CN103193712B - A kind of preparation method of N-BETA-Alanyl-L-histidine - Google Patents
A kind of preparation method of N-BETA-Alanyl-L-histidine Download PDFInfo
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- CN103193712B CN103193712B CN201210002213.9A CN201210002213A CN103193712B CN 103193712 B CN103193712 B CN 103193712B CN 201210002213 A CN201210002213 A CN 201210002213A CN 103193712 B CN103193712 B CN 103193712B
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Abstract
The present invention relates to a kind of preparation method of N-BETA-Alanyl-L-histidine, comprise by phthalyl-N-BETA-Alanyl-L-histidine and organic amine in a solvent reacting by heating slough protecting group, after separating out product, filter, solvent wash, drying, obtain N-BETA-Alanyl-L-histidine product; Or through concentrated, crystallization, filtration and drying, obtain without hydrazine N-BETA-Alanyl-L-histidine product.Its advantage is that method is easy, and cost is low, workable, does not have toxic compounds hydrazine in gained carnosine product, the quality of product is fully ensured and embodies the security of product to health.
Description
Technical field
The invention belongs to organic compound preparation technical field, be specifically related to a kind of preparation method of N-BETA-Alanyl-L-histidine.
Background technology
N-BETA-Alanyl-L-histidine (English name: L-Carnosine, by Russian scientists Gulewitsh and Amiradzibi in 1900 year first in beef detected No. CAS: 305-84-0), mammiferous brain, muscle and other have in the tissue of Substance P and extensively exist, its concentration is approximately 1-20mmol.L in animal body
-1, the content especially in chicken-breasted is high especially.In vivo, it utilizes Beta-alanine and L-Histidine to synthesize by carnosine synthetase, chemistry β-alanyl-L-histidin by name, and its chemical structural formula is as follows:
N-BETA-Alanyl-L-histidine can participate in and regulate the various physiological activities of human body; there is fabulous natural anti-oxidation, scavenging free radicals, act on transition metal chelate, neuroprotective, promotion wound healing and anti-ageing waiting for a long time; and have result for the treatment of to the healing etc. of hypertension, heart trouble, senile cataract, ulcer, so be with a wide range of applications in fields such as medicine, health care, health.
At present; the chemical synthesis process of N-BETA-Alanyl-L-histidine is mainly first by protecting the amino in Beta-alanine with Tetra hydro Phthalic anhydride; be obtained by reacting phthalyl Beta-alanine; intermediate phthalyl-N-BETA-Alanyl-L-histidine is obtained again with L-Histidine condensation; this intermediate hydrazine hydrate sloughs protecting group through hydrazinolysis reaction; again through decolouring, concentrated, crystallization, filtration and drying, obtain product N-BETA-Alanyl-L-histidine.Typical bibliographical information such as publication number is the patent of CN101117334A (novel method of synthesis N-BETA-Alanyl-L-histidine) and CN101284862A (synthetic method of N-BETA-Alanyl-L-histidine), and the non-patent literature (study on the synthesis of N-BETA-Alanyl-L-histidine, Chen Jianhui, Wu Zhigang, build clearly, amino acid and Biological resources, 2008,30,50-52) etc.
Aforesaid method has raw material and is easy to get, and operational path is shorter, and total recovery is advantages of higher comparatively, but, owing to employing hydrazine hydrate in process of production, cause in N-BETA-Alanyl-L-histidine product, have certain hydrazine to remain (about 20ppm).
As the industry is well known, hydrazine belongs to hypertoxic type chemical, has larger harm to HUMAN HEALTH, and the mode entering human body can by sucking, eating and through approach such as skin absorptions, make people occur dizziness, feel sick and make the toxicity symptoms such as central nervous system stimulant.In addition, hydrazine is also considered to a kind of suspect carcinogen.Therefore, how effectively reducing and even the hydrazine removed in N-BETA-Alanyl-L-histidine product remains completely, is that industry is paid close attention to for a long time and thirsts for the technical problem of solution all the time.But, up to now, in published China and foreign countries patent and non-patent literature, all do not have corresponding technology to enlighten prepares without hydrazine carnosine, for this reason, the applicant is through repeatedly exploring, have found the method for dealing with problems, on the basis keeping main flow technology of preparing, phthaloyl is removed by utilizing the deprotecting regent of other non-hydrazines, the source of hydrazine is removed from source, by the detection to the finished product N-BETA-Alanyl-L-histidine product adopting this technology to obtain, prove that the method is completely effective, the hydrazinolysis legal system thoroughly solving current main flow remains a difficult problem for hydrazine in the product of N-BETA-Alanyl-L-histidine, technical scheme described below produces under this background.
Summary of the invention
The problem to be solved in the present invention is to provide a kind of preparation method without hydrazine N-BETA-Alanyl-L-histidine not having hydrazine to remain completely, and nationality is to ensure product quality and to embody N-BETA-Alanyl-L-histidine product to the security of HUMAN HEALTH.
The invention provides the preparation method of following a kind of N-BETA-Alanyl-L-histidine: by phthalyl-N-BETA-Alanyl-L-histidine and organic amine in a solvent reacting by heating slough protecting group and be obtained by reacting N-BETA-Alanyl-L-histidine.The method can further include: through filtration, organic solvent washing, drying after the N-BETA-Alanyl-L-histidine product precipitation obtained after reaction, obtain N-BETA-Alanyl-L-histidine product.Or the method can further include: the N-BETA-Alanyl-L-histidine product obtained after reaction, through concentrated, crystallization, filtration and drying, obtains N-BETA-Alanyl-L-histidine product.
The N-BETA-Alanyl-L-histidine that above-mentioned preparation method of the present invention obtains is without hydrazine N-BETA-Alanyl-L-histidine.
Phthalyl-N-BETA-Alanyl-L-histidine of the present invention has following structural formula:
Described organic amine is recommended as the straight or branched organic amine of 1 to 4 carbon atom, the primary amines (primary amine) such as such as methylamine, ethamine, propylamine, butylamine.
Described organic amine amount is equivalent or excessive, and the mol ratio of such as phthalyl-N-BETA-Alanyl-L-histidine and organic amine is 1: (1 ~ 4).
The described reaction times of sloughing protecting group is recommended as 1 ~ 3 hour.
Described solvent is at least one in water or organic solvent, and described organic solvent is selected from C
1~ C
6alcohol, C
2~ C
6ketone, acetonitrile, at least one in tetrahydrofuran (THF) (THF) or dioxane etc. or their mixed solvent, such as, at least one in methyl alcohol, ethanol, propyl alcohol, butanols, acetone, Virahol, acetonitrile, tetrahydrofuran (THF) or dioxane etc.
The temperature of reaction that described reacting by heating sloughs protecting group is 30 DEG C of extremely backflows, the solvent reflux temperature that described reflux temperature refers to.Further recommendation response temperature is 30 ~ 80 DEG C.
Described washer solvent is C
1~ C
6alcohol, C
2~ C
6ketone, C
2~ C
6ether, C
2~ C
6ester or C
1~ C
6haloalkane at least one, such as, at least one in methyl alcohol, ethanol, propyl alcohol, acetone, Virahol, ether, ethyl acetate or methylene dichloride etc.
Described concentrated, crystallization are recommended to be that the solvothermal adding crystallization is back to precipitation product after decompression or air distillation remove the solvent of dereaction.Described crystallization solvent is C
1~ C
6alcohol, such as methyl alcohol, ethanol or Virahol etc.
The present invention is not owing to using hydrazine hydrate to remove the protecting group of N-BETA-Alanyl-L-histidine; thus the introducing of hydrazine is avoided from source; completely eliminate the possibility that in product, hydrazine is residual, the quality of N-BETA-Alanyl-L-histidine product is fully ensured and embodies the security of product to HUMAN HEALTH.
Embodiment
Content of the present invention is further described with the following Examples, but content of the present invention is not limited only to content involved in embodiment:
Embodiment 1:
To in 250mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 7.12 grams (2mmol) and monomethylamine aqueous solution (30%, mass ratio) 80mL, this mixed system stirs 2 hours at 80 DEG C, and stopped reaction, except desolventizing, add dehydrated alcohol 200mL, stir and reflux, separate out white powdery solids, filter, 20mL washed with diethylether, drying, obtains carnosine product 3.87 grams, productive rate: 88%.Hydrazine is not detected in product.
Embodiment 2:
To in 500mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 14.2 grams (4mmol), methylethylolamine solution (27-30%, mass ratio) 14mL and dehydrated alcohol 350mL, reflux 1 hour.Heat filtering, 2 × 80mL dehydrated alcohol is washed, and 2 × 80mL ether is washed, dry, obtains carnosine product 8.02 grams, productive rate 89%.Hydrazine is not detected in product.
Embodiment 3:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), Virahol 30mL and aqueous methylamine solution (30%, mass ratio) 4mL, reflux 1.5h, heat filtering, 2 × 80mL dehydrated alcohol is washed, and 2 × 80mL ether is washed, dry, obtain carnosine product 1.68 grams, productive rate 74%.
Embodiment 4:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), Virahol 30mL and methylethylolamine solution 4mL (27-30%, mass ratio), reflux 1h, filtered while hot, 2 × 60mL dehydrated alcohol is washed, and 2 × 40mL ether is washed, dry, obtain carnosine product 1.8 grams, productive rate 80%.
Embodiment 5:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), THF 30mL and aqueous methylamine solution (30%, mass ratio) 4mL, reflux 2 hours, except desolventizing, gained solid adds ethanol 100mL and refluxes, and filters, 2 × 60mL anhydrous methanol is washed, drying, obtains carnosine product 1.51 grams, productive rate 69%.
Embodiment 6:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), tetrahydrofuran (THF) 30mL and methylethylolamine solution 4mL (27-30%, mass ratio), refluxes 3 hours, filtered while hot, 2 × 60mL dehydrated alcohol is washed, and 2 × 30mL ethyl acetate is washed, dry, obtain carnosine product 1.60 grams, productive rate 71%.
Embodiment 7:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), dioxane 30mL and aqueous methylamine solution (30%, mass ratio) 4mL, reflux 2 hours, filtered while hot, 2 × 30mL methylene dichloride is washed, drying, obtains carnosine product 2.04 grams, productive rate 90%.
Embodiment 8:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), dioxane 30mL and methylethylolamine solution 5mL (27-30%, mass ratio), reflux 2.5h, except desolventizing, add dehydrated alcohol 100mL, stir and reflux, separate out white powder solid, filter, 20mL washing with alcohol, drying, obtains carnosine product 2.2 grams, productive rate 97%.
Embodiment 9:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), ethanol 30ml and Tri N-Propyl Amine 3.8mL, reflux 2 hours, filter, 20mL washed with isopropyl alcohol, dry, obtain carnosine and produce 2.04 grams, productive rate 90%.
Embodiment 10:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), ethanol 30mL and n-Butyl Amine 99 3.7mL, reflux 2 hours, filter, 20mL absolute ethanol washing, dry, obtain carnosine product 2.14 grams, productive rate 95%.
Embodiment 11:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), water 30ml and ethylamine solution (65-70%, mass ratio) 4mL, reflux 1 hour, except desolventizing, adds 30mL alcohol reflux, cooling, filter, 20mL washing with alcohol, dry, obtain carnosine product 1.37 grams, productive rate 61%.
Embodiment 12:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), acetone 30mL and aqueous methylamine solution (30%, mass ratio) 4mL, heating reflux reaction 2 hours, except desolventizing, adds 30mL alcohol reflux, cooling, filter, 20mL washing with alcohol, dry, obtain carnosine product 1.54 grams, productive rate 68%.
Embodiment 13:
To in 100mL reaction flask, add phthalyl-N-BETA-Alanyl-L-histidine 3.56 grams (1mmol), ethanol 30mL and Isopropylamine 3.0mL, heating reflux reaction 2.5 hours, except desolventizing, add 30mL alcohol reflux, cooling, filter, 20mL washing with alcohol, drying, obtains carnosine product: 1.4 grams, productive rate 62%.
Claims (8)
1. a preparation method for N-BETA-Alanyl-L-histidine, is characterized in that in a solvent with 30 DEG C under reflux temperature, and the organic primary amine of phthalyl-N-BETA-Alanyl-L-histidine and 1 to 2 carbon atom obtains N-BETA-Alanyl-L-histidine after reacting and sloughing protecting group in 1 ~ 3 hour; The mol ratio of described phenyl-diformyl-N-BETA-Alanyl-L-histidine and the organic primary amine of 1 to 2 carbon atom is 1:(1 ~ 4).
2. preparation method according to claim 1, is characterized in that described reaction to be sloughed after protecting group through separating out product, filtration, organic solvent washing and drying, obtaining N-BETA-Alanyl-L-histidine product.
3. preparation method according to claim 1, is characterized in that described reaction to be sloughed after protecting group through concentrated, crystallization, filtration and drying, obtains N-BETA-Alanyl-L-histidine product.
4. the preparation method according to claim 1,2 or 3, is characterized in that described N-BETA-Alanyl-L-histidine product is without hydrazine N-BETA-Alanyl-L-histidine product.
5. preparation method according to claim 1, is characterized in that described solvent is selected from water, C
1~ C
6alcohol, C
2~ C
6ketone, acetonitrile, tetrahydrofuran (THF), dioxane or their mixed solvent.
6. preparation method according to claim 2, is characterized in that described washing organic solvent is C
1~ C
6alcohol, C
2~ C
6ketone, C
2~ C
6ether, C
2~ C
6ester or C
1~ C
6haloalkane at least one.
7. preparation method according to claim 3, is characterized in that described crystallization solvent is C
1~ C
6alcohol.
8. preparation method according to claim 1, is characterized in that described temperature of reaction is 30 ~ 80 DEG C.
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| CN201210002213.9A CN103193712B (en) | 2012-01-05 | 2012-01-05 | A kind of preparation method of N-BETA-Alanyl-L-histidine |
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| CN201210002213.9A CN103193712B (en) | 2012-01-05 | 2012-01-05 | A kind of preparation method of N-BETA-Alanyl-L-histidine |
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| CN103193712B true CN103193712B (en) | 2015-09-16 |
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| CN108047138A (en) * | 2017-12-25 | 2018-05-18 | 湖北泓肽生物科技有限公司 | Preparation method without hydrazine N-BETA-Alanyl-L-histidine |
| CN110419618A (en) * | 2019-07-25 | 2019-11-08 | 李猷 | A kind of animal albumen powder and preparation method thereof rich in carnosine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070050319A (en) * | 2005-11-10 | 2007-05-15 | 주식회사 엔지켐 | Method for producing l-carnosine and derivatives thereof |
| CN101117334A (en) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | Novel method for synthesizing L-carnosine |
-
2012
- 2012-01-05 CN CN201210002213.9A patent/CN103193712B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070050319A (en) * | 2005-11-10 | 2007-05-15 | 주식회사 엔지켐 | Method for producing l-carnosine and derivatives thereof |
| CN101117334A (en) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | Novel method for synthesizing L-carnosine |
Non-Patent Citations (1)
| Title |
|---|
| John Debenham,等."Recent Advances in N-Protection for Amino Sugar Synthesis".《Liebigs Ann.lRecuel》.1997,791-802,尤其是第792页方案1. * |
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Address after: 200032 Shanghai city Xuhui District Fenglin Road No. 354 Co-patentee after: SUZHOU FUSHILAI PHARMACEUTICAL CO., LTD. Patentee after: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Address before: 200032 Shanghai city Xuhui District Fenglin Road No. 354 Co-patentee before: Changshu Fushilai Medicine Chemical Co., Ltd. Patentee before: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences |
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