CN107266451B - Preparation method of rebuximab intermediate - Google Patents

Preparation method of rebuximab intermediate Download PDF

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CN107266451B
CN107266451B CN201610212832.9A CN201610212832A CN107266451B CN 107266451 B CN107266451 B CN 107266451B CN 201610212832 A CN201610212832 A CN 201610212832A CN 107266451 B CN107266451 B CN 107266451B
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CN107266451A (en
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黄雨
刘健
刘相奎
蒋慧娟
朱雪焱
刘飞
王善春
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to the field of organic synthesis and drug synthesis, and particularly relates to a preparation method of a rebuximab intermediate, which comprises the steps of obtaining 2-halo-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine, then obtaining the rebuximab intermediate 2-halo-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formamide through three-step reaction, wherein each step of reaction has high yield and high purity, so the total yield of the whole route is high and is obviously superior to the prior art, the raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, and the reaction reagent is environment-friendly and is particularly suitable for industrial production.

Description

Preparation method of rebuximab intermediate
Technical Field
The invention belongs to the field of organic synthesis and drug synthesis, and particularly relates to a preparation method of a drug for treating advanced breast cancer, namely an intermediate 2-halo-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formamide of Ribociclib, and a related intermediate.
Background
Ribociclib (Ribociclib) is a highly specific CDK4/CDK6 inhibitor developed by Noval, Switzerland, can inhibit the cell cycle of D1/CDK4 and D3/CDK6 in a targeted manner, and block the cell cycle at the G1 stage, thereby playing a role in inhibiting tumor proliferation. Clinical trial results indicate that ribociclib can be used for the treatment of breast cancer, melanoma, non-small cell lung cancer, teratoma, liposarcoma, and glioblastoma. The drug is currently in phase iii clinical trials for advanced breast cancer.
The chemical name of the rebuximab is: 7-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid dimethylamide having the chemical structure shown below:
Figure BDA0000959835770000011
WO2010020675 discloses a preparation method of rebuximab and its key intermediate 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (intermediate 9), which is as follows: .
Figure BDA0000959835770000012
Carrying out nucleophilic aromatic substitution reaction on the compound 1 and the compound 2 to obtain a compound 3; carrying out Sonogashira reaction on the compound 3 and the compound 4 to obtain a compound 5; carrying out cyclization reaction on the compound 5 under alkaline conditions to obtain a pyrimidopyrrole compound 6; acidifying the compound 6 to obtain a compound 7; oxidizing the compound 7 to obtain a compound 8; condensation of compound 8 with dimethylamine gave key intermediate 9.
WO2012064805 discloses another preparation method of intermediate 9, which is as follows:
Figure BDA0000959835770000021
carrying out nucleophilic aromatic substitution reaction on the compound 1 and the compound 2 to obtain a compound 3; carrying out Sonogashira reaction on the compound 3 and the compound 15 to obtain a compound 16; carrying out cyclization reaction on the compound 16 under alkaline condition to obtain a compound 17; compound 17 in the presence of manganese dioxide and sodium cyanide gives intermediate 18 before intermediate 9.
In the synthesis of rebuximab, the preparation of the intermediate 9 is extremely critical, and the disclosed preparation method of the intermediate 9 has the following defects: (1) according to the preparation method disclosed by WO2010020675, the reaction system for preparing the compound 5 from the compound 3 and the compound 4 has many impurities, the purification is not easy, and the product yield is low; the compound 5 is reacted in 3 steps to prepare a compound 8, the products are oily substances, the steps are more, the purification is not easy, and the yield is reduced; the conversion rate of the raw material for preparing the intermediate 9 from the compound 8 is low, so the reaction total yield of the route is low, the operation is complicated, and the method is not suitable for industrial production. (2) According to the preparation method disclosed by WO2012064805, the reaction system for preparing the compound 16 from the compound 3 and the compound 15 has more impurities and low product yield; the compound 16 has high impurity content generated by ring closure reaction, is difficult to remove, and has low product yield; in the process of preparing the intermediate 9 from the compound 17, highly toxic sodium cyanide is used, and the reaction has high requirement on the activation performance of manganese dioxide and poor reaction repeatability, and is not beneficial to industrial production.
Aiming at the existing process defects, a process technology which is simple in process, green and environment-friendly, high in yield and purity and suitable for industrial production is developed, and the method has important practical significance for synthesis of the reburnib and improvement of economic and social benefits.
Disclosure of Invention
The invention provides a preparation method of a compound shown in a formula IV, which comprises the following steps: reacting a compound shown in a formula I with a compound shown in a formula II in the presence of a catalyst and alkali to obtain a compound shown in a formula III, reacting the compound shown in the formula III to obtain a compound shown in a formula IV,
Figure BDA0000959835770000031
wherein X is selected from halogen, preferably bromine, chlorine or iodine, most preferably chlorine;
wherein Y is selected from halogen, preferably bromine, chlorine or iodine, most preferably bromine;
in some embodiments of the invention, the compound of formula I is a compound of formula I-1, the compound of formula III is a compound of formula III-1, and the compound of formula IV is a compound of formula IV-1;
Figure BDA0000959835770000032
in some embodiments of the invention, the catalyst is a palladium catalyst, such as palladium (0) and palladium (II) catalysts, more specifically, the palladium catalyst is selected from one or more of tetrakis (triphenylphosphine) palladium, palladium acetate, 1, 2-bis (diphenylphosphino) ethane dichloropalladium, 1, 3-bis (diphenylphosphino) propane dichloropalladium, 1, 4-bis (diphenylphosphino) butane dichloropalladium, bis (triphenylphosphine) dichloropalladium, bis (cyanophenyl) dichloropalladium, 1' -bis-diphenylphosphino ferrocene dichloropalladium, or tris (dibenzylideneacetone) dipalladium, preferably one or more of tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) dichloropalladium, or bis (cyanophenyl) dichloropalladium, more preferably one or two of tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride, in some embodiments of the invention, the catalyst is selected from tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride;
in some embodiments of the present invention, the base may be an inorganic base or an organic base, more specifically, the base is selected from one or more of tetrabutylammonium fluoride or a hydrate thereof, tetra-n-butylammonium dihydrogenfluoride, tetrabutylammonium dihydrogen phosphate, tetra-n-octylammonium bromide, tetra-n-butylammonium dihydrogenfluoride or a hydrate thereof, tetrabutylammonium bromide or methyltributylammonium bromide, preferably tetrabutylammonium fluoride or a hydrate thereof, more preferably tetrabutylammonium fluoride or a trihydrate thereof, and most preferably tetrabutylammonium fluoride trihydrate;
in some embodiments of the invention, the molar ratio of the compound of formula i to the compound of formula ii is 1: 1-2, and may be 1: 1 to 1.5, and in some embodiments of the invention, the molar ratio of the compound of formula i to the compound of formula ii is about 1: 2 or 1: 1.5;
in some embodiments of the invention, the molar ratio of the compound of formula i to the catalyst is 1: 0.01 to 0.1, preferably 1: 0.02 to 0.08, more preferably 1: 0.05-0.06;
in some embodiments of the invention, the molar ratio of the compound of formula i to base is 1: 0.5 to 10, preferably 1: 1-10;
the compound of the formula III can be separated and then reacted to obtain a compound of a formula IV, or can be reacted without separation to obtain a compound of a formula IV;
in some embodiments of the invention, when the compound of formula iii is isolated and then reacted to provide the compound of formula iv, the molar ratio of the compound of formula i to the base is 1: 0.5 to 3, preferably 1: 1-2.5, most preferably 1: 1.5-2.5, and in some embodiments of the invention, the molar ratio of the compound of formula i to the base is about 1: 1.5 or 1: 2.5;
in some embodiments of the invention, when the compound of formula iii is isolated and then reacted to obtain the compound of formula iv, the reaction of the compound of formula iii to obtain the compound of formula iv is carried out in the presence of a second base, in some embodiments of the invention, the second base is selected from one or more of tetrabutylammonium fluoride or a hydrate thereof, tetra-n-butylammonium dihydrogentrifluoride, tetrabutylammonium dihydrogen phosphate, tetra-n-octylammonium bromide, tetra-n-butylammonium dihydrogentrifluoride or a hydrate thereof, tetrabutylammonium bromide or methyltributylammonium bromide, preferably tetrabutylammonium fluoride or a hydrate thereof, more preferably tetrabutylammonium fluoride or a trihydrate thereof, and most preferably tetrabutylammonium fluoride trihydrate; the molar ratio of the compound of formula iii to the second base is 1: 0.5 to 10, preferably 1: 1-5, in some embodiments of the invention, the molar ratio of the compound of formula iii to the second base is about 1: 2;
in some embodiments of the invention, when the compound of formula iii is reacted without isolation to provide the compound of formula iv, the molar ratio of the compound of formula i to the base may be 1: 2.5-10, preferably 1: 3-10, most preferably 1: 4-10, in some embodiments of the invention, the molar ratio of the compound of formula i to the base is about 1: 5;
in some embodiments of the present invention, when the compound of formula iii is reacted without separation to obtain the compound of formula iv, the base may be added to the reaction system at one time, or may be added to the reaction system in portions, for example, may be added to the reaction system in two times;
in some embodiments of the present invention, the above preparation process is carried out in the presence of a suitable solvent, in some embodiments of the present invention, the solvent is selected from one or more of tetrahydrofuran, dioxane, acetonitrile, toluene, dimethylsulfoxide, N-dimethylformamide, preferably tetrahydrofuran or N, N-dimethylformamide, most preferably tetrahydrofuran;
in some embodiments of the present invention, when the compound of formula iii is isolated and then reacted to obtain the compound of formula iv, the preparation of the compound of formula iii and the preparation of the compound of formula iv may be performed by selecting a suitable solvent, respectively, as desired, and in some embodiments of the present invention, the solvent is selected from one or more of tetrahydrofuran, dioxane, acetonitrile, toluene, dimethylsulfoxide, or N, N-dimethylformamide, preferably tetrahydrofuran or N, N-dimethylformamide, and most preferably tetrahydrofuran;
in some embodiments of the invention, the reaction temperature is 50 to 100 ℃, in some embodiments of the invention, the temperature is 75 ℃ or the boiling point of the reaction system;
when the compound of formula iii is isolated and then reacted to obtain the compound of formula iv, the preparation of the compound of formula iii and the preparation of the compound of formula iv may be carried out at a suitable reaction temperature, for example, 50 to 100 ℃, respectively, and in some embodiments of the present invention, the temperature is 75 ℃ or the boiling point of the reaction system;
the above preparation method may be selected as appropriate for the reaction time, and in some embodiments of the present invention, the reaction time is 0.5 to 48 hours, preferably 12 to 24 hours.
In another aspect, the present invention provides a process for preparing a compound of formula V, comprising reacting a compound of formula IV to prepare a compound of formula V,
Figure BDA0000959835770000051
wherein the compound of formula IV is prepared by the preparation method of the compound of formula IV as described above;
wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the invention, the compound of formula IV is a compound of formula IV-1 and the compound of formula V is a compound of formula V-1;
Figure BDA0000959835770000052
in some embodiments of the invention, the reaction is carried out in the presence of an acid; wherein the acid is selected from organic acid or inorganic acid, wherein the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, and the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, preferably one or more of methanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, and most preferably hydrochloric acid;
in some embodiments of the invention, the molar ratio of compound of formula v to acid is 1: 5-20, preferably 1: 5-15, more preferably 1: 10-12;
in some embodiments of the invention, the preparation of the compound of formula v is carried out in the presence of a suitable solvent selected from tetrahydrofuran, ethyl acetate, N-propyl acetate, isopropyl acetate, dichloromethane, methanol, ethanol, N-propanol, dioxane, acetonitrile, toluene, dimethyl sulfoxide, N-dimethylformamide or a mixture of the above solvents, preferably tetrahydrofuran, ethyl acetate, dichloromethane, methanol, most preferably ethyl acetate or tetrahydrofuran;
in some embodiments of the invention, the reaction temperature is 5 to 30 ℃, preferably 15 to 30 ℃, and in some embodiments of the invention, the reaction temperature is 25 ℃;
the compound of formula V may be prepared by selecting an appropriate reaction time as desired, in some embodiments of the invention the reaction time is from 0.5 to 24 hours, preferably from 5 to 12 hours, and in some embodiments of the invention the reaction time is 8 hours.
In yet another aspect, the invention provides a process for the preparation of a compound of formula VI comprising oxidation of a compound of formula V to prepare a compound of formula VI,
Figure BDA0000959835770000061
wherein the compound of formula v is prepared by a process for the preparation of a compound of formula v as hereinbefore described.
Wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the invention, the compound of formula V is a compound of formula V-1 and the compound of formula VI is a compound of formula VI-1;
Figure BDA0000959835770000062
wherein the compound of formula VI is prepared by selecting suitable oxidation conditions as required, said oxidation conditions being selected from one of the oxidation conditions of (i), (ii), (iii), (iv) or (v): (i) under the alkaline condition, DMSO is used as an oxidant, and is synergistically oxidized with oxalyl chloride in a solvent at low temperature; the base is selected from triethylamine or N, N-diisopropylethylamine; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; the low temperature is-60 to-80 ℃, and preferably-60 to-70 ℃; (ii) pyridine chlorochromate as oxidant is oxidized in the presence of solvent; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iii) oxidizing (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -ketone serving as an oxidizing agent in the presence of a solvent; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iv) oxidizing chromium trioxide, sulfuric acid and water in the presence of a solvent to prepare a Jones oxidant; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (v) oxidizing tetramethylpiperidine nitrogen oxide, bromide and sodium hypochlorite which are used as oxidants under the alkaline condition in the presence of a solvent; the bromide is selected from sodium bromide or potassium bromide; the alkali is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate or potassium hydrogen phosphate, preferably sodium bicarbonate or potassium bicarbonate; the solvent is selected from tetrahydrofuran, dioxane, acetonitrile or acetone, preferably tetrahydrofuran; in some embodiments of the invention, the oxidation conditions are the oxidation conditions of (v);
wherein the preparation of the compound of formula VI is optionally carried out under the protection of nitrogen or argon;
the compound of formula VI may be prepared by selecting a suitable reaction time as desired, in some embodiments of the invention the reaction time is from 0.5 to 48 hours, preferably from 5 to 24 hours, and in some embodiments of the invention the reaction time is 12 hours.
In yet another aspect, the invention provides a process for preparing a compound of formula VII, comprising reacting a compound of formula VI with N, N-dimethylformamide to prepare a compound of formula VII,
Figure BDA0000959835770000071
wherein the compound of formula VI is prepared by a process for the preparation of a compound of formula VI as hereinbefore described;
wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the invention, the compound of formula VI is a compound of formula VI-1, and the compound of formula VII is a compound of formula VII-1;
Figure BDA0000959835770000072
in some embodiments of the invention, the reaction is carried out in the presence of a free radical initiator and an oxidizing agent;
in some embodiments of the invention, the free radical initiator is selected from t-butyl hydroperoxide, di-t-butyl peroxide, t-butyl peroxybenzoate, dibenzoyl peroxide, dicumyl peroxide, cumene hydroperoxide, azobisisobutyronitrile, or cyclohexanone peroxide, preferably one or more of t-butyl hydroperoxide or di-t-butyl peroxide, and most preferably t-butyl hydroperoxide;
in some embodiments of the invention, the oxidant is selected from iodine, cuprous iodide, cuprous chloride, cupric oxide, silver chloride, silver bromide, silver iodide or silver acetate, preferably iodine or cuprous iodide, most preferably iodine;
in some embodiments of the invention, the molar ratio of the compound of formula vi to N, N-dimethylformamide is 1: 20-100, preferably 1: 30-80, most preferably 1: 50-60 parts of;
in some embodiments of the invention, the reaction temperature is 50 to 100 ℃, preferably 60 to 90 ℃, and most preferably 70 to 80 ℃, and in some embodiments of the invention, the reaction temperature is 70 ℃ or 80 ℃;
the compound of formula VI may be prepared by selecting a suitable reaction time as desired, in some embodiments of the invention the reaction time is from 0.5 to 48 hours, preferably from 10 to 36 hours, and in some embodiments of the invention the reaction time is 24 hours.
In a further aspect, the present invention provides a process for the preparation of a compound of formula VII, comprising:
(1) reacting a compound shown in a formula I with a compound shown in a formula II in the presence of a catalyst and alkali to obtain a compound shown in a formula III, reacting the compound shown in the formula III to obtain a compound shown in a formula IV,
(2) the compound of formula IV is reacted to prepare the compound of formula V,
(3) oxidizing the compound of the formula V to prepare a compound of a formula VI,
(4) reacting the compound shown in the formula VI with N, N-dimethylformamide to prepare a compound shown in the formula VII,
Figure BDA0000959835770000081
wherein X is selected from halogen, preferably bromine, chlorine or iodine, most preferably chlorine;
wherein Y is selected from halogen, preferably bromine, chlorine or iodine, most preferably bromine;
in some embodiments of the present invention, the catalyst of step (1) is a palladium catalyst, for example, may be a palladium (0) and palladium (II) catalyst, more specifically, the palladium catalyst is selected from one or more of tetrakis (triphenylphosphine) palladium, palladium acetate, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, 1, 3-bis (diphenylphosphino) propane palladium dichloride, 1, 4-bis (diphenylphosphino) butane palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (cyanophenyl) palladium dichloride, 1' -bis-diphenylphosphino ferrocene palladium dichloride, or tris (dibenzylideneacetone) dipalladium, preferably one or more of tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, or bis (cyanophenyl) palladium dichloride, more preferably one or two of tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride, in some embodiments of the invention, the catalyst is selected from tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride;
in some embodiments of the present invention, the base of step (1) may be an inorganic base or an organic base, and more specifically, the base is selected from one or more of tetrabutylammonium fluoride or a hydrate thereof, tetra-n-butylammonium dihydrogen trifluoride, tetrabutylammonium dihydrogen phosphate, tetra-n-octylammonium bromide, tetra-n-butylammonium dihydrogen trifluoride or a hydrate thereof, tetrabutylammonium bromide or methyltributylammonium bromide; preferably tetrabutylammonium fluoride or a hydrate thereof, more preferably tetrabutylammonium fluoride or a trihydrate thereof, most preferably tetrabutylammonium fluoride trihydrate;
in some embodiments of the invention, the molar ratio of the compound of formula i to the compound of formula ii in step (1) is 1: 1-2, and may be 1: 1 to 1.5, and in some embodiments of the invention, the molar ratio of the compound of formula i to the compound of formula ii is about 1: 2 or 1: 1.5;
in some embodiments of the invention, the molar ratio of the compound of formula i to the catalyst in step (1) is 1: 0.01 to 0.1, preferably 1: 0.02 to 0.08, more preferably 1: 0.05-0.06;
in some embodiments of the invention, the molar ratio of the compound of formula i to base in step (1) is 1: 0.5-10;
wherein the compound shown in the formula III in the step (1) can be separated and then reacted to obtain a compound shown in the formula IV, or can be reacted without separation to obtain a compound shown in the formula IV;
in some embodiments of the invention, the reaction of step (2) is carried out in the presence of an acid; wherein the acid is selected from organic acid or inorganic acid, wherein the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, and the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, preferably one or more of methanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, and most preferably hydrochloric acid;
in some embodiments of the invention, the molar ratio of compound of formula v to acid in step (2) is 1: 5-20, preferably 1: 5-15, more preferably 1: 10-12;
wherein step (3) may be carried out under a suitable oxidation condition selected from one of the following (i), (ii), (iii), (iv) or (v), as required: (i) under the alkaline condition, DMSO is used as an oxidant, and is synergistically oxidized with oxalyl chloride in a solvent at low temperature; the base is selected from triethylamine or N, N-diisopropylethylamine; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; the low temperature is-60 to-80 ℃, and preferably-60 to-70 ℃; (ii) pyridine chlorochromate as oxidant is oxidized in the presence of solvent; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iii) oxidizing (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -ketone serving as an oxidizing agent in the presence of a solvent; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iv) oxidizing chromium trioxide, sulfuric acid and water in the presence of a solvent to prepare a Jones oxidant; the solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (v) oxidizing tetramethylpiperidine nitrogen oxide, bromide and sodium hypochlorite which are used as oxidants under the alkaline condition in the presence of a solvent; the bromide is selected from sodium bromide or potassium bromide; the alkali is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate or potassium hydrogen phosphate, preferably sodium bicarbonate or potassium bicarbonate; the solvent is selected from tetrahydrofuran, dioxane, acetonitrile or acetone, preferably tetrahydrofuran; in some embodiments of the invention, the oxidation conditions are the oxidation conditions of (v);
wherein step (4) is carried out in the presence of a free radical initiator and an oxidizing agent;
in some embodiments of the invention, the molar ratio of the compound of formula vi to N, N-dimethylformamide in step (4) is 1: 20-100, preferably 1: 30-80, most preferably 1: 50-60.
In a further aspect, the invention provides a compound of formula III and a compound of formula IV or a salt thereof,
Figure BDA0000959835770000101
wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine.
In a further aspect, the invention provides the use of a compound of formula III or a compound of formula IV or a salt thereof in the preparation of a compound of formula VII.
In a further aspect, the invention provides the use of a compound of formula iii or a compound of formula iv, or a salt thereof, in the preparation of reburnib.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The terms "halogen" or "halo", as used herein alone or in combination, refer to fluorine, chlorine, bromine and iodine.
In the present application, the compounds of formula I-1 and the compounds of formula II can be prepared by methods known in the art and can also be obtained commercially, and the compounds of formula I-1 and the compounds of formula II used in the examples of the present invention are obtained commercially.
In the present application, the reaction is optionally carried out in a solvent, all solvents used in the present application are commercially available and can be used without further purification, and the reaction is generally carried out under inert nitrogen in an anhydrous solvent.
The compound is made by hand or
Figure BDA0000959835770000102
The software names, and the commercial compounds are under the supplier catalog name.
In the present application, proton nuclear magnetic resonance data are recorded on a BRUKER DRX-400(400MHz) spectrometer with chemical shifts expressed in terms of (ppm) at tetramethylsilane low field; mass spectra were determined on Agilent-Q-Tofmicro YA 019. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode. HPLC column was with Waters Symmetry C18 (4.6X 250mm, 5 μm), mobile phase A was 0.05% aqueous trifluoroacetic acid and mobile phase B was 0.05% acetonitrile trifluoroacetic acid. The thin-layer chromatography silica gel plate adopts an HSG-F254 high-efficiency thin-layer chromatography silica gel precast plate manufactured by a yellow affair silica gel development test factory.
According to the preparation method, the compound of the formula I reacts with 2- (prop-2-yne-1-yloxy) tetrahydro-2H-furan to obtain the compound of the formula III, the compound of the formula III continuously reacts with the compound of the formula IV with or without separation to obtain the compound of the formula IV, and the obtained product is subjected to subsequent reaction to sequentially obtain the compound of the formula V, the compound of the formula VI and the compound of the formula VII, wherein each step of reaction has high yield and high purity, so that the total yield of the whole route is high and is obviously superior to that of the prior art, the raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, and the reaction reagent is environment-friendly and is particularly suitable for industrial production.
Detailed Description
The following examples further illustrate the technical solution of the present invention in non-limiting detail. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. The solvents, reagents, raw materials and the like used in the present invention are all commercially available chemically pure or analytically pure products.
Example 1: preparation of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine (compound of formula III-1)
Figure BDA0000959835770000111
5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (60g, 218mmol), tetrabutylammonium fluoride trihydrate (103g, 326mmol), bis (triphenylphosphine) palladium dichloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (550mL) were added sequentially to a reaction flask, nitrogen was added and 2- (prop-2-yn-1-yloxy) tetrahydro-2H-furan (compound of formula II) (45.6g, 325.5mmol) was added, and after 24 hours of reflux reaction, HPLC analysis indicated that the reaction was complete. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (500mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (400 mL. times.3), water (400 mL. times.3), and saturated brine (400 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, and performing silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate 10: 1, 64.5g of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine are obtained as a light brown oil in yield: 88.2% and 96.2% purity by HPLC analysis.
1H-NMR(400MHz,CDCl3):δ＝8.05(1H,s),5.71(1H,s),4.87-4.85(1H,t,J＝7.0Hz),4.52-4.51(2H,d,J＝7.0Hz),4.47-4.39(1H,m),3.91-3.85(1H,m),3.58-3.54(1H,m),1.76-1.41(14H,m)。
MS m/z[ESI]:336.1[M+1]+。
Example 2: preparation of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine (compound of formula III-1)
5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20g, 72.3mmol), tetrabutylammonium fluoride trihydrate (57g, 180.8mmol), tetrakis (triphenylphosphine) palladium (4.2g, 3.62mmol) and anhydrous tetrahydrofuran (300mL) were added in this order to a reaction flask, and 2- (prop-2-yn-1-yloxy) tetrahydro-2H-furan (20.3g, 144.6mmol) was added under nitrogen, followed by reaction at 75 ℃ for 20 hours, followed by HPLC analysis and completion of the reaction. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (200 mL. times.3), water (200 mL. times.3), and saturated brine (200 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate 10: 1, 19.5g of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine are obtained as a light brown oil in yield: 80.0% and 96.8% purity by HPLC analysis.
Example 3: preparation of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine (compound of formula III-1)
5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (30g, 108.5mmol), tetrabutylammonium fluoride (70.8g, 271.3mmol), bis (triphenylphosphine) palladium dichloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (300mL) were sequentially charged into a reaction flask, and 2- (prop-2-yn-1-yloxy) tetrahydro-2H-furan (22.8g, 162.8mmol) was added under nitrogen protection, followed by reaction at 75 ℃ for 20 hours, followed by HPLC analysis and completion of the reaction. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (200 mL. times.3), water (200 mL. times.3), and saturated brine (200 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate 10: 1, 32.6g of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine are obtained as a light brown oil in yield: 89.1% and 97.4% purity by HPLC analysis.
Example 4: preparation of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (compound of formula IV-1)
Figure BDA0000959835770000121
2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine (64.5g, 192.5mmol), tetrabutylammonium fluoride (prepared into a 1mol/L tetrahydrofuran solution, 150mL) and anhydrous tetrahydrofuran (50mL) are added into a reaction bottle in sequence, the reaction is performed for 12 hours at 90 ℃ under the protection of nitrogen, and the reaction is completed after HPLC analysis. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (200 mL. times.3), water (200 mL. times.3), and saturated brine (200 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate ═ 5: 1, 54.2g of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained as a light brown oil in yield: 84.0% and 98.5% purity by HPLC analysis.
1H-NMR(400MHz,CDCl3):δ＝8.69(1H,s),6.50-6.48(1H,d,J＝7.0Hz),4.90-4.84(2H,m),4.69-4.62(2H,m),3.89-3.83(1H,m),3.58-3.55(1H,m),2.47-2.36(2H,m),2.10-2.04(4H,m),1.75-1.52(8H,m)。
MS m/z[ESI]:358.2[M+Na]+。
Example 5: preparation of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (compound of formula IV-1)
2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyrimidin-4-amine (35g, 104.5mmol) and tetrabutylammonium fluoride (prepared into a 1mol/L tetrahydrofuran solution, 200mL) are sequentially added into a reaction bottle, and the reaction is performed for 12 hours at 90 ℃ under the protection of nitrogen and is analyzed by HPLC (high performance liquid chromatography) and completed. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (200 mL. times.3), water (200 mL. times.3), and saturated brine (200 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate ═ 5: 1, 30.3g of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained as a light brown oil in yield: 86.6% and 98.7% purity by HPLC analysis.
Example 6: preparation of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (compound of formula IV-1)
Figure BDA0000959835770000131
Adding 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (50g, 180.8mmol), tetrabutylammonium fluoride trihydrate (171g, 542.4mmol), bis (triphenylphosphine) palladium dichloride (6.3g, 9.04mmol) and anhydrous tetrahydrofuran (450mL) into a reaction flask in sequence, adding 2- (prop-2-yn-1-yloxy) tetrahydro-2H-furan (35.5g, 253mmol) under the protection of nitrogen, refluxing for 12 hours, supplementing tetrabutylammonium fluoride trihydrate (114g, 361.6mmol), continuing to reflux and stir for 12 hours, and analyzing by HPLC to complete the reaction. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (500mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (400 mL. times.3), water (400 mL. times.3), and saturated brine (400 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate ═ 5: 1, 40.2g of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained as a light brown oil in yield: 66.0% and 98.2% purity by HPLC analysis.
Example 7: preparation of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (compound of formula IV-1)
5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (25g, 90.4mmol), tetrabutylammonium fluoride trihydrate (142g, 452mmol), bis (triphenylphosphine) palladium dichloride (5.2g, 4.52mmol) and anhydrous tetrahydrofuran (230mL) were added to a reaction flask in this order, under nitrogen, 2- (prop-2-yn-1-yloxy) tetrahydro-2H-furan (19g, 135.6mmol) was added, and the reaction was refluxed for 24 hours, analyzed by HPLC and completed. The reaction mixture was cooled to room temperature, the tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300mL) was added, and the mixture was washed with saturated sodium hydrogen sulfate (200 mL. times.3), water (200 mL. times.3), and saturated brine (200 mL. times.1) in this order. Separating the organic phase, concentrating under reduced pressure to obtain crude oil, separating by silica gel column chromatography, wherein the mobile phase is petroleum ether/ethyl acetate ═ 5: 1, 19.6g of 2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine are obtained as a light brown oil in yield: 64.3% and 98.4% purity by HPLC analysis.
Example 8: preparation of (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol (compound of formula V-1)
Figure BDA0000959835770000141
2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (40g, 119.4mmol) and ethyl acetate (400mL) were added to the reaction flask, cooled to 10 deg.C, concentrated hydrochloric acid (40mL) was added dropwise slowly, stirred at room temperature for 8 hours, and analyzed by HPLC for completion of the reaction. Concentrating the reaction solution under reduced pressure to obtain a viscous substance, adding methanol (50mL), slowly dropping the viscous substance into 10% NaOH (300mL) at room temperature, adding n-hexane (100mL) after dropping, continuously stirring for 2 hours, filtering, and vacuum-drying a filter cake at 40 ℃ for 12 hours to obtain 29.4g of light yellow solid (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol, wherein the yield is as follows: 98.0% and 99.6% purity by HPLC analysis.
1H-NMR(400MHz,CDCl3):δ＝8.61(1H,s),6.40(1H,s),4.97-4.89(1H,m),4.81(2H,s),2.42-2.36(2H,m),2.10-2.07(4H,m),1.72-1.71(2H,m)。
MS m/z[ESI]:252.1[M+H]+。
Example 9: preparation of (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol (compound of formula V-1)
2-chloro-7-cyclopentyl-6- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (20g, 59.7mmol) and tetrahydrofuran (200mL) were added to a reaction flask, cooled to 10 deg.C, concentrated hydrochloric acid (20mL) was added dropwise slowly, stirred at room temperature for 8 hours, and analyzed by HPLC for completion of the reaction. Concentrating the reaction solution under reduced pressure to obtain a viscous substance, adding methanol (30mL), slowly dropping the viscous substance into 10% NaOH (150mL) at room temperature, adding n-hexane (60mL) after dropping, continuously stirring for 2 hours, filtering, and vacuum-drying a filter cake at 40 ℃ for 12 hours to obtain 14.6g of light yellow solid (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol, wherein the yield is as follows: 97.3% and 99.2% purity by HPLC analysis.
Example 10: preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carbaldehyde (compound of formula VI-1)
Figure BDA0000959835770000151
(2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol (20.0g, 80mmol), NaBr (0.82g, 8mmol), tetramethylpiperidine nitroxide (0.13g, 0.8mmol) and tetrahydrofuran (300mL) were added to a reaction flask in this order, under nitrogen protection, a sodium hypochlorite solution (5.2% 0.806M 150mL, 120 mmol) was slowly added dropwise in an ice bath, the pH was adjusted to 9.5 with saturated sodium bicarbonate, after dropwise addition, the mixture was stirred at room temperature for 12 hours to complete the reaction for HPLC analysis, and the reaction was washed with 10% citric acid (200 mL. times.1, 0.02 equivalent of KI, 10% sodium thiosulfate (200 mL. times.3), water (200 mL. times.3) and saturated saline (200 mL. times.1) in this order. The organic phase was concentrated under reduced pressure to give 17.1g of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carbaldehyde as a white solid in yield: 86.0% and 96.8% purity by HPLC analysis.
1H-NMR(400MHz,CDCl3):δ＝9.93(1H,s),8.98(1H,s),7.31(1H,s),5.79-5.70(1H,m),2.25-1.72(8H,m)。
MS m/z[ESI]:250.4[M+H]+。
Example 11: preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carbaldehyde (compound of formula VI-1)
(2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) methanol (10.0g, 40mmol), KBr (0.5g, 4mmol), tetramethylpiperidine nitroxide (0.07g, 0.4mmol) and tetrahydrofuran (150mL) were added to a reaction flask in this order, under nitrogen protection, a sodium hypochlorite solution (5.2% 0.806M 150mL, 60 mmol) was slowly added dropwise in an ice bath, the pH was adjusted to 9.5 with saturated sodium bicarbonate, after dropwise addition, the mixture was stirred at room temperature for 12 hours to complete the reaction for HPLC analysis, and the reaction was washed with 10% citric acid (100 mL. times.1, 0.02 equivalent of KI, 10% sodium thiosulfate (100 mL. times.3), water (100 mL. times.3) and saturated saline (100 mL. times.1) in this order. The organic phase was concentrated under reduced pressure to give 8.6g of 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carbaldehyde as a white solid in yield: 86.8% and 96.2% purity by HPLC analysis.
Example 12: preparation of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (compound of formula VII-1)
Figure BDA0000959835770000161
2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formaldehyde (12.0g, 48mmol), iodine (2.4g, 9.6mmol) and N, N-dimethylformamide (200mL) are added into a reaction bottle in sequence, tert-butyl hydroperoxide (70% aqueous solution, 26.3mL, 192mmol) is slowly dropped into the reaction bottle under the protection of nitrogen, reaction is carried out at 70 ℃ for 24 hours after the dropping is finished, and the reaction is analyzed to be complete by HPLC. The reaction solution was cooled to room temperature, a saturated sodium thiosulfate solution (100mL) was slowly added dropwise to the reaction solution, after completion of the addition, extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed with water (200mL × 1) and a saturated saline solution (200mL × 1) in this order, the organic phase was concentrated under reduced pressure to give a light brown crude product, and petroleum ether/ethyl acetate was recrystallized to give 10.2g of a pale yellow solid, 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide, with a yield of 72.8% and an HPLC analytical purity of 98.9%.
1H-NMR(400MHz,CDCl3):δ＝8.77(1H,s),6.51(1H,s),4.90-4.82(1H,m),3.17-3.07(6H,s),2.38-2.33(2H,m),2.08-2.03(4H,m),1.68-1.65(2H,m)。
MS m/z[ESI]:293.1[M+H]+。
Example 13: preparation of 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (compound of formula VII-1)
2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formaldehyde (10.0g, 40mmol), iodine (2.0g, 8mmol) and N, N-dimethylformamide (150mL) are added into a reaction bottle in sequence, tert-butyl hydroperoxide (70% aqueous solution, 27.3mL, 200mmol) is slowly dropped into the reaction bottle under the protection of nitrogen, reaction is carried out at 80 ℃ for 24 hours after the dropping is finished, and the reaction is analyzed to be complete by HPLC. The reaction solution was cooled to room temperature, a saturated sodium thiosulfate solution (80mL) was slowly added dropwise to the reaction solution, after completion of the addition, extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed with water (200mL × 1) and a saturated saline solution (200mL × 1) in this order, the organic phase was concentrated under reduced pressure to give a light brown crude product, and petroleum ether/ethyl acetate was recrystallized to give 8.8g of a pale yellow solid, 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide, with a yield of 75.2% and an HPLC analytical purity of 99.2%.

Claims (61)

1. A process for preparing a compound of formula iv comprising: reacting a compound shown in a formula I with a compound shown in a formula II in the presence of a catalyst and alkali to obtain a compound shown in a formula III, reacting the compound shown in the formula III to obtain a compound shown in a formula IV,
Figure FDA0003174147580000011
wherein,
x is selected from chlorine, Y is selected from bromine;
the catalyst is a palladium catalyst selected from tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride;
the base is selected from tetrabutylammonium fluoride or a hydrate thereof;
the molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1: 1-2;
the molar ratio of the compound of formula I to the catalyst is 1: 0.02-0.08;
the molar ratio of the compound of formula I to the base is 1: 0.5-10;
the preparation method is carried out in the presence of a solvent selected from tetrahydrofuran;
the reaction temperature in the preparation method is 50-100 ℃.
2. The process of claim 1 wherein the base is selected from tetrabutylammonium fluoride or the trihydrate thereof.
3. The method of claim 2, wherein the base is selected from tetrabutylammonium fluoride trihydrate.
4. The process of claim 1 wherein the molar ratio of the compound of formula i to the compound of formula ii is 1: 1-1.5.
5. The process of claim 1 wherein the molar ratio of the compound of formula i to the compound of formula ii is 1: 2.
6. the process of claim 1 wherein the molar ratio of the compound of formula i to the compound of formula ii is 1: 1.5.
7. the process of claim 1, wherein the molar ratio of the compound of formula i to the catalyst is 1: 0.05-0.06.
8. A process according to claim 1, wherein the molar ratio of compound of formula i to base is 1: 1-10.
9. The process of claim 1, wherein the compound of formula III is reacted without isolation to give a compound of formula IV.
10. The process of claim 9, wherein the molar ratio of the compound of formula i to the base is 1: 2.5-10.
11. The process of claim 10, wherein the molar ratio of the compound of formula i to the base is 1: 3-10.
12. The process of claim 11, wherein the molar ratio of the compound of formula i to the base is 1: 4-10.
13. The process of claim 12, wherein the molar ratio of the compound of formula i to the base is 1: 5.
14. a process according to claim 1, wherein the compound of formula iii is isolated and reacted to give a compound of formula iv.
15. The process of claim 14, wherein the molar ratio of the compound of formula i to the base is 1: 0.5-3.
16. The process of claim 15, wherein the molar ratio of the compound of formula i to the base is 1: 1-2.5.
17. The process of claim 16, wherein the molar ratio of the compound of formula i to the base is 1: 1.5-2.5.
18. The process of claim 17, wherein the molar ratio of the compound of formula i to the base is 1: 1.5 or 1: 2.5.
19. the process of claim 18, wherein the reaction of the compound of formula iii to obtain the compound of formula iv is carried out in the presence of a second base selected from tetrabutylammonium fluoride or a hydrate thereof.
20. The method of claim 19, wherein the second base is selected from tetrabutylammonium fluoride or a trihydrate thereof.
21. The method of claim 20, wherein the second base is selected from tetrabutylammonium fluoride trihydrate.
22. The process of claim 19, wherein the molar ratio of the compound of formula iii to the second base is 1: 0.5-10.
23. The process of claim 22, wherein the molar ratio of the compound of formula iii to the second base is 1: 1-5.
24. The process of claim 23, wherein the molar ratio of the compound of formula iii to the second base is 1: 2.
25. the process according to any one of claims 14 to 24, wherein the preparation of the compound of formula iii and the preparation of the compound of formula iv are carried out in the presence of a solvent selected from tetrahydrofuran.
26. The production method of claim 1, wherein the reaction temperature in the production method is 75 ℃ or the boiling point of the reaction system.
27. The process according to any one of claims 14 to 24, wherein the preparation of the compound of formula iii and the preparation of the compound of formula iv are carried out at reaction temperatures selected from the range of 50 to 100 ℃.
28. The production method of claim 27, wherein the reaction temperature is 75 ℃ or the boiling point of the reaction system.
29. A process for the preparation of a compound of formula v, comprising:
(1) preparing a compound of formula iv by the preparation process of any one of claims 1 to 28;
(2) the compound of formula IV is reacted to prepare the compound of formula V,
Figure FDA0003174147580000021
30. the process according to claim 29, wherein the reaction for preparing the compound of formula v is carried out in the presence of an acid.
31. The process according to claim 30, wherein the acid is selected from an organic acid or an inorganic acid, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid, and the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.
32. The process according to claim 31, wherein the acid is one or more selected from the group consisting of methanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid.
33. The method of claim 32, wherein the acid is hydrochloric acid.
34. The process of claim 29, wherein the molar ratio of the compound of formula v to acid is 1: 5-20.
35. The process of claim 34, wherein the molar ratio of the compound of formula v to acid is 1: 5-15.
36. The process of claim 35, wherein the molar ratio of the compound of formula v to acid is 1: 10-12.
37. The process according to claim 29, wherein the compound of formula v is prepared in the presence of a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, N-propyl acetate, isopropyl acetate, dichloromethane, methanol, ethanol, N-propanol, dioxane, acetonitrile, toluene, dimethylsulfoxide, N-dimethylformamide, and mixtures thereof.
38. The method of claim 37, wherein the solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, dichloromethane, and methanol.
39. The method of claim 38, wherein the solvent is selected from ethyl acetate or tetrahydrofuran.
40. The process of claim 29, wherein the reaction temperature for preparing the compound of formula v is 5 to 30 ℃.
41. The process of claim 40, wherein the reaction temperature for preparing the compound of formula V is 15-30 ℃.
42. The process of claim 41, wherein the reaction temperature for preparing the compound of formula V is 25 ℃.
43. A process for preparing a compound of formula vi comprising:
(1) preparing a compound of formula v by the preparation method of any one of claims 29-42;
(2) oxidizing the compound of the formula V to prepare a compound of a formula VI,
Figure FDA0003174147580000031
44. the method of claim 43, wherein the oxidizing conditions of said oxidizing are selected from one of the following (i), (ii), (iii), (iv), or (v):
(i) under the alkaline condition, DMSO is used as an oxidant, and is synergistically oxidized with oxalyl chloride in a solvent at low temperature;
(ii) pyridine chlorochromate as oxidant is oxidized in the presence of solvent;
(iii) oxidizing (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -ketone serving as an oxidizing agent in the presence of a solvent;
(iv) oxidizing chromium trioxide, sulfuric acid and water in the presence of a solvent to prepare a Jones oxidant;
(v) oxidizing tetramethyl piperidine nitrogen oxide, bromide and sodium hypochlorite serving as oxidants under the alkaline condition in the presence of a solvent.
45. The production method of claim 44, wherein the oxidation conditions of the oxidation are the oxidation conditions of (iv).
46. A process for preparing a compound of formula vii, comprising:
(1) preparing a compound of formula vi by the preparation process of any one of claims 43 to 45;
(2) reacting the compound shown in the formula VI with N, N-dimethylformamide to prepare a compound shown in the formula VII,
Figure FDA0003174147580000041
47. the method of claim 46, wherein the reaction is conducted in the presence of a free radical initiator and an oxidizing agent.
48. The method of claim 47, wherein the free radical initiator is selected from the group consisting of t-butyl hydroperoxide, di-t-butyl peroxide, t-butyl peroxybenzoate, dibenzoyl peroxide, dicumyl peroxide, cumene hydroperoxide, azobisisobutyronitrile, and cyclohexanone peroxide.
49. The method according to claim 48, wherein the radical initiator is one or more selected from the group consisting of t-butyl hydroperoxide and di-t-butyl peroxide.
50. The method of claim 49, wherein said free radical initiator is selected from the group consisting of t-butanol hydroperoxide.
51. The method of claim 47, wherein the oxidizing agent is selected from the group consisting of iodine, cuprous iodide, cuprous chloride, cupric oxide, silver chloride, silver bromide, silver iodide, and silver acetate.
52. The process of claim 51 wherein said oxidizing agent is selected from the group consisting of iodine and cuprous iodide.
53. The method of claim 52, wherein said oxidizing agent is selected from the group consisting of iodine.
54. The process of claim 46 wherein the molar ratio of the compound of formula VI to N, N-dimethylformamide is 1: 20-100.
55. The process of claim 54 wherein the molar ratio of the compound of formula VI to N, N-dimethylformamide is 1: 30-80.
56. The process of claim 55 wherein the molar ratio of the compound of formula VI to N, N-dimethylformamide is 1: 50-60.
57. A process according to claim 46, wherein the reaction temperature for the preparation of the compound of formula VII is in the range of 50-100 ℃.
58. A process according to claim 57 for the preparation of a compound of formula VII in which the reaction temperature is in the range 60-90 ℃.
59. A process according to claim 58, wherein the reaction temperature for the preparation of the compound of formula VII is in the range of from 70 to 80 ℃.
60. A process according to claim 59, wherein the reaction temperature for the preparation of the compound of formula VII is 70 ℃ or 80 ℃.
61. Compounds of formula III and IV
Figure FDA0003174147580000051
Wherein X is selected from chlorine.
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