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Preparation method of methyl 4-amino-2-(2-ethylamino)butyrate dihydrochloride

A technology of methyl butyrate and dihydrochloride, which is applied in the preparation of sulfonate esters, carboxylic acid esters/lactones, organic compounds, etc., can solve the problems of not being able to obtain the target product and affecting the yield, etc. Achieve the effect of good reaction selectivity, easy operation and easy control

Active Publication Date: 2017-09-05
CHEMSHUTTLE
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Problems solved by technology

[0002] Diamino acid compounds are very important pharmaceutical intermediates. The hydrolyzate 4-amino-2-(2-ethylamino) of the target compound is reported in the existing literature "Chemmedchem", 2008, 3(10): 1520-1524 Butyric acid dihydrochloride synthesis method, but it is found through experiments that there are shortcomings. The first step will have a by-product of Boc-ethylamine, which seriously affects the yield. The second step of hydrolysis and decarboxylation step is very easy to generate by-product 4-amino Butyric acid, the last methyl ester is easy to close the ring to form a lactam, and the target product cannot be obtained

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  • Preparation method of methyl 4-amino-2-(2-ethylamino)butyrate dihydrochloride

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Embodiment 1

[0024] A preparation method of 4-amino-2-(2-ethylamino) methyl butyrate dihydrochloride, comprising the steps:

[0025] (1) Preparation of 3-(2-bromoethyl)-dihydro-2(3H)-furanone

[0026] Add hydrobromic acid (1450g, 7.25mol, 6.6eq) into a 5-liter three-neck flask at room temperature, add tetrahydropyran-4-carboxylic acid (138.0g, 1.1mol, 1eq) under stirring, heat to 80°C and stir for 12h , TLC monitors raw material after reaction, adds 3000 milliliters of water to reaction solution and extracts with ethyl acetate three times (3 * 1000mL), combines organic layer, washes with water, washes with brine, sodium sulfate is dried, filters, and filtrate is spin-dried to obtain yellow oil 187 g was directly put into the next step without purification, and the HNMR purity was 95%.

[0027] 1 H NMR (400MHz, CDCl 3 )δ4.40(td, J=8.9,2.1Hz,1H),4.23(ddd,J=10.3,9.2,6.4Hz,1H),3.72–3.62(m,1H),3.49(ddd,J=10.3, 8.0, 5.6Hz, 1H), 2.91–2.75 (m, 1H), 2.47 (dddd, J=18.0, 8.1, 6.1, 3.0Hz, 2H), 2.0...

Embodiment 2

[0043] A preparation method of 4-amino-2-(2-ethylamino) methyl butyrate dihydrochloride, comprising the steps:

[0044] (1) Preparation of 3-(2-bromoethyl)-dihydro-2(3H)-furanone

[0045] Add hydrobromic acid (220g, 1.1mol, 1eq) to a 5-liter three-necked flask at room temperature, add tetrahydropyran-4-carboxylic acid (138.0g, 1.1mol, 1eq) under stirring, heat to reflux and stir for 6h, TLC After monitoring the reaction of raw materials, add 3000 milliliters of water to the reaction solution and extract three times with ethyl acetate (3 × 1000 mL), combine the organic layers, wash with water, wash with brine, dry over sodium sulfate, filter, spin the filtrate to obtain 190 g of yellow oil, It was directly put into the next step without purification, and the purity by HNMR was 95%.

[0046] 1 H NMR (400MHz, CDCl 3 )δ4.40(td, J=8.9,2.1Hz,1H),4.23(ddd,J=10.3,9.2,6.4Hz,1H),3.72–3.62(m,1H),3.49(ddd,J=10.3, 8.0, 5.6Hz, 1H), 2.91–2.75 (m, 1H), 2.47 (dddd, J=18.0, 8.1, 6.1, 3.0Hz,...

Embodiment 3

[0062] A preparation method of 4-amino-2-(2-ethylamino) methyl butyrate dihydrochloride, comprising the steps:

[0063] (1) Preparation of 3-(2-bromoethyl)-dihydro-2(3H)-furanone

[0064] Add hydrobromic acid (2200g, 11.0mol, 10eq) into a 5-liter three-neck flask at room temperature, add tetrahydropyran-4-carboxylic acid (138.0g, 1.1mol, 1eq) under stirring, heat to 50°C for 12h, TLC After monitoring the reaction of raw materials, add 3000 milliliters of water to the reaction solution and extract three times with ethyl acetate (3 × 1000 mL), combine the organic layers, wash with water, wash with brine, dry over sodium sulfate, filter, spin the filtrate to obtain 194 g of yellow oil, It was directly put into the next step without purification, and the purity by HNMR was 95%.

[0065] 1 H NMR (400MHz, CDCl 3 )δ4.40(td, J=8.9,2.1Hz,1H),4.23(ddd,J=10.3,9.2,6.4Hz,1H),3.72–3.62(m,1H),3.49(ddd,J=10.3, 8.0, 5.6Hz, 1H), 2.91–2.75 (m, 1H), 2.47 (dddd, J=18.0, 8.1, 6.1, 3.0Hz, 2H), 2...

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Abstract

The invention discloses a preparation method of methyl 4-amino-2-(2-ethylamino)butyrate dihydrochloride. The methyl 4-amino-2-(2-ethylamino)butyrate dihydrochloride is prepared from tetrahydropyran-4-carboxylic acid used as an initial raw material through a ring opening bromination lactone formation ring, a hydrolysis reaction, a Ts reaction on a hydroxyl group, a methyl esterification reaction, an azidation reaction and a hydrogenation reduction reaction. The process route is slightly long, but the yield of every step approaches a theoretic yield, and azide can be purified only through one step; and the preparation method also has the advantages of small polarity and easy purification of the azide, convenience in operation, mild and easily-controlled reaction conditions, and low cost.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method that uses tetrahydropyran-4-carboxylic acid as a raw material, undergoes ring-opening bromination to form lactone, hydrolysis, hydroxyl protection, methylation, azidation, A method for preparing methyl 4-amino-2-(2-ethylamino)butanoate dihydrochloride through a series of reactions such as hydrogenation reduction. Background technique [0002] Diamino acid compounds are very important pharmaceutical intermediates. The hydrolyzate 4-amino-2-(2-ethylamino) of the target compound is reported in the existing literature "Chemmedchem", 2008, 3(10): 1520-1524 Butyric acid dihydrochloride synthesis method, but it is found through experiments that there are shortcomings. The first step will have a by-product of Boc-ethylamine, which seriously affects the yield. The second step of hydrolysis and decarboxylation step is very easy to generate...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07C247/12C07C51/09C07C59/115C07C303/28C07C309/73C07C303/30C07C227/04C07C229/26
CPCC07C51/09C07C227/04C07C247/12C07C303/28C07C303/30C07D307/33C07C59/115C07C309/73C07C229/26
Inventor 赵亮
Owner CHEMSHUTTLE
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