CN114736186B

CN114736186B - Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate

Info

Publication number: CN114736186B
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: 2023-08-08
Anticipated expiration: 2042-05-13
Also published as: CN114736186A

Abstract

The invention discloses a method for synthesizing a Violet Luo Zhongjian body from tert-butyl carbamate, and belongs to the field of medicine synthesis. The method takes 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin as a raw material to carry out substitution reaction with tert-butyl carbamate to obtain N- (2, 2-dimethyl-4H-1, 3-benzo dioxin-6-yl) -2-oxo ethyl) carbamic acid tert-butyl ester. The invention provides a synthesis method of an intermediate of velamerol, which uses cheap and easily available tert-butyl carbamate as a raw material, has mild synthesis reaction conditions and simple operation, shortens a synthesis route by synthesizing the velamerol from the intermediate, reduces production cost and is suitable for industrial production.

Description

Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate

Technical Field

The invention belongs to the field of medicine synthesis, and relates to a method for synthesizing a Violet Luo Zhongjian body from tert-butyl carbamate.

Background

Veland Luo San phenylacetate (Vilanterol trifenatate) is a long acting beta developed by the company Gladin Smith (GSK) ₂ Receptor agonists. The compound preparation of the medicine and the fluticasone furoate and the compound preparation of the medicine and the turnip bromide are approved by the FDA in 5 months and 12 months in 2013 respectively, and are used for treating obstructive pulmonary disease and asthma. Wherein, N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo ethyl) carbamic acid tert-butyl ester is a key intermediate for synthesizing the vilantro, CAS:452339-71-8, molecular formula: c (C) ₁₇ H ₂₃ NO ₅ Molecular weight: 321.37. the structural formulas of the vilanteol and the tert-butyl N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo-ethyl) carbamate are shown as follows:

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

Route one (WO 2003024439, CN 107188813): the 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin is taken as a raw material to undergo substitution reaction with bis (tert-butoxycarbonyl) amine under the action of cesium carbonate, and then a Boc protecting group on N is selectively removed under the action of trifluoroacetic acid to obtain N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo-ethyl) carbamic acid tert-butyl ester.

The route is an original research route developed by the Gelanin Smith pharmaceutical company, the total rate of two steps is only 48.6 percent, the price of bis (t-butoxycarbonyl) amine is expensive, and in the second step of reaction, trifluoroacetic acid can easily remove all two Bocs on N, the selectivity is poor, and the product purification is difficult.

Route two (CN 105646285, guangdong chemical. 2018,45 (05)): 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3]]The dioxin is used as a raw material to convert bromine into amino through a delbine reaction or a staudinger reaction, and then the amino is reacted with Boc ₂ O reacts to obtain N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo ethyl) carbamic acid tert-butyl ester, and the specific synthesis process is as follows:

the reaction route avoids the use of expensive bis (t-butoxycarbonyl) amine and the problem of poor selectivity of removing Boc protecting group from trifluoroacetic acid, but the reaction steps are too long, resulting in lower overall yield.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a method for synthesizing a Violet Luo Zhongjian body from tert-butyl carbamate, wherein the tert-butyl carbamate can be prepared by reacting tert-butyl alcohol with a benzene solution of trifluoroacetic acid in sodium cyanate, and the method is a large amount of chemical raw materials, and has the advantages of simple synthesis process, low price and easy obtainment. 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 preferably tetrahydrofuran; the alkali is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and lithium diisopropylamide, 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 N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo-ethyl) carbamic acid tert-butyl ester of the vilanabro intermediate by only one-step reaction, and the reaction yield is 83 percent.

(2) The use of expensive di (tert-butoxycarbonyl) amine is avoided, and the problem of poor selectivity of removing Boc protecting group from trifluoroacetic acid is avoided.

(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:

to a 5L three-necked flask, tert-butyl carbamate (225 g,1.1 eq) was added, 500mL of tetrahydrofuran was added and stirred to dissolve the tert-butyl carbamate, an LDA (960 mL,2mol/L,1.1 eq) solution was slowly added dropwise at-5-0℃to the flask, the flask was stirred at room temperature for 0.5H with heat preservation after the addition was completed, and then a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500 g,1.0 eq) and 1L of tetrahydrofuran was slowly added dropwise to the flask, and the flask was reacted at heat preservation for 2H after the addition was completed. After completion of the reaction under controlled conditions, the reaction mixture was concentrated, then saturated sodium hydrogencarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the solution was separated, the organic layer was washed with water (2L) and saturated brine (2L), respectively, 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, stirred at room temperature for crystallization, and 467g of a white powdery solid was obtained by filtration, the yield was 83%, and the purity was 99.1%.

Example 2:

to a 5L three-necked flask, tert-butyl carbamate (225 g,1.1 eq) was added, tetrahydrofuran (500 mL) was added and stirred to dissolve the mixture, a solution of potassium tert-butoxide (217 g,1.1 eq) was slowly added to the system at-5-0℃and stirred at a constant temperature for 0.5 hours after the addition was completed, and then a solution prepared from 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500 g,1.0 eq) and 1L tetrahydrofuran was slowly added dropwise to the reaction system, followed by a reaction at a constant temperature for 2 hours after the addition was completed. After completion of the reaction under controlled conditions, the reaction mixture was concentrated, then saturated sodium hydrogencarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the solution was separated, the organic layer was washed with water (2L) and saturated brine (2L), respectively, 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, and crystallization was carried out at room temperature with stirring, and filtration was carried out to obtain 456g of white powdery solid, yield 81%, purity 99.1%.

Example 3:

to a 5L three-necked flask, tert-butyl carbamate (225 g,1.1 eq) was added, tetrahydrofuran (500 mL) was added and stirred at room temperature, a solution of potassium tert-butoxide (217g, 1.1 eq) was slowly added at room temperature, stirred for 0.5H after the addition was completed, and then a solution of 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500 g,1.0 eq) and 1L tetrahydrofuran was slowly added dropwise to the reaction system, and the reaction was allowed to stand for 2H after the addition was completed. After completion of the reaction under controlled conditions, the reaction mixture was concentrated, then saturated sodium hydrogencarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the solution was separated, the organic layer was washed with water (2L) and saturated brine (2L), respectively, 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, stirred at room temperature for crystallization, and 433g of white powdery solid was obtained by filtration, with a yield of 77% and a purity of 97.3%.

Example 4:

to a 5L three-necked flask, tert-butyl carbamate (205 g,1.0 eq) was added, tetrahydrofuran (500 mL) was added and stirred at room temperature, a solution of potassium tert-butoxide (196 g,1.0 eq) was slowly added at room temperature, stirred for 0.5H after the addition was completed, and then a solution of 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (500 g,1.0 eq) and 1L tetrahydrofuran was slowly added dropwise to the reaction system, and the reaction was allowed to stand at a constant temperature for 2H after the addition was completed. After completion of the reaction under controlled conditions, the reaction mixture was concentrated, then saturated sodium hydrogencarbonate solution (2L) and ethyl acetate (2L) were added, the residue was dispersed with stirring, the solution was separated, the organic layer was washed with water (2L) and saturated brine (2L), respectively, 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, stirred at room temperature for crystallization, and 405g of white powdery solid was obtained by filtration, with a yield of 72% and a purity of 98.7%.

Example 5:

to a 5L three-necked flask was added cesium carbonate (66.54 g), acetonitrile (600 mL), 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin (58.4 g) and bis (t-butoxycarbonyl) amine (44.56 g), followed by mechanical stirring, room temperature reaction for 24 hours, dilution with water (1L), extraction with diethyl ether (1L), washing of the organic layer with brine (1L), drying, concentration to give a yellow solid, recrystallization in 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 24.4g in 28% yield.

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

While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.

Claims

1. A method for synthesizing a vilantro Luo Zhongjian body from tert-butyl carbamate takes 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 to perform substitution reaction in a solvent to obtain a vilantro intermediate N- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxo ethyl) tert-butyl carbamate, which comprises the following specific synthesis processes:

the solvent is tetrahydrofuran; the molar ratio of the 6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin to the tert-butyl carbamate is 1:1.1, the reaction temperature is-5-0 ℃, and the alkali is one of potassium tert-butoxide and lithium diisopropylamide.