CN114736186A

CN114736186A - Method for synthesizing vilanterol intermediate from tert-butyl carbamate

Info

Publication number: CN114736186A
Application number: CN202210524284.9A
Authority: CN
Inventors: 张启龙; 许坤; 张文成; 王红磊; 惠爱玲; 汪崇文
Original assignee: Anhui Dexinjia Biopharm Co ltd
Current assignee: Anhui Dexinjia Biopharm Co ltd
Priority date: 2022-05-13
Filing date: 2022-05-13
Publication date: 2022-07-12
Anticipated expiration: 2042-05-13
Also published as: CN114736186B

Abstract

The invention discloses a method for synthesizing a vilanterol intermediate from tert-butyl carbamate, belonging to the field of drug synthesis. The method takes 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin as a raw material to perform substitution reaction with tert-butyl carbamate to obtain N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) tert-butyl carbamate. The invention provides a synthetic method of a vilanterol intermediate, which uses cheap and easily available tert-butyl carbamate as a raw material, has mild synthetic reaction conditions and simple operation, shortens the synthetic route of vilanterol synthesized by the intermediate, reduces the production cost, and is suitable for industrial production.

Description

Method for synthesizing vilanterol intermediate from tert-butyl carbamate

Technical Field

The invention belongs to the field of drug synthesis, and relates to a method for synthesizing a vilanterol intermediate from tert-butyl carbamate.

Background

Vilanterol trihydronate is a long-acting beta developed by Kulanin Schker (GSK)₂A receptor agonist. Its compound preparation with furoic acid fluticasone and umeclidinium bromideThe compound preparation is approved by FDA in 5 months and 12 months in 2013 respectively, and is used for treating obstructive pulmonary disease and asthma. Wherein, the N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamic acid tert-butyl ester is a key intermediate for synthesizing vilanterol, CAS: 452339-71-8, formula: c₁₇H₂₃NO₅Molecular weight: 321.37. the structural formulae of vilanterol and tert-butyl N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamate are shown below:

currently, there are two main routes for the synthesis of tert-butyl N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamate.

Route one (WO2003024439, CN 107188813): 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin is taken as a raw material to carry out substitution reaction with bis (tert-butyloxycarbonyl) amine under the action of cesium carbonate, and then one Boc protecting group on N is selectively removed under the action of trifluoroacetic acid to obtain N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamic acid tert-butyl ester.

The route is an original research route developed by Kulansu Schke pharmaceutical company, the total rate of two steps is only 48.6%, bis (tert-butyloxycarbonyl) amine is expensive, and trifluoroacetic acid in the second step reaction can easily remove two Bocs on N, so that the selectivity is poor, and the product is difficult to purify.

Route two (CN105646285, guangdong chemical industry 2018,45 (05)): 6-Bromoacetyl-2, 2-dimethyl-4H-benzo [1,3]]Converting bromine into amino group by using dioxin as raw material through a Delbin reaction or a Staudinger reaction, and then reacting with Boc₂The N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamic acid tert-butyl ester is obtained by O reaction, and the specific synthesis process is as follows:

the reaction route avoids using expensive bis (tert-butyloxycarbonyl) amine and simultaneously avoids the problem of poor selectivity of trifluoroacetic acid for removing Boc protecting group, but the reaction step is too long, so that the total yield is low.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a method for synthesizing a vilanterol intermediate from tert-butyl carbamate, wherein the tert-butyl carbamate can be prepared by the reaction of tert-butyl alcohol and a benzene solution of trifluoroacetic acid in sodium cyanate, and is a large amount of chemical raw materials, simple in synthesis process, low in price and easy to obtain. The invention takes 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin as a raw material and tert-butyl carbamate, and adds strong base into a solvent at low temperature to carry out substitution reaction, and the technical scheme is as follows:

the solvent is one of acetonitrile, tetrahydrofuran, DMF, 1, 4-dioxane and N-methyl pyrrolidone, and tetrahydrofuran is preferred; the alkali is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and lithium diisopropylamide, and preferably lithium diisopropylamide; the molar ratio of the 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin serving as a raw material to the tert-butyl carbamate is 1: 1.1; the reaction temperature is-5-0 ℃.

The invention has the beneficial effects that:

(1) the invention can obtain the vilanterol intermediate N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamic acid tert-butyl ester by only one-step reaction, and the reaction yield is 83 percent.

(2) Avoids using expensive bis (tert-butyloxycarbonyl) amine and simultaneously avoids the problem of poor selectivity of trifluoroacetic acid for removing Boc protecting group.

(3) The invention shortens the synthetic route, has simple post-treatment, reduces the production cost and is suitable for industrial production.

Detailed Description

Example 1:

adding tert-butyl carbamate (225g, 1.1eq) into a 5L three-neck flask at room temperature, adding 500mL of tetrahydrofuran, stirring for dissolving, turning the system to-5-0 ℃, slowly and dropwise adding LDA (960mL, 2mol/L, 1.1eq) solution, keeping the temperature and stirring for 0.5H after the addition is finished, then slowly adding a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500g, 1.0eq) and 1L of tetrahydrofuran into the reaction system, and keeping the temperature and reacting for 2H after the addition is finished. After the neutralization reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was stirred and dispersed, the organic layer was separated, washed with water (2L) and saturated brine (2L), and then dried over anhydrous sodium sulfate, magnesium sulfate was removed by filtration, the solvent was removed by vacuum concentration, isopropyl ether (1L) was added, crystallized by stirring at room temperature, and filtered to obtain 467g of white powdery solid, yield 83%, purity 99.1%.

Example 2:

adding tert-butyl carbamate (225g, 1.1eq) into a 5L three-neck flask at room temperature, adding tetrahydrofuran (500mL) and stirring for dissolving, bringing the system to-5-0 ℃, slowly adding potassium tert-butoxide (217g, 1.1eq) solution, keeping the temperature and stirring for 0.5H after the addition is finished, then slowly adding a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500g, 1.0eq) and 1L tetrahydrofuran into the reaction system, and keeping the temperature and reacting for 2H after the addition is finished. After the reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the liquid was separated, the organic layer was washed with water (2L) and saturated brine (2L), and then dried over anhydrous sodium sulfate, magnesium sulfate was removed by filtration, the solvent was removed by vacuum concentration, isopropyl ether (1L) was added, crystallization was performed with stirring at room temperature, and the filtrate was filtered to obtain 456g of a white powdery solid with a yield of 81% and a purity of 99.1%.

Example 3:

adding tert-butyl carbamate (225g, 1.1eq) into a 5L three-neck flask at room temperature, adding tetrahydrofuran (500mL) and stirring for dissolving, slowly adding potassium tert-butoxide (217g, 1.1eq) solution at room temperature, stirring for 0.5H after the addition is finished, then slowly dropwise adding a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500g, 1.0eq) and 1L tetrahydrofuran into a reaction system, and preserving heat for 2H after the addition is finished. After the reaction was completed, the reaction solution was concentrated, then saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the liquid was separated, the organic layer was washed with water (2L) and saturated brine (2L), and then dried over anhydrous sodium sulfate, magnesium sulfate was removed by filtration, the solvent was removed by vacuum concentration, isopropyl ether (1L) was added, crystallization was performed with stirring at room temperature, and filtration gave 433g of white powdery solid, 77% yield and 97.3% purity.

Example 4:

adding tert-butyl carbamate (205g, 1.0eq) into a 5L three-neck flask at room temperature, adding tetrahydrofuran (500mL), stirring for dissolving, slowly adding a potassium tert-butoxide (196g, 1.0eq) solution at room temperature, stirring for 0.5H after adding, then slowly dropwise adding a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500g, 1.0eq) and 1L tetrahydrofuran into a reaction system, and preserving heat for reacting for 2H after adding. After the neutralization reaction was completed, the reaction solution was concentrated, then a saturated sodium bicarbonate solution (2L) and ethyl acetate (2L) were added, the residue was stirred and dispersed, liquid separation was performed, the organic layer was washed with water (2L) and a saturated saline solution (2L), and then dried with anhydrous sodium sulfate, magnesium sulfate was removed by filtration, the solvent was removed by vacuum concentration, isopropyl ether (1L) was added, crystallization was performed under stirring at room temperature, and a white powdery solid was obtained by filtration in a yield of 72% and a purity of 98.7%.

Example 5:

A5L three-necked flask was charged with cesium carbonate (66.54g), acetonitrile (600mL), 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxine (58.4g) and bis (t-butoxycarbonyl) amine (44.56g), reacted at room temperature for 24 hours with mechanical stirring, diluted with water (1L), extracted with diethyl ether (1L), and the organic layer was washed with brine (1L), dried, concentrated to give a yellow solid, and recrystallized from diethyl ether to give di- (t-butyl) 2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyliminodicarbonic acid as a white crystalline solid in 24.4g at 28% yield.

Trifluoroacetic acid (10.2mL) was added to a stirred solution of di- (tert-butyl) 2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyliminodicarbonate (46.37g) and dichloromethane (500mL) at 20 ℃ and stirred for 4 hours. Aqueous sodium hydroxide (0.5M, 400mL) was added to the reaction mixture, stirred for half an hour, and the solution was separated. The organic layer was washed with water (500mL), dried, concentrated, and recrystallized from ether to give 15.15g of tert-butyl N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamate in 43% yield.

Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims

1. A method for synthesizing a vilanterol intermediate from tert-butyl carbamate uses 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin as a raw material and tert-butyl carbamate, and adds strong base at low temperature in a solvent to carry out substitution reaction to obtain the vilanterol intermediate N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) tert-butyl carbamate, wherein the specific synthesis process is as follows:

2. the method for synthesizing vilanterol intermediate from tert-butyl carbamate according to claim 1, wherein the solvent is one of acetonitrile, tetrahydrofuran, DMF, 1, 4-dioxane, N-methylpyrrolidone.

3. The method for synthesizing vilanterol intermediate from tert-butyl carbamate according to claim 1, wherein the base is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide.

4. The method for synthesizing vilanterol intermediate from tert-butyl carbamate according to claim 1, wherein the molar ratio of 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxine to tert-butyl carbamate is 1: 1.1.

5. The method for synthesizing vilanterol intermediate from tert-butyl carbamate according to claim 1, wherein the reaction temperature is-5 to 0 ℃.