CN103073618A - Preparation method for benzyloxycarbonyl alanyl alanine - Google Patents
Preparation method for benzyloxycarbonyl alanyl alanine Download PDFInfo
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- CN103073618A CN103073618A CN201310013700XA CN201310013700A CN103073618A CN 103073618 A CN103073618 A CN 103073618A CN 201310013700X A CN201310013700X A CN 201310013700XA CN 201310013700 A CN201310013700 A CN 201310013700A CN 103073618 A CN103073618 A CN 103073618A
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- carbobenzoxy
- cbz
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- alanine
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Abstract
The invention relates to a preparation method for two peptides, in particular to the preparation method for benzyloxycarbonyl alanyl alanine, and mainly solves the technical problem that the conventional synthetic method is not suitable for industrial production. The invention adopts the following technical scheme: the preparation method comprises the steps as follows: 1, adding L-alanine methyl ester hydrochloride into dichloromethane, adding organic alkali and benzyloxycarbonyl alanine, carrying out ice-bath treatment, dropwise adding a dichloromethane solution of N,N'-dicyclohexyl carbodiimide, reacting overnight, filtering out dicyclohexylurea, rotationally steaming to remove dichloromethane, carrying out conventional treatment to obtain a white solid, and re-crystallizing to obtain benzyloxycarbonyl alanyl alanine methyl ester; and 2, dissolving benzyloxycarbonyl alanyl alanine methyl ester in alcohol, adding a sodium hydroxide solution for saponification reaction, and carrying out conventional treatment to obtain benzyloxycarbonyl alanyl alanine as a final product.
Description
Technical field
The present invention relates to a kind of preparation method of two peptides, particularly a kind of preparation method of carbobenzoxy-(Cbz) alanyl-alanine.
Background technology
The synthetic of two peptides is the simplest during the simplest polypeptide synthesizes, taken off the carboxyl of a part by the free carboxy of the free amine group of a part and an one's share of expenses for a joint undertaking, the synthetic liquid phase that is particularly useful for of two peptides is synthesized, synthetic two peptides of different amino acid have different method of condensing, introduced carbodlimide method in " polypeptide is synthetic " this this book by Science Press's publication in September, 1985, active ester method, mixed anhydride method, the methods such as trinitride method, specifically be applied on two different amino acid, need to apply in a flexible way, through retrieval, not find the preferred method of the compound of same sequence, the carbobenzoxy-(Cbz) alanyl-alanine is a kind of polypeptide commonly used, have several different methods to finish, existing method fecund amount is little, is unsuitable for suitability for industrialized production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of carbobenzoxy-(Cbz) alanyl-alanine mainly solves the technical problem that existing synthetic method is unsuitable for suitability for industrialized production.Thinking of the present invention: carbobenzoxy-(Cbz) L-Ala and alanine methyl ester hydrochloride by
N,
N'The condensation of-dicyclohexylcarbodiimide gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters, and then saponification obtains the carbobenzoxy-(Cbz) alanyl-alanine.
Technical scheme of the present invention: a kind of preparation method of carbobenzoxy-(Cbz) alanyl-alanine, it is characterized in that its preparation concrete steps are, the first step reaction: the alanine methyl ester hydrochloride is joined in the methylene dichloride, add organic bases, amount of substance is 1 ~ 1.3 times of alanine methyl ester hydrochloride, adds the carbobenzoxy-(Cbz) L-Ala, and amount of substance is 0.8 ~ 1.2 times of alanine methyl ester hydrochloride, ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, with
N,
N'-dicyclohexylcarbodiimide amount of substance is 1 ~ 1.2 times of carbobenzoxy-(Cbz) L-Ala, and the elimination dicyclohexylurea (DCU) is spent the night (12-16 hour) in reaction, revolve and boil off methylene dichloride, adding ethyl acetate, sodium hydrogen carbonate solution washing organic layer, dilute hydrochloric acid washing organic layer, saturated common salt water washing organic layer, ethyl acetate is dry, filters, evaporate to dryness, get white solid, recrystallization gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters; The second step reaction: carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution, its amount of substance is 1 ~ 1.2 times of carbobenzoxy-(Cbz) L-Ala, saponification, complete after, concentrated, the ether washing adds ethyl acetate, and adjust pH is to acid, ethyl acetate extraction, the washing organic layer, organic layer is dry, suction filtration, concentrated, the carbobenzoxy-(Cbz) alanyl-alanine is separated out, the ether washing obtains product.
Described organic bases is selected from a kind of in an alkali metal salt, metal alkylide lithium compound or the amido lithium compound of aminated compounds, alcohol, a kind of in preferred methylamine, sodium ethylate, butyllithium or the lithium diisopropyl amido.
Beneficial effect of the present invention: the present invention is according to concrete aminoacid sequence and blocking group characteristics; provide a kind of corresponding two peptides production method; analyze after deliberation; suitable amino acid and condensing agent have been selected; suitable crystallization recrystallization method; purity is more than 98%, and yield reaches more than 85%, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1:
The alanine methyl ester hydrochloride is joined in the methylene dichloride, add methylamine, amount of substance is 1 times of alanine methyl ester hydrochloride, adds the carbobenzoxy-(Cbz) L-Ala, and amount of substance is 0.8 times of alanine methyl ester hydrochloride, and ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, with
N,
N'-dicyclohexylcarbodiimide amount of substance is 1 times of carbobenzoxy-(Cbz) L-Ala, and reaction is spent the night, the elimination dicyclohexylurea (DCU), revolve and boil off methylene dichloride, adding ethyl acetate, sodium hydrogen carbonate solution washing organic layer, dilute hydrochloric acid washing organic layer, saturated common salt water washing organic layer, ethyl acetate is dry, filters, evaporate to dryness, white solid, recrystallization gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters; Carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution, its amount of substance is 1 times of carbobenzoxy-(Cbz) L-Ala, saponification, complete after, concentrated, the ether washing adds ethyl acetate, transfers pH value to acid, ethyl acetate extraction, the washing organic layer, organic layer is dry, suction filtration, concentrated, the carbobenzoxy-(Cbz) alanyl-alanine is separated out, the ether washing obtains product.Purity 98.1%, yield 85%.
The qualitative analysis of product:
Mass spectrum: molecular weight 294.3 records result 295.20 [M+H] ﹢ 317.15 [M+Na] ﹢ 611.50 [2M+Na] ﹢
Nucleus magnetic hydrogen spectrum: solvent methyl-sulfoxide chemical shift 1.198 1.222 1.266 1.267 1.290 peak area 6.49 chemical shift 2.511 peak area graph thinning displacement study 4.083 peak area 1.07 chemical shift 4.199 peak area 1.00 chemical shift 5.018 peak area 1.92 chemical shift 6.028 peak area graph thinning displacement study 7.306 7.337 7.342 7.359 7.429 7.454 7.455 peak area 5.27 chemical shift 8.133 8.155 8.158 peak area 1.02 chemical shift 12.557 peak areas 0.95.
Embodiment 2:
The alanine methyl ester hydrochloride is joined in the methylene dichloride, add sodium ethylate, amount of substance is 1.3 times of alanine methyl ester hydrochloride, adds the carbobenzoxy-(Cbz) L-Ala, and amount of substance is 1.2 times of alanine methyl ester hydrochloride, and ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, with
N,
N'-dicyclohexylcarbodiimide amount of substance is 1.2 times of carbobenzoxy-(Cbz) L-Ala, and reaction is spent the night, the elimination dicyclohexylurea (DCU), revolve and boil off methylene dichloride, adding ethyl acetate, sodium hydrogen carbonate solution washing organic layer, dilute hydrochloric acid washing organic layer, saturated common salt water washing organic layer, ethyl acetate is dry, filters, evaporate to dryness, white solid, recrystallization gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters; Carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution, its amount of substance is 1.2 times of carbobenzoxy-(Cbz) L-Ala, saponification, complete after, concentrated, the ether washing adds ethyl acetate, transfers pH value to acid, ethyl acetate extraction, the washing organic layer, organic layer is dry, suction filtration, concentrated, the carbobenzoxy-(Cbz) alanyl-alanine is separated out, the ether washing obtains product.Purity 99.2%, yield 90%.The qualitative analysis is with embodiment 1.
Embodiment 3:
The alanine methyl ester hydrochloride is joined in the methylene dichloride, add butyllithium, amount of substance is 1.1 times of alanine methyl ester hydrochloride, adds the carbobenzoxy-(Cbz) L-Ala, and amount of substance is 1 times of alanine methyl ester hydrochloride, and ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, with
N,
N'-dicyclohexylcarbodiimide amount of substance is 1.1 times of carbobenzoxy-(Cbz) L-Ala, and reaction is spent the night, the elimination dicyclohexylurea (DCU), revolve and boil off methylene dichloride, adding ethyl acetate, sodium hydrogen carbonate solution washing organic layer, dilute hydrochloric acid washing organic layer, saturated common salt water washing organic layer, ethyl acetate is dry, filters, evaporate to dryness, white solid, recrystallization gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters; Carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution, its amount of substance is 1.1 times of carbobenzoxy-(Cbz) L-Ala, saponification, complete after, concentrated, the ether washing adds ethyl acetate, transfers pH value to acid, ethyl acetate extraction, the washing organic layer, organic layer is dry, suction filtration, concentrated, the carbobenzoxy-(Cbz) alanyl-alanine is separated out, the ether washing obtains product.Purity 99.3%, yield 87%.The qualitative analysis is with embodiment 1.
Embodiment 4:
The alanine methyl ester hydrochloride is joined in the methylene dichloride, add lithium diisopropyl amido, amount of substance is 1.1 times of alanine methyl ester hydrochloride, adds the carbobenzoxy-(Cbz) L-Ala, and amount of substance is 0.9 times of alanine methyl ester hydrochloride, and ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, with
N,
N'-dicyclohexylcarbodiimide amount of substance is 1.1 times of carbobenzoxy-(Cbz) L-Ala, and reaction is spent the night, the elimination dicyclohexylurea (DCU), revolve and boil off methylene dichloride, adding ethyl acetate, sodium hydrogen carbonate solution washing organic layer, dilute hydrochloric acid washing organic layer, saturated common salt water washing organic layer, ethyl acetate is dry, filters, evaporate to dryness, white solid, recrystallization gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters; Carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution, its amount of substance is 1.2 times of carbobenzoxy-(Cbz) L-Ala, saponification, complete after, concentrated, the ether washing adds ethyl acetate, transfers pH value to acid, ethyl acetate extraction, the washing organic layer, organic layer is dry, suction filtration, concentrated, the carbobenzoxy-(Cbz) alanyl-alanine is separated out, the ether washing obtains product.Purity 99.3%, yield 89%.The qualitative analysis is with embodiment 1.
Claims (5)
1. the preparation method of a carbobenzoxy-(Cbz) alanyl-alanine is characterized in that its preparation concrete steps are,
The first step reaction: the alanine methyl ester hydrochloride is joined in the methylene dichloride, add organic bases, add the carbobenzoxy-(Cbz) L-Ala again, ice bath drips
N,
N'The dichloromethane solution of-dicyclohexylcarbodiimide, reaction is spent the night, and the elimination dicyclohexylurea (DCU) is revolved and is boiled off methylene dichloride, obtains white solid and carry out recrystallization after routine is processed, and gets carbobenzoxy-(Cbz) alanyl-alanine methyl esters;
Second step reaction: carbobenzoxy-(Cbz) alanyl-alanine methyl esters is dissolved in the alcohol, adds sodium hydroxide solution and carry out saponification reaction, process obtaining the finished product through routine.
2. the preparation method of a kind of carbobenzoxy-(Cbz) alanyl-alanine according to claim 1, it is characterized in that in the reaction of the described the first step that organic bases is selected from a kind of in an alkali metal salt, metal alkylide lithium compound or the amido lithium compound of aminated compounds, alcohol.
3. the preparation method of a kind of carbobenzoxy-(Cbz) alanyl-alanine according to claim 2 is characterized in that organic bases is selected from a kind of in methylamine, sodium ethylate, butyllithium or the lithium diisopropyl amido.
4. the preparation method of a kind of carbobenzoxy-(Cbz) alanyl-alanine according to claim 1, it is characterized in that in the described the first step reaction, the organic bases amount of substance is 1 ~ 1.3 times of alanine methyl ester hydrochloride, and carbobenzoxy-(Cbz) L-Ala amount of substance is 0.8 ~ 1.2 times of alanine methyl ester hydrochloride
N,
N'-dicyclohexylcarbodiimide amount of substance is 1 ~ 1.2 times of carbobenzoxy-(Cbz) L-Ala.
5. the preparation method of a kind of carbobenzoxy-(Cbz) alanyl-alanine according to claim 1 is characterized in that the sodium hydroxide amount of substance is 1 ~ 1.2 times of carbobenzoxy-(Cbz) L-Ala in the described second step reaction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773228A (en) * | 2021-10-28 | 2021-12-10 | 上海吉奉生物科技有限公司 | Synthesis method of N-benzyloxycarbonyl-3-iodo-L-alanine methyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4339534A (en) * | 1979-04-06 | 1982-07-13 | De Forenede Bryggerier A/S | Process for enzymatic production of peptides |
| CN1683391A (en) * | 2005-03-02 | 2005-10-19 | 厦门大学 | Synthetic method for N(2)-L-alanyl-L-glutamine dipeptide |
| CN101891686A (en) * | 2010-07-20 | 2010-11-24 | 吉尔生化（上海）有限公司 | Synthesizing method of N-beta-alanyl-(tau-methyl) histidine |
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- 2013-01-15 CN CN201310013700XA patent/CN103073618A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4339534A (en) * | 1979-04-06 | 1982-07-13 | De Forenede Bryggerier A/S | Process for enzymatic production of peptides |
| CN1683391A (en) * | 2005-03-02 | 2005-10-19 | 厦门大学 | Synthetic method for N(2)-L-alanyl-L-glutamine dipeptide |
| CN101891686A (en) * | 2010-07-20 | 2010-11-24 | 吉尔生化（上海）有限公司 | Synthesizing method of N-beta-alanyl-(tau-methyl) histidine |
Non-Patent Citations (3)
| Title |
|---|
| PAVLA REJMANOVA等: "Polymers Containing Enzymatically Degradable Bonds, 2 a) Poly[N-(2-hydroxypropyl)methacrylamide] Chains Connected by Oligopeptide Sequences Cleavable by Chymotrypsin b）", 《MACROMOLECULAR CHEMISTRY AND PHYSICS》, vol. 182, no. 7, 31 July 1981 (1981-07-31), pages 1899 - 1915 * |
| 王德心: "《固相有机合成 原理及应用指南》", 30 September 2004, article "第四章 固相肽合成", pages: 117 * |
| 王镜岩等: "《生物化学（上）》", 30 September 2002, article "第4章 蛋白质的共价结构", pages: 192 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773228A (en) * | 2021-10-28 | 2021-12-10 | 上海吉奉生物科技有限公司 | Synthesis method of N-benzyloxycarbonyl-3-iodo-L-alanine methyl ester |
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Application publication date: 20130501 |