclic group" or "5-to 6-membered heterocyclic group". The term "3-12 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O, B, P, si and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 3-membered rings such as aziridinyl, oxacyclopropaneyl and thiacyclopropanyl; 4-membered rings such as azetidinyl, oxetanyl and thietanyl; 5-membered rings such as dihydrofuryl, tetrahydrofuryl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dihydropyrrolyl, dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulphuryl), oxazolidin-2-one, triazolinyl, oxadiazolinyl and thiadiazolinyl; or a 6-membered ring such as dihydropyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, dihydropyridinyl, thiacyclohexane, dithianyl, dioxanyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl, azepanyl, oxepinyl and thiepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
The term "C 6-20 Aryl "is understood to mean a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partial aromaticity of 6 to 20 carbon atoms, preferably" C 6-14 Aryl "or" C 6-10 Aryl ". The term "C 6-14 Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C 6-14 Aryl group "), in particular a ring having 6 carbon atoms (" C 6 Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C 9 Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms (') "C 10 Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C 13 Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C) 14 Aryl), such as anthracenyl.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl", "5-10 membered heteroaryl", "5-6 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can in each case be benzo-fused. The term "5-6 membered heteroaryl" is to be understood as a monovalent monocyclic aromatic ring system having 5 or 6 ring atoms, which comprises 1 to 3 heteroatoms each independently selected from N, O and S, and which may be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.
The term "leaving group" as used herein, unless otherwise indicated, shall mean a charged or uncharged atom or group that is liberated during a substitution or displacement reaction. Suitable examples include, but are not limited to, H, F, br, cl, I, mesylate, tosylate, and the like.
The target compound may be isolated according to known methods, for example by extraction, filtration, recrystallization or column chromatography.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Description of the abbreviations of the reagents:
DCM: methylene dichloride
DIEA: n, N-diisopropylethylamine
TEA: triethylamine
THF: tetrahydrofuran (THF)
MeOH: methanol
MTBE: tert-butyl methyl ether
2-MeTHF: 2-methyltetrahydrofuran
Pd/C: wet palladium on carbon (Pb mass fraction of 50%)
NBS: n-bromosuccinimide
(BPin) 2 : biboric acid pinacol ester
PE: petroleum ether
EA: acetic acid ethyl ester
SEM-Cl:2- (trimethylsilyl) ethoxymethyl chloride
And (3) DHP:3, 4-dihydro-2H-pyrans
ACN: acetonitrile
Example 1 preparation of intermediate 1- (6-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-1-yl) ethan-1-one (IN-03):
Figure BDA0003876559350000161
s1: 6-fluoroindole (500g, 3.70mol) was dissolved in acetic acid (5L), and sodium cyanoborohydride (581g, 9.25mol) was added in portions at 0-5 ℃ and then reacted at room temperature for 3 hours. Pouring the reaction solution into water (5L), adjusting the pH with 50% aqueous sodium hydroxide solution in an ice-water bath to =10, extracting the aqueous phase with ethyl acetate (5l × 3), washing the resulting organic phase with saturated brine (5l × 2), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain 490g of a colorless oily liquid; the colorless oily liquid was dissolved in dichloromethane (7.35L), sodium bicarbonate (902g, 10.73mol) was added, acetyl chloride (837g, 10.73mol) was added at 0 deg.C, and the mixture was stirred at room temperature for 16 hours. Filtering the reaction solution, concentrating the filtrate under reduced pressure to obtain crude product, pulping the crude product with methyl tert-butyl ether (2.45L) at room temperature for 6H, filtering under reduced pressure to obtain filter cake, and vacuum drying to obtain 535g of 1- (6-fluoroindolin-1-yl) ethane-1-ketone (IN-01) as light yellow solid with yield of 80%, HPLC purity of 96.4%, LC-MS [ M + H ]] + ：180.2。
S2: IN-01 (14 g) was weighed out and dissolved IN DCM (140mL, 10V), NBS (15.3g, 1.1eq) was added IN 3 portions (10-15 min intervals) at room temperature, and reacted at room temperature for 2h. Adding 70mL of DCM into the reaction solution for extraction, washing an aqueous layer by 200mL of saturated sodium sulfite aqueous solution, extracting by using 70mL of DCM, and combining organic layers extracted twice; washing the obtained organic layer by 100mL of saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate to dryness to obtain a crude product; adding MTBE (40 mL) into the crude product, pulping at 40 deg.C for 4H, vacuum filtering, rinsing the filter cake with 20mL MTBE, and drying to obtain 18.0g of 1- (5-bromo-6-fluoroindolin-1-yl) ethane-1-ketone (IN-02) as gray solid with yield of 90.0%, HPLC purity of 97.1%, LC-MS [ M + H ]] + ：257.9。
S3: weighing IN-02 (18g, 69.8mmol, 1eq), (BPin) 2 (35.5g，2eq)、KOAc(20.5g，3eq)、Pd(dppf)Cl 2 (5.0 g, 0.1eq) was added to 1, 4-dioxane (180mL, 10V), and the temperature was raised to 110 ℃ under the protection of nitrogen, and the reaction was maintained for 2 hours. Then cooling the reaction solution to room temperature, concentrating to dryness, and adding EA (300 mL) to dissolve the concentrated product; filtering the obtained solution through silica gel (the using amount of the silica gel is 70 g), rinsing the silica gel by EA (200 mL), combining the filtrates, and concentrating to dry to obtain a crude product of 42g; adding PE/EA (volume ratio PE/EA =15/1, 90 mL) into the crude product, pulping at room temperature for 8h, rinsing by PE (36 mL) to obtain 17.3g of 1- (6-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-1-yl) ethane-1-one (IN-03) which is an earthy yellow solid with the yield of 77% and the content of 94%, and LC-MS (M + H)] + ：306.1。
Example 2 Synthesis of intermediate 4-bromo-3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (IN-10)
Figure BDA0003876559350000171
4-bromo-3-nitro-1H-pyrazole (40 g) was weighed and dissolved in THF (400mL, 10V); adding NaH (12.5g, 1.5eq) in 2-4 batches at the temperature of 0-5 ℃, preserving the temperature for 0.5h at the temperature of 0-5 ℃, and dropwise adding SEM-Cl (41.6g, 1.2eq); then the reaction system is heated to room temperature and is kept for reaction for 2h. Adding water (600 mL) into the reaction solution, extracting for 1 time by EA (500 mL), extracting for two times by EA (300 mL), and combining organic phases; the organic phase was washed once with ammonium chloride solution (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to give 70.2g of crude product. Adding n-heptane (50 mL) into the crude product, pulping at room temperature for 3H, rinsing with PE (50 mL) to obtain 51.2g of white solid, namely 4-bromo-3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (IN-10), wherein the yield is 76%, the HPLC purity is 96.8%, and LC-MS (M + H)] + ：322.0。
Example 3 Synthesis of intermediate 6-fluoro-5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline hydrochloride (S02)
Figure BDA0003876559350000172
S1: weighing IN-10 (16.5g, 1.0eq), IN-03 (1691, 1eq) and K 2 CO 3 (2 eq) and Pd (dppf) Cl 2 (0.05 eq) was added to 1, 4-dioxane/H 2 In O (4/1, 130mL/32mL, 10V), the temperature was raised to 80 ℃ under nitrogen protection, and the reaction was carried out for 2 hours. The resulting reaction was allowed to cool to room temperature, filtered through silica gel (60 g silica gel), and the silica gel was rinsed with 300mL EA, and the filtrates were combined. To the filtrate was added 300mL of water, and the mixture was extracted twice with 200mL of EA, and the organic phase was washed with 300mL of saturated brine 1 time and concentrated to give 33g of crude product. The crude product was slurried with methanol (100 mL) at 50 ℃ for 4H, PE (50 mL) rinsed to give 15.5g of 1- (6-fluoro-5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indolin-1-yl) ethyl-1-one (IN-04) as a pale yellow solid IN 71% yield and 96% HPLC purity. LC-MS [ M + H ]] + ：421.1。
S2: IN-04 (5.0 g, 11.9mmol) and hydrochloric acid (3 mol/L)/tetrahydrofuran (10 mL/10 mL) are added into a sample bottle to be used as a reaction solvent, and the mixture is reacted for 14 hours at the temperature of 55 ℃ (balloon sealing); supplementing hydrochloric acid (3 mol/L)/tetrahydrofuran (2 mL/2 mL), and reacting for 4h; then, hydrochloric acid (3 mol/L)/tetrahydrofuran (1 mL/1 mL) was added, and the reaction was carried out for 3.5 hours. Then, 13ml × 5 of water was added to the reaction solution with stirring; the reaction was filtered and the filter cake was washed with 13mL and 6mL of MTBE in that order and then treated with a diaphragm pump at 50 ℃ for 1H to give 2.8g of 6-fluoro-5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline hydrochloride (S02) as a gray solid product in 56% yield and 96.18% HPLC purity. LC-MS [ M + H ]] + ：379.1。
Example 4 Synthesis of intermediate 4-bromo-3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (IN-12)
Figure BDA0003876559350000181
4-bromo-3-nitro-1H-pyrazole (5.6 kg, 29.2mol) was dissolved in THF (45L), tsOH (5.0 kg, 29.2mol) and DHP (12.3 kg, 146mol) were added, and the mixture was heated to 75 ℃ under nitrogen atmosphere and then the reaction was carried outAnd the time is 16 hours. Cooling the reaction solution to room temperature, concentrating, adding ethyl acetate (28L) for dissolving, washing with water (28L × 2), separating, extracting the water layer with ethyl acetate (28L × 3), and combining the organic phases; the organic phase was washed with saturated brine (28L), separated, and concentrated to give crude product. The crude product was slurried with n-heptane/methyl tert-butyl ether (5.6 l. LC-MS [ M + H ]] + ：278.9。
Example 5 Synthesis of intermediate 6-fluoro-5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline (IN-17) and its hydrochloride salt (S03)
Figure BDA0003876559350000182
S1: weighing IN-03 (400g, 1.3 mol), IN-12 (276g, 1mol) and K 2 CO 3 (276g, 2mol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (73g, 0.1mol) was added to a reactor containing 1, 4-dioxane (4L) and H 2 In a three-necked bottle of O (1L), N 2 The displacement is carried out three times, and the reaction is carried out for 16h at 80 ℃. The system was cooled to room temperature and ethyl acetate (2L) and H were added 2 Diluting with O (2L), stirring, and filtering to obtain filtrate; standing the filtrate for layering, washing the organic phase with saturated saline solution (2L), and concentrating to obtain crude product; the crude product was slurried with ethanol (1.2L) at 60 ℃ for 4H, filtered under reduced pressure to give a filter cake, and vacuum dried to give 380g of 1- (6-fluoro-5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indolin-1-yl) ethan-1-one (IN-16) as a gray solid IN 77% yield. HPLC purity 91.6%. LC-MS [ M + H ]] + ：375.2。
S2: IN-16 (20g, 53.4mmol) was added to THF: meOH: H 2 In a mixed system of O = 1. Cooling the reaction liquid to 20-30 ℃, filtering, and adding H into the filtrate 2 O(20mL) stirring, separating, adding a 5% citric acid aqueous solution to the organic phase to adjust pH =5 to 7, separating, concentrating the organic phase, adding DCM (200 mL), filtering over silica gel (20 g), and concentrating the filtrate to obtain a crude 6-fluoro-5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline (IN-17).
Pulping the IN-17 crude product with ethanol (60 mL) at room temperature for 2h, and filtering; the obtained product was dispersed in 160mL of EA, and an ethyl acetate solution of HCl (1.2eq, 4m, 40ml) was added to the system to form a salt, and 60mL of isopropyl alcohol was added thereto, followed by stirring and concentration to obtain 15.8g of 6-fluoro-5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline hydrochloride (S03), with a yield of 80% and an HPLC purity of 98.7%.
LC-MS[M+H] + ：333.1。
Example 6 preparation of the compound 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345), method 1:
Figure BDA0003876559350000191
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preparation of 4-nitrophenyl 6-fluoro-5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline-1-carboxylate (T345-01):
s02 (5 g,1eq,11.9 mmol) and 60mL of ACN were charged into a reaction flask, DIEA (5.12g, 3eq) was added under ice-bath, after all the solution was dissolved, phenyl p-nitrochloroformate (3.06g, 1.15eq) was added, and after all the solution was added, the reaction was allowed to return to room temperature for 1 hour. Then adding 60mL of water into the reaction solution for quenching, stirring for 30min, and filtering; the filter cake was rinsed with 30mL ACN/water (V/V = 1/1) and treated with a diaphragm pump to give 6.2g of T345-01 as a pale yellow solid with an HPLC purity of 94.6% (at this time the water was not fully drained, overweight, calculated as the overall yield with the preparation of T345-02). LC-MS [ M + H ]] + ：544.1。
Preparation of 6-fluoro-N- (3-methoxybenzyl) -5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T345-02):
adding T345-01 (6g, 1eq, 11mmol) and T345-01 (1eq, 11mmol) into a reaction bottle,Cesium carbonate (7.2g, 2eq) in THF (60 mL)/water (30 mL) as solvent; then adding 3-methoxybenzylamine (2.25g, 1.5eq) in three batches, reacting for 18h at 60 ℃, and detecting that the raw material is remained; then, 3-methoxybenzylamine (0.75g, 0.5eq) was added in 2 portions and reacted for 3 hours. Adding 136mL of water and 91mL of EA into the reaction solution for extraction, and taking an organic phase; washing the organic phase with 91mL 10% sodium carbonate and 0.2% diluted hydrochloric acid (100mL x 2) in sequence, adding hydrochloric acid until the pH of the water layer is 3-4; the organic layer was washed with 91mL saturated sodium chloride, dried and rotary evaporated to give 6.1g of an orange oil. The orange oil is dissolved in 60mL of absolute ethanol, no solid is precipitated at the bottom, and the orange oil is filtered, rotary evaporated and dried. The obtained solid is pulped for 2h at room temperature by MTBE/PE (50 mL/50 mL), and the bottom oil phase is taken out, rotated, evaporated and dried to obtain 4.8g of T345-02 as an orange bubble solid. The HPLC purity was 96.3%, and the total yield of the two steps of the preparation of T345-01 and the preparation of T345-02 was 82.4%. LC-MS [ M + H ]] + ：542.2。
Preparation of 5- (3-amino-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345-03):
t345-02 (7.2g, 1eq), ammonium chloride (2.9g, 4eq), reduced iron powder (2.8g, 3.7eq), ethanol (120mL, 16V) and water (60mL, 8V) were charged into a reaction flask, and the reaction solution was reacted at 80 ℃ for 3 hours under nitrogen protection. Then 12.5g of diatomite is added into the reaction liquid, the mixture is stirred for 30min, the mixture is filtered, the filtrate is concentrated to remove ethanol, filter cakes are washed by 200mL of EA, the filtrate is combined, then the mixture is washed by 400mL of saturated sodium bicarbonate and 400mL of saturated common salt water in sequence, the orange solid 6.5g is obtained after rotary evaporation and drying, the obtained solid is added with MTBE (50 mL) and pulped for 12h at room temperature, the mixture is filtered, the filter cake is dried, and 5.7g of T345-03 is obtained, the white solid is similar to white solid, the HPLC purity is 97%, and the yield is 85%. LC-MS [ M + H ]] + ：512.2。
Preparation of 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345):
t345-03 (1eq, 5.5 g) and 3M hydrochloric acid (55 mL)/EtOH (220 mL) were charged into a reaction flask and reacted at 80 ℃ for 2 hours (condenser tube, balloon seal). Adding 100mL of water into the reaction solution, adding sodium carbonate solid to adjust the pH to 8-9 under the ice bath condition, and filtering to remove sodium carbonateConcentrating the filtrate to remove ethanol, extracting with THF/EA (1/1, 100mL/100 mL), washing with 120mL saline, concentrating the organic phase, and drying to obtain yellow foamy solid 4.3g; the resulting solid was then slurried with additional MTBE/EA (45 mL/9mL, V/V =5: 1) at room temperature for 5h, filtered, and the filter cake dried to give 3.9g of compound T345 as a solid, 92.4% HPLC purity, 90% yield. LC-MS [ M + H ]] + ：382.1。
1 H NMR(400MHz,DMSO-d 6 ) δ 11.69 (s, 1H), 7.61 (d, J =12.9hz, 1h), 7.46 (s, 1H), 7.31 (dd, J =11.5,6.1hz, 2h), 7.24 (t, J =8.0hz, 1h), 6.93-6.87 (m, 2H), 6.80 (dd, J =7.3,1.9hz, 1h), 4.59 (s, 2H), 4.31 (d, J =5.8hz, 2h), 3.99 (t, J =8.7hz, 2h), 3.74 (s, 3H), 3.12 (t, J =8.5hz, 2h). Example 7 preparation of the compound 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345), method 2
Figure BDA0003876559350000211
Preparation of 6-fluoro-N- (3-methoxybenzyl) -5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T345-01'):
1.35L of methylene chloride was measured and added to the reaction flask, followed by stirring. 120g of triphosgene is weighed into a reaction bottle under the protection of nitrogen and stirred. Cooling the reaction solution to-5 ℃, controlling the temperature to-5 ℃, dropwise adding dichloromethane solution of 3-methoxybenzylamine (168g of 3-methoxybenzylamine is weighed and dissolved in 1.35L of dichloromethane), and stirring for 30 +/-10 minutes at-5 ℃; 660g of triethylamine is dripped at the temperature of minus 5 to 10 ℃, and the mixture is stirred for 20 +/-10 minutes at the temperature of minus 5 to 10 ℃ after dripping; controlling the temperature to be between 5 ℃ below zero and 10 ℃, and adding 300g of S03 in batches (adding the mixture in three batches at an interval of about 5 to 10 min); then the temperature of the reaction liquid is increased to 10-20 ℃, and the reaction is carried out for 2 hours and 35 minutes under the condition of heat preservation. 1.5L of purified water and 3L of methanol were weighed into a reaction flask and stirred at 5-15 ℃ for 30 minutes. The reaction solution was filtered and 600mL of methanol was measured to rinse the filter cake once. The resulting filter cake was dried at 49 ℃ under a vacuum of-0.10 MPa for 16 hours to give 312.8g of T345-01' as a yellow solid in a yield of 77.60% and a purity of 99.4% by HPLC. LC-MS [ M + H ]] + ：496.1。
Preparation of 5- (3-amino-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345-02'):
3L of tetrahydrofuran was measured and added to the reaction flask, followed by stirring. 30g of 50% wet palladium on carbon was weighed into a reaction flask and stirred. Weighing 300g of T345-01', adding the mixture into a reaction bottle, stirring, and adding N 2 The replacement was performed 3 times, and hydrogen was used 3 times. Keeping the pressure less than or equal to 50psi, heating the reaction system to 40-50 ℃, and keeping the temperature for reaction for 6 hours. Cooling the reaction liquid to 10-20 ℃, and N 2 The replacement was performed 3 times. The reaction solution was filtered through a pad of 1-2 cm of celite, and the filter cake was rinsed with 1.2L of tetrahydrofuran. Concentrating the filtrate at 45 deg.C under-0.09 MPa, adding 1.2L methanol into the concentrated solution, and concentrating at 45 deg.C under-0.09 MPa. At the end of the concentration, a concentrate of T345-02' (as a semi-fluid liquid) was obtained, the theoretical amount for this step was calculated to be 281.85g, and the next feed was made at the theoretical amount for this step. Purity by HPLC was 99.5%.
LC-MS[M+H] + ：466.2。
Preparation of 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-methoxybenzyl) indoline-1-carboxamide (T345):
methanol (1.4L), T345-02' (282 g) and 4M HCl methanol solution (1.2L) are added into a reaction bottle, then the temperature is raised to 40-50 ℃, and the reaction is carried out for 3 hours under the condition of heat preservation. 2.82L of tert-butyl methyl ether is weighed and added into a reaction bottle, and the temperature is reduced to 5-15 ℃. The reaction solution was filtered to obtain a crude product. Adding the crude product into a reaction flask, adding 2.82L of purified water and 2.82L of 2-methyltetrahydrofuran, and adding Na while stirring 2 CO 3 And (5) solid, adjusting the pH value of the solution to 8-9. Stirring the obtained system, standing and layering; adding 1.4L of purified water into an organic phase, stirring, standing, layering, taking the organic phase, concentrating the organic phase at 45 ℃ and the vacuum degree of minus 0.10MPa to 560-850 mL (2-3V, namely 2-3 times of the volume of the raw material), then taking 564mL of acetonitrile, adding the acetonitrile into the concentrated solution, and concentrating the acetonitrile at 45 ℃ and the vacuum degree of minus 0.10MPa to 560-850 mL (2-3V); 846mL of methanol and 3.4L of acetonitrile are weighed into the concentrated solution, heated to 65 ℃, and stirred for 2 hours. Cooling the system to 5-15 ℃, preserving the heat for 1 hour, filtering, and taking 282mAnd leaching the filter cake once by using L acetonitrile. Drying the obtained filter cake at 45 ℃ and vacuum degree of-0.10 MPa for 12-16 hours to obtain 149.50g of T345 which is a white-like solid with yield of 64.74% and purity of 99.9% detected by HPLC, wherein the product meets the requirements of impurity limit control and related gene toxic impurity control.
LC-MS[M+H] + ：382.1。
1 H NMR(400MHz,DMSO-d 6 )δ11.69(s,1H),7.61(d,J＝12.9Hz,1H),7.46(s,1H),7.31(dd,J＝11.5,6.1Hz,2H),7.24(t,J＝8.0Hz,1H),6.93–6.87(m,2H),6.80(dd,J＝7.3,1.9Hz,1H),4.59(s,2H),4.31(d,J＝5.8Hz,2H),3.99(t,J＝8.7Hz,2H),3.74(s,3H),3.12(t,J＝8.5Hz,2H)。
Example 8 preparation of the compound 5- (3-amino-1H-pyrazol-4-yl) -N- (3-cyano-5-fluorobenzyl) -6-fluoroindoline-1-carboxamide (T348):
Figure BDA0003876559350000231
preparation of 3- (bromomethyl) -5-fluorobenzonitrile (T348-01):
under nitrogen protection, 3-fluoro-5-methylbenzonitrile (50g, 370mmol) was dissolved in acetonitrile (500 mL), NBS (69g, 388.5 mmol) and AIBN (1.4 g,7.5 mmol) were added, and the mixture was heated to 80 ℃ to react for 3 hours. Filtering the reaction solution, and concentrating the filtrate to obtain a crude product. The crude product was slurried with petroleum ether/ethyl acetate (V/V = 5/1) at room temperature for 8h, filtered, and the filter cake was dried under vacuum at 60 ℃ to give 60g of tj348-01 as a yellow solid in 75.8% yield. LC-MS [ M + H ]] + :213.9。
Preparation of 3- (aminomethyl) -5-fluorobenzonitrile (T348-02):
t348-01 (60g, 280mmol) was dissolved in ammonia (5L) and tetrahydrofuran (100 mL), and the reaction was carried out at 80 ℃ for 6h. The reaction was extracted with dichloromethane (900ml × 3) and the organic phases were combined; the organic phase was washed with saturated brine (200ml × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 35g of t348-02 as a yellow solid with a yield of 83%. LC-MS [ M + H ]] + :151.1。
Preparation of N- (3-cyano-5-fluorobenzyl) -6-fluoro-5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T348-03):
adding T345-01 (6 g,1eq, 11mmol) and cesium carbonate (7.2g, 2eq) into a reaction bottle, and taking THF (60 mL)/water (30 mL) as a solvent; then T348-02 (2.5g, 16.5mmol) was added in three portions and reacted at 60 ℃ for 24 hours. Adding 136mL of water and 91mL of EA into the reaction solution for extraction, and taking an organic phase; sequentially using 91mL of 10% sodium carbonate and 0.2% diluted hydrochloric acid (100mL x 2 for washing) to the organic phase, wherein the water layer is alkaline, and adding hydrochloric acid until the pH value of the water layer is 3-4; the organic layer was washed with 91mL saturated sodium chloride and dried by rotary evaporation to give 6.0g of a yellow oil. The obtained oily matter is dissolved in 60mL of absolute ethyl alcohol, no solid is precipitated at the bottom, and the oily matter is filtered and then is subjected to rotary evaporation and drying to obtain a bubble solid. The obtained foamy solid is beaten with MTBE/PE (60 mL/50 mL) for 1h at room temperature, after filtration, the filtrate is rotary evaporated and dried to obtain 4.5g of T348-03 as a pale yellow solid with the yield: 73.7 percent. LC-MS [ M + H ]] + ：545.6。
Preparation of 5- (3-amino-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) -N- (3-cyano-5-fluorobenzyl) -6-fluoroindoline-1-carboxamide (T348-04):
under nitrogen protection, T348-03 (4.5g, 8.3mmol), ammonium chloride (1.8g, 33.2mmol), reduced iron powder (1.9g, 33.2mmol), ethanol (90 mL) and water (45 mL) were charged into a reaction flask and reacted at 80 ℃ for 2 hours. Then 9g of diatomite is added into the reaction liquid, the mixture is stirred for 30min, the mixture is filtered, the filtrate is concentrated to remove ethanol, filter cakes are washed by 90mL of EA, the filtrates are combined, then the combined filtrates are washed by 180mL of saturated sodium bicarbonate and 180mL of saturated salt water in sequence, 6.1g of yellow solid is obtained after rotary evaporation and drying, the obtained solid is added with MTBE (45 mL) and pulped for 16h at room temperature, the filtration is carried out, the filter cake is dried, 3.6g of T348-04 is obtained as off-white solid, and the yield is 84.5%. LC-MS [ M + H ]] + ：525.6。
Preparation of 5- (3-amino-1H-pyrazol-4-yl) -N- (3-cyano-5-fluorobenzyl) -6-fluoroindoline-1-carboxamide (T348):
t348-04 (3.6 g,6.9 mmol), 3M hydrochloric acid (30 mL)/EtOH (120 mL) was added to the reaction flask and reacted at 80 ℃ for 1.5h (condenser tube, balloon seal). Adding 80mL of water into the reaction solution, adding sodium carbonate solid to adjust the pH to 8-9 under the ice bath condition, and filtering to remove sodium carbonateThe solid, filtrate was concentrated to remove ethanol, then extracted with THF/EA (1/1, 50mL/50 mL), washed once with 50mL brine, the resulting organic phase was concentrated and dried to give 3.1g of a pink foamy solid, which was slurried with MTBE/EA (36 mL/6mL, 6. LC-MS [ M + H ]] + ：395.2。
1 H NMR(400MHz,DMSO-d 6 )δ8.01(d,J＝1.1Hz,1H),7.76–7.71(m,1H),7.67(d,J＝1.6Hz,1H),7.64(s,1H),7.60-7.55(m,2H),7.32(d,J＝7.8Hz,1H),4.39(d,J＝5.7Hz,2H),4.07(t,J＝8.7Hz,2H),3.16(t,J＝8.6Hz,2H)。
Example 9 preparation of the compound 5- (3-amino-1H-pyrazol-4-yl) -N- (3, 5-difluorobenzyl) -6-fluoroindoline-1-carboxamide (T364):
Figure BDA0003876559350000251
preparation of N- (3, 5-difluorobenzyl) -6-fluoro-5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T364-01):
135mL of methylene chloride was measured and added to the reaction flask, followed by stirring. Triphosgene (12g, 40.4 mmol) was weighed into a reaction flask and stirred under nitrogen. Cooling the reaction solution to-5 ℃, controlling the temperature to-5 ℃, dropwise adding a dichloromethane solution of (3, 5-difluorophenyl) methylamine (obtained by weighing 11.6g of (3, 5-difluorophenyl) methylamine and dissolving in 135mL of dichloromethane), and stirring at-5 ℃ for 30min; then triethylamine (65.4g, 646.4mmol) is dripped at the temperature of-5 to 10 ℃, and the mixture is stirred for 20min at the temperature of-5 to 10 ℃ after the dripping is finished; continuously controlling the temperature to be-5-10 ℃, and adding 30g S03 in batches (adding in three batches with the interval of about 5-10 min); heating the obtained reaction system to 10-20 ℃, and reacting for 2.5h under the condition of heat preservation. 150mL of purified water and 300mL of methanol were weighed into a reaction flask, and stirred at 5-15 ℃ for 30min. The reaction solution was filtered, and 100mL of methanol was measured and the filter cake was rinsed once. Drying the obtained filter cake at 49 ℃ under the vacuum degree of-0.10 MPa for 16H to obtain 32g of T364-01 as yellow solid with the yield of 79.0 percent and the HPLC purity of 90.2 percent, and LC-MS (LC-MS) M + H] + ：502.1。
Preparation of 5- (3-amino-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -N- (3, 5-difluorobenzyl) -6-fluoroindoline-1-carboxamide (T364-02):
weighing 300mL of tetrahydrofuran, adding into a reaction bottle, and stirring; weighing 1g of 50% wet palladium carbon, adding into a reaction bottle, and stirring; weighing 10g of T364-01 (20 mmol), adding into a reaction flask, stirring, and N 2 The replacement was performed 3 times, and the hydrogen replacement was performed 3 times. Keeping the pressure less than or equal to 50psi, heating the reaction system to 40-50 ℃, and keeping the temperature for reaction for 6 hours. Cooling the reaction liquid to 10-20 ℃, and N 2 The replacement was performed 3 times. The reaction solution was filtered through a pad of 20g of celite, and the filter cake was rinsed with 120mL of tetrahydrofuran. Concentrating the obtained filtrate at 45 deg.C under vacuum degree of-0.09 MPa, adding 120mL methanol into the concentrated solution, and concentrating at 45 deg.C under vacuum degree of-0.09 MPa. After the end of the concentration, T364-02 is obtained as a semifluid and the next charge is carried out in the amount corresponding to the amount theoretically used in this step (9.4 g).
LC-MS[M+H] + ：472.2。
Preparation of 5- (3-amino-1H-pyrazol-4-yl) -N- (3, 5-difluorobenzyl) -6-fluoroindoline-1-carboxamide (T364):
adding 140mL of methanol, the theoretical amount T364-02 and 120mL of 4M HCl methanol solution into a reaction flask, then heating to 40-50 ℃, and carrying out heat preservation reaction for 3 hours. Measuring 140m L of tert-butyl methyl ether, adding the tert-butyl methyl ether into a reaction bottle, cooling the reaction solution to 5-15 ℃, and filtering to obtain a crude product. The crude product was added to the reaction flask, 282mL of purified water and 282mL of tetrahydrofuran were added, and Na was added with stirring 2 CO 3 Adjusting the pH value of the solution to 8-9, stirring, standing, layering, adding 140mL of purified water into the organic phase, stirring, standing, layering, concentrating the organic phase at 45 ℃ and under the vacuum degree of-0.10 MPa to 20-30 mL (2-3V), measuring 60mL of acetonitrile, adding the acetonitrile into the concentrated solution, concentrating at 45 ℃ and under the vacuum degree of-0.10 MPa to 20-30 mL (2-3V), measuring 80mL of methanol and 320mL of acetonitrile, adding the acetonitrile into the concentrated solution, heating to 65 ℃, and stirring for 2h. Cooling the obtained system to 5-15 ℃, preserving heat for 1h, then filtering, drying a filter cake at 45 ℃ under the vacuum degree of-0.10 MPa for 12h to obtain T364.3 g which is off-white solid, wherein the yield is 81.8 percent, and the HPLC purity is 95.19％。LC-MS[M+H] + ：388.1。
1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),7.60(d,J＝12.8Hz,1H),7.47(d,J＝1.8Hz,1H),7.41(t,J＝5.9Hz,1H),7.31(d,J＝8.0Hz,1H),7.15–6.99(m,3H),4.62(s,2H),4.35(d,J＝5.8Hz,2H),4.02(t,J＝8.7Hz,2H),3.14(t,J＝8.5Hz,2H)。
Example 10 preparation of the compound (S) -5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (1- (3-fluoro-5-methoxyphenyl) -2-hydroxyethyl) indoline-1-carboxamide (T365):
Figure BDA0003876559350000261
preparation of 2- ((tert-butyldimethylsilyl) oxy) -1- (3-fluoro-5-methoxyphenyl) ethan-1-one (T365-01):
magnesium turnings (10.5g, 439mmol) and iodine (0.001eq, 56mg) were added to anhydrous tetrahydrofuran (50 mL), and a solution of 3-bromo-5-fluoroanisole (750g, 365.8mmol) in tetrahydrofuran (350 mL) was added dropwise over 0.5h, under nitrogen. The resulting reaction was added dropwise to a solution of 2- ((tert-butyldimethylsilyl) oxy) -N-methoxy-N-methylacetamide (93.9g, 402.4 mmol) in tetrahydrofuran (400 mL) at 0 ℃ and reacted at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (300 mL), and the resulting reaction solution was extracted with ethyl acetate (600ml × 2), washed with saturated brine (500 mL), and concentrated under reduced pressure to give a crude product. And (3) using n-hexane for crude products: ethyl acetate (V: V = 20) was slurried at room temperature for 6h, filtered, and the filter cake was dried under vacuum at 60 ℃ for 12h to give 91g of t365-01 as a pale yellow solid in 72% yield.
MS[M+H] + ＝299.1。
Preparation of (R, Z) -N- (2- ((tert-butyldimethylsilyl) oxy) -1- (3-fluoro-5-methoxyphenyl) ethylene) -2-methylpropane-2-sulfinamide (T365-02):
t365-01 (91g, 305.4 mmol) and (R) - (+) -tert-butylsulfinamide (44.3g, 366.4 mmol) were dissolved in 1, 4-dioxane (900 mL), tetraisopropyl titanate (216.8g, 763.3 mmol) was added, nitrogen blanketed, and refluxed for 12h. Cooling the reaction solution, and pouring into the reactorEthyl acetate (800 mL), then poured into saturated brine (200 mL) with rapid stirring, filtered, the filter cake washed with ethyl acetate (500 mL), the resulting filtrate washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. After the obtained filtrate was concentrated, the residue was extracted with petroleum ether: ethyl acetate (V: V = 5) was slurried at room temperature for 4h, filtered, and the filter cake was vacuum dried for 12h to give 86g of ti 365-02 as a pale white solid in yield: 70 percent. MS [ M + H ]] + ：402.1。
Preparation of (S) -N- ((S) -2- ((tert-butyldimethylsilyl) oxy) -1- (3-fluoro-5-methoxyphenyl) ethyl) -2-methylpropane-2-sulfinamide (T365-03):
t365-02 (15.6 g,38.9 mmol) was dissolved in dry tetrahydrofuran (140 mL) under nitrogen protection, 1moL/L borane tetrahydrofuran (116mL, 116.7 mmol) was added at-70 deg.C, the reaction was allowed to react for 3h at-70 deg.C, and then quenched by slowly adding water (100 mL). The reaction mixture was extracted with ethyl acetate (200ml × 2), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product obtained was purified with methyl tert-butyl ether: ethyl acetate (V: V = 3) was slurried at room temperature for 2h, rotary evaporated to dryness to give 12.2g of ti 365-03 as a yellow solid in 78% yield. MS [ M + H ]] + ：404.1。
Preparation of (S) -2-amino-2- (3-fluoro-5-methoxyphenyl) ethane-1-ol hydrochloride (T365-04):
t365-03 (12g, 29.76mmol) was dissolved in methanol (120 mL), and 4M HCl in methanol (24 mL) was added and stirred at room temperature for 16h. The reaction solution was concentrated under reduced pressure to obtain 6g of T365-04 as a white solid in yield: 91 percent. MS [ M + H ]] + ：186.0。
Preparation of (S) -6-fluoro-N- (1- (3-fluoro-5-methoxyphenyl) -2-hydroxyethyl) -5- (3-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T365-05):
adding T345-01 (6 g,1eq, 11mmol) and cesium carbonate (7.2g, 2eq) into a reaction bottle, and taking THF (60 mL)/water (30 mL) as a solvent; then T365-04 (3.6g, 16.5mmol) is added in three portions and reacted for 18h at 60 ℃. Adding 136mL of water and 91mL of EA into the obtained reaction solution for extraction, and taking an organic phase; washing the organic phase with 91mL 10% sodium carbonate and 0.2% diluted hydrochloric acid (100mL x 2) in sequence, adding hydrochloric acid until the pH of the water layer is 3-4; the organic layer was washed with 91mL saturated sodium chloride and dried by rotary evaporation to give 6.5g of a yellow oil. The obtained oily substance is dissolved in 60mL of absolute ethyl alcohol, no solid is precipitated at the bottom, and the oily substance is filtered, rotated, evaporated and dried to obtain a bubble solid. Pulping the obtained foamy solid with EA/PE (100 mL/50 mL) at room temperature for 12h, filtering, and rotary evaporating the filtrate to dry to obtain 5.3g of T365-05 as a light white solid with the yield: 82 percent.
LC-MS[M+H] + ：590.1。
(S) -5- (3-amino-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) -6-fluoro-N- (1- (3-fluoro-5-methoxyphenyl) -2-hydroxyethyl) indoline-1-carboxamide (T365-06):
t365-05 (5.3 g, 9mmol), ammonium chloride (1.9g, 36mmol), reduced iron powder (2.0 g, 36mmol), ethanol (100 mL) and water (50 mL) are added into a reaction bottle, and the mixture is reacted for 3 hours at 80 ℃ under the protection of nitrogen. Then 10g of diatomite is added into the reaction liquid, the mixture is stirred for 30min, the mixture is filtered, the filtrate is concentrated to remove ethanol, a filter cake is washed by 100mL of EA, the filtrates are combined, and then washed by 200mL of saturated sodium bicarbonate and 200mL of saturated common salt water in sequence, after rotary evaporation and drying, 7.0g of light yellow solid is obtained, the obtained solid is added with n-hexane (42 mL) and pulped for 3h at 40 ℃, the mixture is filtered, and the filtrate is dried by rotary evaporation to obtain 4.3g of T365-06 as white solid with the yield of 86%.
LC-MS[M+H] + ：560.2。
Preparation of (S) -5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (1- (3-fluoro-3-methoxyphenyl) -2-hydroxyethyl) indoline-1-carboxamide (T365):
t365-06 (4.3g, 7.7mmol), 3M hydrochloric acid (30 mL)/EtOH (120 mL) were added to a reaction flask and reacted at 80 ℃ for 3h (condenser, balloon seal). Adding 80mL of water into the reaction solution, adding sodium carbonate solid to adjust the pH to 8-9 under the ice bath condition, and filtering to remove sodium carbonate solid; the filtrate was concentrated to remove ethanol, extracted with 2-MeTHF/EA (1/1, 50mL/50 mL), washed once with 50mL of brine, and the organic phase was concentrated and dried to give 3.6g of a pale pink foamy solid. The resulting foamy solid was slurried with MTBE/acetonitrile (30 mL/6mL, 2/1) at room temperature for 4h, filtered, and the filter cake dried to give T365 2.9g, yield 87.9%, HPLC purity 99.1%.LC-MS[M+H] + ：430.1。
1 H NMR(400MHz,DMSO-d 6 )δ11.67(s,1H),7.55(d,J＝12.8Hz,1H),7.46(s,1H),7.31(d,J＝8.0Hz,1H),6.86–6.79(m,3H),6.72–6.67(m,1H),4.94(s,1H),4.82(dd,J＝13.6,7.5Hz,1H),4.58(s,2H),4.14–4.02(m,2H),3.77(s,3H),3.67–3.59(m,2H),3.14(t,J＝8.9Hz,2H)。
EXAMPLE 11 preparation of the compound 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-fluoro-5-methoxybenzyl) indoline-1-carboxamide (T385)
Figure BDA0003876559350000291
Preparation of 6-fluoro-N- (3-fluoro-5-methoxybenzyl) -5- (3-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) indoline-1-carboxamide (T385-01):
135mL of methylene chloride was measured and added to the reaction flask, followed by stirring. Triphosgene (12g, 40.4 mmol) was weighed into a reaction flask and stirred under nitrogen. Cooling the reaction liquid to-5 ℃, dropwise adding a dichloromethane solution of 3-fluoro-5-methoxybenzylamine (12.5 g of 3-fluoro-5-methoxybenzylamine is dissolved in 135mL of dichloromethane) at the temperature of-5 ℃ and stirring for 30min at-5 ℃; triethylamine (65.4g, 646.4mmol) is dripped at the temperature of minus 5 to 10 ℃, and the triethylamine is stirred for 20min at the temperature of minus 5 to 10 ℃ after the dripping is finished; controlling the temperature to be-5-10 ℃, and adding 30g of S03 in batches (adding in three batches with the interval of about 5-10 min). Heating the obtained reaction liquid to 10-20 ℃, and reacting for 2.5h under the condition of heat preservation. 150mL of purified water and 300mL of methanol were weighed into a reaction flask, and stirred at 5-15 ℃ for 30min. The reaction solution was filtered and 100mL of methanol was measured to rinse the filter cake once. Drying the obtained filter cake at 49 ℃ under a vacuum degree of-0.10 MPa for 16H to obtain 35g of T385-01 as a yellow solid with a yield of 84.3 percent and an HPLC purity of 86.9 percent] + ：514.2。
Preparation of 5- (3-amino-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -6-fluoro-N- (3-fluoro-5-methoxybenzyl) indoline-1-carboxamide (T385-02):
600mL of tetrahydrofuran was measured and added to the reaction flask, followed by stirring. Weighing2g 50% wet palladium on carbon was added to the reaction flask and stirred. Weighing 20g of T385-01 (39 mmol) and adding the mixture into a reaction bottle, stirring, and adding N 2 The replacement was performed 3 times, and the hydrogen replacement was performed 3 times. Keeping the pressure less than or equal to 50psi, heating the reaction solution to 40-50 ℃, and keeping the temperature for reaction for 8 hours. Cooling the reaction liquid to 10-20 ℃, and N 2 The replacement was performed 3 times. The reaction solution was filtered through a pad of 40g of celite, and 240mL of tetrahydrofuran was weighed to rinse the filter cake. Concentrating the obtained filtrate at 45 deg.C under vacuum degree of-0.09 MPa, adding 240mL methanol into the concentrated solution, and concentrating at 45 deg.C under vacuum degree of-0.09 MPa. After the end of the concentration, T385-02 is obtained as a semifluid liquid, which is fed in the next step in the amount theoretically required for this step (18.8 g).
LC-MS[M+H] + ：484.1。
Preparation of 5- (3-amino-1H-pyrazol-4-yl) -6-fluoro-N- (3-fluoro-5-methoxybenzyl) indoline-1-carboxamide (T385):
140mL of methanol was measured and added to the reaction flask, and the theoretical amount T385-02 obtained in the above step was added to the reaction flask. 240mL4M HCl methanol solution was measured and added to the reaction flask. Then heating to 40-50 ℃, and reacting for 3 hours under the condition of heat preservation. 280mL of tert-butyl methyl ether is measured and added into a reaction bottle, and the temperature is reduced to 5-15 ℃. Filtering the reaction solution to obtain a crude product, adding the crude product into a reaction flask, adding 480mL of purified water and 480mL of ethanol, and adding Na under stirring 2 CO 3 And (5) solid, adjusting the pH value of the solution to 8-9. Stirring, standing and layering; adding 140mL of purified water into the organic phase, stirring, standing and layering; taking the organic phase, and concentrating the organic phase at 45 ℃ and the vacuum degree of-0.10 MPa to 35-60 mL (2-3V); weighing 120mL of acetonitrile, adding the acetonitrile into the concentrated solution, and concentrating the acetonitrile to 35-60 mL (2-3V) at 45 ℃ under the vacuum degree of-0.10 MPa; 100mL of methanol and 300mL of acetonitrile were weighed out and added to the concentrated solution, and the mixture was stirred for 2 hours while the temperature was raised to 65 ℃. Cooling the obtained solution to 5-15 ℃, preserving heat for 1h, filtering, drying the obtained filter cake at 45 ℃ under the vacuum degree of-0.10 MPa for 18h to obtain 12.7g of T385 as a white solid, wherein the yield is 78.8 percent and the HPLC purity is 98.56 percent. LC-MS [ M + H ]] + ：400.1。
1 H NMR(400MHz,DMSO-d 6 )δ7.61(d,J＝12.8Hz,1H),7.51(s,1H),7.37(t,J＝5.9Hz,1H),7.30(d,J＝8.0Hz,1H),6.76–6.66(m,3H),4.30(d,J＝5.8Hz,2H),4.01(t,J＝8.7Hz,2H),3.76(s,3H),3.13(t,J＝8.4Hz,2H)。
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (10)

1. An intermediate compound represented by formula M01, or a pharmaceutically acceptable salt thereof:
Figure FDA0003876559340000011
wherein Q is an amino protecting group 1, such as SEM, THP, boc, or trityl;
q is preferably SEM or THP.
2. The intermediate compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, formate, acetate, trifluoroacetate, sulfate, methanesulfonate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cypionate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate, pectate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, camphorate, undecanoate, or succinate; preferably, the pharmaceutically acceptable salt is the hydrochloride salt of the compound of formula M01.
3. A process for preparing an intermediate compound of formula M01, comprising the steps of:
Figure FDA0003876559340000012
a1 Compound M01-3 reacts with compound M01-2 to give compound M01-1;
a2 Removing the protecting group R from the compound M01-1 to obtain a compound shown as a formula M01;
wherein Q has the definition of claim 1; r is an amino protecting group 2, for example acetyl, benzyloxycarbonyl or trifluoroacetyl; r is preferably acetyl or benzyloxycarbonyl; g is a group capable of reacting with X 1 Groups undergoing coupling reactions, e.g. when G is boronic acid or pinacol boronic ester, X 1 Is Cl, br or I; when G is Cl, br or I, X 1 Is a boronic acid group or a pinacol boronic acid ester group;
preferably, when G is a boronic acid group or a pinacol boronic ester group, X is 1 Is Cl, br or I.
4. The process according to claim 3, wherein in step A1) the reaction is carried out with the aid of a catalyst comprising a palladium catalyst, such as Pd (dppf) Cl 2 、PdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 Or Pd 2 (dba) 3 At least one of;
preferably, in step A1), the reaction is carried out under the action of a base, which is an inorganic base, such as sodium carbonate, potassium carbonate or cesium carbonate;
preferably, in step A2), when Q is SEM and R is acetyl, the acetyl group is deacetylated using an acid; the acid is an inorganic acid; the inorganic acid is hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; the reaction is carried out in the presence of a solvent A, wherein the solvent A is one or a mixture of water, methanol, ethanol, ethyl acetate or 1, 4-dioxane; the molar ratio of the acid to M01-1 is (0.5-5): 1; preferably, the molar ratio of the acid to M01-1 is (2.5-5): 1; preferably, the acid is hydrochloric acid; preferably, the reaction temperature of the reaction is 50-60 ℃; preferably, the reaction time of the reaction is 16-35h;
when Q is THP and R is acetyl, removing acetyl by using alkali; the base isIs lithium hydroxide, lithium hydroxide hydrate or piperidine, preferably lithium hydroxide monohydrate; the reaction is carried out in the presence of a solvent B, wherein the solvent B is one or a mixture of water, methanol, ethanol, tetrahydrofuran and 1, 4-dioxane; preferably, the solvent B is THF/MeOH/H 2 A mixed solvent of O; the molar ratio of the alkali to M01-1 is (10-25): 1;
when R is benzyloxycarbonyl, the reaction is carried out in the presence of Pd/C and hydrogen.
5. The process according to claim 3 or 4, wherein the process for the preparation of compound M01-2 comprises the following steps:
Figure FDA0003876559340000021
b1 Compound 6-fluoroindole (M01-2-3) is reacted with a reducing agent and a compound providing an R group to give compound M01-2-2;
b2 Compound M01-2-2 reacts with a halogenating agent to obtain compound M01-2-1;
b3 Compound M01-2-1 with a compound providing a G group to give compound M01-2;
wherein R has the definition set forth in claim 3; g is selected from boric acid group or pinacol borate group; x 2 Is Cl, br or I;
preferably, in step B1), the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride or potassium borohydride;
preferably, in step B1), the compound providing the R group is RX 3 Or an acid anhydride compound containing R, X 3 Is halogen, RX 3 For example chloroacetyl, bromoacetyl or benzyl chloroformate, and the anhydride compound containing R is for example trifluoroacetic anhydride;
preferably, in step B1), the temperature of the reaction is 0-10 ℃;
preferably, step B1) further comprises a step of purifying the product after the reaction is completed: pulping the product with at least one of methyl tert-butyl ether, isopropyl acetate, n-heptane, petroleum ether or isopropanol; the pulping time is 1-8h; the pulping temperature is room temperature;
preferably, in step B2), the halogenating agent is NCS, NBS or NIS;
preferably, in step B3), the compound providing a G group is a bis-pinacol boronate, triisopropyl borate, trimethyl borate, triethyl borate or pinacol borane.
6. The process according to claim 3 or 4, wherein the process for the preparation of compound M01-3 comprises the following steps:
Figure FDA0003876559340000031
c) Reacting the compound M01-3-1 with a compound for providing Q to obtain a compound M01-3;
wherein, Q and X 1 Having the definition set forth in claim 3;
preferably, in step C), the compound providing Q is 2- (trimethylsilyl) ethoxymethyl chloride, 3, 4-dihydro-2H-pyran, di-tert-butyldicarbonate or trityl chloride;
preferably, after the reaction of step C) is finished, the method further comprises the step of purifying the product: the purification is a beating of the product with at least one solvent system of n-heptane/methyl tert-butyl ether (v/v = 10/1), n-heptane/isopropyl acetate (v/v = 8/1), petroleum ether/ethyl acetate (v/v = 12/1) or methyl tert-butyl ether/isopropanol = (v/v = 20/1); preferably, the pulping temperature is room temperature; preferably, the beating time is 3-18h.
7. The process according to any one of claims 3 to 6, wherein the process for preparing the intermediate compound represented by the formula M01 comprises the steps of:
s1: dissolving 6-fluoroindole in a solvent 1, and adding cyano sodium borohydride for reaction to obtain colorless oily liquid; dissolving the colorless oily liquid IN a solvent 2, and adding acetyl chloride IN the presence of a base 1 to react to prepare a compound shown IN a formula IN-01;
Figure FDA0003876559340000032
the solvent 1 is acetic acid, and the volume-to-mass ratio of the solvent 1 to 6-fluoroindole is (5-10) mL/g; the solvent 2 is dichloromethane, and the volume-mass ratio of the solvent 2 to the 6-fluoroindole is (10-15) mL/g;
the alkali 1 is sodium bicarbonate, and the molar ratio of the alkali 1 to acetyl chloride is 1:1;
s2: dissolving the compound of the formula IN-01 IN a solvent 3, and adding N-bromosuccinimide to react to prepare the compound of the formula IN-02;
Figure FDA0003876559340000041
the solvent 3 is DCM; the volume-mass ratio of the solvent 3 to the IN-01 is (8-12) mL/g;
s3: dissolving a compound of formula IN-02 IN solvent 4 IN the presence of a base 2 and a catalyst with (BPin) 2 Reacting to prepare a compound shown IN a formula IN-03;
Figure FDA0003876559340000042
the solvent 4 is 1, 4-dioxane, and the volume-mass ratio of the solvent 4 to the IN-02 compound is (10-12) mL/g;
the base 2 is potassium acetate (KOAc); the catalyst is a palladium catalyst;
s4: dissolving 4-bromo-3-nitro-1H-pyrazole IN solvent 5, and reacting with IN-SM1 under alkaline condition to prepare compound of formula M02
Figure FDA0003876559340000043
Q is SEM or THP;
the IN-SM1 is SEM-Cl or 3, 4-dihydro-2H-pyran;
s5: dissolving a compound shown IN a formula M02 and a compound shown IN a formula IN-03 IN a solvent 6, and reacting IN the presence of a base 4 and a catalyst to obtain a compound shown IN a formula M03;
Figure FDA0003876559340000044
q is SEM or THP;
the volume-mass ratio of the solvent 6 to the compound of the formula M02 is (5-10) mL/g; the solvent 6 is a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water in the mixed solvent is (4-5): 1;
the base 4 is K 2 CO 3 The molar ratio of the base 4 to the compound of the formula M02 is (2-3): 1;
in the step S5, the catalyst is a palladium catalyst;
s6: deacetylating the compound of formula M03 to give a compound of formula M01;
Figure FDA0003876559340000051
q is SEM or THP.
8. A process for the preparation of the hydrochloride salt of an intermediate compound of formula M01 as claimed in claim 1 or 2:
reacting an intermediate compound represented by formula M01 with HCl solution to prepare S01:
Figure FDA0003876559340000052
wherein Q has the definition set forth in claim 1;
the HCl solution is hydrochloric acid, HCl methanol solution, HCl ethanol solution, HCl ethyl acetate solution, HCl 1, 4-dioxane solution or HCl tetrahydrofuran solution;
the molar ratio of HCl to M01 in the reaction system is (1-3): 1; when Q is THP, it is preferably 1.2.
9. Use of an intermediate compound of formula M01 as claimed in claim 1 or 2 for the preparation of a compound of formula I.
Figure FDA0003876559340000053
10. A process for the preparation of a compound of formula I, comprising the steps of:
Figure FDA0003876559340000061
wherein Y is unsubstituted or optionally substituted by one or two R y Substituted sub-C 1-20 An alkyl group;
ring C is unsubstituted or optionally substituted with one, two, three or four R c Substituted with the following groups: c 1-20 Alkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl;
q is an amino protecting group 1, for example SEM, THP, boc or trityl; q is preferably SEM or THP;
each R y ，R c Identical or different, independently of one another, H, halogen, nitro, nitroso, CN, OH, SH, oxo (= O), or unsubstituted or optionally substituted by one, two or three R 1 Substituted groups as follows: c 1-12 Alkyl, C optionally containing one, two or more heteroatoms 1-12 An alkyl group;
R 1 is oxo (= O), halogen, CN, OH, SH, NH 2 Or COOH;
preferably, Y is sub-C 1-6 Alkyl or OH-substituted alkylene 1-6 An alkyl group; ring C is unsubstituted or optionally substituted with one, two, three or four R c Substituted C 6-14 An aryl group; each R c The same or differentIndependently of one another, H, halogen, CN, OH or C 1-6 An alkoxy group;
preferably, Y is methylene, ethylene, propylene or OH substituted ethyl; ring C is unsubstituted or optionally substituted by one, two or three R c Substituted phenyl; each R c Identical or different, independently of one another, is H, F, CN or methoxy; preferably, ring C is
Figure FDA0003876559340000062
Step 1), reacting a compound M01 with a compound A to obtain a compound I-2;
step 2) reducing the nitro group of the compound I-2 into amino group to obtain a compound I-3;
step 3), removing the amino protecting group Q from the compound I-3 to obtain a compound I;
preferably, in step 1), the reaction is carried out in the presence of an acylating agent which converts the secondary amine in the compound M01 and the NH in the compound A in the reaction system 2 Linking through carbonyl group to generate compound of formula I-2; preferably, the acylating agent is p-nitrophenyl chloroformate, triphosgene or N, N-carbonyldiimidazole;
preferably, in the step 2), the reduction reaction of the nitro group to amino group is performed under the action of a catalyst, wherein the catalyst is iron powder, zinc powder, palladium carbon or palladium hydroxide;
preferably, in step 3), the reaction for removing the amino protecting group Q is carried out in the presence of an acid; preferably, the acid is an organic acid or an inorganic acid; more preferably, the acid is at least one of HCl, p-toluenesulfonic acid, acetic acid, or trifluoroacetic acid; the molar ratio of the acid to I-3 is (2-25): 1, for example (2-20): 1; preferably, when Q is SEM, the reaction temperature of the reaction is 70-90 ℃, and when Q is THP, the reaction temperature of the reaction is 30-60 ℃; preferably, the reaction time of the reaction is 2 to 10h, e.g. 1.5 to 3h, 2 to 3h, 4 to 8h.
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