CN110240598B - Process for preparing carboxamide derivatives and intermediate compounds thereof - Google Patents

Process for preparing carboxamide derivatives and intermediate compounds thereof Download PDF

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CN110240598B
CN110240598B CN201910176600.6A CN201910176600A CN110240598B CN 110240598 B CN110240598 B CN 110240598B CN 201910176600 A CN201910176600 A CN 201910176600A CN 110240598 B CN110240598 B CN 110240598B
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CN110240598A (en
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刘福萍
匡远卓
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of an N- (pyridine-2-yl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide derivative shown in a formula (I) or an enantiomer thereof and an intermediate compound thereof. The method has the advantages of high reaction yield, good product purity, simple post-treatment method, greatly reduced cost, strong process operability and greatly improved process safety. Therefore, the preparation method is more suitable for industrial application.

Description

Process for preparing carboxamide derivatives and intermediate compounds thereof
The present application claims priority from chinese patent application CN2018101960919, having a filing date of 2018, 3, 9. The present application refers to the entirety of the above-mentioned chinese patent application.
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and particularly relates to a preparation method and application of an FGFR4 inhibitor intermediate.
Background
Fibroblast Growth Factor Receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor, comprising 4 receptor subtypes FGFR1, FGFR2, FGFR3 and FGFR4, respectively. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and various body functions of adults. FGFR is an important target for tumor targeted therapy research, with aberrant expression in a variety of human tumors, including gene amplification, mutation, and overexpression.
FGFR4 is a member of the FGFR receptor family, and forms dimers on the cell membrane by binding to its ligand fibroblast growth factor 19 (FGF 19), which can cause phosphorylation of critical tyrosine residues within FGFR4 itself, thereby activating intracellular multiple downstream signaling pathways that play an important role in cell proliferation, survival and anti-apoptotic processes. FGFR4 is overexpressed in many cancers and is a predictor of tumor malignancy invasion. Reducing and lowering FGFR4 expression can reduce cell proliferation and promote apoptosis. More and more recent studies indicate that about one third of liver cancer patients continuously activate FGF19/FGFR4 signaling pathway, and the signaling pathway is a main carcinogen factor for liver cancer occurrence of the patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, and the like.
The incidence rate of liver cancer is the first of the world of high living in China, and new and dead patients account for about half of the total number of liver cancer in the world each year. At present, the incidence rate of liver cancer in China is about 28.7/10 ten thousand, 394770 new cases exist in 2012, and the liver cancer becomes the third largest malignant tumor with the death rate inferior to that of stomach cancer and lung cancer. Primary liver cancer onset is a multifactorial and multi-step complex process, with strong invasiveness and poor prognosis. Surgical treatments such as liver resection and liver transplantation can increase survival in some patients, but only limited patients can undergo surgical treatment, and most patients after surgery still have a poor prognosis due to recurrence and metastasis. Sorafenib is the only liver cancer therapeutic drug approved in the market at present, and the clinic can only prolong the total survival time of about 3 months, and the therapeutic effect is not ideal, so that development of liver cancer system therapeutic drugs targeting new molecules is urgently needed. FGFR4 is a major carcinogen for a significant portion of liver cancer, and the development of small molecule inhibitors thereof has great potential for clinical application.
At present, some FGFR inhibitors are used as antitumor drugs to enter clinical research stage, but the FGFR inhibitors are mainly aimed at FGFR1, FGFR2 and FGFR3, the activity inhibition on FGFR4 is weak, and the inhibition on FGFR1-3 has target related side effects such as hyperphosphatemia and the like. The FGFR4 high-selectivity inhibitor can effectively treat cancer diseases caused by abnormal FGFR4 signal paths, can avoid related side effects such as hyperphosphatemia and the like caused by FGFR1-3 inhibition, and has great application prospect in the field of tumor targeted therapy aiming at the high-selectivity small molecule inhibitor of FGFR4.
One class of FGFR4 inhibitors is disclosed in patent WO2017198149, wherein representative compounds are chemical names: (R) -N- (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) -7-formyl-6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide, prepared by:
the patent takes 2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridine-3-formaldehyde as a raw material to prepare (R) -N- (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridine-2-yl) -7-formyl-6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -formamide, and the (R) -N- (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridine-2-yl) -7-formyl-6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -formamide, and then the (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridine-2-yl) pyridine-7-formyl-carbonyl-7-carbonyl-1-naphthyridine-1-yl-methyl-1-butyl alcohol as a final product.
Disclosure of Invention
In order to solve the problems in the prior art, the inventor develops a novel method for preparing the compound shown in the formula (I) in a long-term research and development process, and the method has the advantages of high reaction yield, mild reaction conditions, mature process and stable quality, and is very suitable for industrial application.
In one aspect, the invention provides a preparation method of an intermediate shown in a formula (I) or a stereoisomer thereof, which comprises the following steps of; the intermediate shown in the formula (I) is obtained by reacting the intermediate shown in the formula (III) with the intermediate shown in the formula (II) or a stereoisomer thereof in the presence of alkali.
The reaction formula is as follows:
wherein R is 1 Selected from halogen, hydroxy, mercapto, cyano, thiocyano, nitro, azido, C 1-8 Alkyl or C 2-8 Alkenyl, preferably halogen, hydroxy, mercapto, cyano, thiocyano, nitro, azido, C 1-4 Alkyl or C 2-4 Alkenyl groups;
R 2 selected from phenyl and benzyl.
In the present invention, the stereoisomers refer to enantiomers generated by having chiral carbon or C 2-4 Alkenyl-derived cis-trans isomers.
In the present invention, the intermediate stereoisomer of formula (II) may be in R configuration or S configuration, and specifically, may be a compound represented by formula (II-1) or formula (II-2):
in the present invention, the intermediate stereoisomer of formula (I) may be in R configuration or S configuration, specifically, may be a compound represented by formula (I-1) or formula (I-2):
preferably, the base is an organic base or an inorganic base, and the organic base includes, but is not limited to, one or more selected from pyridine, quinoline, isoquinoline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, trimethylamine, triethylamine or N, N-diisopropylethylamine; more preferably 4-dimethylaminopyridine or 4-pyrrolidinylpyridine. Inorganic bases include, but are not limited to, naOH, na 2 CO 3 、NaHCO 3 、KOH、K 2 CO 3 、KHCO 3 One or more of sodium acetate or potassium acetate.
Preferably, the molar ratio of the base to the intermediate of formula (III) is from 0.08:1 to 0.5:1; preferably 0.1:1 to 0.3:1.
Preferably, the reaction of the intermediate of formula (III) with the intermediate of formula (II) or a stereoisomer thereof is carried out in an aprotic solvent, preferably but not limited to one or more of benzene, toluene, xylene, chloroform, tetrahydrofuran, dioxane, pyridine, quinoline, isoquinoline, N-dimethylformamide, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone or dimethylsulfoxide, suitable for the present invention. Notably, the aprotic solvent and the base may be the same substance, such as one or more selected from pyridine, quinoline, and isoquinoline.
Preferably, the mass-to-volume ratio g/ml of the intermediate formula (III) to the aprotic solvent is 1:6-1:20; preferably 1:8 to 1:15; more preferably 1:10 to 1:15.
Preferably, the molar ratio of the intermediate formula (III) to the intermediate formula (II) or stereoisomers thereof is from 1:1 to 1:1.5; preferably 1:1.1 to 1:1.2.
Preferably, the reaction temperature for preparing the intermediate shown in the formula (I) or the stereoisomer thereof is 80-150 ℃; preferably 80-120 ℃; more preferably 90-100 ℃.
In another aspect, the present invention provides an intermediate of formula (II):
wherein R is 1 Selected from halogen, hydroxy, mercapto, cyano, thiocyano, nitro, azido, C 1-8 Alkyl or C 2-8 Alkenyl, preferably halogen, hydroxy, mercapto, cyano, thiocyano, nitro, azido, C 1-4 Alkyl or C 2-4 Alkenyl groups; r is R 2 Selected from phenyl or benzyl.
Preferably, the intermediate represented by formula (II) may be selected from any one of the following compounds:
on the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“C 1-8 Alkyl "means straight chain alkyl groups including 1 to 8 carbon atoms and branched alkyl groups, preferably straight chain alkyl groups including 1 to 4 carbon atoms and branched alkyl groups, and alkyl groups means saturated aliphatic hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl and the like.
"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, C 2-8 Alkenyl refers to straight or branched alkenyl groups containing 2 to 8 carbon atoms. Straight or branched alkenyl groups of 2 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl and the like.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the method has the advantages of high reaction yield, good product purity, simple post-treatment method, greatly reduced cost, strong process operability and greatly improved process safety. Therefore, the preparation method is more suitable for industrial application.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gi min i C150X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the present invention were carried out under continuous magnetic stirring, with the solvent being a dry solvent, unless otherwise specified.
Example 1
Raw material 6-amino-4-chloronicotinonitrile (7.5 g,54.7 mmol), N, N-diisopropylethylamine (17.65 g,136.8 mmol) was added to xylene (45 mL), and raw material ((R) -1-methoxypropane-2-amine hydrochloride) (7.5 g,59.7 mmol) was added to the system. The temperature was raised to 140℃and the reaction was carried out for 6 hours, after which the reaction was completed by HPLC. Cooling, concentrating to remove xylene, dissolving the obtained crude product with ethyl acetate (60 mL), adding 2g of active carbon, and stirring for 2 hours. Suction filtration, washing of the filter cake with ethyl acetate (30 mL), concentration of the filtrate gave (R) -6-amino-4- ((1-methoxypropane-2-yl) amino) nicotinonitrile (8.5 g, yield 75.3%, purity 98%).
Example 2
The compound (R) -6-amino-4- ((1-methoxypropane-2-yl) amino) nicotinonitrile (8.5 g,41.2 mmol) was dissolved in dichloromethane (120 mL), followed by pyridine (11.7 g,147.9 mmol). Cooled toPhenyl chloroformate (17.1 g,109.2 mmol) was added dropwise to the reaction system at 0-5℃and the reaction mixture was kept at a temperature of less than 10 ℃. After the addition, the temperature was raised to 25℃and the reaction was carried out for 3 hours. The reaction was monitored by HPLC. The reaction solution was washed with water (120 mL) and saturated brine (120 mL) once each, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Ethyl acetate (25 mL) was added to the crude product, the temperature was raised to 60℃and n-heptane (100 mL) was added dropwise with stirring to precipitate a solid. Cooling to room temperature, and filtering to obtain diphenyl (R) - (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridin-2-yl) -lambda 4 Azane dicarboxylic acid ester (15.1 g, 82.0% yield, 98.0% purity).
1 H NMR(400MHz,CDCl 3 )δ8.39(s,1H),7.42-7.38(m,4H),7.29-7.25(m,2H),7.22-7.20(m,4H),6.92(s,1H),5.38(d,J＝7.2Hz,1H),3.88-3.82(m,1H),3.53-3.49(m,1H),3.44-3.41(m,1H),3.37(s,3H),1.31(d,J＝6.4Hz,3H)；
MS m/z(ESI):447.1[M+H] + 。
Example 3
The reaction flask was charged with the compound 3- ((2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -1, 3-oxazepan-2-one (120.0 g,0.358 mol), diphenyl (R) - (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) - λ 4 Azanedicarboxylate (191.7 g,0.429 mol), 4-dimethylaminopyridine (8.7 g,0.0712 mol), toluene (1200 mL). Heating to 90-100deg.C, and stirring for 2 hr. Sampling HPLC detects complete reaction of the raw materials, cooling to room temperature, and drying the reaction liquid to obtain (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridine-2-yl) -7- (dimethoxy methyl) -6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -formamide (193.5 g, yield 95.2%, purity 97.7%).
1 H NMR(400MHz,CDCl 3 )δ13.70(s,1H),8.18(s,1H),7.60(s,2H),5.41(s,1H),5.12(d,J＝7.8Hz,1H),4.73(s,2H),4.20-4.11(m,2H),4.06-3.99(m,2H),3.93(s,1H),3.52-3.48(m,7H),3.46-3.42(m,1H),3.39(s,3H),3.26-3.21(m,2H),2.83(t,J＝6.2Hz,2H),2.03-1.95(m,2H),1.91-1.83(m,2H),1.67-1.62(m,2H),1.31(d,J＝6.6Hz,3H)；
MS m/z(ESI):568.3[M+H] + 。
Example 4
The reaction flask was charged with the compound 3- ((2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -1, 3-oxazepan-2-one (120.0 g,0.358 mol), diphenyl (R) - (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) - λ 4 Azanedicarboxylate (175.9 g, 0.390 mol), 4-dimethylaminopyridine (4.37 g,0.0358 mol), toluene (960 mL). Heating to 90-100deg.C, and stirring for 2 hr. Sampling HPLC detects that the raw material is reacted completely, cooling to room temperature, and drying the reaction liquid to obtain (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridine-2-yl) -7- (dimethoxy methyl) -6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -formamide (192.9 g, yield 95.0%, purity 97.5%).
MS m/z(ESI):568.3[M+H] + 。
Example 5
The reaction flask was charged with the compound 3- ((2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -1, 3-oxazepan-2-one (120.0 g,0.358 mol), diphenyl (R) - (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) - λ 4 Azanedicarboxylate (192.0 g,0.430 mol), 4-dimethylaminopyridine (13.1 g,0.107 mol), toluene (1800 mL). Heating to 90-100deg.C, and stirring for 2 hr. Sampling HPLC to detect that the raw materials are completely reacted, cooling to room temperature, and drying the reaction liquid to obtain (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridin-2-yl) -7- (dimethoxy methyl)) -6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (192.7 g, 94.9% yield, 97.3% purity).
MS m/z(ESI):568.3[M+H] + 。
Example 6
The reaction flask was charged with the compound 3- ((2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -1, 3-oxazepan-2-one (120.0 g,0.358 mol), dibenzyl (R) - (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) - λ 4 Azanedicarboxylate (186.8 g, 0.390 mol), 4-dimethylaminopyridine (4.37 g,0.0358 mol), toluene (960 mL). Heating to 90-100deg.C, and stirring for 2 hr. Sampling HPLC detects that the raw material is reacted completely, cooling to room temperature, and drying the reaction liquid to obtain (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridine-2-yl) -7- (dimethoxy methyl) -6- ((2-carbonyl-1, 3-oxazepan-3-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -formamide (192.9 g, yield 95.1%, purity 97.8%).
MS m/z(ESI):568.3[M+H] + 。
Example 7
The reaction flask was charged with the compound 3- ((2- (dimethoxymethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -1, 3-oxazepan-2-one (120.0 g,0.358 mol), dibenzyl (R) - (5-cyano-4- ((1-methoxypropane-2-yl) amino) pyridin-2-yl) - λ 4 Azanedicarboxylate (203.9 g,0.430 mol), 4-dimethylaminopyridine (13.1 g,0.107 mol), toluene (1800 mL). Heating to 90-100deg.C, and stirring for 2 hr. Sampling HPLC detects that the raw materials are reacted completely, cooling to room temperature, and drying reaction liquid to obtain (R) -N- (5-cyano-4- ((1-methoxy propane-2-yl) amino) pyridine-2-yl) -7- (dimethoxy methyl) -6- ((2-carbonyl-1, 3-oxazepan-3-yl)Methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (193.3 g, 95.2% yield, 97.7% purity).
MS m/z(ESI):568.3[M+H] + 。

Claims (13)

1. A preparation method of an intermediate shown in a formula (I) or a stereoisomer thereof, which is characterized in that the intermediate shown in the formula (III) and the intermediate shown in the formula (II) or the stereoisomer thereof react in the presence of alkali to obtain the intermediate shown in the formula (I) or the stereoisomer thereof;
the reaction formula is as follows:
wherein R is 1 Selected from halogen, cyano, thiocyano, nitro;
R 2 selected from phenyl and benzyl;
the alkali is 4-dimethylaminopyridine.
2. The process for producing an intermediate represented by the formula (I) or a stereoisomer thereof according to claim 1, wherein R 1 Selected from cyano groups.
3. The process for the preparation of an intermediate of formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the molar ratio of base to intermediate of formula (III) is from 0.08:1 to 0.5:1.
4. The process for the preparation of an intermediate of formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the molar ratio of base to intermediate of formula (III) is from 0.1:1 to 0.3:1.
5. The process for producing an intermediate represented by the formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the reaction of the intermediate of the formula (III) with the intermediate of the formula (II) or a stereoisomer thereof is carried out in an aprotic solvent selected from one or more of benzene, toluene, xylene, tetrahydrofuran, dioxane, pyridine, quinoline, isoquinoline, N-dimethylformamide, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone or dimethylsulfoxide.
6. The process for producing an intermediate of formula (I) or a stereoisomer thereof according to claim 5, wherein the mass to volume ratio g/ml of the intermediate of formula (III) to the aprotic solvent is from 1:6 to 1:20.
7. The process for producing an intermediate of formula (I) or a stereoisomer thereof according to claim 5, wherein the mass to volume ratio g/ml of the intermediate of formula (III) to the aprotic solvent is from 1:8 to 1:15.
8. The process for producing an intermediate of formula (I) or a stereoisomer thereof according to claim 5, wherein the mass to volume ratio g/ml of the intermediate of formula (III) to the aprotic solvent is from 1:10 to 1:15.
9. The process for producing an intermediate of formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the molar ratio of the intermediate of formula (III) to the intermediate of formula (II) or a stereoisomer thereof is from 1:1 to 1:1.5.
10. The process for producing an intermediate of formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the molar ratio of the intermediate of formula (III) to the intermediate of formula (II) or a stereoisomer thereof is from 1:1.1 to 1:1.2.
11. The process for producing an intermediate of the formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the reaction temperature is from 80 to 150 ℃.
12. The process for producing an intermediate of the formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the reaction temperature is from 80 to 120 ℃.
13. The process for producing an intermediate of the formula (I) or a stereoisomer thereof according to claim 1 or 2, wherein the reaction temperature is from 90 to 100 ℃.
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