CN1532205A - Method for producing carnosine - Google Patents
Method for producing carnosine Download PDFInfo
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- CN1532205A CN1532205A CNA03117485XA CN03117485A CN1532205A CN 1532205 A CN1532205 A CN 1532205A CN A03117485X A CNA03117485X A CN A03117485XA CN 03117485 A CN03117485 A CN 03117485A CN 1532205 A CN1532205 A CN 1532205A
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- alanine
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- carbobenzoxy
- carnosine
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Abstract
The present invention relates to the production process of carnosine and belongs to the field of medicine chemical technology. The production process includes synthesizing N-carbobenzoxy-beta-alanine with beta-alanine, preparing the intermediate with the N-carbobenzoxy-beta-alanine, reacting the intermediate and histidine to obtain protective dipeptide, and hydrogenolyzing protective dipeptide to obtain carnosine. The production process features the intermediate N-carbobenzoxy-beta-alanine-N'-maloylimine ester, which is prepared through reaction of N-carbobenzoxy-beta-alanine, N-maloylimine and dicyclohexylcarbodiimide; the protective dipeptide, which is N-carbobenzoxy-beta-alanine histidine prepared with the intermediate and the mixture of histidine, ethyl aceate and inorganic alkali through reaction at pH 3-4; and the hydrogenolysis of the protective dipeptide and subsequent concentration and crystallization to obtain carnosine.
Description
Technical field
The present invention relates to a kind of production method of carnosine.Belong to field of medicine and chemical technology.
Background technology
The method of existing preparation carnosine mainly contains following several:
1. from the synthetic Z-β-Ala of β-Ala, generate N-carbobenzoxy-(Cbz)-β-alanyl hydrazine (N-Z-β-Ala-NHNH with the hydrazine reaction again
2), and then generate N-carbobenzoxy-(Cbz)-β-alanyl nitrine (Z-β-Ala-N with Sodium Nitrite reaction
3), then with L-Histidine methyl esters (L-His.OMe) react the protection dipeptides, get L-carnosine (L-Carnosine) (referring to R.H.Sifferd, etal., J.Biol.Chem.1935,108,753) through hydrolysis, hydrogenolysis.The deficiency of this route is intermediate Z-β-Ala-N
3Relate to the hydrazine compound of severe toxicity and explosive triazo-compound, production danger is bigger, to having relatively high expectations of production environment and equipment.
2. for overcoming above-mentioned shortcoming, there is scientist to propose, synthetic dihydro-1,3-thiazoles-2 from β-Ala, 4-diketone intermediate, further with His reaction, L-carnosine (L-Carnosine) (referring to F.J.Vinick et al., J.Org.Chem.1983,48 (3), 392).The shortcoming of this method is easily to produce polypeptide, and quality product is wayward, and poisonous sulfide causes serious environmental to pollute;
3. in addition; the somebody proposes following method: Beta-alanine is protected with tertbutyloxycarbonyl; get the tertbutyloxycarbonyl Beta-alanine; obtain N-tert-butoxycarbonyl--N '-maloyl imines ester (Boc-β-Ala.Osu) with succinyl hydroxyl imines (HOSu) reaction again; again with L-His react dipeptides, protecting group is gone in acidifying, transfers iso-electric point again; crystallization gets L-carnosine (L-Carnosine) (referring to T.I.Skoblik et al., RU2030422).The shortcoming of this method is that cost is higher, is not suitable for suitability for industrialized production.
Summary of the invention
The purpose of this invention is to provide a kind of easy to be reliable, steady quality, the method for the production carnosine that level of safety is high.
The production method of carnosine of the present invention comprises that (β-Ala) synthesizes N-carbobenzoxy-(Cbz)-Beta-alanine (N-Z-β-Ala) from Beta-alanine; make an intermediate by N-carbobenzoxy-(Cbz)-Beta-alanine again; intermediate and histidine reaction must be protected dipeptides; get carnosine (Carnosine) through hydrogenolysis; feature of the present invention is that described intermediate is by N-carbobenzoxy-(Cbz)-Beta-alanine and N-maloyl imines (HOSu); N-carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (intermediate of N-Z-β-Ala.OSu) is made in dicyclohexylcarbodiimide (DCC) reaction; this intermediate again with Histidine and water; ethyl acetate; the mixed solution of mineral alkali reacts; being protected under the pH=3-4 condition, (Z-β-Ala-His) is again at palladium/carbon (Pd/C) catalyst for dipeptides N-carbobenzoxy-(Cbz)-β-Bing Anxianzuansuan; pressure is to concentrate after the hydrogenolysis under the 0.5-2.5MPa condition; crystallization gets carnosine (Carnosine).
Present method utilizes N-maloyl imines to activate the carboxyl of N-carbobenzoxy-(Cbz)-Beta-alanine under the effect of dicyclohexylcarbodiimide, Acibenzolar intermediate N carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (N-Z-β-Ala.OSu) of excellent stability, this intermediate is difficult for decomposing under alkaline condition, and be easy to and amino reaction, racemization simultaneously seldom.Connect reactive polypeptide with this intermediate and amino acid, can not protect amino acid whose carboxyl, thereby shorten operational path; Do not use the Sodium Nitrite and the hydrazine of severe toxicity in the method, do not produced volatile triazo-compound in the process simultaneously, thereby the level of safety height.
Compare with class methods with aforementioned having now, advantage of the present invention is: method is easy, and technology is simple, and is workable; Starting material are cheap and easy to get, and cost is low; Environmental pollution is little.
Content of the present invention further illustrates with the following Examples, but content of the present invention is not limited only to content related among the embodiment.
Embodiment
Make in the usual way earlier N-carbobenzoxy-(Cbz)-Beta-alanine (N-Z-β-Ala):
1. add 40% sodium hydroxide (NaOH) solution 250L in the reactor, water 250L and β-Ala160kg, temperature is controlled at below 10 ℃, slowly drips chloroformic acid benzyl ester (Z-Cl) 307kg, and by dripping 40% sodium hydroxide (NaOH) simultaneously, control pH9-10.Stirring reaction 20 hours, the AcOEt extracting impurities, acidifying AcOEt extracted products, then with concentrating hydrochloric acidization to PH=2-3, ethyl acetate (AcOEt) 200kg * 3 extracted products, 50kg * 2 washing adds siccative anhydrous sodium sulphate (Na
2SO
4) drying, condensing crystal, N-carbobenzoxy-(Cbz)-Beta-alanine (364kg of N-Z-β-Ala),
Refabrication intermediate N carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (Z-β-Ala.OSu):
2. in reactor, add AcOEt 800kg, N-carbobenzoxy-(Cbz)-Beta-alanine (200 kg of N-Z-β-Ala), N-maloyl imines (HOSu) 94.4kg, be cooled to below 20 ℃, drip the solution of dicyclohexylcarbodiimide (DCC) 185Kg and ethyl acetate (AcOEt) 300kg, controlled temperature 20-30 ℃, 20 hours reaction times, leach dicyclohexylurea (DCU) (DCU), condensing crystal, N-carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (intermediate 287.6kg of Z-β-Ala.OSu)
3. in reactor, add entry 720kg, ethyl acetate (AcOEt) 400kg, anhydrous sodium carbonate (Na
2CO
3) 119kg, L-L-Histidine hydrochloride (L-His.HCl) 143.6kg; add intermediate N carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (Z-β-Ala.OSu) in the time of 35-40 ℃ in batches; reacted 20 hours; be acidified to pH=5, behind ethyl acetate (AcOEt) 100kg * 2 extracting impurities, transfer pH=3-4; be concentrated into dried; add the crystallization of ethanol (EtOH) desalination, must protect dipeptides N-carbobenzoxy-(Cbz) alanyl-L-Histidine (239.5kg of Z-β-Ala-L-His)
4. ((10%, w/w%) 4kg feeds H at normal temperatures for Z-β-Ala-L-His) 200kg, Pd/C to add gained protection dipeptides N-carbobenzoxy-(Cbz) alanyl-L-Histidine in entry 400kg, 95% ethanol EtOH 300kg, " 3. " in the hydrogenolysis still
2Hydrogenolysis is kept pressure 1.2MPa, and 15 hours time, filtering Pd/c then concentrates and is oily matter, and crystallisation by cooling gets L-carnosine (L-Carnosine) 113kg, yield 90%.Product appearance: off-white powder; Product purity: 99.6% (HPLC area normalization method); [α]
D 20:+22.0 ° of (c=1.0, H
2O); M.p.:246.0-251.7 ℃ (dec.).
L-L-Histidine hydrochloride among the embodiment also can be used instead and be the other forms of salt of L-Histidine or L-Histidine (as: L-Histidine acetate, L-Histidine vitriol etc.).
The synthetic route of D-carnosine (D-Carnosine), ratio of components, reaction conditions, yield are consistent with the L-carnosine, only use the other forms of salt of raw material D-His or D-His.HCl or its instead when three-step reaction and get final product.
Claims (1)
1; a kind of production method of carnosine; comprise that (β-Ala) synthesizes N-carbobenzoxy-(Cbz)-Beta-alanine (N-Z-β-Ala) from Beta-alanine; make an intermediate by N-carbobenzoxy-(Cbz)-Beta-alanine again; intermediate and histidine reaction must be protected dipeptides; get carnosine (Carnosine) through hydrogenolysis; it is characterized in that described intermediate is by N-carbobenzoxy-(Cbz)-Beta-alanine and N-maloyl imines (HOSu); N-carbobenzoxy-(Cbz)-Beta-alanine-N '-maloyl imines ester (intermediate of N-Z-β-Ala.OSu) is made in dicyclohexylcarbodiimide (DCC) reaction; this intermediate again with Histidine and water; ethyl acetate; the mixed solution of mineral alkali reacts; being protected under the pH=3-4 condition, (Z-β-Ala-His) is again at palladium/carbon (Pd/C) catalyst for dipeptides N-carbobenzoxy-(Cbz)-β-Bing Anxianzuansuan; pressure is to concentrate after the hydrogenolysis under the 0.5-2.5MPa condition; crystallization gets carnosine (Carnosine).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB03117485XA CN1318444C (en) | 2003-03-19 | 2003-03-19 | Method for producing carnosine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB03117485XA CN1318444C (en) | 2003-03-19 | 2003-03-19 | Method for producing carnosine |
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| Publication Number | Publication Date |
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| CN1532205A true CN1532205A (en) | 2004-09-29 |
| CN1318444C CN1318444C (en) | 2007-05-30 |
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|---|---|---|---|
| CNB03117485XA Expired - Fee Related CN1318444C (en) | 2003-03-19 | 2003-03-19 | Method for producing carnosine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100408566C (en) * | 2006-09-07 | 2008-08-06 | 重庆大学 | Method for preparing analogue of carnosine |
| CN100465285C (en) * | 2006-12-07 | 2009-03-04 | 伍曾利 | Method for extracting carnosine |
| CN105461632A (en) * | 2016-01-04 | 2016-04-06 | 湖北泓肽生物科技有限公司 | Preparing method for N-acetyl-L-carnosine |
| CN106083992A (en) * | 2016-06-17 | 2016-11-09 | 四川松麒医药科技有限公司 | Preparation method, product and the application of a kind of carnosine derivant |
| CN110835369A (en) * | 2019-12-02 | 2020-02-25 | 苏州天马医药集团天吉生物制药有限公司 | Method for synthesizing liraglutide |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2030422C1 (en) * | 1990-04-27 | 1995-03-10 | Фармацевтическое акционерное общество "Феррейн" | Method of synthesis of carnosine |
-
2003
- 2003-03-19 CN CNB03117485XA patent/CN1318444C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100408566C (en) * | 2006-09-07 | 2008-08-06 | 重庆大学 | Method for preparing analogue of carnosine |
| CN100465285C (en) * | 2006-12-07 | 2009-03-04 | 伍曾利 | Method for extracting carnosine |
| CN105461632A (en) * | 2016-01-04 | 2016-04-06 | 湖北泓肽生物科技有限公司 | Preparing method for N-acetyl-L-carnosine |
| CN105461632B (en) * | 2016-01-04 | 2018-01-09 | 湖北泓肽生物科技有限公司 | A kind of preparation method of N acetyl L carnosines |
| CN106083992A (en) * | 2016-06-17 | 2016-11-09 | 四川松麒医药科技有限公司 | Preparation method, product and the application of a kind of carnosine derivant |
| CN106083992B (en) * | 2016-06-17 | 2019-08-20 | 四川松麒医药科技有限公司 | A kind of preparation method, product and the application of carnosine derivative |
| CN110835369A (en) * | 2019-12-02 | 2020-02-25 | 苏州天马医药集团天吉生物制药有限公司 | Method for synthesizing liraglutide |
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|---|---|
| CN1318444C (en) | 2007-05-30 |
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Assignee: SICHUAN SHIFANG SANGAO BIOCHEMISTRY INDUSTRIAL CO., LTD. Assignor: Sichuan Sangao Biochemical Co., Ltd. Contract record no.: 2012510000021 Denomination of invention: Method for producing carnosine Granted publication date: 20070530 License type: Exclusive License Open date: 20040929 Record date: 20120401 |
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