Method of producing rimantadine

专利摘要:
A low temperature and pressure process for preparing rimantadine in high yields from 1-adamantyl methyl ketoxime is provided. The process comprises contacting a solution of the ketoxime with hydrogen in the presence of a platinum on carbon catalyst at a low temperature and pressure, e.g., room temperature and a pressure of about 25-115 psia (170-790 KPa) are preferred.
公开号:SU1327786A3
申请号:SU853915007
申请日:1985-05-21
公开日:1987-07-30
发明作者:Лию Джон-Ий-Хуа
申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
IPC主号:

专利说明:

11327786
This invention relates to an improved process for the preparation of riman-adin, a known antiviral agent, from 1-adamantyl methyl ketone
The aim of the invention is to increase the yield of the target product.
bo ho
Ro hell Pt you and 2, 2, For Ka Ka lo with respect to you in a row, then 25 days after another
Example KB A flask for hydrogenation according to Parr was charged with 0.35 g of 5% Pt / C, 1.9 g of 1-adamantylmethyl ketoxime, 230 ml of ethanol and 2.0 ml of cond. hydrochloric acid. The cramps are flushed with hydrogen, after which the hydrogenation reaction is initiated. The pressure was set at 2.34 atm at room temperature and reacted overnight. The catalyst was then removed by filtration and washed with 50 ml of ethanol. Collected solutions are distilled under vacuum. The residue (white solid) was dissolved in 70 ml of water and extracted twice with 50 ml of ether. The ether layer is discarded. The aqueous layer is basified to pH 10-13 with sodium hydroxide and extracted twice with 100 ml of ether. The ether layer is dried with sodium hydroxide and magnesium sulfate, which is then removed by filtration. The dried ether layer is then treated with hydrochloric gas to precipitate rimantadine hydrochloride. The solid is collected by filtration and dried to obtain 1.6 g of rimantadine hydrochloride (yield 75%).
Example 2: 8.0 g of 1-adamantylmethyl ketoxime, 200 ml of glacial acetic acid and 2.8 g of 5% Et / C are placed in a Parr hydrosolate flask. The hydrogenation process continues overnight at a pressure of 2.70 atm and room temperature. The catalyst is then removed by filtration and the acetic acid solution is concentrated to one third of the original volume by vacuum distillation. 200 ml of water is added to this solution, after which the solution is alkalinized with sodium hydroxide than a milky solution. The last three times extracted with methylene chloride (100 ml). The methylene chloride layers are dried with magnesium sulfate, which is then removed by filtration. The methylene chloride solution is distilled under vacuum to obtain 7.1 g of a clear liquid
five
0
Rimantadine free base (yield 96%).
Example 3. In a Parr hydrogenation flask, 13.7 g of 1-adamantylmethyl ketoxime, 4.0 g of 5% Pt / C and 200 ml of glacial acetic acid are placed. Then the flask is purged with hydrogen and continue to hydrogenate for 2.25 hours under a hydrogen pressure of 2.0-2.40 atm at room temperature. Then stop flushing the hydrogen, flushing the flask further. during the night. The catalyst is removed, and the acetic acid solution is distilled by vacuum; about one third of the initial volume is concentrated. 150 ml of water are added and the mixture is basified with sodium hydroxide to obtain a milky solution. This solution is extracted twice with methylene chloride (100 ml each). The methylene chloride solution is dried with magnesium sulfate, which is then removed 5 by filtration. The clear methylene chloride solution is treated with chlorine-hydrogen gas, and a white solid is formed. The mixture is treated with 100 ml of ethyl acetate, resulting in the formation of an additional amount of solid, which is collected by filtration. Only 11.4 g of rimantadine hydrochloride is obtained (yield 75%),
Example 4. A mixture consisting of 4.0 g of 5% Pt / C, 16.0 g of 1-adamantylmethyl ketoxime and 100 ml of glacial acetic acid was placed in a Parr hydrogenation flask. The mixture is then purged with hydrogen at 2.4 atm at room temperature. The hydrogenation process is continued overnight. The catalyst is filtered off, and the filtrate is concentrated to one third of the initial volume under vacuum (10-20. Mm). To this concentrated acetic acid solution was added 400 ml of ethyl acetate. Hydrochloric gas is bubbled through the ethyl acetate solution, in the code of which a white solid precipitates. This substance is collected by filtration to obtain 71.1. g of rimantadine hydrochloride (yield 96%).
Example 5. 50 parts by weight was charged to the hydrogenation reactor. 1-adamantylamine ketoxime, 288 weight,. H. glacial acetic acid and 14.3 parts by weight;
0
five
0
five
0
55
5% Pt / C catalyst. The whole system is purged three times with nitrogen and then purged with hydrogen. Hydrogenation is carried out for 10 hours at 20-34 ° C and under a hydrogen pressure of 6.52-9.49 atm with slow stirring.
The reaction system is purged with nitrogen and the catalyst is removed by filtration. Acetic acid solution is concentrated under vacuum by distillation 180 parts by weight acetic acid. The acetic acid concentrate is then diluted with 991 parts by weight. ethyl acetate. To this homogeneous solution, while slowly stirring, is added slowly. 10.46 weight.h. anhydrous hydrogen chloride. The resulting precipitate of rimantadine hydrochloride is collected by filtration. The white solid is washed with fresh ethyladetate and dried in a vacuum oven at 70-75 C. The weight of the dried product is 52.5 parts by weight. (yield 91%).
Example (comparative). 1- Adamantyl ketoxime (2.0 g) is dissolved in 200 ml of ethanol and mixed with 1.0 ml of conc. hydrochloric acid. This solution is poured into a flask for hydrogenation according to Parr. Then 1.0 g of PtOg is added. The process of hydrogenation under a pressure of 2.40 atm at room temperature is the compound of the Compounder L. Joffe
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Lenno After the period of hydrogenation (2 days), the catalyst is removed. The filtrate is distilled to dryness. 100 ml of water are added to the residue. The insoluble material is removed by filtration, and the aqueous layer is made alkaline with sodium hydroxide. The aqueous layer is extracted with ether, and the ether layer is separated and dried with potassium hydroxide tablets and then with magnesium sulfate. The resulting solution is distilled to remove the solvent. 1.0 g of rimantadine is obtained as a free base (yield: 54%).
I The proposed method allows to significantly increase the yield of the target product.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining rimantadine by reducing 1-adamantylmethyl ketoxime with hydrogen S in the presence of a platinum catalyst on coal under pressure in an acidic medium, characterized in that platinum is used as a platinum catalyst to increase the yield of the target product and the process is carried out at a temperature of 20-34 With and pressure of 2-9.5 atm.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US3352912A|1963-07-24|1967-11-14|Du Pont|Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes|

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JPS5581841A|1978-12-15|1980-06-20|Kao Corp|1-tricyclo 4.3.1.12,5 undecane|US5019482A|1987-08-12|1991-05-28|Asahi Kasei Kogyo Kabushiki Kaisha|Polymer/oxime ester/coumarin compound photosensitive composition|

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JP4625637B2|2002-02-22|2011-02-02|シャイアエルエルシー|Active substance delivery system and method for protecting and administering an active substance|

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EP2753320A1|2011-09-08|2014-07-16|Merz Pharma GmbH & Co. KGaA|Use of adamantane derivatives for the treatment of actinic keratosis|

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WO2017093354A1|2015-11-30|2017-06-08|INSERM |Nmdar antagonists for the treatment of diseases associated with angiogenesis|

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RU2635991C2|2016-03-18|2017-11-17|Открытое акционерное общество "Ирбитский химико-фармацевтический завод"|Method of producing rimantadine hydrochloride|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US06/613,374|US4551552A|1984-05-23|1984-05-23|Process for preparing rimantadine|

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