CN111196760A - Preparation method of tomoxetine hydrochloride - Google Patents
Preparation method of tomoxetine hydrochloride Download PDFInfo
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- CN111196760A CN111196760A CN201811369723.3A CN201811369723A CN111196760A CN 111196760 A CN111196760 A CN 111196760A CN 201811369723 A CN201811369723 A CN 201811369723A CN 111196760 A CN111196760 A CN 111196760A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tomoxetine hydrochloride for treating attention deficit hyperactivity disorder. The invention adopts commercially available (E) The (E) -N-methyl-3-phenyl-2-propylene-1-amine is used as a starting material, and the tomoxetine hydrochloride is prepared by addition, substitution and salification. The preparation method provided by the invention has the advantages of simple preparation process, simplicity and convenience in operation, higher yield, suitability for industrial production and capability of providing sufficient raw material medicines for research and development of medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a medicine for treating hyperactivity, namely tomoxetine hydrochloride.
Background
Tomoxetine hydrochloride (atomoxetine hydrochloride), chemical name: (R) -N-methyl-3- (2-methylphenoxy) -3-phenyl-1-propylamine hydrochloride, developed by Lilly pharmaceutical company in the united states and obtained U.S. FDA approval in 11 months 2002, and marketed in the united states in 1 month 2003. For Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents, tomoxetine hydrochloride is a selective inhibitor of presynaptic norepinephrine transporter, which prolongs the norepinephrine activity released in synaptic clefts, and it has great market prospects as the first large number of trials to confirm that effective ADHD-specific therapeutic non-excitatory drugs hold great promise. The structure is as follows:
disclosure of Invention
The invention aims to provide a preparation method of a novel medicine of tomoxetine hydrochloride for treating attention deficit hyperactivity disorder. The method has the advantages of mild reaction conditions of all the procedures, simple operation, low production cost, suitability for industrial production, recyclable solvent and little environmental pollution.
The invention prepares a compound II by adding and oxidizing a compound I; the compound II and the compound III are subjected to substitution reaction to obtain a compound IV, the compound IV and hydrogen chloride gas are subjected to salt formation in an organic solvent to obtain a final product of tomoxetine hydrochloride, and the synthetic route is as follows:
the first step is the addition (1) and oxidation (2) reaction of the compound I and the compound II, wherein the addition reaction is carried out on a chiral catalyst (+) -diisopinocampheylboron (+) - (Ipc)2Reacting in the presence of BH; the molar ratio of the chiral catalyst to the compound I is 0.01: 1-0.1: 1, wherein the preferred molar ratio is 0.02: 1; the oxidation reaction (2) can be selected from H2O2(ii) a The alkali used is potassium hydroxide with low price.
The solvent used in the addition reaction in the step one can be one or a mixture of any two of tetrahydrofuran, acetonitrile, methanol, DMF, diethyl ether, isopropyl ether and ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether; compounds I and H2O2Is 1: 1.
Step one is at (+) - (Ipc)2BH、H2O2And carrying out hydroboration-oxidation at the temperature of 25-30 ℃ to generate a compound II with an R configuration.
In the second step, the compound II and o-fluorotoluene (III) are subjected to substitution reaction under an alkaline condition to generate a compound IV, the used alkali is low-cost potassium hydroxide, the reaction solvent can be one or any two mixed solvents of N, N-dimethylformamide, dioxane, dimethyl sulfoxide, 1, 3-dimethyl imidazolidinone and N-methyl pyrrolidone, and the preferable solvent is dimethyl sulfoxide.
The reaction temperature of the second step is 100-125 ℃.
The solvent used for salifying in the third step is one of acetone, isopropanol or tetrahydrofuran; the reaction temperature is 45-70 ℃.
The raw material (compound I) and the reagent related to the invention are commercially available.
The mass-volume ratio of the compound to the solvent is 1 (1-20), and the unit is g/mL. I.e., units of compound in g and solvent in mL.
Detailed description of the preferred embodiment
The present invention is described in more detail below with reference to examples, but the present invention is not limited thereto.
Example one
To a 500mL three-necked flask was added ethylene glycol dimethyl ether (150 mL) at room temperature and slowly added (+) - (Ipc) in portions2BH (6.2g), and compound I (15.0g, 102.04mmol) was added slowly further dropwise to the system, and the reaction was carried out for 2 h at 30 ℃. TLC monitors the reaction to be complete, hydrogen peroxide (3.46 g, 102.04mmol) and potassium hydroxide are slowly added dropwise, and the reaction is carried out for 2 h at room temperature after the addition is finished; TLC monitored the reaction complete and stopped the reaction. Extracting with anhydrous ether, extracting with chloroform, mixing extractive solutions, washing with saturated salt water to pH 8.0, and drying with anhydrous magnesium sulfate to obtain light yellow solid compound II 13.6g with yield of 90.67%.
Example two
Adding the compound II (10.0g, 60.97mmol), dimethyl sulfoxide (AR, 50 mL) and potassium hydroxide (17.0 g, 303.57 mmol) into a 250 mL three-necked flask in sequence, heating and stirring, controlling the temperature at 130 ℃ and stirring for 1h, dropwise adding the compound III (6.71 g, 60.97mmol) into the reaction system, continuing controlling the temperature at 130 ℃ to react, monitoring the completion of the reaction by TLC, and stopping the reaction. Cooling a reactant system to room temperature, adding 100ml of ethyl acetate and 100ml of water into the reaction system, fully stirring and standing to separate an organic phase, washing the organic phase twice with 200ml of water, drying the organic phase by using anhydrous sodium sulfate, performing suction filtration, collecting filtrate into a single-mouth bottle, adding 100ml of an ethyl acetate solution of oxalic acid (7.6 g, 84.44 mmol), performing suction filtration to collect a filter cake, performing forced air drying at 50 ℃ to obtain 19.0g of a white-like solid, dissolving the solid in 170ml of isopropanol, heating and refluxing for 1h, cooling to room temperature and performing suction filtration, and performing forced air drying on the filter cake at 50 ℃ to obtain 17.0g of a qualified product, wherein the yield is 89.51%.
Example three
Adding a compound IV (10.0g, 39.22mmol) into a 250 mL three-necked flask, adding acetone (100 mL), stirring for dissolving, controlling the temperature of the system to 70 ℃, introducing hydrogen chloride gas to adjust the pH of the system to be = 1-2, precipitating a large amount of precipitate, stirring for crystallizing, performing suction filtration, and drying a filter cake by blowing at 50 ℃ to obtain a compound V with the purity of 99.03%, the yield of 76% and white powder.
Claims (9)
1. A preparation method of tomoxetine hydrochloride is characterized by comprising the following steps:
step one, preparing an intermediate compound II from a compound I through addition and oxidation;
secondly, carrying out substitution reaction on the intermediate compound II and the compound III to obtain an intermediate compound IV;
salifying with hydrogen chloride gas in an organic solvent to obtain the tomoxetine hydrochloride, wherein the specific synthetic route is as follows:
2. the process for the synthesis of tomoxetine hydrochloride according to claim 1, wherein the step of performing the addition reaction and the oxidation reaction in the presence of a chiral catalyst, wherein the chiral catalyst in the addition reaction is (+) -diisopinocampheylboron [ (+) - (Ipc)2BH](ii) a The oxidant is H2O2(ii) a The alkali used is potassium hydroxide with low price.
3. The preparation method according to claim 2, wherein the reaction solvent in the first step is one or a mixture of any two of tetrahydrofuran, acetonitrile, methanol, DMF, diethyl ether, isopropyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether.
4. The process according to claim 1, wherein the reaction temperature in the first step is-20 to 30 ℃, preferably 25 to 30 ℃.
5. The preparation method according to claim 2, wherein the molar ratio of the chiral catalyst to the compound I is 0.01: 1-0.1: 1, preferably 0.02: 1.
6. The preparation method according to claim 1, wherein in the second step, the compound II is substituted with o-fluorotoluene (III) under basic conditions to form the compound IV, the base used is low-cost potassium hydroxide, and the reaction solvent can be one or a mixture of any two of N, N-dimethylformamide, dioxane, dimethyl sulfoxide, 1, 3-dimethyl imidazolidinone and N-methylpyrrolidone, preferably dimethyl sulfoxide.
7. The method according to claim 1, wherein the reaction temperature in the second step is 100-125 ℃.
8. The preparation method according to claim 1, wherein the solvent used for the step III salt formation is one of acetone, isopropanol or tetrahydrofuran; among them, acetone is preferred.
9. The preparation method according to claim 1, wherein the reaction temperature in the third step is 45-70 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811369723.3A CN111196760A (en) | 2018-11-17 | 2018-11-17 | Preparation method of tomoxetine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811369723.3A CN111196760A (en) | 2018-11-17 | 2018-11-17 | Preparation method of tomoxetine hydrochloride |
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| CN111196760A true CN111196760A (en) | 2020-05-26 |
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| CN201811369723.3A Pending CN111196760A (en) | 2018-11-17 | 2018-11-17 | Preparation method of tomoxetine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
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2018
- 2018-11-17 CN CN201811369723.3A patent/CN111196760A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527114A (en) * | 2021-06-15 | 2021-10-22 | 海南卓科制药有限公司 | Preparation method of tomoxetine hydrochloride |
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Application publication date: 20200526 |