CN114437022A - Preparation method of duloxetine intermediate - Google Patents

Abstract

The invention provides a preparation method of a duloxetine intermediate, which relates to the technical field of chemical synthesis. The invention includes the following steps: (1) 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide, After paraformaldehyde and dimethyl methanol are mixed, 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride is obtained; (2) 3-dimethylamino-1-(2 -Thienyl)-1-acetone hydrochloride is dissolved in methanol solution to obtain mixed solution 1, and sodium borohydride is added to carry out redox reaction to obtain (RS)-N,N-dimethyl-3-hydroxy-3-( 2-thienyl)propylamine; (3) Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in a mixture of toluene and methanol, add dropwise S-almond acid to give S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The present invention uses the phosphotungstic acid loaded with zirconia-titania as a catalyst, thereby accelerating the reaction speed, improving the reaction yield, and avoiding the generation of by-products.

Description

A kind of preparation method of duloxetine intermediate

technical field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a duloxetine intermediate.

Background technique

Duloxetine is an anti-anxiety, depressant, mainly norepinephrine and serotonin reuptake inhibitor, with dual channels, usually in the form of hydrochloride. Since duloxetine is unstable and easily degraded in an acidic environment, it is suitable to make duloxetine or its salt into an enteric preparation to resist the destruction of the drug by gastric juice.

The pharmacological mechanism of duloxetine hydrochloride is as follows: the exact mechanism of duloxetine hydrochloride antidepressant and central analgesic effect is not yet clear, but it is believed to be related to the enhancement of serotonergic and noradrenergic functions of the central nervous system. Preclinical studies have shown that duloxetine hydrochloride is a strong inhibitor of neuronal serotonin and norepinephrine reuptake, and has a relatively weak inhibitory effect on dopamine reuptake. The results of in vitro studies show that duloxetine hydrochloride has no significant affinity for dopaminergic receptors, adrenergic receptors, cholinergic receptors, histaminergic receptors, opioid receptors, glutamate receptors, and GABA receptors. . Duloxetine hydrochloride does not inhibit monoamine oxidase.

Published patent application number CN200710028364.0 discloses a preparation method of (S)-duloxetine key intermediate. The invention is based on 3-dimethylamino-1-(2-thienyl)- 1-Lactone hydrochloride as raw material, using chiral monosulfonyldiamide-ruthenium catalyst and formate as hydrogen source reagent, prepared (S) by asymmetric transfer hydrogenation in appropriate organic solvent -N,N-Dimethyl-3-hydroxy-3-(2-thienyl)propanamine hydrochloride. The method does not need nitrogen protection, has mild reaction conditions, simple operation, high reaction yield and enantioselectivity, and is expected to provide a simple and effective new method for the industrial production of (S)-duloxetine.

The preparation method of the duloxetine intermediate in the prior art has the advantages of long reaction time, cocoa reaction conditions, low yield and high cost.

SUMMARY OF THE INVENTION

In view of this, the present application provides a method for preparing a duloxetine intermediate, using 2-acetylthiophene as a raw material to prepare 3-dimethylamino 1-(2-thienyl)-1- Acetone hydrochloride, reduced by sodium borohydride to obtain (RS) N,N-monomethyl 3-hydroxy 3-(2-thienyl)propylamine, and then resolved with S-(+)-mandelic acid to obtain ( S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine. By using the phosphotungstic acid loaded with zirconia-titanium oxide as a catalyst, the reaction speed is accelerated, the raw materials are saved, the reaction time is shortened, the reaction yield is improved, and the generation of by-products can be avoided at the same time.

The present invention is a preparation method of a duloxetine intermediate, comprising the following steps;

(1) Mix 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide (as

；As a catalyst, its addition amount is 4-4.6% of 2-acetylthiophene), paraformaldehyde and dimethyl methanol (solvent) after mixing, the molar amount of paraformaldehyde is 1.4 times that of 2-acetylthiophene, stirring reaction 7 -8h, the molar ratio of 2-acetylthiophene and concentrated hydrochloric acid is 13-14:1, after quenching, suction filtration, washing and drying the filter cake to obtain 3-dimethylamino-1-(2-thienyl)-1 - Acetone hydrochloride, its structural formula is

;

In this step, under the environment of concentrated hydrochloric acid, 2-acetylthiophene and paraformaldehyde undergo Mannich reaction, and the reaction mechanism is shown below. Protonation of the carbonyl, nucleophilic addition of the amine to the carbonyl, deprotonation, electron transfer on the nitrogen, removal of water, and an imide ion intermediate can be obtained. The amount of hydrochloric acid added in this reaction determines the degree and speed of the Mannich reaction. In this application, the molar ratio of 2-acetylthiophene and concentrated hydrochloric acid is 13-14:1, which can well ensure the effective progress of the reaction and ensure the production of Rate.

The phosphotungstic acid supported by zirconia and titania is used as a catalyst, and zirconia and titania are particles with nanometer particle size. The supported catalyst is easy to separate the reaction liquid, expand the specific surface area of the catalyst, and improve the catalytic activity. The ratio of the number of surface atoms to the total number of atoms in nanoparticles increases dramatically with decreasing nanoparticle size. This surface effect makes nanomaterials have a large specific surface area. The huge specific surface area and severely mismatched bond energy lead to the appearance of many active centers, the increase of surface steps and roughness, and the appearance of non-chemical equilibrium and non-integer coordination valences on the surface. difference. Nanomaterials have a wide range of applications in the field of catalysis, and metallic nanoparticles as catalysts can greatly improve the catalytic effect. In this application, phosphotungstic acid is loaded with two kinds of nano-sized titanium oxide and zirconia, which can achieve the purpose of improving the catalytic effect. , such as P, Si, Fe, Note Co, etc.) and polyatoms (also known as coordination atoms, such as Mo, W, V, Nb, etc.) according to a certain structure through the coordination of oxygen atoms to form a type of oxygen-containing polyacid. Heteropolyacids have a definite structure. Heteropolyanions are primary structures. Heteropolyanions and counter cations form a secondary structure. The arrangement of heteropolyanions, counter cations and crystal water in three-dimensional space is a tertiary structure. Among traditional heteropolyacids, phosphotungstic acid has the highest acidity. Another important property of heteropolyacids is its unique "quasi-liquid phase" behavior. Due to its cage-like structure like zeolite, there are certain gaps between the heteropolyacid anions in the bulk phase, and some smaller polar molecules (such as water, alcohol, ammonia, pyridine, etc.) can enter the heteropolyacid. within the body. Therefore, the changes that occur on the surface of the heteropolyacid can rapidly spread everywhere in the bulk phase. In this way, in addition to surface catalysis, the solid heteropolyacid catalyst can also have the characteristics of homogeneous catalysis reaction like the concentrated sulfuric acid catalyst, which greatly enhances the catalytic ability of the heteropolyacid.

2-Acetylthiophene main use: used as solvent, extractant, pharmaceutical intermediate. In this application, 2-acetylthiophene is used as a raw material for the preparation of duloxetine intermediate (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine. The Mannich reaction of zirconium-titanium oxide phosphotungstic acid is used as a catalyst with paraformaldehyde.

(2) Dissolve 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride in methanol

The mixed solution 1 is obtained in the liquid, the pH value is adjusted to 11-12 with sodium hydroxide, sodium borohydride is added, and the redox reaction is carried out. Sodium has strong selective reducibility, a small amount of sodium borohydride can reduce nitrile to aldehyde, and excess amount can be reduced to amine. If the amount of sodium borohydride is small, impurity aldehydes will be generated. In this application, the molar ratio of 3-dimethylamino-1-(2-thienyl)-1-propanone hydrochloride and sodium borohydride is 10:6- 6.5, after the reaction is completed, add acetone to the reaction solution, evaporate the solvent under reduced pressure, then carry out suction filtration, drying, and recrystallization (using ethyl acetate, which is a commonly used substance in the organic purification process) to obtain (RS)-N, N-Dimethyl-3-hydroxy-3-(2-thienyl)propylamine;

3-Dimethylamino-1-(2-thienyl)-1-propanone hydrochloride generates amine through the reduction of sodium borohydride. During this reaction, the amount of sodium borohydride added will affect the generation of amine, and its production should be strictly controlled. The amount added can avoid the formation of by-products.

(3) Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in methyl

S-mandelic acid (chiral resolving agent) was added dropwise to the mixture of benzene and methanol, and reacted at 80-84 °C for 50-65 min to obtain a white solid (S-N,N-dimethyl-3-hydroxy-3-(2 -Thienyl)propylamine·S-(+)-mandelate), (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine, molar ratio of S-mandelic acid In a ratio of 1:1-1.2, the white solid was dissolved in water, extracted, washed and dried to obtain S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The extraction was as follows: After the white solid was dissolved in water, the pH value was adjusted to 11-12, extracted with ethyl acetate, and washed with saturated brine; S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine was used The methanol solution was purified by recrystallization. The structural formula of S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine is;

The main function of this step is to carry out chiral resolution, dissolving (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in a mixture of toluene and methanol, S- Mandelic acid races as a resolving agent. (RS)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)propylamine is racemic and optically resolved by diastereomeric salt formation.

The present invention adopts amine methylation reaction to prepare 3-dimethylamino 1-(2-thienyl)-1-acetone hydrochloride with 2-acetylthiophene as raw material, and is reduced by sodium borohydride to obtain (RS)N,N -Monomethyl 3-hydroxy 3-(2-thienyl)propylamine, and then resolved with S-(+)-mandelic acid to obtain (S)-(-)-N,N-dimethyl-3- Hydroxy-3-(2-thiophene)propylamine. By using the phosphotungstic acid loaded with zirconia-titanium oxide as a catalyst, the reaction speed is accelerated, the reaction time is shortened, and the reaction yield is improved.

Practical implementation

The present invention will be described in detail below with reference to specific embodiments.

Example 1

A preparation method of a duloxetine intermediate, comprising the following steps;

(1) Mix 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide (as

It is a catalyst, its addition amount is 4% of 2-acetylthiophene), paraformaldehyde and dimethyl methanol solvent are mixed, the molar amount of paraformaldehyde is 1.4 times that of 2-acetylthiophene, stirring reaction 7h, 2-acetylthiophene The molar ratio of thiophene and concentrated hydrochloric acid is 13:1. After quenching, suction filtration, washing and drying the filter cake to obtain 3-dimethylamino-1-(2-thienyl)-1-propanone hydrochloride;

(2) Dissolve 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride in methanol

The mixed solution 1 was obtained in the liquid, the pH value was adjusted to 11 with sodium hydroxide, sodium borohydride was added to carry out the redox reaction, the reaction time was 5h, the temperature of the redox reaction was 28 ℃, 3-dimethylamino-1 The molar ratio of -(2-thienyl)-1-acetone hydrochloride and sodium borohydride was 10:6. After the reaction was completed, acetone was added to the reaction solution, the solvent was evaporated under reduced pressure, and then suction filtration, drying, and weighting were carried out. Crystallization to obtain (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine;

(3) Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in methyl

S-mandelic acid was added dropwise to the mixture of benzene and methanol, and reacted at 80 °C for 50 min to obtain a white solid (S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine·S-(+) -mandelate), (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine, S-mandelic acid in a molar ratio of 1:1, add water to the white solid After dissolving, extracting, washing and drying to obtain S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. Extracted with ethyl acetate, washed with saturated brine; S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine was purified by recrystallization from methanol solution.

The calculated total yield of S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in this example is 67.6%.

Example 2

A preparation method of a duloxetine intermediate, comprising the following steps;

(1) Mix 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide (as

It is a catalyst whose addition amount is 4.6% of 2-acetylthiophene), paraformaldehyde and dimethyl methanol (solvent) after mixing, the molar amount of paraformaldehyde is 1.4 times that of 2-acetylthiophene, and the reaction is stirred for 8h, 2 -The molar ratio of acetylthiophene and concentrated hydrochloric acid is 14:1, after quenching, suction filtration, washing and drying the filter cake to obtain 3-dimethylamino-1-(2-thienyl)-1-propanone hydrochloride;

(2) Dissolve 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride in methanol

The mixed solution 1 was obtained in the liquid, the pH value was adjusted to 12 with sodium hydroxide, sodium borohydride was added to carry out the redox reaction, the reaction time was 6h, the temperature of the redox reaction was 32 °C, The molar ratio of -(2-thienyl)-1-acetone hydrochloride and sodium borohydride was 10:6.5. After the reaction was completed, acetone was added to the reaction solution, the solvent was evaporated under reduced pressure, and then suction filtration, drying, and weighting were carried out. Crystallization to obtain (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine;

(3) Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in methyl

S-mandelic acid was added dropwise to the mixture of benzene and methanol and reacted at 84°C for 65 min to obtain a white solid (the white solid was S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine·S- (+)-mandelate), (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine, S-mandelic acid in a molar ratio of 1: 1.2, the described The white solid is dissolved in water, extracted, washed and dried to obtain S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The extraction is as follows: after the white solid is dissolved in water, the pH value is adjusted. 12, extracted with ethyl acetate, washed with saturated brine; S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine was purified by recrystallization from methanol solution.

The calculated total yield of S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in this example is 66.2%.

Example 3

A preparation method of a duloxetine intermediate, comprising the following steps;

(1) Mix 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide (as

It is a catalyst, its addition amount is 4.3% of 2-acetylthiophene), paraformaldehyde and dimethyl methanol solvent are mixed, the molar amount of paraformaldehyde is 1.4 times that of 2-acetylthiophene, stirring reaction for 7.5h, 2- The molar ratio of acetylthiophene and concentrated hydrochloric acid is 13.5:1, after quenching, suction filtration, washing and drying the filter cake to obtain 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride;

(2) Dissolve 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride in methanol

The mixed solution 1 was obtained in the liquid, the pH value was adjusted to 11.5 with sodium hydroxide, sodium borohydride was added to carry out the redox reaction, the reaction time was 5.5h, the temperature of the redox reaction was 30 °C, The molar ratio of 1-(2-thienyl)-1-acetone hydrochloride and sodium borohydride was 10:6.3. After the reaction was completed, acetone was added to the reaction solution, the solvent was evaporated under reduced pressure, and then suction filtration, drying, Recrystallization (using ethyl acetate, a material commonly used in organic purifications) gave (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine;

(3) Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in methyl

S-mandelic acid was added dropwise to the mixture of benzene and methanol, and reacted at 83 °C for 55 min to obtain a white solid (S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine·S-(+) -mandelate), (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine, S-mandelic acid in a molar ratio of 1:1.1, add water to the white solid After dissolving, extracting, washing and drying to obtain S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. Extracted with ethyl acetate, washed with saturated brine; S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine was purified by recrystallization from methanol solution.

The calculated total yield of S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in this example is 65.3%.

The present invention adopts amine methylation reaction to prepare 3-dimethylamino 1-(2-thienyl)-1-acetone hydrochloride with 2-acetylthiophene as raw material, and is reduced by sodium borohydride to obtain (RS)N,N -Monomethyl 3-hydroxy 3-(2-thienyl)propylamine, and then resolved with S-(+)-mandelic acid to obtain (S)-(-)-N,N-dimethyl-3- Hydroxy-3-(2-thiophene)propylamine. By using the phosphotungstic acid loaded with zirconia-titanium oxide as a catalyst, the reaction speed is accelerated, the raw materials are saved, the reaction time is shortened, the reaction yield is improved, and the generation of by-products can be avoided at the same time.

Claims (9)

1. a preparation method of duloxetine intermediate, is characterized in that, comprises the following steps; After mixing 2-acetylthiophene, concentrated hydrochloric acid, phosphotungstic acid loaded with zirconia-titanium oxide, paraformaldehyde, and dimethyl methanol, the reaction was stirred for 7-8 hours, quenched and filtered with suction, and the filter cake was washed and dried to obtain 3-Dimethylamino-1-(2-thienyl)-1-propanone hydrochloride; Dissolve 3-dimethylamino-1-(2-thienyl)-1-acetone hydrochloride in methanol solution to obtain mixed solution 1, adjust the pH value to be basic, add sodium borohydride for redox reaction, and react After completion, add acetone to the reaction solution, remove the solvent, and then perform suction filtration, drying and recrystallization to obtain (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine; Dissolve (RS)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine in a mixture of toluene and methanol, then add S-mandelic acid dropwise, and react at 80-84°C for 50-65min , to obtain a white solid, which is dissolved in water, extracted, washed, and dried to obtain S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. 2. The preparation method of a duloxetine intermediate according to claim 1, wherein the 3-dimethylamino-1-(2-thienyl)-1-propanone described in step (2) The molar ratio of hydrochloride and sodium borohydride is 10:6-6.5. 3 . The method for preparing a duloxetine intermediate according to claim 1 , wherein the pH value of the mixed solution 1 in step (2) is 11-12. 4 . 4. the preparation method of a kind of duloxetine intermediate according to claim 3, is characterized in that, the time of described redox reaction is 5-6h. 5. The preparation method of a duloxetine intermediate according to claim 1, wherein step (3) further comprises adding S-N,N-dimethyl-3-hydroxy-3-(2-thiophene) base) propylamine was purified by recrystallization from methanol solution. 6 . The preparation method of a duloxetine intermediate according to claim 1 , wherein the molar ratio of 2-acetylthiophene and concentrated hydrochloric acid in step (1) is 13-14:1. 7 . 7 . The method for preparing a duloxetine intermediate according to claim 6 , wherein the molar amount of paraformaldehyde in step (1) is 1.4 times that of 2-acetylthiophene. 8 . 8. The preparation method of a duloxetine intermediate according to claim 1, wherein in step (3), (RS)-N,N-dimethyl-3-hydroxy-3-(2 The molar ratio of -thienyl)propylamine and S-mandelic acid is 1:1-1.2. 9. the preparation method of a kind of duloxetine intermediate according to claim 8, is characterized in that, described extraction is, after white solid is dissolved in water, adjust pH value to be 11-12, use ethyl acetate Extracted and washed with saturated brine.