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Tamiflu intermediate and synthesis method thereof

A synthetic method and intermediate technology, applied in the field of Tamiflu intermediate and its synthesis, can solve the problems of non-recyclable, high catalyst price, etc., and achieve the effects of good stereoselectivity, high target content and high yield

Inactive Publication Date: 2011-09-14
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The intermediate (12) is deprotected, acyl azidated, rearranged and Michael and other simple reactions to obtain the final product Tamiflu. This synthesis process is simple and the yield of the intermediate is high. It is an ideal Tamiflu intermediate Synthetic method, but the catalyst (8) is expensive and cannot be recycled, which has become the main obstacle to its low-cost industrial application

Method used

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  • Tamiflu intermediate and synthesis method thereof
  • Tamiflu intermediate and synthesis method thereof
  • Tamiflu intermediate and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: See the aforementioned comparative example 2 for the synthesis circuit.

[0032] Step 1): 25 °C, o-nitrobenzoic acid (38.6g, 0.231mol) and (R)-N,N-dimethylbenzylamine prolinol silyl ether (3) (25.4g, 0.058mol) Pre-stir for 30 minutes, add 3-pentoxyacetaldehyde (1) (225g, 1.73 mol) and 3-nitroacrylate (2) (168g, 1.16mol) in dichloromethane (2L) after salt formation After the reactants were stirred at 25 °C for 24 hours, the solvent was removed under reduced pressure, and the n-hexane (2L) was dissolved and filtered. The solids could be used for the catalytic reaction again, and the filtrate containing product (4) was directly used in the next reaction.

[0033] Step 2): Add 2-(diethoxy, phosphoryl) ethyl acrylate (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg, 3.47mol) to the filtrate at 0°C and keep it at 0°C Stir for 3h, remove the solvent under reduced pressure, add ethanol (3L) to the above crude product, and stir for 15min at 25°C.

[0034] Step 3): Add p-...

Embodiment 2

[0036] Embodiment 2: The synthesis circuit is as follows,

[0037]

[0038] Step 1): 25 °C, pre-stir chloroacetic acid (21.8g, 0.231mol) and (R)-N,N-dimethylbenzylamine prolinol (3) (25.4g, 0.058mol) for 30min After salt formation, add 3-pentoxyacetaldehyde (1) (225g, 1.73 mol) and 3-nitroacrylate ethyl (2) (168g, 1.16mol) in dichloromethane (2L) solution, the reactant After stirring for 40 min at 25 °C, the solvent was removed under reduced pressure, and the n-hexane (2L) was dissolved and filtered. The solids could be used for the catalytic reaction again, and the filtrate containing product (4) was directly used in the next reaction.

[0039] Step 2): Add 2-(diethoxy, phosphoryl) ethyl acrylate (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg, 3.47mol) to the filtrate at 0°C. Stir for 3h at C, remove the solvent under reduced pressure, add ethanol (3L) to the above crude product, and stir for 15min at 25°C.

[0040] Step 3): Add p-methylthiophenol (716.7g, 5.78mol) at -15°C an...

Embodiment 3

[0042] Embodiment 3: The synthesis circuit is as follows,

[0043]

[0044] Step 1): 25 °C, pre-stir chloroacetic acid (21.8g, 0.231mol) and (R)-N,N-dimethylbenzylamine prolinol (3) (35.1g, 0.058mol) for 30 Minutes, after salt formation, add 3-pentoxyacetaldehyde (1) (225g, 1.73 mol) and ethyl 3-nitroacrylate (2) (168g, 1.16mol) in dichloromethane (2L) solution, react After stirring for 40 minutes at 25 °C, the solvent was removed under reduced pressure. After dissolving in n-hexane (2L), it was filtered. The solids could be used for catalytic reaction again, and the filtrate containing product (4) was directly used in the next reaction.

[0045] Step 2): Add 2-(diethoxy, phosphoryl) ethyl acrylate (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg, 3.47mol) to the filtrate at 0°C and keep it at 0°C Stir for 3h, remove the solvent under reduced pressure, add ethanol (3L) to the above crude product, and stir for 15min at 25°C.

[0046] Step 3): Add p-methylthiophenol (716.7g, 5.78mo...

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Abstract

The invention relates to a Tamiflu intermediate and a synthesis method thereof, solving the technical problems of effectively reducing the production cost of the Tamiflu intermediate and effectively improving the yield of the Tamiflu intermediate and the content of the Tamiflu intermediate in a product. The method comprises the following steps: 1) catalytic reaction: in an organic solvent, reacting 3-pentyloxy acetaldehyde (1) and 3-nitro ethyl acrylate (2) in a molar ratio of 2: (1-2) in the presence of salt which is prepared by premixing (R)-N,N-dimethlbenzylamine prolinol silicon ether (3) with Bronzed acid in a molar ratio of 1: (1-8), so as to obtain an addition product (4); 2) carrying out reaction on the addition product (4) and 2-(diethoxy, phosphoryl) ethyl acrylate (5) in a molar ratio of 1: (1-2) and carrying out a reaction on cesium carbonate and the 2-(diethoxy, phosphoryl) ethyl acrylate (5) in a molar ratio of 2:1, so as to produce a produce (6); and 3) carrying out michael addition on the product (6) and p-methylthiophenol in a molar ratio of 1: (2-10), so as to obtain cyclohexane derivative, namely Tamiflu intermediate.

Description

Technical field [0001] The invention belongs to the technical field of chemical synthesis and synthesis of high-activity biological drug intermediates. Specifically, it is a Tamiflu intermediate and its synthesis method. Background technique [0002] In 2009, the H5N1 influenza virus raged around the world, and the hidden dangers of such viruses still exist. Oseltamivir phosphate (Tamiflu), as a neuraminidase inhibitor, can effectively treat human influenza A and B. Many The country plans to mass-produce this drug to prevent a pandemic. The development of such specific drugs and their intermediates has become a global research focus. [0003] Hayashi et al. (Angew.Chem.Int.Ed., 2009,48,1-5) reported in 2009 the use of (R)-diphenylprolinol silyl ether (8) to catalyze the synthesis of Tamiflu intermediates (12) Methods: [0004] [0005] The intermediate (12) is then subjected to simple reactions such as deprotection, acyl azide, rearrangement, and Michael to obtain the final produ...

Claims

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Application Information

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IPC IPC(8): C07C323/61C07C319/18
Inventor 徐利文史子惠来国桥沈浩蒋剑雄蒋可志邓元
Owner HANGZHOU NORMAL UNIVERSITY
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