CN113880911A - Synthesis method of glycyl-L-tyrosine - Google Patents

Synthesis method of glycyl-L-tyrosine Download PDF

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CN113880911A
CN113880911A CN202111078247.1A CN202111078247A CN113880911A CN 113880911 A CN113880911 A CN 113880911A CN 202111078247 A CN202111078247 A CN 202111078247A CN 113880911 A CN113880911 A CN 113880911A
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tyrosine
glycyl
dioxane
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CN113880911B (en
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杨庆垂
阮海燕
李健雄
汪黎明
吴伟伟
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Hubei Huntide Biotech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a method for synthesizing glycyl-L-tyrosine, belonging to the technical field of organic synthesis. The method comprises the steps of taking glycine as an initial raw material, and finally obtaining the glycyl-L-tyrosine with high purity through amino protection, acyl chlorination, peptide grafting, deprotection and refining. The method has the advantages of cheap and easily obtained starting raw materials, mild conditions, high kettle efficiency, simple and controllable impurities and the like, and provides a feasible scheme for the process research of glycyl-L-tyrosine.

Description

Synthesis method of glycyl-L-tyrosine
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly discloses a synthetic method of glycyl-L-tyrosine.
Background
As one of the main components of parenteral nutrition preparation compound amino acid (15) dipeptide (2) injection, glycyl-L-tyrosine belongs to artificially synthesized dipeptide amino acid, and mainly provides L-tyrosine for patients to ensure hyperthyroidism so as to promote protein synthesis. Therefore, glycyl-L-tyrosine has wide development space in the medical field.
The currently disclosed synthetic methods of glycyl-L-tyrosine mainly comprise the following steps:
the method comprises the following steps: U.S. Pat. No. 4, 6197998, 1 reports a synthetic scheme using chloroacetyl chloride and L-tyrosine as starting materials, which is acylated, aminolyzed, and purified to obtain glycyl-L-tyrosine. Although the steps are short, the chloroacetyl chloride as the starting material is high in price, a large amount of ammonia water and ammonium carbonate are needed, the kettle efficiency is very low, the reaction time is too long, and the industrial three wastes are high.
The second method comprises the following steps: european patent EP311057 (1998) reports a synthetic scheme in which N-succinimide and benzyloxycarbonylglycine are first prepared into an active ester, then condensed with tyrosine ethyl ester to form a peptide by a condensing agent, and then hydrolyzed to obtain glycyl tyrosine.
The third scheme is as follows: chinese patent CN103172695B reports a synthesis scheme using glycine and L-tyrosine as starting materials, in which glycine directly reacts with thionyl chloride to prepare glycine chloride hydrochloride, and then the glycine chloride hydrochloride is condensed with tyrosine under an alkaline condition to generate glycyl tyrosine, in the scheme, the amino group of glycine is not protected and directly prepares acyl chloride, and the reaction product is very complex, so that the yield of the target product is very low and is difficult to purify, and industrial production cannot be realized.
Therefore, the development of an industrial method for synthesizing glycyl-L-tyrosine, which has the advantages of low cost, high kettle efficiency, small wastewater amount and controllable impurities, is a problem to be solved urgently at present.
Disclosure of Invention
The invention provides a method for synthesizing glycyl-L-tyrosine, which has the following reaction equation:
Figure RE-GDA0003398861260000021
wherein R is selected from benzyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, fluorenyl methoxycarbonyl, phthaloyl, p-toluenesulfonyl or trifluoroacetyl, etc.
The invention provides a method for synthesizing glycyl-L-tyrosine, which comprises the following steps:
(1) in a solvent A, glycine, a base A and a compound R react at 0-120 ℃ to obtain a compound I, wherein the molar ratio of the glycine to the base A to the compound R is 1: 0.5-3.0: 1.0-2.5. Wherein, the compound R is selected from benzyl chloride, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, fluorenyl methoxy carbonyl chloride, phthalic anhydride, p-toluenesulfonyl chloride or trifluoroacetic anhydride, etc.; preferably fluorenyl methoxycarbonyl chloride, phthalic anhydride or trifluoroacetic anhydride.
(2) In a solvent B, reacting a compound I, DMF and thionyl chloride at 25-80 ℃ to obtain a compound II, wherein the molar ratio of the compound I to the DMF to the thionyl chloride is 1: 0.01-0.5: 1-3.
(3) Dissolving L-tyrosine and alkali B in a solvent C to obtain a solvent C system, dissolving a compound II in a solvent D, dropwise adding the solvent C system, and reacting at 0-30 ℃ to obtain a compound III, wherein the molar ratio of the compound II to the alkali B to the L-tyrosine is 1: 0.5-3: 0.8-2.5.
(4) When R is benzyl or benzyloxycarbonyl, reacting a compound III with hydrogen in a solvent E under the action of a catalyst at 25-60 ℃ to obtain a compound IV, wherein the mass ratio of the compound III to the catalyst is 1: 0.1-0.5, the pressure of hydrogen is 0.01-1 Mpa;
when R is methoxycarbonyl or ethoxycarbonyl, reacting a compound III with strong acid or strong base in a solvent F at 0-50 ℃ to obtain a compound IV, wherein the molar ratio of the compound III to the strong acid or strong base is 1: 1-4;
when R is fluorenyl methoxycarbonyl, phthaloyl, p-toluenesulfonyl or trifluoroacetyl, reacting a compound III with organic amine or inorganic amine at 25-75 ℃ in a solvent G to obtain a compound IV, wherein the molar ratio of the compound III to the organic amine or the inorganic amine is 1: 1-3.
Wherein, the solvent A is selected from toluene, dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran or dioxane, etc., the alkali A is selected from triethylamine, pyridine, DBU, sodium carbonate, potassium carbonate or sodium hydroxide, etc., and dioxane, dichloromethane or trichloromethane are preferred.
The solvent B is selected from toluene, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, dioxane or acetone, and is preferably toluene or trichloromethane.
Wherein, the solvent C is selected from water, toluene, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, dioxane or acetone, etc., and is preferably water or acetone; the solvent D is selected from toluene, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, dioxane or acetone, and the like, and is preferably trichloromethane or acetone; the base B is selected from triethylamine, pyridine, DBU, sodium carbonate, potassium carbonate or sodium hydroxide, etc., preferably sodium hydroxide (corresponding to water) or triethylamine (corresponding to organic solvent).
Wherein, the solvent E is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, etc., and the catalyst is selected from palladium carbon or Raney nickel, etc.
Wherein, the solvent F is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, etc., and the strong acid or strong base is selected from sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid or hydrobromic acid, etc.
Wherein, the solvent G is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, etc., preferably water, methanol or tetrahydrofuran; the organic amine or inorganic amine is selected from ammonia, hydrazine hydrate, piperidine, ethanolamine, cyclohexylamine or DBU, etc., preferably ammonia, hydrazine hydrate or piperidine.
The method comprises the steps of taking glycine as an initial raw material, and finally obtaining the glycyl-L-tyrosine with high purity through amino protection, acyl chlorination, peptide grafting, deprotection and refining. The method has the advantages of cheap and easily obtained starting raw materials, mild conditions, high kettle efficiency, simple and controllable impurities and the like, and provides a feasible scheme for the process research of glycyl-L-tyrosine. Specifically, the first scheme is a route which can be industrially produced at present, but in the ammonolysis process, 10-20 times of the volume of ammonia water is usually required to be added, and the volume of materials and the volume of ammonium carbonate solution are added, so that the kettle efficiency is relatively low. The solvent volume of the method is within 5 times of that of the materials, and the kettle efficiency is high. In addition, the method is a continuous-feeding reaction, does not need purification in the middle, reduces operation, basically realizes a one-pot method for reaction, and is suitable for industrial production. Meanwhile, the method can purify the product only by adopting a recrystallization method, the concentration of the obtained product is more than 99 percent, the L-tyrosine is less than or equal to 0.3 percent, and other impurities are less than or equal to 0.1 percent, which accords with the regulations of United states pharmacopoeia.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
The synthetic route of the glycyl-L-tyrosine provided by the invention is as follows:
Figure RE-GDA0003398861260000041
the above synthetic route is illustrated by R-group as fluorenyl-methoxycarbonyl, benzyl and ethoxycarbonyl. The R group may be any other group selected from those defined above. One skilled in the art can make adjustments to one or more steps without departing from the spirit of the present invention, and such changes are within the scope of the present application.
Synthesis of Compound I
1.1 adding 260ml dioxane, glycine (86.33 g, 1.15 mol), triethylamine (151.79 g, 1.50 mol) into a 1L three-necked bottle, stirring uniformly, dropwise adding fluorenyl methoxy carbonyl chloride (310.44 g, 1.20 mol) at the temperature of 15-35 ℃, reacting at normal temperature for 5-6h after dropwise adding, after the reaction, concentrating under reduced pressure below 50 ℃ to dryness, and directly carrying out the next reaction, wherein the molar yield is 100%.
1.2 adding 300ml of dichloromethane, glycine (86.33 g, 1.15 mol) and pyridine (118.52 g, 1.50 mol) into a 1L three-necked bottle, stirring uniformly, dropwise adding benzyl chloride (151.90 g, 1.20 mol) at the controlled temperature of 15-35 ℃, reacting at normal temperature for 5-6h after dropwise adding, concentrating under reduced pressure below 50 ℃ until the mixture is dried after the reaction is finished, and directly carrying out the next reaction, wherein the molar yield is 100%.
1.3 adding 300ml of trichloromethane, glycine (86.33 g, 1.15 mol), triethylamine (118.52 g, 1.50 mol), ethyl chloroformate (130.22 g, 1.2 mol) into a 1L three-necked bottle, keeping the temperature for 5-6h, after the reaction is finished, concentrating under reduced pressure below 50 ℃ to dryness, and directly carrying out the next reaction, wherein the molar yield is 100%.
Synthesis of (di) Compound II
2.1 putting 300ml of trichloromethane, a compound I and DMF (7.3 g, 0.1 mol) into a 1L reaction bottle, stirring and mixing uniformly, dropwise adding thionyl chloride (154.66 g, 1.3 mol) at the temperature of below 40 ℃, heating to 55-65 ℃, preserving heat for reaction for 3-4h, after the reaction is finished, concentrating under reduced pressure at the temperature of below 65 ℃ until the reaction is dried, and directly carrying out the next reaction, wherein the molar yield is 100%.
2.2 put 400ml toluene, compound I, DMF (10.95 g, 0.15 mol) into a 1L reaction bottle, stir and mix evenly, control to drip thionyl chloride (178.45 g, 1.5 mol) below 40 ℃, heat up to 55-65 ℃ after finishing dripping, keep warm and react for 3-4h, after finishing the reaction, concentrate under reduced pressure below 65 ℃ to dry, directly carry on the next reaction, the molar yield is counted as 100%.
Synthesis of (III) Compound
3.1 putting 550ml of water and L-tyrosine (181.19 g, 1.00 mol) into a 2L reaction bottle, stirring and dispersing uniformly, controlling the temperature to be 5-15 ℃, adding sodium hydroxide (60 g, 1.50 mol), keeping the temperature and stirring for 30min after the addition, dissolving a compound II in 300ml of trichloromethane, controlling the temperature to be 0-25 ℃, dropwise adding the compound II into an L-tyrosine system, completing the dropwise addition, reacting at room temperature for 3-5h, separating out a water phase after the reaction is completed, adjusting the pH =4-6, and concentrating under reduced pressure below 60 ℃ until the mixture is dried to obtain a compound III, directly carrying out the next reaction, wherein the molar yield is 100%.
3.2 putting 300ml of acetone and L-tyrosine (181.19 g, 1.00 mol) into a 2L reaction bottle, stirring and dispersing uniformly, controlling the temperature to be 5-15 ℃, adding triethylamine (202.38 g, 2.00 mol), keeping the temperature and stirring for 30min after the addition is finished, dissolving a compound II into 250ml of acetone, controlling the temperature to be 0-25 ℃, dropwise adding the compound II into an L-tyrosine system, completing the dropwise addition, reacting at room temperature for 3-5h, adjusting the pH =4-6 after the reaction is finished, and concentrating under reduced pressure below 50 ℃ until the compound II is dried to obtain a compound III, wherein the molar yield is 100%.
Synthesis of (tetra) Compound IV
4.1 when R is fluorenyl methoxycarbonyl, adding 650ml of tetrahydrofuran, the compound III and piperidine (127.54 g, 1.5 mol) into a 2L reaction bottle, stirring at normal temperature for 5-6h, after the reaction is finished, concentrating under reduced pressure below 50 ℃ until the mixture is dried, adding 476ml of water and 1000ml of ethanol for recrystallization to obtain the compound IV, wherein the total molar yield is 75%, the liquid phase purity of the product is 99.3%, L-tyrosine is less than or equal to 0.3%, and other single impurities are less than or equal to 0.1%.
4.2 when R is benzyl, adding 500g of water and 500g of methanol, a compound III and 25g of 5% palladium carbon into a high-pressure reaction kettle, uniformly stirring, introducing hydrogen to 0.5-0.8Mpa, heating to 50-60 ℃, reacting for 5-6 hours, filtering, concentrating under reduced pressure below 60 ℃ until the reaction is finished, adding 480ml of water and 1000ml of isopropanol, and recrystallizing to obtain a compound IV, wherein the total molar yield is 72%, the liquid phase purity of the product is 99.2%, the L-tyrosine content is less than or equal to 0.3%, and the other single impurities are less than or equal to 0.1%.
4.3 when R is o-ethoxycarbonyl, 600ml of dioxane, a compound III and 365g of 30% hydrochloric acid (3.00 mol) are added into a 2L reaction bottle, the temperature is gradually increased to 40-50 ℃, the reaction is carried out for 4-5 hours, after the reaction is finished, the temperature is reduced to normal temperature, the filtration is carried out, the filtrate is concentrated under reduced pressure below 60 ℃ until the filtrate is dried, 476ml of water and 1000ml of ethanol are added for recrystallization, and the compound IV is obtained, the total molar yield is 60%, the liquid phase purity of the product is 99.5%, L-tyrosine is less than or equal to 0.3%, and other single impurities are less than or equal to 0.1%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

1. A method for synthesizing glycyl-L-tyrosine is characterized in that the reaction equation is as follows:
Figure RE-FDA0003398861250000011
wherein R is selected from benzyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, fluorenyl methoxycarbonyl, phthaloyl, p-toluenesulfonyl or trifluoroacetyl.
2. A method of synthesizing glycyl-L-tyrosine according to claim 1, wherein R is selected from fluorenyl methoxy carbonyl, benzyl or ethoxy carbonyl.
3. The method of synthesizing glycyl-L-tyrosine according to claim 1, which comprises:
(1) in a solvent A, glycine, a base A and a compound R react at 0-120 ℃ to obtain a compound I, wherein the molar ratio of the glycine to the base A to the compound R is 1: 0.5-3.0: 1.0-2.5, wherein the compound R is selected from benzyl chloride, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, fluorenyl methoxy carbonyl chloride, phthalic anhydride, p-toluenesulfonyl chloride or trifluoroacetic anhydride;
(2) in a solvent B, reacting a compound I, DMF and thionyl chloride at 25-80 ℃ to obtain a compound II, wherein the molar ratio of the compound I to the DMF to the thionyl chloride is 1: 0.01-0.5: 1-3;
(3) dissolving L-tyrosine and alkali B in a solvent C to obtain a solvent C system, dissolving a compound II in a solvent D, dropwise adding the solvent C system, and reacting at 0-30 ℃ to obtain a compound III, wherein the molar ratio of the compound II to the alkali B to the L-tyrosine is 1: 0.5-3: 0.8-2.5;
(4) when R is benzyl or benzyloxycarbonyl, reacting a compound III with hydrogen in a solvent E under the action of a catalyst at 25-60 ℃ to obtain a compound IV, wherein the mass ratio of the compound III to the catalyst is 1: 0.1-0.5, and the pressure of the hydrogen is 0.01-1 Mpa;
when R is methoxycarbonyl or ethoxycarbonyl, reacting a compound III with strong acid or strong base in a solvent F at 0-50 ℃ to obtain a compound IV, wherein the molar ratio of the compound III to the strong acid or strong base is 1: 1-4;
when R is fluorenyl methoxycarbonyl, phthaloyl, p-toluenesulfonyl or trifluoroacetyl, reacting a compound III with organic amine or inorganic amine at 25-75 ℃ in a solvent G to obtain a compound IV, wherein the molar ratio of the compound III to the organic amine or the inorganic amine is 1: 1-3.
4. A process for the synthesis of glycyl-L-tyrosine according to claim 3, characterized in that the solvent a is selected from toluene, dichloromethane, chloroform, methanol, ethanol, tetrahydrofuran or dioxane, and the base a is selected from triethylamine, pyridine, DBU, sodium carbonate, potassium carbonate or sodium hydroxide.
5. A process for the synthesis of glycyl-L-tyrosine according to claim 3, characterized in that the solvent B is selected from toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, dioxane or acetone.
6. The method for synthesizing glycyl-L-tyrosine according to claim 3, wherein the solvent C is selected from water, toluene, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, dioxane or acetone, the solvent D is selected from toluene, dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, dioxane or acetone, and the base B is selected from triethylamine, pyridine, DBU, sodium carbonate, potassium carbonate or sodium hydroxide.
7. The method for synthesizing glycyl-L-tyrosine as claimed in claim 3, characterized in that the solvent E is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, and the catalyst is selected from palladium carbon or Raney nickel.
8. A process for the synthesis of glycyl-L-tyrosine according to claim 3, characterized in that the solvent F is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, and the strong acid or base is selected from sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid or hydrobromic acid.
9. A process for the synthesis of glycyl-L-tyrosine according to claim 3, characterized in that the solvent G is selected from water, methanol, ethanol, acetone, tetrahydrofuran or dioxane, and the organic or inorganic amine is selected from ammonia, hydrazine hydrate, piperidine, ethanolamine, cyclohexylamine or DBU.
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