阅读说明：本技术 一种稠合三环衍生物制备方法及中间体 (Preparation method and intermediate of fused tricyclic derivative ) 是由 李瑶 李升� 石宗军 陈雷 王文晶 张国彪 张晨 严庞科 郑伟 于 2019-12-25 设计创作，主要内容包括：本发明提供了一种稠合三环衍生物的制备方法以及中间体。所述稠合三环衍生物具有式(Ⅰ)所示的结构。所述制备方法原料易得、步骤简单,适宜大规模工业化生产。<Image he="319" wi="203" file="DDA0002333625370000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a preparation method and an intermediate of fused tricyclic derivative. The fused tricyclic derivative has a structure shown in a formula (I). The preparation method has the advantages of easily available raw materials and simple steps, and is suitable for large-scale industrial production.)

1. A preparation method of the compound shown in the formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that the compound is prepared by taking the compound shown in the formula (1-6) as a raw material,

2. the production method according to claim 1,

the catalyst used in the reaction is selected from supported metal catalysts or metal complexes, the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh, and palladium carbon is more preferable.

3. The production method according to claim 2,

the solvent used in the reaction is selected from any one or a mixture of any several of ethers, esters or alcohols, preferably any one or a mixture of any several of tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol; more preferably a mixture of methanol/tetrahydrofuran and methanol/ethyl acetate in any ratio.

4. The production method according to any one of claims 1 to 3, further comprising producing a compound of formula (1-6) starting from the compound of formula (1-5),

5. the production method according to claim 4,

the base used in the reaction is selected from organic base or inorganic base, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide;

the solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion.

6. The production method according to claim 4 or 5, further comprising producing a compound of formula (1-5) from the compound of formula (1-4),

7. the method according to claim 6, wherein the reaction mixture is heated to a temperature in the reaction mixture

The base used in the reaction is selected from organic or inorganic bases, preferably KOH, NaOH, LiOH, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide.

8. The production method according to claim 6 or 7, further comprising producing a compound of formula (1-4) from the compound of formula (1-3),

9. the method according to claim 8, wherein the reaction mixture is heated to a temperature in the reaction mixture

The reducing agent used in the reaction is selected from NaBH₄、LiBH₄Tetra methyl ammonium triacetoxyborohydride, borane and hydrogen.

10. The method according to claim 9, wherein the reaction mixture is heated to a temperature in the reaction mixture

The solvent used in the reaction is selected from ethers, esters, organic acids or alcohols, preferably any one of ethanol, methanol, acetic acid, tetrahydrofuran, dimethyl sulfide and ethyl acetate or a mixture of any several of them in any proportion.

11. The production method according to claim 8, 9 or 10, further comprising producing a compound of formula (1-3) from the compound of formula (1-2),

12. a preparation method of the compound shown in the formula (1-3) and a stereoisomer or a pharmaceutically acceptable salt thereof comprises the steps of preparing the compound shown in the formula (1-2) as a raw material,

13. the method according to claim 11 or 12, wherein the reaction mixture is heated to a temperature in the reaction mixture

The catalyst used in the reaction is selected from organic bases, preferably n-butyllithium, isobutyllithium, tert-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide;

the alkali used in the reaction is selected from NaH and KH;

the solvent used in the reaction is selected from any one of alkanes or ethers or a mixture of any several of them in any proportion, and preferably is any one of tetrahydrofuran, diethyl ether, methyl tert-ether and n-hexane or a mixture of any several of them in any proportion.

14. The production method according to any one of claims 11 to 13, further comprising producing a compound of formula (1-2) from the compound of formula (1-1),

15. the method according to claim 14, wherein the reaction mixture is heated to a temperature in the reaction mixture

The base used in the reaction is selected from tertiary amines, preferably triethylamine, trimethylamine, diisopropylethylamine, pyridine;

the solvent used in the reaction is selected from any one or any mixture of alkyl, ether and substituted benzene, preferably any one or any mixture of dichloromethane, tetrahydrofuran, toluene and diethyl ether.

16. A process for the preparation of a compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof,

a, taking a formula (1-1) as a raw material, and reacting with phenylsulfonyl chloride to prepare a compound of a formula (1-2);

b, taking the formula (1-2) as a raw material, and reacting the raw material with ethyl acetoacetate in the presence of a catalyst to prepare a compound of the formula (1-3);

c, taking the formula (1-3) as a raw material, and reacting the raw material with a reducing agent to prepare a compound of the formula (1-4);

d, taking the formula (1-4) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-5);

e, taking the formula (1-5) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-6);

f, taking the formula (1-6) as a raw material, and reacting under the condition of a catalyst to obtain the compound shown in the formula (I).

17. The method of claim 16, wherein the step of preparing the composition is carried out in a batch process

a, the base used in the reaction is selected from tertiary amine, preferably triethylamine, trimethylamine, diisopropylethylamine and pyridine;

b, the catalyst used in the reaction is selected from organic bases, preferably n-butyllithium, isobutyllithium, tert-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide;

c, the reducing agent used in the reaction is selected from NaBH₄、LiBH₄Tetramethylammonium triacetoxyborohydride, borane, hydrogen;

d, the base used in the reaction is selected from organic bases or inorganic bases, preferably KOH, NaOH, LiOH, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide and sodium ethoxide;

e, the alkali used in the reaction is selected from organic alkali or inorganic alkali, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide; the solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion;

the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex, the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh, and palladium carbon is more preferable.

18. An intermediate for the preparation of a compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof,

Technical Field

The invention relates to the field of medicines, in particular to a preparation method and an intermediate of a fused tricyclic derivative.

Background

The voltage-gated calcium channel is composed of an alpha 1 subunit and accessory protein alpha 2, beta, gamma subunits. The α 2 protein can modulate the density and voltage-dependent kinetics of calcium channels (Felix et al (1997) J.neuroscience 17:6884- & 6891; Klugbauer et al (1999) J.neuroscience 19:684- & 691; Hobom et al (2000) Eur.J.neuroscience 12:1217- & 1226; and Qin et al (2002) mol.Pharmacol.62:485- & 496). Compounds that exhibit high affinity binding to voltage-dependent calcium channel subunit α 2 have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are 4 subtypes of α 2 protein, each encoded by a different gene. The α 2 subtypes 1 and 2 show high affinity with pregabalin, while the α 2 subtypes 3 and 4 have no significant drug binding force.

However, the proportion of gabapentin that greatly ameliorates the pain in diabetic peripheral neuropathy patients is about 60% (Acta neurol. Scand.101:359 371,2000), and pregabalin, although it is better tolerated than gabapentin, is less safe and has the potential to abuse or cause patient dependence (Am J Health SystPharm.2007; 64(14): 1475-1482).

There remains a great need to develop new compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α 2.

PCT/CN2017/101364 discloses a fused tricyclic gamma-amino acid derivative, a preparation method and application thereof in medicine, which have good biological activity, and also discloses an intermediate compound shown as a formula (I) for preparing the derivative and a preparation method thereof,

disclosure of Invention

It is an object of the present invention to provide a process for the preparation of fused tricyclic derivatives.

It is another object of the present invention to provide a process for preparing intermediates of fused tricyclic derivatives.

The invention provides a preparation method of a compound shown in a formula (I) and a stereoisomer or pharmaceutically acceptable salt thereof, which is characterized in that the compound is prepared by taking a compound shown in a formula (1-6) as a raw material,

some embodiments of the present invention are a method for preparing a compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound is prepared by reacting a compound of formula (1-6) as a raw material in the presence of a catalyst.

Some embodiments of the present invention are directed to a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1-6) is prepared by reacting a compound of formula (I) with a catalyst in the presence of a catalyst, wherein the catalyst is selected from a supported metal catalyst or a metal complex, preferably a supported metal catalyst or a metal complex of which the metal is selected from Pt, Pd, Ni, Ru, Ir, or Rh, more preferably palladium on carbon or raney nickel.

Some embodiments of the present invention are a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1-6) is prepared by reacting a compound of formula (I) with a catalyst in the presence of a metal catalyst or a metal complex, preferably a supported metal catalyst or a metal complex in which the metal is selected from Pt, Pd, Ni, Ru, Ir, or Rh, more preferably palladium on carbon, raney nickel;

the solvent used in the reaction is selected from any one or a mixture of any several of ethers, esters or alcohols, preferably any one or a mixture of any several of tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol; more preferably a mixture of methanol/tetrahydrofuran, methanol/ethyl acetate in any ratio.

Some embodiments of the present invention are a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1-6) is prepared by reacting a compound of formula (I) with a catalyst at a temperature selected from 0-100 ℃ or under reflux of a reaction solution.

Some embodiments of the present invention are a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is prepared by reacting a compound of formula (1-6) as a raw material in the presence of a catalyst, wherein the mass ratio of the compound of formula (1-6) to the catalyst is: 1: 0.1-1: 1; preferably, 1:0.1, or 1: 0.2 or 1: 0.3 or 1: 0.5 or 1:1.

some embodiments of the present invention are a method for preparing a compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, which is characterized in that the compound of formula (1-6) is prepared by reacting the compound of formula (I) as a raw material in the presence of a catalyst

Wherein the catalyst is selected from supported metal catalysts or metal complexes, preferably supported metal catalysts or metal complexes of metals selected from Pt, Pd, Ni, Ru, Ir or Rh, more preferably palladium carbon and Raney nickel;

the solvent used in the reaction is selected from any one or a mixture of any several of ethers, esters or alcohols, preferably any one or a mixture of any several of tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol; more preferably a mixture of methanol/tetrahydrofuran, methanol/ethyl acetate in any ratio;

the reaction temperature is 0-100 ℃ or the reaction liquid is refluxed;

the mass ratio of the compound of the formula (1-6) to the catalyst is: 1: 0.1-1: 1; preferably, 1:0.1, or 1: 0.2 or 1: 0.3 or 1: 0.5 or 1:1.

the invention provides a preparation method of a compound shown in a formula (I-6) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (1-6) is prepared by taking a compound shown in the formula (1-5) as a raw material,

some embodiments of the present invention are a method for preparing a compound represented by formula (I-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (1-5) is used as a raw material to prepare the compound represented by formula (I-6) under an alkaline condition, wherein the base is selected from an organic base or an inorganic base, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide.

Some embodiments of the present invention are a method for preparing a compound of formula (I-6) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (1-5) is used as a raw material to prepare the compound of formula (I-6) under alkaline conditions, wherein

The solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (1-5) is used as a raw material to prepare the compound represented by formula (I-6) under an alkaline condition, and the reaction temperature is a reflux temperature of a reaction solution.

Some embodiments of the present invention are a method for preparing a compound of formula (I-6) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (1-5) is prepared under basic conditions to obtain the compound of formula (I-6), wherein the molar ratio of the compound of formula (1-5) to the base is selected from: 1:1-1:3.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-6) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-5) is used as a raw material to prepare a compound represented by formula (I-6) under an alkaline condition, wherein the base is selected from an organic base or an inorganic base, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide;

the solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion;

the reaction temperature is the reflux temperature of the reaction liquid;

the molar ratio of the compound of formula (1-5) to the base is selected from: 1:1-1:3.

The invention provides a preparation method of a compound shown in a formula (I-6) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (1-5) is prepared by taking a compound shown in the formula (1-4) as a raw material,

some embodiments of the present invention are directed to a method for preparing a compound represented by formula (I-5), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (1-4) is used as a starting material to prepare a compound represented by formula (1-5) under basic conditions, and the base used in the reaction is selected from organic bases or inorganic bases, preferably KOH, NaOH, LiOH, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide or sodium ethoxide. The invention provides a preparation method of a compound shown in a formula (I-4) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (1-4) is prepared by taking a compound shown in the formula (1-3) as a raw material,

some embodiments of the present invention are a method for preparing a compound represented by formula (I-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-4) is prepared from a compound represented by formula (1-3) in the presence of a reducing agent selected from NaBH₄、LiBH₄Tetra methyl ammonium triacetoxyborohydride, borane and hydrogen.

Some embodiments of the present invention are a process for preparing a compound of formula (I-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound of formula (1-4) is prepared starting from a compound of formula (1-3) in the presence of a reducing agent, optionally a pressurized catalytic hydrogenation of the reducing agent system; the catalyst used for the catalysis is selected from supported metal catalysts or metal complexes, preferably the supported metal catalysts or metal complexes of metals selected from Pt, Pd, Ni, Ru, Ir or Rh, and more preferably palladium carbon and Raney nickel.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-4) is prepared from a compound represented by formula (1-3) in the presence of a reducing agent selected from NaBH₄、LiBH₄Tetramethylammonium triacetoxyborohydride, borane, hydrogen; the solvent used in the reaction is selected from any one or a mixture of any several of ethers, esters, organic acids or alcohols, preferably any one or a mixture of any several of ethanol, methanol, acetic acid, tetrahydrofuran, dimethyl sulfide and ethyl acetate.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-4) is prepared from a compound represented by formula (1-3) as a raw material in the presence of a reducing agent at a temperature selected from 0 to 40 ℃.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (1-4) is prepared from a compound represented by formula (1-3) as a starting material in the presence of a reducing agent, wherein the molar ratio of the compound represented by formula (1-3) to the reducing agent is: 1:1-2:1.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-4) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-4) is prepared from a compound represented by formula (1-3) as a starting material in the presence of a reducing agent,

the reducing agent used in the reaction is selected from NaBH₄、LiBH₄Tetramethylammonium triacetoxyborohydride, borane, hydrogen;

the solvent used in the reaction is selected from any one or a mixture of any several of ethers, esters or alcohols, preferably any one or a mixture of any several of ethanol, methanol, acetic acid, tetrahydrofuran, dimethyl sulfide and ethyl acetate;

the temperature is selected from 0-40 ℃;

the molar ratio of the compound of formula (1-3) to the reducing agent: 1:1-2:1.

The invention provides a preparation method of a compound shown in a formula (I-3) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (1-3) is prepared by taking a compound shown in the formula (1-2) as a raw material,

some embodiments of the present invention are a method for preparing a compound represented by formula (I-3) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-3) is prepared using a compound represented by formula (1-2) as a starting material in the presence of a catalyst,

the catalyst used in the reaction is selected from organic bases, preferably n-butyllithium, isobutyllithium, tert-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-3) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-3) is prepared from a compound represented by formula (1-2) in the presence of a catalyst, and a base used in the reaction is selected from NaH and KH.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-3) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-3) is prepared using a compound represented by formula (1-2) as a starting material in the presence of a catalyst,

the solvent used in the reaction is selected from any one of alkanes or ethers or a mixture of any several of them in any proportion, and preferably is any one of tetrahydrofuran, diethyl ether, methyl tert-ether and n-hexane or a mixture of any several of them in any proportion.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-3) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-3) is prepared using a compound represented by formula (1-2) as a starting material in the presence of a catalyst,

the reaction temperature is-10-40 ℃;

some embodiments of the present invention are a process for preparing a compound represented by formula (I-3) and stereoisomers or pharmaceutically acceptable salts thereof, wherein a compound represented by formula (1-3) is prepared from a compound represented by formula (1-2) in the presence of a catalyst, and the molar ratio of the compound represented by formula (1-2) to the catalyst is 0.5:1 to 1:1.5, preferably 0.5:1 to 1:1.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-3) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-3) is prepared using a compound represented by formula (1-2) as a starting material in the presence of a catalyst,

the catalyst used in the reaction is selected from organic bases, preferably n-butyllithium, isobutyllithium, tert-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide;

the alkali used in the reaction is selected from NaH and KH;

the solvent used in the reaction is selected from any one of alkanes or ethers or a mixture of any several of them in any proportion, preferably any one of tetrahydrofuran, diethyl ether, methyl tert-ether and n-hexane or a mixture of any several of them in any proportion;

the reaction temperature is-10-40 ℃;

the molar ratio of the compound of formula (1-2) to the catalyst: 0.5:1 to 1:1.5, preferably 0.5:1 to 1:1.

The invention provides a preparation method of a compound shown in a formula (I-2) and a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (1-2) is prepared by taking a compound shown in the formula (1-1) as a raw material,

some embodiments of the present invention are a method for preparing a compound represented by formula (I-2) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-2) is prepared under basic conditions using a compound represented by formula (1-1) as a starting material,

the base used in the reaction is selected from tertiary amines, preferably triethylamine, trimethylamine, diisopropylethylamine and pyridine.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-2) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-2) is prepared under basic conditions using a compound represented by formula (1-1) as a starting material,

the solvent used in the reaction is selected from any one or any mixture of alkyl, ether and substituted benzene, preferably any one or any mixture of dichloromethane, tetrahydrofuran, toluene and diethyl ether.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-2) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-2) is prepared under basic conditions using a compound represented by formula (1-1) as a starting material, at a reaction temperature of 0-40 ℃.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-2) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-2) is prepared under basic conditions using a compound represented by formula (1-1) as a starting material,

the molar ratio of the compound of formula (1-1) to the phenylsulfonyl chloride is from 1:1 to 1:5, preferably from 1:1 to 1: 2.

Some embodiments of the present invention are a method for preparing a compound represented by formula (I-2) and stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the compound represented by formula (1-2) is prepared under basic conditions using a compound represented by formula (1-1) as a starting material,

the base used in the reaction is selected from tertiary amines, preferably triethylamine, trimethylamine, diisopropylethylamine and pyridine;

the solvent used in the reaction is selected from any one or a mixture of any several of alkanes, ethers and substituted phenyl in any proportion, preferably any one or a mixture of any several of dichloromethane, tetrahydrofuran, toluene and diethyl ether in any proportion;

the reaction temperature is 0-40 ℃;

the molar ratio of the compound of formula (1-1) to the phenylsulfonyl chloride: 1:1 to 1:5, preferably 1:1 to 1: 2.

The invention provides a preparation method of a compound shown in a formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof,

a, taking a formula (1-1) as a raw material, and reacting with phenylsulfonyl chloride to prepare a compound of a formula (1-2);

b, taking the formula (1-2) as a raw material, and reacting the raw material with ethyl acetoacetate under an alkaline condition to prepare a compound of the formula (1-3);

c, taking the formula (1-3) as a raw material, and reacting the raw material with a reducing agent to prepare a compound of the formula (1-4);

d, taking the formula (1-4) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-5);

e, taking the formula (1-5) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-6);

f, taking the formula (1-6) as a raw material, and reacting under the condition of a catalyst to obtain the compound shown in the formula (I).

The invention relates to a preparation method of a compound shown in a formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein a, the compound shown in the formula (1-2) is prepared by taking the formula (1-1) as a raw material and reacting the compound with phenylsulfonyl chloride, and a base used in the reaction is selected from tertiary amine, preferably triethylamine, trimethylamine, diisopropylethylamine and pyridine; b, taking the formula (1-2) as a raw material, and reacting the raw material with ethyl acetoacetate under an alkaline condition to prepare a compound of the formula (1-3), wherein a catalyst used in the reaction is selected from organic bases, preferably n-butyl lithium, isobutyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide;

c, taking the formula (1-3) as a raw material, and reacting with a reducing agent to prepare the compound shown in the formula (1-4), wherein the reducing agent used in the reaction is selected from NaBH₄、LiBH₄Tetramethylammonium triacetoxyborohydride, borane, hydrogen;

taking the formula (1-4) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-5), wherein the base used in the reaction is selected from organic bases or inorganic bases, preferably KOH, NaOH, LiOH, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide and sodium ethoxide;

e, taking the formula (1-5) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-6), wherein the alkali used in the reaction is selected from organic alkali or inorganic alkali, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide; the solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion;

the catalyst used for the reaction of the compound of the formula (I) obtained by taking the formula (1-6) as a raw material and reacting under the catalyst condition is selected from a supported metal catalyst or a metal complex, wherein the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh, and palladium carbon is more preferred.

Some embodiments of the invention are a process for the preparation of a compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof, wherein

a, taking the formula (1-1) as a raw material, and reacting the raw material with phenylsulfonyl chloride to prepare a compound of the formula (1-2), wherein the base used in the reaction is selected from tertiary amine, preferably triethylamine, trimethylamine, diisopropylethylamine and pyridine; the solvent used in the reaction is selected from any one of alkanes, ethers and substituted phenyl or a mixture of any several of them in any proportion, preferably any one of dichloromethane, tetrahydrofuran, toluene and diethyl ether or a mixture of any several of them in any proportion; still further included are molar ratios of the compound of formula (1-1) to the phenylsulfonyl chloride: 1:1 to 1:5, preferably 1:1 to 1: 2; further comprises the reaction temperature of 0-40 ℃;

b, taking the formula (1-2) as a raw material, and reacting the raw material with ethyl acetoacetate under an alkaline condition to prepare a compound of the formula (1-3), wherein a catalyst used in the reaction is selected from organic bases, preferably n-butyl lithium, isobutyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide and potassium bistrimethylsilyl amide; further comprises the reaction using a base selected from NaH, KH; the solvent used in the reaction is selected from any one of alkanes or ethers or a mixture of any several of them in any proportion, preferably any one of tetrahydrofuran, diethyl ether, methyl tert-ether and n-hexane or a mixture of any several of them in any proportion; still further comprising the molar ratio of the compound of formula (1-2) to the catalyst: 0.5:1 to 1:1.5, preferably 0.5:1 to 1: 1; further comprises the reaction temperature of-10 to 40 ℃;

c, taking the formula (1-3) as a raw material, and reacting with a reducing agent to prepare the compound shown in the formula (1-4), wherein the reducing agent used in the reaction is selected from NaBH₄、LiBH₄Tetramethylammonium triacetoxyborohydride, borane, hydrogen; further comprises a solvent used in the reaction is selected from any one of ethers, esters or alcohols or a mixture of any several of them in any proportion, preferably any one of ethanol, methanol, acetic acid, tetrahydrofuran, dimethyl sulfide and ethyl acetate or a mixture of any several of them in any proportion; still further included are the molar ratios of the compounds of formulae (1-3) to the reducing agent: 1:1-2: 1; still further comprising the temperature is selected from the range of 0-40 ℃.

Taking the formula (1-4) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-5), wherein the base used in the reaction is selected from organic bases or inorganic bases, preferably KOH, NaOH, LiOH, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide and sodium ethoxide;

e, taking the formula (1-5) as a raw material, and reacting under an alkaline condition to obtain a compound of the formula (1-6), wherein the alkali used in the reaction is selected from organic alkali or inorganic alkali, preferably potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide; the solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion; further comprises a solvent used in the reaction is any one or a mixture of any several of acetic anhydride, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone in any proportion; still further included are compounds of formula (1-5) and a base in a molar ratio selected from: 1:1-1:3, and further comprises the step of controlling the reaction temperature to be the reflux temperature of the reaction liquid;

taking the formula (1-6) as a raw material, reacting under the condition of a catalyst to obtain the compound of the formula (I), wherein the catalyst used for the reaction is selected from a supported metal catalyst or a metal complex, the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh, and palladium carbon is more preferable; further comprises a solvent used in the reaction is selected from any one of ethers, esters or alcohols or a mixture of any several of them in any proportion, preferably any one of tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol or a mixture of any several of them in any proportion; more preferably a mixture of methanol/tetrahydrofuran, methanol/ethyl acetate in any ratio; further comprises the mass ratio of the compound shown in the formula (1-6) to the catalyst: 1: 0.1-1: 1; preferably, 1:0.1, or 1: 0.2 or 1: 0.3 or 1: 0.5 or 1: 1; further comprises the reaction temperature is 0-100 ℃ or the reaction liquid is refluxed.

The invention provides an intermediate for preparing a compound shown in a formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof,

unless stated to the contrary, the terms used in the specification and claims have the following meanings.

When the compound of the general formula exists in a chiral center, the compound of the general formula can be a racemate or an optical isomer except for a clear mark.

When the present invention relates to a compound substituted with a plurality of substituents, each substituent may be the same or different.

When the present invention relates to a compound containing a plurality of hetero atoms, the hetero atoms may be the same or different.

The elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the elemental carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by 1 to 5 of their corresponding isotopes, wherein isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F¹⁹Isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"Metal complex" means that the coordination unit is composed of a metal and a ligand, and when a metal is combined with a plurality of ligands, the ligands may be the same or different. The metal is selected from transition metals, non-limiting examples include zero-or high-valent compounds of Co, Ni, Ru, Pd, Ir, or Rh; non-limiting examples of the ligand include Cl^-、OAc^-、CN^-、COD、PPh₃、P(i-Pr)₃、PCy₃、P(o-MeOPh)₃、P(p-MeOPh)₃、Ph₂P(CH₂)₃PPh₂、Ph₂P(CH₂)₂PPh₂、Ph₂P(CH₂)₄PPh₂、Ph₂P(CH₂)₂PPh₂(dppe)、Ph₂P(CH₂)₃PPh₂(dppp), dppp, dppb, dppe, dba, BINAP, TDMPP, TMPP, TMSPP, P (O-O-methoxyphenyl)₃P (O-P-methoxyphenyl)₃Pyridine, n-Bu₃P、t-Bu₃P、(MeO)₃P、AsPh₃、P(OEt)₃. The metal complexes may contain, in addition to the coordination units, simple ions selected from Cl, or may be absent^-、BF₄ ^-、PF₆ ^-、CF₃SO₃ ^-、B(C₆F₅)₄ ^-、B(C₆H₅)₄ ^-、Al(OC(CF₃)₃)₄ ^-Or [ B [3,5- (CF)₃)₂C₆H₃]₄]^-. Non-limiting examples of metal complexes include Pd (OAc)₂、PdCl₂(PPh₃)₂、Pd(PPh₃)₄、PdCl₂(dppf)、Pd(dba)₂、(dppp)NiCl₂、(R)-Ru(OAc)₂BINAP、(Ph₃P)₃·RuClH、[(Ph)₃P]₃RuCl₂、[(Ph)₃P]₃Ru(CO)H₂、Ph₃P)₃·IrH、Ir(dppe)₂、Ph₃P)₃RhCl, ((4R,5R) - (+) -O- [ 1-benzyl-1- (5-methyl-2-phenyl-4, 5-dihydrooxazol-4-yl) -2-phenylethyl](dicyclohexylphosphine sulfite) (1,5-COD) Iridium (I) tetrakis (3, 5-bis (trifluoromethyl) phenylboronate, (R) -Ru (OAc)₂BINAP、(R)-(+)-[Ru(MeO-BIPHEP)(C₆H₆)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C₆H₆)Cl]Cl, (R) -Ir (Tol-SDP) (COD) Cl, (R) - (+) -Ir (MeO-BIPHEP) (COD) Cl or from Pd (OAc)₂、PdCl₂With AsPh₃、n-Bu₃P、(MeO)₃P、Ph₂P(CH₂)₂PPh₂(dppe)、Ph₂P(CH₂)₃PPh₂(dppp) in the presence of a catalyst system.

The "supported catalyst" is prepared by supporting catalytic active components on the surface of a carrier, and commonly used carriers include alumina carriers, silica gel carriers, activated carbon carriers and certain natural products such as pumice, diatomite and the like.

"supported metal catalyst" refers to a supported catalyst whose catalytically active component is a metal selected from the group consisting of transition metals, non-limiting examples including but not limited to Co, Ni, Ru, Pd, Ir, or Rh; non-limiting examples of supported metal catalysts include, but are not limited to, palladium on carbon, raney nickel, and the like.

Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift () at 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), deuterated acetonitrile (CD)₃CN), internal standard Tetramethylsilane (TMS).

The MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.

The ratio shown by the silica gel column chromatography is volume ratio.