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CN-122010951-A - New preparation method of reboxetine

CN122010951ACN 122010951 ACN122010951 ACN 122010951ACN-122010951-A

Abstract

The invention discloses a new preparation method of reboxetine. The invention specifically discloses a preparation method of reboxetine, which comprises the following steps of (1) carrying out substitution reaction on a compound 4 and a compound 5 in a solvent in the presence of alkali and a phase transfer catalyst to generate a compound 6, and (2) carrying out a protecting group removal reaction on the compound 6 in the presence of acid in the solvent to obtain reboxetine. The preparation method disclosed by the invention is simple to operate, mild in reaction condition, low in cost and easy to obtain raw materials, avoids using a noble metal catalyst, and is suitable for large-scale production.

Inventors

  • YU WEI
  • ZHANG YUXIN
  • ZHANG LU
  • TIAN PINGPING
  • FU YUJIA
  • ZHANG WANBIN
  • WU LIANG
  • GAO FENG
  • LI JING
  • LIAO KUI
  • CAO JIAOJIAO
  • Sajid Ur Lehman Brothers
  • JIANG XIMING

Assignees

  • 上海上药第一生化药业有限公司
  • 上海交通大学

Dates

Publication Date
20260512
Application Date
20260113

Claims (10)

  1. 1. A method for preparing reboxetine, comprising the steps of: ; (1) In a solvent, carrying out substitution reaction 1 on the compound 4 and the compound 5 in the presence of alkali and a phase transfer catalyst to generate a compound 6; (2) In a solvent, in the presence of acid, the compound 6 is subjected to a protecting group removal reaction to obtain reboxetine.
  2. 2. The method of claim 1, wherein one or more of any of the following conditions are satisfied: (1) In the substitution reaction 1, the solvent is selected from one or more of ether solvents, amide solvents, sulfoxide solvents and aromatic solvents, wherein the ether solvents are preferably tetrahydrofuran or 1, 4-dioxane, the amide solvents are preferably N, N-dimethylformamide or N, N-dimethylacetamide, the sulfoxide solvents are preferably dimethyl sulfoxide, and the aromatic solvents are preferably toluene; (2) In the substitution reaction 1, the base is an inorganic base or an organic base, preferably an alkali metal carbonate, an alkali metal phosphate and an alkali metal hydride, more preferably potassium carbonate, cesium carbonate, potassium phosphate or sodium hydride, for example, potassium carbonate or cesium carbonate, and the organic base is preferably potassium t-butoxide, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminide, 1, 8-diaza [5,4,0] undecene-7 or tetramethylguanidine; (3) In the substitution reaction 1, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphonium salt phase transfer agent, wherein the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide, more preferably tetra-n-butyl ammonium iodide, tetra-n-butyl ammonium bromide or tetra-n-butyl ammonium chloride, such as tetra-n-butyl ammonium bromide, and the quaternary phosphonium salt phase transfer catalyst is preferably triphenylphosphine methyl halide or tetraphenylphosphine halide, such as triphenylphosphine methyl phosphine bromide or tetraphenylphosphine bromide; (4) In the substitution reaction 1, the molar volume ratio of the compound 4 to the solvent is 0.1-1 mol/L, preferably 0.2-0.6 mol/L, for example 0.2 mol/L or 0.4 mol/L; (5) In the substitution reaction 1, the molar ratio of the compound 5 to the compound 4 is (1-2): 1, preferably (1.2-1.8): 1, for example, 1.5:1; (6) In the substitution reaction 1, the molar ratio of the base to the compound 4 is (1-2): 1, preferably (1.2-1.8): 1, for example, 1.5:1; (7) In said substitution reaction 1, the molar ratio of said phase transfer catalyst to said compound 4 is (0.02-0.3): 1, preferably (0.05-0.15): 1, for example 0.1:1; (8) The temperature of the substitution reaction 1 is 0 to 120 o C, preferably 90 to 110 o C, for example 100 o C; (9) The time for the substitution reaction 1 is 12 to 48 h, preferably 18 to 30 h, for example 24 to h; (10) The substitution reaction 1 further comprises the following post-treatment steps of cooling to room temperature after the reaction is finished, respectively adding water and ethyl acetate, stirring and separating liquid, extracting the water phase with ethyl acetate, combining the organic layers, washing with water and saturated sodium chloride in sequence, and removing the solvent to obtain a compound 6; Preferably, in the substitution reaction 1, the base is an inorganic base, and when the base is an inorganic base, the solvent is preferably an amide solvent or a sulfoxide solvent, more preferably N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, for example, N-dimethylformamide.
  3. 3. The method of claim 1, wherein one or more of any of the following conditions are satisfied: (1) In the protecting group removal reaction, the solvent is one or more selected from halogenated hydrocarbon solvents, ester solvents, ketone solvents, alcohol solvents, ether solvents, aromatic hydrocarbon solvents and nitrile solvents, wherein the halogenated hydrocarbon solvents are preferably methylene dichloride, the ester solvents are preferably ethyl acetate, the ketone solvents are preferably acetone, the alcohol solvents are preferably methanol or ethanol, the ether solvents are preferably tetrahydrofuran or 1, 4-dioxane, the aromatic hydrocarbon solvents are preferably toluene, the nitrile solvents are preferably acetonitrile, the halogenated hydrocarbon solvents, the ester solvents or the aromatic hydrocarbon solvents are preferably methylene dichloride, ethyl acetate or toluene; (2) In the protecting group removal reaction, the acid is hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, preferably hydrochloric acid or trifluoromethanesulfonic acid, more preferably, the hydrochloric acid is added in the form of a 5M hydrochloric acid solution; (3) In the protecting group removal reaction, the acid is added dropwise; (4) In the protecting group removal reaction, the molar volume ratio of the compound 6 to the solvent is 0.1-1 mol/L, preferably 0.2-0.6 mol/L, for example 0.4 mol/L; (5) In the protecting group removal reaction, the molar ratio of the acid to the compound 6 is (2-8) 1, preferably (4-6) 1, for example 5:1; (6) The temperature of the protecting group removal reaction is 0-60 o C, preferably 10-40 o C, for example 20-30 o C; (7) The time for the protecting group removal reaction is 0.5 to 6 hours, preferably 1 to 3 hours, for example 2 hours; (8) The protecting group removal reaction further comprises the following post-treatment steps of regulating the pH value to 7+/-0.5 by using a saturated sodium hydroxide solution, extracting by using ethyl acetate, merging organic layers, washing by using saturated saline water, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, recrystallizing the crude product by using ethyl acetate and normal hexane, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain reboxetine; Preferably, the preparation method meets one or both of the following arbitrary conditions: (1) In the protecting group removal reaction, the molar volume ratio of the compound 4 to the solvent is 0.1-1 mol/L, preferably 0.2-0.6 mol/L, for example 0.4 mol/L; (2) In the protecting group removal reaction, the molar ratio of the acid to the compound 4 is (2-8): 1, preferably (4-6): 1, for example, 5:1.
  4. 4. The preparation method according to claim 1, wherein the preparation method of reboxetine further comprises the steps of carrying out an oxidation reaction of compound 3 in a solvent in the presence of an oxidizing agent to form compound 4; ; preferably, the preparation method meets one or more of any of the following conditions: (1) In the oxidation reaction, the solvent is an alcohol solvent, an ether solvent, an amide solvent, a sulfoxide solvent or a nitrile solvent, wherein the alcohol solvent is preferably methanol or ethanol, the ether solvent is preferably tetrahydrofuran or 1, 4-dioxane, the amide solvent is preferably N, N-dimethylformamide or N, N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, the nitrile solvent is preferably acetonitrile, and the solvent is preferably a nitrile solvent; (2) In the oxidation reaction, the oxidant is potassium hydrogen persulfate double salt, the potassium hydrogen persulfate double salt is preferably added in the form of aqueous solution, the volume ratio of the water to the solvent is preferably 1:1, preferably, the aqueous solution is added dropwise, and the addition temperature of the aqueous solution is preferably 0-15 ℃; (3) In the oxidation reaction, the molar volume ratio of the compound 3 to the solvent is 0.1-1 mol/L, preferably 0.2-0.5 mol/L, for example 0.32 mol/L; (4) In the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8) 1, preferably (4-6) 1, for example 5:1; (5) The temperature of the oxidation reaction is 0-40 o ℃, preferably 0-25 ℃; (6) The oxidation reaction is carried out for a period of time ranging from 2 to 12h, preferably from 4 to 6 h, for example 5 h; (7) The oxidation reaction further comprises the following post-treatment steps of concentrating under reduced pressure to remove acetonitrile, extracting with ethyl acetate, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and adding tetrahydrofuran and n-hexane into the crude product to recrystallize to obtain a compound 4.
  5. 5. The process according to claim 4, wherein the process further comprises the step of subjecting compound 2 to aminolysis with dimethylamine in a solvent to form compound 3; ; preferably, the preparation method meets one or more of any of the following conditions: (1) In the aminolysis reaction, the solvent is selected from one or more of halogenated hydrocarbon solvents, ester solvents, ketone solvents, alcohol solvents, ether solvents, amide solvents, sulfoxide solvents and nitrile solvents, wherein the halogenated hydrocarbon solvents are preferably methylene dichloride, the ester solvents are preferably ethyl acetate, the ketone solvents are preferably acetone, the alcohol solvents are preferably methanol or ethanol, the ether solvents are preferably tetrahydrofuran or 1, 4-dioxane, the amide solvents are preferably N, N-dimethylformamide or N, N-dimethylacetamide, the sulfoxide solvents are preferably dimethyl sulfoxide, the nitrile solvents are preferably acetonitrile, and the alcohol solvents are preferably methanol or ethanol; (2) In the aminolysis reaction, the dimethylamine is added in the form of dimethylamine methanol solution, wherein the dimethylamine methanol solution is preferably 2M dimethylamine methanol solution, and preferably, the dimethylamine methanol solution is added at a controlled temperature of 0-10 o C; (3) In the aminolysis reaction, the molar volume ratio of the compound 2 to the solvent is 0.5-3 mol/L, preferably 1-2 mol/L, for example 1.3 mol/L; (4) In the aminolysis reaction, the molar ratio of the dimethylamine to the compound 2 is (1-2) 1, preferably (1-1.5) 1, for example 1.1:1; (5) The aminolysis reaction temperature is 0-40 o C, preferably 20-30 o C; (6) The aminolysis reaction takes place for a period of time of 8 to 32 h, preferably 12 to 20 h, for example 16 h; (7) The aminolysis reaction further comprises the following post-treatment steps of concentrating to obtain a crude product, and adding tetrahydrofuran into the crude product for pulping to obtain the compound 3.
  6. 6. The preparation method of claim 5, wherein the preparation method of reboxetine further comprises the steps of carrying out substitution reaction 2 between the compound 1 and bromocyclopentane in the presence of a base in a solvent to produce a compound 2; ; preferably, the preparation method meets one or more of any of the following conditions: (1) In the substitution reaction 2, the solvent is selected from one or more of ether solvents, nitrile solvents, amide solvents, sulfoxide solvents and aromatic solvents, wherein the ether solvents are preferably tetrahydrofuran or 1, 4-dioxane, the nitrile solvents are preferably acetonitrile, the amide solvents are preferably N, N-dimethylformamide or N, N-dimethylacetamide, the sulfoxide solvents are preferably dimethyl sulfoxide, the aromatic solvents are preferably toluene, and the solvents are preferably amide solvents or ether solvents, preferably N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide, more preferably N, N-dimethylformamide; (2) In the substitution reaction 2, the base is an inorganic base or an organic base, preferably an alkali metal carbonate, alkali metal phosphate and alkali metal hydride, more preferably potassium carbonate, cesium carbonate, potassium phosphate or sodium hydride, preferably potassium tert-butoxide, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminamide, triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5,4,0] undecene-7, pyridine, piperidine, quinoline or tetramethylguanidine, preferably the base is an inorganic base, preferably potassium carbonate or cesium carbonate, for example potassium carbonate; (3) In the substitution reaction 2, the molar volume ratio of the compound 1 to the solvent is 0.2-2 mol/L, preferably 0.6-1.2 mol/L, for example 0.9 mol/L; (4) In the substitution reaction 2, the molar ratio of the bromocyclopentane to the compound 1 is (1-2): 1, preferably (1-1.5): 1, for example, 1.2:1; (5) In the substitution reaction 2, the molar ratio of the base to the compound 1 is (1-2): 1, preferably (1.2-1.8): 1, for example, 1.5:1; (6) In the substitution reaction 2, the molar ratio of the phase transfer catalyst to the compound 1 is (0.02-0.3): 1, preferably (0.05-0.15): 1, for example 0.1:1; (7) The substitution reaction 2 is carried out under an inert gas atmosphere, preferably under nitrogen; (8) The temperature of the substitution reaction 2 is 60-100 o C, preferably 90-100 o C, for example 100 o C; (9) The time for the substitution reaction 2 is 3 to 12 h, more preferably 4 to 8 h, for example 6 h; (10) The substitution reaction 2 further comprises the following post-treatment steps of cooling to room temperature, adding saturated ammonium chloride for quenching reaction, then adding water and ethyl acetate, stirring for separating liquid, extracting the water phase by using ethyl acetate, combining organic layers, washing by using water and saturated sodium chloride in sequence, removing the solvent to obtain a crude product, and carrying out column chromatography by using ethyl acetate and normal hexane to obtain the compound 2.
  7. 7. The process according to claim 6, wherein in the substitution reaction 2, the substitution reaction is carried out in the presence of a phase transfer catalyst, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphonium salt phase transfer agent, the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide, more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride, for example tetra-n-butylammonium bromide, the quaternary phosphonium salt phase transfer catalyst is preferably triphenylphosphine methyl halide or tetraphenylphosphine halide, for example triphenylphosphine methyl bromide or tetraphenylphosphine bromide.
  8. 8. A process for the preparation of compound 2 comprising the steps of: In a solvent, in the presence of alkali, carrying out substitution reaction 2 on the compound 1 and bromocyclopentane to generate a compound 2; ; Preferably, the reaction conditions of the substitution reaction 2 are as described in claim 6 or 7.
  9. 9. A preparation method of the compound 3 comprises the following steps of carrying out an aminolysis reaction of the compound 2 and dimethylamine in a solvent to generate the compound 3; ; Preferably, the reaction conditions of the aminolysis reaction are as described in claim 5.
  10. 10. A process for producing compound 6, which comprises the steps of subjecting compound 4 to substitution reaction 1 with compound 5 in a solvent in the presence of a base and a phase transfer catalyst to produce compound 6; ; Preferably, the reaction conditions of the substitution reaction 1 are as defined in claim 2.

Description

New preparation method of reboxetine Technical Field The invention belongs to the technical field of organic compounds, and relates to a novel preparation method of reboxetine. Background Reboxetine succinate (Ribociclib Succinate) is a CDK4/6 inhibitor developed by the company nova and is mainly used to treat advanced or metastatic breast cancer, HR positive, HER2 negative. The medicine can inhibit proliferation of cancer cells by preventing cell cycle progression, thereby remarkably prolonging progression free survival time (PFS), improving life quality of patients, and meeting medical requirements of patients with subtype breast cancer. Breast cancer is the most common malignant tumor of women in China and is also an important public health problem in China. Compared with other types of breast cancer, the premenopausal advanced breast cancer has the advantages of higher malignancy degree, poorer prognosis and rapid increase of incidence rate, and is a big hot spot problem in the current breast cancer treatment. In 2023, day 1 and day 19, reboxetine was approved by the national drug administration (NMPA), and this time of reboxetine harvest is a major breakthrough in breast cancer treatment, opening a new era for the treatment of pre-menopausal breast cancer patients. Therefore, the development of a simple and efficient method for preparing reboxetine (Ribociclib) is certainly of great significance. The literature reports that the synthetic route of reboxetine is mainly as follows: the method comprises the following steps: The method for synthesizing the reboxetine reported in the original patent US20120115878 is that 5-bromo-2, 4-dichloropyrimidine is used as a raw material, a key mother nucleus is obtained through nucleophilic substitution, coupling, cyclization, hydrolysis, oxidation and other reactions, and then the key mother nucleus is subjected to Buchwald-Hartwig coupling and Boc protection with 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester to generate the reboxetine. The whole route is longer, 9 steps are needed (2 steps of self-preparation of the coupling fragment are needed), and the total yield is 12%. The use of expensive palladium catalysts twice and the highly toxic sodium cyanide result in higher production costs. Method two, CN106749259A The patent reports the use of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde and ethyl N-cyclopentylglycine as starting materials, followed by substitution, dehydration condensation, hydrolysis, acid amine condensation, oxidation, substitution and Boc deprotection to give the final product reboxetine. Wherein, the ethyl N-cyclopentylglycine and the 4-chloro-2- (methylthio) pyrimidine-5-formaldehyde are expensive, and need one or more additional steps to prepare, which is not suitable for industrial production. Method III US 2020/0339588 The route method improves the original patent route, reduces the use of expensive palladium catalyst and virulent sodium cyanide, and can obtain the reboxetine with the yield of 17% in 7 steps, but the yield in the second step is only medium, and separation and purification are difficult, so that the overall production efficiency is not high. Disclosure of Invention The invention aims to overcome the defects that the prior art is expensive in starting raw materials, high in production cost, multiple in steps and low in total yield and is unsuitable for industrial production due to the use of a noble metal palladium catalyst and a highly toxic chemical sodium cyanide, and provides a novel preparation method of reboxetine. The method has the advantages of simple operation, mild reaction conditions, low-cost and easily-obtained raw materials, no noble metal catalyst, and suitability for large-scale production. The specific technical scheme for realizing the aim of the invention is as follows: The invention provides a preparation method of reboxetine, which comprises the following steps: ; (1) In a solvent, carrying out substitution reaction 1 on the compound 4 and the compound 5 in the presence of alkali and a phase transfer catalyst to generate a compound 6; (2) In a solvent, in the presence of acid, the compound 6 is subjected to a protecting group removal reaction to obtain reboxetine. In some embodiments of the invention, the base in the substitution reaction 1 is an inorganic base or an organic base, preferably an alkali metal carbonate, alkali metal phosphate and alkali metal hydride, more preferably potassium carbonate, cesium carbonate, potassium phosphate or sodium hydride, for example potassium carbonate or cesium carbonate, and the organic base is preferably potassium tert-butoxide, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminide, 1, 8-diazabicyclo [5,4,0] undecene-7 or tetramethylguanidine, more preferably lithium bistrimethylsilylaminide. In some embodiments of the present invention, in the substitution reaction 1, the solvent is selected from one or more o