Method for synthesizing oseltamivir phosphate without using nitrine

A technology for oseltamivir phosphate and compounds, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid amides, etc., can solve the problem of severe reaction conditions for removing phosphonate groups, not particularly suitable for industrial production, and difficult to achieve. problems such as industrial production routes, to achieve the effects of high yield, convenient operation, and industrial production safety

Active Publication Date: 2013-09-18
GUANGZHOU TROJAN PHARMATEC LTD
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  • Abstract
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Problems solved by technology

[0007] In 2009, Roche published a route to synthesize oseltamivir phosphate from shikimic acid (see Angew. Chem. Int. Ed. 2009, 48 (31) , 5760-5762; US2009 / 0076296; CN101801914) Although the whole route is short, azide compounds are still used, and the reaction conditions for removing phosphonate groups are severe, so it is difficult to become a good industrial production route
[0008] Kim published another route to synthesize oseltamivir phosphate from shikimic acid in 2012 (Tetrahedron Lett. 2012, 53 (13), 1561-1563; ), also using dangerous chemical azide compounds, domestic Shi Xiaoxin et al published four routes for the synthesis of oseltamivir phosphate starting from shikimic acid, but the dangerous compound sodium azide is still used, which is not particularly suitable for industrial production

Method used

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  • Method for synthesizing oseltamivir phosphate without using nitrine
  • Method for synthesizing oseltamivir phosphate without using nitrine
  • Method for synthesizing oseltamivir phosphate without using nitrine

Examples

Experimental program
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Effect test

Embodiment 1

[0065] (3R, 4R, 5R)-4-hydroxy-3-(1-ethylpropoxy)-5-N-acetylamino-1-cyclohexene-1-carboxylic acid ethyl ester (Compound III):

[0066] Ethyl (3R, 4R, 5S)-4,5-epoxy-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (Compound II) (7.50g, 29.49 mmol ) Place in a flask, add 120 ml acetonitrile, stir at room temperature, slowly add boron trifluoride ether (6.27g, 44.18 mmol), stir at room temperature for 4 h, add 15 ml water, stir at room temperature for 3 h, neutralize with potassium carbonate After stirring at room temperature for 15 hours, adding 150 ml ethyl acetate and 120 ml water for extraction, the resulting organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate obtained was concentrated to obtain compound III (8.78g, 28.00mmol) with a yield of 95% .

[0067] The performance parameters and spectral data of the obtained compound III are as follows:

[0068] Mp 98.1-98.6 ℃. [α] D 25 = -171.0 ( c 2.0, CHCl 3 )

[0069] 1 H NM...

Embodiment 2

[0072] (3R, 4R, 5R)-4-Methanesulfonyloxy-3-(1-ethylpropoxy)-5-N-acetylamino-1-cyclohexene-1-carboxylic acid ethyl ester (Compound IV ) Preparation:

[0073] Put compound III (6.00 g, 19.14 mmol) in a flask, add 120 ml of ethyl acetate, stir under an ice bath, then add triethylamine (2.90 g, 28.7 mmol) and DMAP (0.23 g, 1.88 mmol), Methanesulfonyl chloride (3.29 g, 28.7 mmol) was slowly dropped into the reaction solution, reacted at 0°C for 0.5 h, 50 ml of water was added and stirred for 0.5 h, the organic layer was separated and washed once with 50 ml of water, and the obtained organic layer was dried with anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was evaporated under reduced pressure to obtain compound IV (7.10 g, 18.15 mmol) as a pale yellow oil with a yield of 95%.

[0074] The performance parameters and spectral data of the obtained compound IV are as follows:

[0075] [α] D 25 = -117.7 ( c 1.3, CHCl 3 ).

[0076] 1 H NMR (Acetone-d 6...

Embodiment 3

[0080] Preparation of (3R, 4R, 5R)-4, 5-N-acetylaziridine-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (compound V):

[0081] Put compound IV (3.00 g, 7.67 mmol) in a flask, then add 90 ml of N,N-dimethylformamide, stir under a water bath, add 60% sodium hydride (0.61 g, 15.31 mmol) in portions, and react 6. h, add 100 ml of dichloromethane, add 40 ml of water under ice bath, extract, and then wash the obtained organic layer with 40 ml of water, and dry the obtained organic layer with anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was evaporated under reduced pressure to obtain compound V (2.01 g, 6.81 mmol) as a pale yellow oil with a yield of 89%.

[0082] The performance parameters and spectral data of the obtained compound V are as follows:

[0083] [α] D 20 = –46.0 ( c 1.6, CHCl 3 ).

[0084] 1 H NMR (CDCl 3 ) δ 0.91 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.48-1.64 (m, 4H), 2.14 (s, 3...

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Abstract

The invention discloses a method for synthesizing oseltamivir phosphate without using nitrine. The method comprises the following steps of: sequentially performing an epoxy ring-opening reaction, a hydroxyl acylation reaction, an intramolecular substitution reaction for ring formation, a selective ring-opening reaction, a reaction for removing tertiary-butyl and a phosphoric acid salt forming reaction on a raw material namely (3R, 4R, 5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-ethyl ester carboxylate to obtain a product namely oseltamivir phosphate. The method is safe and high in efficiency and yield; compared with the prior art, the method has the biggest advantage that toxic explosive chemicals such as sodium azide and trimethyl-phosphine are not used, and is rich in raw material source and capable of performing large-scale production, so that the method can better meet requirements for strategic reserve of medicaments for preventing and treating bird flus by all human beings.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemicals, and relates to a preparation method of medicine, in particular to an azide-free method for synthesizing oseltamivir phosphate. Background technique [0002] The full chemical name of Oseltamivir phosphate is (3R, 4R, 5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1- Ethyl carboxylate phosphate is an effective drug for the prevention and treatment of bird flu. A few years ago, when bird flu brought harm to human society, it was the oseltamivir phosphate (trade name Tamiflu) jointly developed by Gilead Company of the United States and Roche Company of Switzerland, which made the bird flu that harmed humans The flu is under control. Afterwards, many countries listed oseltamivir phosphate as a national strategic reserve drug in case of emergency. Oseltamivir phosphate is a neuraminidase inhibitor, and its drug design can be found in: Nature.1993, 363, 418; WO91 / 16320; ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/52C07C231/12
Inventor 郑庆泉黄爱珉
Owner GUANGZHOU TROJAN PHARMATEC LTD
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