Environment-friendly technology for preparing ketoleucine calcium in aqueous phase

A technology of calcium ketoleucine and green process is applied in the field of pharmaceutical synthesis, which can solve the problems of flammability and explosiveness, many reaction steps, long steps, etc., and achieves the effects of solving pollution problems, good product quality and few reaction steps.

Active Publication Date: 2014-09-24
SHAOXING MINSHENG PHARMA
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Problems solved by technology

[0003] According to literature reports, there are mainly the following methods for synthesizing calcium ketoleucine now: The first method: the Hein method, which is a relatively classic synthetic route, but the reagents used, raw materials, and the post-treatment process adopted are limited. The specific operation process is also different in the existing journal documents (Chemical Times, 2007, 21 (12): 5-8) and patent documents (CN101514154, CN102030631, US5565575, JP59199652, CN101607888), but there is a common Features: A large amount of organic solvents are used in the preparation of crude products, and organic solvents are also required in refining
The second method is to use dehydroamino acid as starting material, through amino protection, ester hydrolysis, cyclization, and ring-opening hydrolysis reaction to obtain ketoleucine (Bulletin of the Chemical Society of Japan.1980,53(10):2905 -2909;Chemical&pharmaceutical bulletin.1996,69(7),2079 -2090), this route has long steps, expensive reagents, and irritating and corrosive organic reagents such as acid chloride and tetrahydrofuran
The third method uses the erlenmeyer ring closure reaction method to synthesize key intermediates. Compared with the Heine method, the route is relatively novel, but due to the loss of more molecular weight during the hydrolysis process, it is not conducive to atom economy, and due to the use of a large amount of acetic anhydride , which is highly toxic, irritating, flammable and explosive, and will also cause great pollution to the environment
The fourth method is to use L-leucine as raw material to obtain ketoleucine through hydroxylation, esterification, oxidation and hydrolysis (Fine and Specialty Chemicals, 2009, 17(6): 27-29; organic preparations and procedures international,1989,21(1):75-82), this method uses a large amount of organic solvents, such as dichloromethane, ethyl acetate, ethanol, toluene, etc. for reaction and post-treatment, and also involves concentrated sulfuric acid , hydrogen peroxide and other dangerous reagents, there are many reaction steps, the cost is high, and it does not meet the requirements of green chemical development

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  • Environment-friendly technology for preparing ketoleucine calcium in aqueous phase

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Embodiment 1

[0035] Preparation of isobutylene hydantoin

[0036] Add 300kg of drinking water, 78kg of hydantoin, 5.0kg of 30% industrial liquid caustic soda and 9.0kg of monoethanolamine into the 1000L reactor. After the reaction solution was warmed up to be clear, 56 kg of isobutyraldehyde was slowly added dropwise to the reaction system. After dripping, keep refluxing for 8-12 hours, the reaction solution is cooled to room temperature, 36% hydrochloric acid is added dropwise to adjust the pH value to 5.0 (weakly acidic), after the addition, the reaction solution is slowly cooled to 8-10℃ And stir for 90 minutes. After the stirring, the material was filtered to obtain 123.6 kg of wet product. The wet product was dried to obtain 110.1 kg of isobutylene hydantoin, with a yield of 91.5%.

[0037] Preparation of ketoleucine calcium

[0038] Into the reactor, 240kg of drinking water and 267kg of 30% industrial liquid caustic soda were added in sequence. The reactor was replaced with vacuum nitro...

Embodiment 2

[0041] In the reactor, 220 kg of drinking water and 260 kg of 33% industrial liquid caustic soda were added in sequence. The reactor was replaced with vacuum nitrogen for three times and refluxed for 100 minutes under the protection of nitrogen. The temperature of the reaction liquid was lowered to 80°C, and 74.3 kg of isobutylene hydantoin was added to the reaction system. After adding, the temperature is raised to reflux, and the temperature is kept and refluxed for 90-100 minutes. Drop 76kg of 42% calcium chloride aqueous solution with mass concentration, keep stirring for 15min after adding, filter the material while it is hot, and collect the filtrate. The temperature of the filtrate was lowered to 55°C, 35% hydrochloric acid was added with a mass concentration, the pH value was adjusted to 2.0, and the vacuum nitrogen was replaced 2 to 3 times. Add 33% industrial liquid caustic soda to adjust the pH to 8.30 again. After cooling to 30°C, drop 89.2 kg of 42% calcium chlori...

Embodiment 3

[0044] Add 200kg of drinking water to the reaction kettle, and 260kg of 29% industrial liquid caustic soda with a mass concentration of 29%. The reaction kettle is replaced by vacuum nitrogen three times, and refluxed for 100min under nitrogen protection. After adding, heat up to reflux, keep reflux for 90-100min, add 81.8kg of 38% calcium chloride aqueous solution dropwise, keep and stir for 15min after adding, filter the material while it is hot, collect the filtrate; cool the filtrate to 50℃, slowly Add 34% hydrochloric acid with a mass concentration of hydrochloric acid to adjust the pH to 1.2, and vacuum nitrogen replacement for 2 to 3 times; add a mass concentration of 29% industrial liquid caustic soda to adjust the pH to 8.00, after cooling to 30°C, dropwise add a mass concentration of 38% chlorine 96kg of calcium chloride aqueous solution, after adding the heat preservation reaction for 60min, cooling to 8℃, keeping and stirring for 100min, filtering to obtain 76kg of c...

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Abstract

The invention relates to an environment-friendly technology for preparing ketoleucine calcium in an aqueous phase. Isobutylidene hydantoin and a calcium chloride aqueous solution serve as raw materials, and water serves as a solvent. The environment-friendly technology comprises the steps that heating reflux hydrolysis is carried out on the isobutylidene hydantoin in water and industrial liquid alkali, the calcium chloride aqueous solution is dropwise added, the mixed solution is filtered, filtered liquid is collected and cooled, hydrochloric acid acidification is carried out, vacuum nitrogen displacement is carried out, caustic soda liquid is added for alkalization, cooling is carried out, the calcium chloride aqueous solution is dropwise added, calcium salt is obtained, cooling is carried out, a crude product is obtained through filtering, the crude product is refined in purification water, and a ketoleucine calcium refined product is obtained. The environment-friendly technology for preparing the ketoleucine calcium in the aqueous phase has the advantages of being easy to operate, simple in steps, high in yield coefficient, good in product quality, environmentally friendly and the like. According to the environment-friendly technology for preparing the ketoleucine calcium in the aqueous phase, the environment-friendly water is adopted as the solvent completely, the requirement of green chemistry development is met, the pollution problem is solved from the source, and the environment-friendly technology is suitable for industrialized mass production.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a green process for preparing calcium ketoleucine in an aqueous phase. Background technique [0002] Ketoleucine calcium is a kind of α-keto acid salt. First of all, ketoleucine calcium is mainly used as an auxiliary drug to be effectively used in the treatment of urinary system diseases; secondly, α-keto acid and its derivatives have shown an increasingly broad application in food, daily chemicals and medicine. Application prospects: in food applications, it can be used as a component of sports nutrition drinks; in functional skin care cosmetics, it can play a good role in moisturizing, anti-wrinkle, anti-shrinking, anti-aging and anti-allergic effects; in medical applications, compound Alpha-keto acid tablets can be used as adjuvant drugs to treat the damage caused by chronic renal insufficiency, and can be used as a specific drug for the treatment of uremia. For...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/185C07C51/41C07C51/487C07C51/43C01F11/18
CPCC07C51/06C07C51/412C07C51/42C07C51/487C07D233/96C07C59/185
Inventor 邢亚军傅小明雷志新
Owner SHAOXING MINSHENG PHARMA
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