CN108341797B

CN108341797B - Synthesis method of duloxetine intermediate

Info

Publication number: CN108341797B
Application number: CN201710055513.6A
Authority: CN
Inventors: 和国栋; 张风
Original assignee: Chongqing Changjie Pharmaceutical Co ltd; Chongqing Shenghuaxi Pharmaceutical Co Ltd
Current assignee: Chongqing Changjie Pharmaceutical Co ltd; Chongqing Shenghuaxi Pharmaceutical Co Ltd
Priority date: 2017-01-25
Filing date: 2017-01-25
Publication date: 2021-04-27
Anticipated expiration: 2037-01-25
Also published as: CN108341797A

Abstract

The invention relates to a novel synthesis method of a duloxetine intermediate (S) -N-methyl-3-hydroxy-3- (2-thienyl) -1-propylamine (compound 1). The method uses thiophene and succinic acidTaking anhydride as a raw material, and obtaining a duloxetine intermediate (compound 1) through Friedel-crafts acylation, esterification, aminolysis, asymmetric hydrogenation and oxidative degradation.

Description

Synthesis method of duloxetine intermediate

Technical Field

The invention relates to a synthesis method of a duloxetine intermediate (compound 1), belonging to the field of pharmaceutical chemistry. Compound 1 has the structure:

。

background

Duloxetine (Duloxetine) is an antidepressant drug developed by the li-shi corporation, a 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI), and is marketed in the united states in 8 months in 2004. Duloxetine has the following structure:

。

duloxetine inhibits the reuptake of 5-hydroxytryptamine and norepinephrine by neurons, thereby increasing the concentration of both central neurotransmitters in the brain and spinal cord, and is useful for treating certain mood disorders such as depression and anxiety, and relieving central pain such as diabetic peripheral neuropathic pain and fibromyalgia in women. Duloxetine also acts on 5-hydroxytryptamine and norepinephrine receptors in the urinary tract to increase the nervous tone and contractile capacity of the urinary sphincter muscle, and is therefore also effective in treating stress urinary incontinence in women. Has huge market potential and is worthy of clinical and market attention.

Duloxetine and its preparation are described in us patents USP5023269 and USP 49565688 and also tetrahedron letters, 31, (49), 1990, 7101-. Seven different synthetic routes have also been reported in Drugs of the future 2000, 25 (9) 907-. These syntheses involve either the resolution of key intermediates or the stereospecific reduction of keto groups to alcohols.

(S) -N-methyl-3-hydroxy-3- (2-thienyl) -1-propylamine (Compound 1) is a key intermediate for the synthesis of duloxetine. Compound 1 has the structure:

。

at present, a chemical resolution method is mostly adopted, and CN1747947 adopts chiral acid as a resolving agent to prepare I, and the main defect is that chemical resolution can only obtain one enantiomer generally, so the theoretical yield of the chemical resolution is only 50% at most, the utilization rate of raw materials is low, at least half of isomers cannot be recycled, the cyclic utilization rate of compounds is low, and the requirements of green chemistry and atomic economy are not met.

Asymmetric synthesis is also found in the preparation of compound 1, CN101104614 uses chiral catalyst to reduce original carbonyl group to hydroxyl group asymmetrically, the main disadvantage is that the optical rotation value of the obtained chiral intermediate is low, the root is that the methylamino structure in the molecule has strong complexation effect on the chiral catalyst, the worldwide patent WO2008074858a1 and european patent EP1506965a1 respectively use different methods to derivatize methylamino group and then obtain good effect in asymmetric catalysis, but the process is tedious and has low industrial value due to multi-step conversion of functional groups.

Disclosure of Invention

The invention provides a preparation method of (S) -N-methyl-3-hydroxy-3- (2-thienyl) -1-propylamine (compound 1), which has the advantages of cheap raw materials, high yield, little environmental pollution and high product quality. The synthetic route is as follows:

。

the preparation method of the duloxetine chiral intermediate takes thiophene and succinic anhydride as raw materials, and obtains the duloxetine intermediate (compound 1) through Friedel-crafts acylation, esterification, ammonolysis, asymmetric hydrogenation and oxidative degradation, and specifically comprises the following steps:

step 1, succinic anhydride and thiophene are condensed to form a compound 2 under the action of aluminum trichloride, wherein the used solvent is inert halogenated hydrocarbon, preferably dichloromethane.

And 2, converting the compound 2 and alcohol into ester by the action of a catalyst, wherein the alcohol used is straight-chain or straight-chain alcohol with carbon number of 1-8, and the catalyst used is protonic acid or Lewis acid, preferably concentrated sulfuric acid.

And 3, aminolysis of the compound 3 and methylamine in a solvent-free or inert solvent to convert the compound into a compound 4, wherein the solvent is a straight-chain or straight-chain alcohol with 1-8 carbon atoms, preferably ethanol.

And 4, carrying out pressure hydrogenation on the compound 4 in a solvent and a hydrogen source under the co-catalysis of a metal catalyst and a phosphine-containing chiral ligand to obtain an optically pure compound 5, wherein the metal catalyst is a platinum group metal salt or a complex thereof, and 1, 5-cyclooctadiene rhodium chloride dimer is preferred. Wherein the phosphine-containing chiral ligand is tert-butyl Josiphos. And has the following structure:

。

and 5, degrading the compound 5 into the compound 1 in a solvent under the action of an oxidant, wherein the oxidant used is lead tetraacetate and bistrifluoroacetoxyiodobenzene, and the bistrifluoroacetoxyiodobenzene is preferred.

Compared with the prior art, the invention has the following beneficial effects: the method is simple and feasible, the prepared target product has high yield, the optical purity is as high as 99 percent, the purification difficulty is low, and the method is suitable for large-scale production research.

The present invention is further illustrated by the following examples, and various substitutions and combinations made according to the common knowledge and conventional means in the art are included in the scope of the present invention.

Detailed Description

The following chromatographic conditions were used in the present invention, and the raw materials used were all commercially available:

HPLC chromatography System A

HPLC chromatography System B

。

Example 1

Adding 24ml of thiophene, 30g of succinic anhydride and 200ml of dichloromethane into a 500ml three-necked bottle, stirring and cooling to 0-5 ℃, adding 36g of anhydrous aluminum trichloride in batches, stirring for 17 hours at room temperature after the addition is finished, pouring the reaction solution into 500ml of crushed ice, stirring for half an hour, separating an organic layer, washing the organic layer with 500ml of clear water, drying magnesium sulfate, evaporating to dryness, adding 200ml of isopropyl ether, stirring for crystallization, performing suction filtration, and performing forced air drying on the solid at 50-60 ℃ for 12 hours under normal pressure to obtain 44.7g of the solid with the yield of 81%.

Example 2

100g of Compound 2 (water content: less than 0.1%), 300ml of methanol and 10ml of concentrated sulfuric acid were added to a 500ml three-necked flask, and the mixture was refluxed for 12 hours. The reaction was stopped after less than 0.1% of compound 2 remained (chromatographic system a). After the reaction is finished, partial methanol is recovered by atmospheric distillation, the residue is cooled to room temperature, then 400ml of dichloromethane and 500ml of clear water are added, extraction and layering are carried out, an organic layer is washed once by 300ml of saturated sodium bicarbonate, a dichloromethane layer is dried and evaporated to dryness, 101g of yellow oily matter is obtained, and the yield of the yellow oily matter can be directly used for the next reaction, wherein the yield of the yellow oily matter is 94%.

Example 3

Adding the 100 compound 3 obtained in the previous step into a 500ml three-necked bottle, adding 350ml of methylamine ethanol solution and 1g of sodium ethoxide, heating to 40-50 ℃, keeping the temperature and reacting for 12 hours, stopping the reaction after less than 0.1% of the compound 3 remains (a chromatographic system A), distilling the reaction solution to dryness under reduced pressure, adding 300ml of isopropanol into the residue, precipitating a solid, cooling to 0-10 ℃, stirring for 5 hours, carrying out suction filtration, washing a filter cake with 50ml of isopropanol, and drying the solid by blowing at 50-60 ℃ under normal pressure for 12 hours to obtain 89g of the solid with the yield of 89.7%.

Example 4

60g of compound 4, 30mg of 1, 5-cyclooctadienerhodium chloride dimer and (R, S) tert-butyl Josiphos were added to a 1L stainless steel autoclave under nitrogen protection, 400ml of methanol was finally added, the autoclave was closed, the gas in the autoclave was replaced with nitrogen 3 times, and then the reaction was hydrogenated at 45 to 50 ℃ for 5 hours under a hydrogen pressure of 10kg, the reaction was monitored by HPLC, and the compound 4 remained less than 0.1%, and then the reaction was terminated (chromatography System A). Concentrating the reaction solution to dryness, adding 200ml of methyl tert-butyl ether into the residue, stirring at room temperature for 1 hour, performing suction filtration, washing the filter cake with 50ml of isopropanol, and performing forced air drying on the solid at the temperature of 50-60 ℃ for 12 hours under normal pressure to obtain 55g of solid, wherein the yield is 90.1%, the HPLC purity is more than 97%, and the optical purity is more than 98% ee (chromatographic system B).

Example 5

In a 500ml three-necked flask, 10g of the compound 5 solid and 40ml of acetonitrile were charged, and after dissolving and clearing by stirring, 40ml of water was added, bis-trifluoroacetyl iodobenzene was added and then the temperature of the reaction solution was raised to reflux for 4 hours, and the reaction was terminated after less than 0.1% of the compound 4 remained (chromatography system a). The reaction was poured into 400ml of ice water, the pH of the solution was adjusted to 8 to 9 with aqueous ammonia, 200ml of dichloromethane was added, the layers were separated by extraction, the dichloromethane layer was dried over magnesium sulfate, concentrated to dryness under reduced pressure, 90ml of n-hexane was added to the residue, crystal 3 was stirred at room temperature, the cake was washed with 20ml of n-hexane, and the solid was air-dried at 40 to 50 ℃ under normal pressure for 5 hours to give 4.8g of a solid in a yield of 56%, an HPLC purity of more than 96% and an optical purity of more than 99% ee (chromatography system B).

Claims

1. The synthesis method of the duloxetine intermediate compound 1 is structurally characterized in that the structural formula of the compound 1 is shown in the specification

(ii) a The method comprises the following steps:

1) under the action of aluminum trichloride, succinic anhydride and thiophene are condensed to form a compound 2, and the structural formula of the compound is as follows:

wherein the solvent is dichloromethane;

2) converting compound 2 and methanol into compound 3 by the action of a catalyst, wherein the structural formula of the compound is as follows:

therein is describedThe catalyst used is concentrated sulfuric acid;

3) aminolysis of compound 3 and methylamine in an inert solvent to convert compound 4, which has the structural formula:

wherein the solvent used is ethanol;

4) carrying out pressure hydrogenation on the compound 4 in a solvent and a hydrogen source under the common catalysis of a metal catalyst and a chiral ligand containing phosphine to obtain an optically pure compound 5, wherein the structural formula of the optically pure compound is as follows:

wherein the metal catalyst is 1, 5-cyclooctadiene rhodium chloride dimer, the phosphine chiral ligand is chiral tert-butyl Josiphos, and the structural formula of the tert-butyl Josiphos is shown in the specification

；

5) And degrading the compound 5 into a compound 1 in a solvent under the action of an oxidant, wherein the oxidant used is bis-trifluoroacetoxyiodobenzene.