CN103408497A - L-carnosine preparation method - Google Patents
L-carnosine preparation method Download PDFInfo
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- CN103408497A CN103408497A CN2013102989644A CN201310298964A CN103408497A CN 103408497 A CN103408497 A CN 103408497A CN 2013102989644 A CN2013102989644 A CN 2013102989644A CN 201310298964 A CN201310298964 A CN 201310298964A CN 103408497 A CN103408497 A CN 103408497A
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Abstract
The present invention discloses an L-carnosine preparation method, which is characterized in that N-BOC-beta-alanine and L-histidine methyl ester hydrochloride are subjected to an aminolysis reaction under strong base catalysis, and the acid is subjected to deprotection to obtain the product, wherein the total yield of the two-step process is up to 72-75%. The preparation method has characteristics of significant process shortening, simple operation, high yield, good purity, low cost and the like, and is a process suitable for industrial production.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of preparation method of N-BETA-Alanyl-L-histidine.
Background technology
N-BETA-Alanyl-L-histidine is comprised of Beta-alanine and L-Histidine, is a kind of natural active dipeptides, generally exists only in the mammalian organism tissue content 0.1～0.3%.N-BETA-Alanyl-L-histidine has the natural anti-oxidation effect, delays senility, and can also control the blood sugar for human body effect simultaneously, and its derivative L-carnosine zinc goes on the market as a kind of medicine of novel antiulcer agent class at present.Visible, N-BETA-Alanyl-L-histidine has good biological curative effect, and social required quantity is large, but the pure natural N-BETA-Alanyl-L-histidine can't satisfying the market supplies with, and research and development chemosynthesis N-BETA-Alanyl-L-histidine is significant.
The at present chemosynthesis of N-BETA-Alanyl-L-histidine mainly be take Beta-alanine and L-Histidine and is starting raw material, through amido protecting, activated carboxylic, formation peptide bond, deprotection, obtains product.(amino acid and Biological resources 2008 such as patent 200810024360.X and Chen Jianhui; 30 (1): 50-52) report is synthetic as follows: Beta-alanine forms phthalyl-Beta-alanine by Tetra hydro Phthalic anhydride; thereby protection is amino; carboxyl forms phthalyl-β-alanyl chloride by sulfur oxychloride; with the L-Histidine of trimethylchlorosilane protection, form peptide bond again; deprotection, obtain product again.This route yield is low, and during peptide bond formed, easily racemization, affected purity.
(the Shasad S such as Shasad S; Devid S; Michoel D T; Hans H L Coupling of functional hydrogen bonds in pyridoxal-5-phosphate-enzyme model systems observed by solid-state NMR spectosscopy ［ foreign language periodicals ］ 2007 (14)) report: chloroformic acid benzyl ester protection Beta-alanine; with N-hydroxy-succinamide activated carboxyl under the dicyclohexylcarbodiimide condensation; with L-Histidine, react again; hydrogenolysis, obtain N-BETA-Alanyl-L-histidine.This class methods yield is high, pollute little, but long reaction time, and need the hydrogenation deprotection, and the supplementary material cost is higher.
(the Zhang Qingyan such as patent 200910153641.X and Zhang Qingyan; The remaining water storehouse; Huo Cui sprouts synthetic ［ journal article ］-chemical engineering and the equipment 2010 (5) of zinc L-carnosine) report: L-Histidine and tetrahydrochysene-1,3-thiazoles-2,4-diketone open loop acidylate prepares N-BETA-Alanyl-L-histidine.Though this method step is few, yield still can, " three wastes " problem is difficult to resolve certainly, and cost is large, is difficult to industrialization.
(the Li Chunrong such as patent 201010102105.X and Li Chunrong; Permitted faithful and upright; The study on the synthesis ［ journal article ］ of Wang Hui natural antioxidants N-BETA-Alanyl-L-histidine-South China Normal University's journal (natural science edition) 2007 (2)) report: with L-Histidine and ethyl cyanacetate in sodium alkoxide condensation pyroreaction, synthetic N-cyanogen acetyl-L-Histidine, hydrogenation again, obtain N-BETA-Alanyl-L-histidine.This route reaction step is few, the agent that do not need protection, but the ethyl cyanacetate activity is not high, and yield is too low, only has 35%, pyroreaction, easily racemization.
Although the route of the synthetic N-BETA-Alanyl-L-histidine of report is a lot of at present, is difficult to scale operation more, obtains good income.Find one step be few, yield is high, the concrete significance of N-BETA-Alanyl-L-histidine synthetic method of easy industrialization, safety and environmental protection.
Summary of the invention
The object of the present invention is to provide that a kind of technique is simple, yield is good, the N-BETA-Alanyl-L-histidine synthetic route of safety and environmental protection.
The synthetic method of N-BETA-Alanyl-L-histidine of the present invention, is characterized in that N-BOC-Beta-alanine methyl ester hydrochloride and L-Histidine aminolysis reaction under highly basic catalysis, and sour deaminizating protection, obtain product, and two step overall yields are up to 72～75%.
Below N-BETA-Alanyl-L-histidine syntheti c route of the present invention is described in detail:
N-of the present invention (N-BOC-propionyl)-L-Histidine is prepared and is obtained by N-BOC-Beta-alanine methyl ester hydrochloride and L-Histidine, (1.1～1.2eq) at highly basic (under 1.2～1.5eq) catalysis for L-Histidine, highly basic has precedence over sodium alkoxide, sodium hydride, butyllithium etc., more preferably in sodium hydride, aprotic polar solvent comprises THF, DMF, DMSO etc., have precedence over DMSO, volume doubly measures 8～10, temperature of reaction has precedence over 60～150 ℃, more preferably in 120～125 ℃, reaction times has precedence over 3～7h, more preferably in 5～6h.
N-BETA-Alanyl-L-histidine of the present invention is prepared and is obtained by the de-BOC protection under acidic conditions of N-(N-BOC-propionyl)-L-Histidine, and the acid of employing comprises hydrochloric acid, Hydrogen bromide, trifluoroacetic acid etc., room temperature reaction 1.5～2.0h.
The advantage of technique of the present invention: with the Beta-alanine methyl ester hydrochloride of amino BOC protection under the highly basic effect with the L-Histidine aminolysis, more direct BOC deprotection, reduce the cyano group hydrogenating reduction with respect to current technique, obviously Cost reduction.
The accompanying drawing explanation
Accompanying drawing is N-BETA-Alanyl-L-histidine preparation method's of the present invention reaction scheme.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented take technical solution of the present invention under prerequisite, provided at length embodiment and process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
The preparation of N-(N-BOC-propionyl)-L-Histidine
To reactor, add L-Histidine 11～12Kg, N-BOC-Beta-alanine methyl ester hydrochloride 15.4Kg and DMSO80～100L, slowly add sodium ethylate 5.2～6.5Kg, be warming up to 120～125 ℃, reaction 5～6h, reaction finishes, and is cooled to 50 ℃, slowly add concentrated hydrochloric acid to adjust pH=2～3, then be evaporated to 12～15L, be cooled to room temperature, add 50～55L acetone, ice bath stirs, and separates out coarse-grain, filters, obtain crude product, weight yield 30～32Kg.
Embodiment 2
The preparation of N-(N-BOC-propionyl)-L-Histidine
To reactor, add L-Histidine 11～12Kg, N-BOC-Beta-alanine methyl ester hydrochloride 15.4Kg and DMSO80～100L, slowly add sodium hydride 1.9～2.1Kg, be warming up to 120～125 ℃, reaction 5～6h, reaction finishes, and is down to room temperature, slowly add concentrated hydrochloric acid to adjust pH=2～3, then be evaporated to 12～15L, then be cooled to room temperature, add 50～55L acetone, ice bath stirs, and separates out coarse-grain, filters, obtain crude product, weight yield 32～34Kg.
Embodiment 3
The preparation of N-BETA-Alanyl-L-histidine
To reactor, add N-(N-BOC-propionyl)-L-Histidine 30Kg, add formic acid 60～70L stirring and dissolving, the hydrochloric acid of 4mol/L/aqueous isopropanol 30L, room temperature reaction 1.5～2.0h, with rare sodium bicarbonate, adjust pH=7～8, add ethanol 20～25L, crystallize out, filter, the ether washing, dry, obtain product 26～29Kg, total recovery 72～75%.
Claims (7)
1. the preparation method of a N-BETA-Alanyl-L-histidine, its special character is, the N-BETA-Alanyl-L-histidine of described preparation is to take N-BOC-Beta-alanine methyl ester hydrochloride and L-Histidine to be starting raw material, under highly basic catalysis, reacts, then the protection of hydrochloric acid deaminizating, obtain N-BETA-Alanyl-L-histidine.
2. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1 is characterized in that: the catalyzer highly basic that the aminolysis reaction of the first step ester adopts comprises sodium alkoxide, sodium hydride, butyllithium etc., catalytic amount 1.2～1.5eq.
3. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1, it is characterized in that: the solvent of the aminolysis reaction of the first step ester is that aprotic polar solvent comprises THF, DMF, DMSO etc., and solvent volume doubly measures 8～10.
4. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1, is characterized in that: 120～125 ℃ of the temperature of the aminolysis reaction of the first step ester, reaction times 5～6h.
5. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1 is characterized in that: the acid that the protective reaction of second step deaminizating is adopted comprises hydrochloric acid, Hydrogen bromide, trifluoroacetic acid etc., room temperature reaction 1.5～2.0h.
6. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1, it is characterized in that: the protective reaction of second step deaminizating is room temperature reaction 1.5～2.0h.
7. the preparation method of N-BETA-Alanyl-L-histidine according to claim 1 is characterized in that: the synthetic N-BETA-Alanyl-L-histidine of totally two steps, and reaction conditions is easy, and process costs is low, and yield is higher, meets the preparation method of suitability for industrialized production.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565607A (en) * | 2016-10-11 | 2017-04-19 | 湖北泓肽生物科技有限公司 | Synthetic method of L-carnosine |
| CN106699668A (en) * | 2017-02-12 | 2017-05-24 | 江苏诚信药业有限公司 | Process system and method for preparing carnosine |
| JP2019135220A (en) * | 2018-02-05 | 2019-08-15 | 株式会社トクヤマ | Manufacturing method of l-carnosine and derivative thereof |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
| CN112300267A (en) * | 2019-07-30 | 2021-02-02 | 苏州鲲鹏生物技术有限公司 | Preparation and purification method of recombinant human insulin |
| CN112480206A (en) * | 2020-12-30 | 2021-03-12 | 音芙医药科技(上海)有限公司 | Efficient synthesis method of L-carnosine |
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| US4359416A (en) * | 1981-07-13 | 1982-11-16 | Pfizer Inc. | Process for preparing L-carnosine |
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| CN102250011A (en) * | 2011-06-08 | 2011-11-23 | 常熟富士莱医药化工有限公司 | Decoloration method in preparation of L-carnosine |
| CN102311390A (en) * | 2011-09-23 | 2012-01-11 | 常熟富士莱医药化工有限公司 | Preparation method for L-carnosine |
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2013
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Patent Citations (4)
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| US4359416A (en) * | 1981-07-13 | 1982-11-16 | Pfizer Inc. | Process for preparing L-carnosine |
| RU2030422C1 (en) * | 1990-04-27 | 1995-03-10 | Фармацевтическое акционерное общество "Феррейн" | Method of synthesis of carnosine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565607A (en) * | 2016-10-11 | 2017-04-19 | 湖北泓肽生物科技有限公司 | Synthetic method of L-carnosine |
| CN106565607B (en) * | 2016-10-11 | 2019-03-26 | 湖北泓肽生物科技有限公司 | A kind of synthetic method of N-BETA-Alanyl-L-histidine |
| CN106699668A (en) * | 2017-02-12 | 2017-05-24 | 江苏诚信药业有限公司 | Process system and method for preparing carnosine |
| JP2019135220A (en) * | 2018-02-05 | 2019-08-15 | 株式会社トクヤマ | Manufacturing method of l-carnosine and derivative thereof |
| CN111196837A (en) * | 2018-11-20 | 2020-05-26 | 皕达生物科技(上海)有限公司 | Preparation method of polaprezinc and polaprezinc preparation |
| CN111196837B (en) * | 2018-11-20 | 2023-07-28 | 皕达生物科技(上海)有限公司 | Preparation method of polyprenone and polyprenone preparation |
| CN112300267A (en) * | 2019-07-30 | 2021-02-02 | 苏州鲲鹏生物技术有限公司 | Preparation and purification method of recombinant human insulin |
| CN112480206A (en) * | 2020-12-30 | 2021-03-12 | 音芙医药科技(上海)有限公司 | Efficient synthesis method of L-carnosine |
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Application publication date: 20131127 |