CN101870670A

CN101870670A - A kind of synthetic method of cyclobutylamine-2-carboxylic acid

Info

Publication number: CN101870670A
Application number: CN 201010210785
Authority: CN
Inventors: 金建忠; 孙娜波; 常东亮; 张�杰
Original assignee: JIAXING INSTITUTE OF APPLIED CHEMISTRY AND ENGINEERING CHINESE ACADEMY OF SCIENCES; Zhejiang Shuren University
Current assignee: JIAXING INSTITUTE OF APPLIED CHEMISTRY AND ENGINEERING CHINESE ACADEMY OF SCIENCES; Zhejiang Shuren University
Priority date: 2010-06-28
Filing date: 2010-06-28
Publication date: 2010-10-27

Abstract

本发明涉及一种合成环丁胺-2-羧酸的新方法，其特征是以γ-丁内酯为原料，经过在红磷存在下溴代，然后同醇作用生成相应的酯，生成的酯同二苯基甲胺作用环合得到四元环合物，氢解开环，制备消旋的环丁胺-2-羧酸，过程污染小，纯化方便，操作简单。The present invention relates to a new method for synthesizing cyclobutylamine-2-carboxylic acid, which is characterized in that γ-butyrolactone is used as raw material, brominated in the presence of red phosphorus, and then reacted with alcohol to generate the corresponding ester. The ester is cyclized with diphenylmethylamine to obtain a four-membered ring compound, and the ring is opened by hydrogenolysis to prepare racemic cyclobutylamine-2-carboxylic acid. The process has little pollution, is easy to purify, and is simple to operate.

Description

A kind of synthetic method of cyclobutylamine-2-carboxylic acid

Technical field

The present invention relates to a kind of method of synthetic cyclobutylamine-2-carboxylic acid.

Background technology

L-(-)-cyclobutylamine-2-carboxylic acid is first the native annulus butylamine that exists in plant known to the mankind, though it distributes seldom at occurring in nature, its derivative is present in the different natural products, is very important active medical components.On structure, this compound is the analogue of proline(Pro), and as the amino acid of a non-protein source, it plays alternative proline(Pro) and participates in synthesizing of bacterioprotein, thereby has germicidal action widely.

L-(-)-cyclobutylamine-2-carboxylic acid is a kind of very important medicine intermediate, and present studies show that with this compound is the pharmaceutical prod such as antagonist, cathepsin K inhibitor of medicine, the VLA-4 of the intermediate inhibitor that can synthesize thrombin inhibitors Melagatran (Melagatran) and Exenta, angiotensin-converting enzyme, radiotherapeutic sensitizer, mammary cancer.

Foreign literature is more about the synthetic method report of cyclobutylamine-2-carboxylic acid, nineteen fifty-five Fowden (Nature, 1955,17:347-348) reported first get α-bromo-γ-An Jidingsuan by γ-An Jidingsuan through the α bromo-reaction, the latter handles cyclisation with hydrated barta and gets the cyclobutylamine-2-carboxylic acid of racemization, method is simple, but overall yield is not high; Yamada etc. (Agric Biol Chem, 1973,37 (3): 649-652) from butyrolactam, with methyl-sulfate handle after the NBS bromination again hydrolysis get α-bromo-γ-An Jidingsuan, get the cyclobutylamine-2-carboxylic acid of racemization at last with the hydrated barta cyclisation; (Bull Soc Chim Fr such as nineteen sixty-eight Pichat; 1968; 10:4079-4081) beta-propiolactone open loop, hydrogenation are obtained intermediate with potassium cyanide; protect with phthalic imidine then; bromo under the condition of red phosphorus again; obtain the 4-aminobutyric acid of bromo with the salt acid treatment, can obtain the cyclobutylamine-2-carboxylic acid of racemization at last through cyclization.

Existing synthetic method is complex steps not only, the operational requirement height, and also cost is very high, and the pollution in the reaction also is troubling problem, and none is fit to scale operation in the aforesaid method.Perhaps environmental pollution big (generation of a large amount of lacrimators) perhaps needs a large amount of silica gel and eluting solvent to come purified product, perhaps needs the oil pump of highest attainable vacuum to come refined product, perhaps reaction conditions is very harsh, perhaps complex operation, route is very long, can't realize industrialization.

Summary of the invention

The object of the present invention is to provide a kind of novel method of synthetic cyclobutylamine-2-carboxylic acid.

The present invention is raw material with the gamma-butyrolactone, through bromo esterification, cyclization, hydrogenolysis open loop, and the cyclobutylamine-2-carboxylic acid of preparation racemization, process is polluted little, and purifying is convenient, and is simple to operate.

A kind of synthetic novel method of the present invention to cyclobutylamine-2-carboxylic acid, form by following steps:

(1) from gamma-butyrolactone bromo under the condition of red phosphorus, generate corresponding ester with the alcohol effect then, wherein gamma-butyrolactone is represented with formula (1), 2,4-dibromo-butyric acid ester is represented with formula (2);

(2) 2,4-dibromo-butyric acid esters are with the effect of phenylbenzene methylamine, and cyclization obtains four-membered ring compound, N-diphenyl-methyl-2, and 4-dibromo cyclobutylamine-2-carboxylic acid ester is represented with formula (3);

(3) N-diphenyl-methyl-2,4-dibromo cyclobutylamine-2-carboxylic acid ester catalytic hydrogenolysis obtains the cyclobutylamine-2-carboxylic acid of racemization, and cyclobutylamine-2-carboxylic acid is represented with formula (4);

Alcohol in the described step (1) is methyl alcohol, ethanol, Virahol, the trimethyl carbinol.

Ring-closure reaction in the described step (2) is to have next time at acetonitrile, salt of wormwood that drip adds the phenylbenzene methylamine, dropping time 0.5～2h, return time 4～35h.

Hydrogenolysis operation in the described step (3) is with N-diphenyl-methyl-2, and 4-dibromo cyclobutylamine-2-carboxylic acid ester is dissolved in the methyl alcohol, the logical hydrogen stirring reaction of heating under the katalysis of catalyst P d-C; Described temperature is 80～120 ℃, and pressure is 0.5～5MPa, and the reaction times is 5～30h.The products therefrom cooling is filtered, and concentrating filter liquor is separated out white solid, filters, and gets cyclobutylamine-2-carboxylic acid.

The inventive method process is polluted little, and purifying is convenient, and is simple to operate.

Embodiment

Following examples are to further specify of the present invention, are not limitations of the present invention.

Embodiment 1

2, the preparation of 4-DIBROMOBUTYRATE

Add the 600g gamma-butyrolactone in reaction flask, red phosphorus 3g is heated to 110 ℃, dripping bromine 1130g, and control rate of addition holding temperature is at 115～120 ℃.When temperature of reaction descends, add red phosphorus 2g, continue to drip bromine, approximately 2h drips off.At 115 ℃ of degree reaction 1h, cool to room temperature is cooled to 0 ℃ of degree again, adds 240g refrigerated methyl alcohol, after adding, feeds anhydrous hydrogen chloride to saturated.Remove cryostat, stirring at room 8h.Take off layer, add the equal-volume ethyl acetate, with 5% yellow soda ash, saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates successively, and obtaining crude product is 1954g, and gas phase analysis content is 79%, and thick yield is 89%.

Embodiment 2

2, the preparation of 4-dibromo-butyric acid ethyl ester

Add the 600g gamma-butyrolactone in reaction flask, red phosphorus 3g is heated to 110 ℃, dripping bromine 1130g, and control rate of addition holding temperature is at 115～120 ℃.When temperature of reaction descends, add red phosphorus 2g, continue dripping bromine, approximately 2h drips off.At 115 ℃ of reaction 1h, cool to room temperature is cooled to 0 ℃ again, adds 360g refrigerated ethanol, after adding, feeds anhydrous hydrogen chloride to saturated.Remove cryostat, stirring at room 9h.Layer is taken off in layering, adds the equal-volume ethyl acetate, and with 5% yellow soda ash, saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates successively, and obtaining crude product is 1902g, and gas phase analysis content is 84%, and thick yield is 87%.

Embodiment 3

2, the preparation of the 4-dibromo-butyric acid tert-butyl ester

Add the 600g gamma-butyrolactone in reaction flask, red phosphorus 3g is heated to 110 ℃, drips bromine 1130g, and control rate of addition holding temperature is at 115～120 ℃.When temperature of reaction descends, add red phosphorus 2 grams, continue dripping bromine, approximately 2h drips off.At 115 ℃ of reaction 1h, cool to room temperature adds the 542g trimethyl carbinol, after adding, feeds anhydrous hydrogen chloride to saturated.Remove cryostat, stirring at room 10h.Layer is taken off in layering, adds the equal-volume ethyl acetate, and with 5% yellow soda ash, saturated sodium-chloride washing, anhydrous sodium sulfate drying concentrates successively, and obtaining crude product is 2401g, and gas phase analysis content is 73%, and thick yield is 82%.

Embodiment 4

N-diphenyl-methyl-2, the preparation of 4-dibromo ring butylamine acid methyl esters

Add 2 in the reaction flask, 4-DIBROMOBUTYRATE 1kg (crude product, content 79%), acetonitrile/water (900mL/36mL), salt of wormwood 500g, reflux together.Drip acetonitrile (400mL) solution of phenylbenzene methylamine 660g, about 1h drips complete, backflow 10h.Reaction finish to be filtered, and filtrate concentrates, and adds the 600mL ethyl acetate, uses 5% yellow soda ash successively, and water washing is to neutral, concentrate the about 910g of crude product, the gas phase content analysis is 63%, yield is 64%.

Embodiment 5

N-diphenyl-methyl-2, the preparation of 4-dibromo ring butylamine acetoacetic ester

Add dibromo-butyric acid ethyl ester 1kg (crude product) (content 84%), acetonitrile/water (900mL/36mL), salt of wormwood 500g, reflux together in the reaction flask.Drip acetonitrile (400mL) solution of phenylbenzene methylamine 660g, about 2h drips complete, backflow 12h.Reaction finish to be filtered, and filtrate concentrates, and adds the 600mL ethyl acetate, uses 5% yellow soda ash successively, and water washing is to neutral, concentrate the about 790g of crude product, gas phase analysis content 68%, yield are 56%.

Embodiment 5

N-diphenyl-methyl-2, the preparation of the 4-dibromo cyclobutylamine-2-carboxylic acid tert-butyl ester

Add dibromo-butyric acid tert-butyl ester 1kg (crude product) (content 73%), acetonitrile/water (900mL/36mL), salt of wormwood 398g, reflux together in the reaction flask.Drip acetonitrile (400mL) solution of phenylbenzene methylamine 528g.About 3h drips complete, backflow 15h.Reaction finish to be filtered, and filtrate concentrates, and adds the 600mL ethyl acetate, uses 5% yellow soda ash successively, and water washing is to neutral, concentrate the about 822g of crude product, gas phase analysis content is 54%, yield is 55%.Product is condensed into solid at low temperatures, and obtaining pure product behind the chloroform recrystallization is white solid, and fusing point is 58 ℃.

The preparation of embodiment 6 cyclobutylamine-2-carboxylic acids (4)

Diphenyl methyl azetidine-2-carboxylic acid tert-butyl ester of 10g is dissolved in the anhydrous methanol of 200mL, adds 1g 5% palladium carbon, charge into nitrogen once, hydrogen charges into three times, and adding pressure is 5MPa, elevated temperature to 100 ℃, and stirring velocity is 150 rev/mins.Reaction 10h, cooling is reacted to normal temperature.Get rid of hydrogen, charge into nitrogen once.Take out reaction solution, filter, concentration of reaction solution to original volume half, cool off, separate out the white solid 0.3g of first part, with 100mL water washing palladium carbon,, obtain solid with aqueous solution evaporate to dryness, then with adding 100mL ethanol, be stirred to solid and elute, filter, obtain second section white solid 2.4 grams from wall.Merge two portions solid, obtain 2.7 grams, yield is 90%.

Fusing point: product decomposes in beginning flavescence more than 210 ℃.

¹HNMR(500MHz，D ₂O)：δ4.52(t，J＝9.1，1H)，4.13-3.42(m，2H)，2.81-2.06(m，2H).

¹³C?NMR(500MHz，D ₂O)：175.8，65.2，47.3，26.5.

Anal.Calcd?for?C ₄H ₇NO ₂：C，47.52；H，6.98；N，13.86?Found：C，47.41；H，7.02；N，13.81.

Claims

1. A novel method for synthesizing cyclobutylamine-2-carboxylic acid, consisting of the following steps:

(1) Bromination of γ-butyrolactone under the condition of red phosphorus, and then react with alcohol to generate corresponding ester, wherein γ-butyrolactone is represented by formula (1), and 2,4-dibromobutyrate is represented by Formula (2) expresses;

(2) 2,4-dibromobutyrate reacts with diphenylmethylamine, and the ring is closed to obtain a four-membered ring compound, N-benzhydryl-2,4-dibromocyclobutylamine-2-carboxylic acid Esters are represented by formula (3);

(3) N-benzhydryl-2,4-dibromocyclobutylamine-2-carboxylate catalytic hydrogenolysis obtains racemic cyclobutylamine-2-carboxylic acid, and cyclobutylamine-2-carboxylic acid is Formula (4) represents;

2. according to a kind of novel method of synthesizing cyclobutylamine-2-carboxylic acid according to claim 1, it is characterized in that the alcohol of described step (1) is methanol, ethanol, Virahol, tert-butyl alcohol.

3. according to a kind of novel method of synthesizing cyclobutylamine-2-carboxylic acid according to claim 1, it is characterized in that the cyclization reaction in the described step (2) is to reflux and drop diphenyl diphenyl in the presence of acetonitrile and salt of wormwood For methylamine, the dropping time is 0.5~2h, and the reflux time is 4~35h.

4. according to a kind of new method of synthesizing cyclobutylamine-2-carboxylic acid according to claim 1, the hydrogenolysis reaction operation in the described step (3) is to use N-benzhydryl-2,4-dibromo Cyclobutylamine-2-carboxylate is dissolved in methanol, under the catalysis of the catalyst Pd-C, it is pressurized and heated to pass hydrogen and stirred for reaction; the temperature is 80-120°C, the pressure is 0.5-5MPa, and the reaction time is 5 to 30 hours; the resulting product was cooled, filtered, and the filtrate was concentrated to precipitate a white solid, which was filtered to obtain cyclobutylamine-2-carboxylic acid.