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Synthetic method of dolutegravir key intermediate (R)-3-aminobutanol

A technology for the synthesis of aminobutanol, which is applied in the preparation of aminohydroxyl compounds, chemical instruments and methods, and the preparation of organic compounds, etc., which can solve the danger of using diazomethane, difficulty in obtaining R-alanine, and unsuitability for industrial production and other problems, to achieve the effect of improving optical purity, high product yield, and avoiding the use of dangerous raw materials

Inactive Publication Date: 2017-05-31
HENAN NORMAL UNIV
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Problems solved by technology

[0003] At present, the synthetic method of R-3-aminobutanol reported in the literature mainly contains the following several kinds: 1, obtain by direct ester reduction of chiral R-3-aminobutyrate, although this method has few steps, chiral The R-3-aminobutyric acid ester is difficult to obtain, and the price is expensive, the enantiomeric excess value (e.e. value) is not high, and the reduction yield is low, can't industrialized production; 2, with chiral R-alanine As the starting material, after being protected by the amino group, the carbon chain is extended by diazomethane to become a β-amino acid ester, and then deprotected to obtain the target product. The disadvantage of this method is that R-alanine with high chiral purity is difficult to obtain, and Diazomethane is dangerous to use and is not suitable for industrialized production; 3, taking crotonate as raw material and reacting with R-(+)-α-phenethylamine to generate a group of diastereoisomers with two chiral centers, through After separation by silica gel column chromatography, a single isomer is obtained, and then R-3-aminobutanol is obtained through ester reduction and debenzylation. This route has fewer steps and easy-to-obtain raw materials. It is a promising method for industrial production. However, there are still some problems. Since the e.e. value of the product obtained in the first step is close to 0, the loss in the splitting process is relatively large, and it is difficult to split. The method of column chromatography is used in the splitting process, which is not suitable for industrial production. LiAlH, which is expensive and dangerous to operate 4 As a reducing agent, it cannot be scaled up for production

Method used

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Experimental program
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Effect test

Embodiment 1

[0019]

[0020] Add R-(+)-α-phenylethylamine (400g, 3.3mol) and ethyl acetoacetate (476g, 3.66mol) to the reaction flask equipped with water separator and reflux condenser, then add toluene (700mL) , pass in argon gas for inert gas protection, gradually heat up to reflux reaction, as the reaction progresses, pay attention to observe the amount of water separated from the water separator, when it remains stable and no longer increases, the reaction is basically over, and it takes about 3 -5h, the reaction liquid is light yellow, TLC monitors (ethyl acetate:n-hexane=1:5, v / v) the raw material reacts completely, finally evaporates the toluene under reduced pressure at 50°C, and then evaporates the unreacted under reduced pressure at 90°C Complete ethyl acetoacetate, finally (1R,2R) and (1R,2S)-3-(1'-methylbenzylamine)-2-butenoic acid ethyl ester (compound 3,720g, yield 93.6%) .

Embodiment 2

[0022]

[0023] Double bond reduction: add NaBH to the reaction flask 4 (108g, 2.85mol) and methyl tert-butyl ether (MTBE, 2100mL), start stirring and cool down to -5°C, slowly drop compound 3 (300g, 1.29mol), control the reaction temperature at -5-0°C, After about 0.5h of dripping, keep the temperature and dropwise add 1500mL of methyl tert-butyl ether solution dissolved with 320g of pyridine hydrobromide, about 6h of dripping, after dripping, keep stirring for 0.5h, monitor by TLC (EA:PE=1: 5, v / v) The raw material reacts completely, then cool down to below -10°C and slowly add water dropwise. During the dripping process, gas is generated and the temperature rises. Control the dripping rhythm to keep the temperature not exceeding -10°C. After dripping water, add a certain amount of water. An appropriate amount of aqueous sodium hydroxide solution (mass concentration is 20%) makes the pH value of the reaction solution reach neutral, directly transfers to a separatory funne...

Embodiment 3

[0029]

[0030] Take compound 5 (52g, 0.19mol) and add it to a single-necked bottle, add water (100mL) and stir it into a paste, then slowly add potassium carbonate aqueous solution (mass concentration: 15%, 100g) dropwise, oily liquid gradually appears after the dropwise addition , then slowly add MTBE (100mL) to gradually dissolve the resulting oily liquid, and finally the reaction liquid is divided into two phases, the upper organic phase is separated, and anhydrous MgSO is added to the organic phase 4 (10 g) was dried and filtered with suction, and the filtrate was evaporated to remove the solvent to obtain free compound 5.

[0031] First add THF (90mL) into the reaction flask, pass through argon for inert gas protection, drop the temperature to 5°C and add NaBH 4 (21.5g, 0.51mol) and ZnCl 2 (34g, 0.25mol), then slowly add the free compound 5 dropwise, control the internal temperature at 5-10°C, drop it in about 2.5 hours, take a sample TLC to monitor the complete reac...

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Abstract

The invention discloses a synthetic method of dolutegravir key intermediate (R)-3-aminobutanol. The synthesis route is disclosed in the invention, and is suitable for industrialized large-scale production of (R)-3-aminobutanol; product optical purity is increased effectively; using of raw materials dangerous in operation is avoided; product yield is extremely high; and the synthetic method is suitable for industrialized popularization and application.

Description

technical field [0001] The invention belongs to the technical field of synthesis of dolutegravir, in particular to a method for synthesizing the key intermediate (R)-3-aminobutanol of dolutegravir. Background technique [0002] R-3-Aminobutanol is an important intermediate in the synthesis of the anti-AIDS integrase inhibitor Dolutegravir. Compared with the existing HIV integrase inhibitors Raltegravir and Evitagravir, the drug is safer Compared with Merck's anti-HIV / AIDS drug raltegravir, dolutegravir has not only achieved comparable efficacy in phase III clinical trials, but also does not need to be combined with drug accelerators. Very strong drug resistance properties, and the dosage is once a day. The quality and price of R-3-aminobutanol have a very important impact on the quality and production cost of dolutegravir. In addition, R-3-aminobutanol can also be derivatized into β-lactam, which can then be used to synthesize penem antibiotics. Therefore, the research on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C215/08
CPCC07C213/00C07C227/06C07C227/16C07C227/34C07C215/08C07C229/14
Inventor 李伟毛龙飞索华俊姜玉钦徐桂清
Owner HENAN NORMAL UNIV
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