CN103204905A - Method for synthesizing tetra-glycylglycine - Google Patents
Method for synthesizing tetra-glycylglycine Download PDFInfo
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Abstract
The invention provides a sequential synthesis method of tetra-glycylglycine. The method includes steps: 1, producing glycylglycine after condensating and ring opening of glycine; 2, producing tri-glycylglycine after activated ester condensation of glycylglycine and N-protected glycine and deprotection; and 3, producing tetra-glycylglycine after activated ester condensation of tri-glycylglycine and N-protected glycine and deprotection.
Description
Technical field
The present invention relates to a kind of synthetic method of four peptidylglycines, belong to chemosynthesis technical field.
Background technology
Glycylglycine reaches the stablizer that pharmaceutically is used as blood preservation and pharmaceutical grade protein cytochrome C aqueous injection as biochemical reagents in biological study.Three peptidylglycines are main raw materials of synthetic renal functional imaging medicine.Four peptidylglycines are that four glycine molecules form by the orderly link of peptide bond, it and three peptidylglycines, glycylglycine all obtain important application at polypeptide and medicine aspect synthetic, four sweet peptides are important small peptides of synthetic antithrombotic drug Bivalirudin, see patent CN201110170669.1, CN200910028793.7, CN 200980152943.3.
At present, synthetic employing glycine high temperature dehydration in glycerine of glycylglycine, through basic hydrolysis, the acid neutralization, the alcohol crystallization gets product, and in this method, having added water in the glycerine as comprehensive usefulness can not apply mechanically, postorder is handled and is produced sodium-chlor, and tighter for using the impurity requirement as finished product, it is qualified to be difficult to.Three peptidylglycines adopt chloroacetyl chloride and glycylglycine to react the ammonia solution under alkaline condition again and obtain, but single the mixing of this technology controlling and process is difficult to reach 0.2%.Four peptidylglycines mainly adopt ester condensation reaction in organic solvent of Z-GLY-GLY-OSU and GLY-GLY, hydrogenolysis gets product again, and bad because of the solvability of Z-GLY-GLY-OSU in this reaction, yield is lower, and glycylglycine wants esterification to need again to react in organic solvent, and cost is corresponding higher.
Summary of the invention
Purpose of the present invention is the shortcoming that overcomes above-mentioned technology, and a kind of method of synthetic four peptidylglycines is provided, this method adopts the synthesis mode in proper order of kinds of protect combination, and when synthesizing glycylglycine, ethylene glycol can be applied mechanically, postorder is handled and is not produced sodium-chlor, product percent of pass height; When synthesizing three peptidylglycines, can guarantee that the product list is assorted below 0.2%, purity is (HPLC) more than 99.0%; When synthetic four peptidylglycines, reactant solubility is good, the yield height, and esterification need not to carry out in organic solvent, and cost is low.Technical scheme is:
The synthetic method of a kind of four sweet ammonia phthaleins adopts synthesis method in proper order, the steps include:
1, produces glycylglycine after the glycine condensation open loop;
2, glycylglycine and through the glycine Acibenzolar condensation of N-protected is produced three peptidylglycines behind the deprotection;
3, four peptidylglycines are produced in the glycine Acibenzolar condensation of three peptidylglycines and N-protected behind the deprotection.
The concrete steps of described synthetic glycylglycine are to get ethylene glycol, glycine, the mixing stirring, be warming up to 170-175 ℃ of reaction, after reacting completely, add and be water-cooled to room temperature, the centrifugal crude product that gets adds hydrochloric acid hydrolysis again, cools off the centrifugal solid that gets, add lithium hydroxide solution and regulate PH5.5-6, add decolorizing with activated carbon, add alcohol filter the glycylglycine crude product, water recrystallization again, add alcohol, filtration washing is qualified to chlorine, the dry glycylglycine that gets.Or
Get ethylene glycol mother liquor, glycine, mix and stir, be warming up to 170-175 ℃ of reaction, after reacting completely, be cooled to room temperature, the centrifugal crude product that gets, crude product adds the 2N lithium hydroxide aqueous solution in 30-40 ℃ of insulation 30-60 minute, with in the hydrochloric acid and PH5.5-6.0, add the refining decolouring of activated carbon, add alcohol filter the glycylglycine crude product, water recrystallization again, add alcohol, filtration washing, the dry glycylglycine that gets.
The concrete steps of described synthetic three peptidylglycines are, water, glycine are mixed, keep PH=9-10 with the 4N aqueous sodium hydroxide solution, keep 5-10 ℃ of temperature, be added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC again, in 25-30 ℃ of reaction, originally react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid, splash in glycylglycine, water, the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, use in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-three peptidylglycines; Again Z-three peptidylglycines, ethyl acetate, Pa/C are mixed, stir down and feed hydrogen, the 0.1-0.Mpa that keep-ups pressure is in 30-40 ℃ of hydrogenolysis, treat that hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving, filtered and recycled Pa/C, filtrate concentrates, and adds alcohol, filter three peptidylglycines.Or
The concrete steps of described synthetic four peptidylglycines are: water, glycine are mixed, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC, in 25-30 ℃ of reaction, originally react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid; Splash into three peptidylglycines, water, in the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, use in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-four peptidylglycines, with Z-four peptidylglycines, ethyl acetate, Pa/C mixes, and stirs to feed hydrogen down, 0.1-0.Mpa keep-ups pressure, in 30-40 ℃ of hydrogenolysis, hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving, filtered and recycled Pa/C, filtrate concentrates, add alcohol, filter four peptidylglycines.
The concrete steps of described synthetic four peptidylglycines are, water, glycine are mixed, keep PH=9-10 with the aqueous sodium hydroxide solution of 4N, keep 5-10 ℃ of temperature, be added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC, in 25-30 ℃ of reaction, react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid; This Z-GLY-OSU/ acetic acid ethyl fluid is splashed into three peptidylglycines, water, in the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, with in the hydrochloric acid and PH=2.2-2.5, stir centrifugal Z-gly-gly-gly-gly-OH, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-four peptidylglycines, with Z-four peptidylglycines, ethyl acetate, Pa/C mixes, and stirs down and feeds hydrogen, and 0.1-0.Mpa keep-ups pressure, in 30-40 ℃ of hydrogenolysis, hydrogenolysis fully after, filter four peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving filtered and recycled Pa/C, filtrate concentrates, and adds alcohol, filter four peptidylglycines.
This method adopts the synthesis mode in proper order of kinds of protect combination, and when synthesizing glycylglycine, ethylene glycol can be applied mechanically, and postorder is handled and do not produced sodium-chlor, product percent of pass height; When synthesizing three peptidylglycines, can guarantee that the product list is assorted below 0.2%, purity is (HPLC) more than 99.0%; When synthesizing four peptidylglycines, reactant solubility is good, the yield height, and do not need esterification, and also need not in organic solvent, to carry out, cost is low.
Embodiment
Below describe the present invention in detail with embodiment;
One, synthetic glycylglycine
Embodiment 1:
In the 100L oil bath pan, add 50L ethylene glycol, the 10KG glycine, stirring is warming up to 170-175 ℃ of reaction 45-60 minute, be cooled to 60 ℃, add 10L water, be cooled to the centrifugal 8KG crude product that gets of room temperature, crude product added the 15L hydrochloric acid hydrolysis 1-2 minute, cooled off the centrifugal solid 7KG of getting, add lithium hydroxide solution and regulate PH5.5-6, add about 0.2KG activated carbon, refining decolouring, adds 2-3 times of alcohol filter pair 5KG peptidylglycine crude products, water recrystallization again, add 2-3 times of alcohol, filtration washing is qualified to chlorine, the dry glycylglycine 3.5KG (content 99.2%) that gets.This routine reaction formula is as follows:
Embodiment 2:
In the 100L oil bath pan, add the centrifugal ethylene glycol mother liquor of 50L1., the 10KG glycine, stirring is warming up to 170-175 ℃ of reaction 45-60 minute, be cooled to 60 ℃, add 10L water, be cooled to the centrifugal 8.2KG crude product that gets of room temperature, crude product adds 20L 2N lithium hydroxide aqueous solution in 30-40 ℃ of insulation 30-60 minute, with in the hydrochloric acid and PH5.5-6.0, add the refining decolouring of about 0.2KG activated carbon, adds 2-3 times of alcohol filter pair 5KG peptidylglycine crude products, water recrystallization again, add 2-3 times of alcohol, filtration washing, the dry glycylglycine 3.8KG (content 99.0%) that gets.This routine reaction formula is as follows:
Two, synthetic three peptidylglycines
See following reaction formula:
Embodiment 3:
In the retort of 100L, add 50 water, glycine 15KG, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester 37KG, drip the natural temperature reaction in back, TLC faces measured reaction to chloroformic acid benzyl ester and reacts completely, and adds the 30L ethyl acetate, uses in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing dry 27KG Z-glycine; 26.6KG is added the 100L ethyl acetate add 12KG HOSU, 23KG DCC, in 25-30 ℃ of reaction 36 hours, TLC point plate to carbobenzoxyglycine originally reacted completely, and filters out solid and gets 1,20L Z-GLY-OSU/ acetic acid ethyl fluid; Branch is got 60L Z-GLY-OSU/ acetic acid ethyl fluid and is splashed into (13 KG glycylglycines, 50L water, the sodium bicarbonate mixed solution of 17KG) in, in room temperature reaction 24 hours, TLC point plate is to Z-GLY-OSU reaction more than 98.0% (liquid phase monitoring), reaction end is told ethyl acetate layer, extract the upper strata diamicton 50L/ time with ethyl acetate again, with in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, oven dry 15.7KG gets the pure product (99.5% of Z-three peptidylglycines, HPLC), with 10KG Z-three peptidylglycines, the 50L ethyl acetate, 50G Pa/C mixes, stir and to feed hydrogen hydrogen down, the 0.1-0.Mpa that keep-ups pressure was in 30-40 hydrogenolysis 28 hours, TLC point plate hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds 6-8 times of water, rising temperature for dissolving filtered and recycled Pa/C 48G, filtrate concentrates, add 1 times of alcohol, filter 6KG three peptidylglycines, again the water recrystallization once 5.5KG three peptidylglycines (content: 99.6%).
Embodiment 4:
In the retort of 100L, add 50 water, glycine 15KG, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester 37KG, drip the natural temperature reaction in back, TLC faces measured reaction to chloroformic acid benzyl ester and reacts completely, and adds the 30L ethyl acetate, uses in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing dry 27KG Z-glycine; 26.6KG is added the 100L ethyl acetate add 12KG HOSU, 23KG DCC, in 25-30 ℃ of reaction 36 hours, TLC point plate to carbobenzoxyglycine originally reacted completely, and filters out solid and gets 1,20L Z-GLY-OSU/ acetic acid ethyl fluid; Branch is got 60L Z-GLY-OSU/ acetic acid ethyl fluid and is splashed into (13 KG glycylglycines, 50L water, the sodium bicarbonate mixed solution of 17KG) in, in room temperature reaction 24 hours, TLC point plate is to Z-GLY-OSU reaction more than 98.0% (liquid phase monitoring), reaction end is told ethyl acetate layer, extract the upper strata diamicton 50L/ time with ethyl acetate again, with in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, oven dry 15.7KG gets the pure product (99.5% of Z-three peptidylglycines, HPLC), with 10KG Z-three peptidylglycines, the 50L ethyl acetate, 50G Pa/C mixes, stir and to feed hydrogen hydrogen down, the 0.1-0.Mpa that keep-ups pressure was in 30-40 hydrogenolysis 28 hours, TLC point plate hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds 6-8 times of water, rising temperature for dissolving filtered and recycled Pa/C 48G, filtrate concentrates, add 1 times of alcohol, filter 6KG three peptidylglycines, again the water recrystallization once 5.5KG three peptidylglycines (content: 99.6%).
Three, synthetic four peptidylglycines
Acibenzolar and the glycine reactant deprotection of the Acibenzolar that synthesizes the glycylglycine that can pass through N-protected of four peptidylglycines and three peptidylglycines of glycylglycine reaction deprotection or N-protected obtain, but the Acibenzolar of this N-protected of two kinds has solubleness relatively poor in organic solvent, and yield is low; The mode of N-protected also has multiple, but synthetic with the carbobenzoxy-(Cbz) protection, and the impurity of product low (less than 0.2%) is so we have finally selected the Acibenzolar of carbobenzoxyglycine and glycylglycine to synthesize step by step.
See following reaction formula:
Embodiment 5:
In the retort of 100L, add 50 water, glycine 15KG, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester 37KG, drip the natural temperature reaction in back, TLC faces measured reaction to chloroformic acid benzyl ester and reacts completely, and adds the 30L ethyl acetate, uses in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing dry 27KG Z-glycine; 26.6KG is added the 100L ethyl acetate add 12KG HOSU, 23KG DCC, in 25-30 ℃ of reaction 36 hours, TLC point plate to carbobenzoxyglycine originally reacted completely, and filters out solid and gets 1,20L Z-GLY-OSU/ acetic acid ethyl fluid; Branch is got 60L Z-GLY-OSU/ acetic acid ethyl fluid and is splashed into (18 KG, three peptidylglycines, 50L water, the sodium bicarbonate mixed solution of 17KG) in, in room temperature reaction 24 hours, TLC point plate is to Z-GLY-OSU reaction more than 98.0% (liquid phase monitoring), reaction end is told ethyl acetate layer, extract the upper strata diamicton 50L/ time with ethyl acetate again, with in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, oven dry 24.7KG gets the pure product (99.5% of Z-three peptidylglycines, HPLC), with 10KG Z-three peptidylglycines, the 50L ethyl acetate, 40G Pa/C mixes, and stirs down and feeds hydrogen hydrogen, and 0.1-0.Mpa keep-ups pressure, in 30-40 hydrogenolysis 28 hours, TLC point plate hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds 6-8 times of water, rising temperature for dissolving filtered and recycled Pa/C 35G, filtrate concentrates, and adds 1 times of alcohol, filter 12KG four peptidylglycines, again the water recrystallization once 5.5KG four peptidylglycines (content: 99.6%, single assorted less than 0.2%).
Embodiment 6:
In the retort of 100L, add 50 water, glycine 15KG, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester 37KG, drip the natural temperature reaction in back, TLC faces measured reaction to chloroformic acid benzyl ester and reacts completely, and adds the 30L ethyl acetate, uses in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing dry 27KG Z-glycine; 26.6KG is added the 100L ethyl acetate add 12KG HOSU, 23KG DCC, in 25-30 ℃ of reaction 36 hours, TLC point plate to carbobenzoxyglycine originally reacted completely, and filters out solid and gets 1,20L Z-GLY-OSU/ acetic acid ethyl fluid; Branch is got 60L Z-GLY-OSU/ acetic acid ethyl fluid and is splashed into (13 KG glycylglycines, 50L water, the sodium bicarbonate mixed solution of 17KG) in, in room temperature reaction 24 hours, TLC point plate is to Z-GLY-OSU reaction more than 98.0% (liquid phase monitoring), reaction end is told ethyl acetate layer, extract the upper strata diamicton 50L/ time with ethyl acetate again, with in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, the oven dry 15.7KG get the pure product of Z-three peptidylglycines (99.5%, HPLC); With 10KG Z-three peptidylglycines, the 50L ethyl acetate, 50G Pa/C mixes, stir and to feed hydrogen hydrogen down, the 0.1-0.Mpa that keep-ups pressure was in 30-40 hydrogenolysis 28 hours, TLC point plate hydrogenolysis is complete, filter four peptidylglycines and Pa/C mixture, this mixture adds 6-8 times of water, rising temperature for dissolving filtered and recycled Pa/C 48g, filtrate concentrates, and adds 1 times of alcohol, filter 6KG four peptidylglycines, again the water recrystallization once 5.5KG four peptidylglycines (content: 99.6%, single assorted less than 0.2%).
Claims (4)
1. the synthetic method of a peptidylglycine adopts synthesis method in proper order, the steps include:
(1), produces glycylglycine after the glycine condensation open loop;
(2), glycylglycine and through the glycine Acibenzolar condensation of N-protected, produce three peptidylglycines behind the deprotection;
(3), the glycine Acibenzolar condensation of three peptidylglycines and N-protected, produce four peptidylglycines behind the deprotection.
2. the synthetic method of as claimed in claim 1 four sweet ammonia phthaleins, it is characterized in that, the concrete steps of described synthetic glycylglycine are, get ethylene glycol, glycine, mix and stir, be warming up to 170-175 ℃ of reaction, after reacting completely, be cooled to room temperature, the centrifugal crude product that gets adds hydrochloric acid hydrolysis again, cool off the centrifugal solid that gets, add lithium hydroxide solution and regulate PH5.5-6, add decolorizing with activated carbon, add alcohol filter the glycylglycine crude product, water recrystallization again, add alcohol, filtration washing impurity is qualified, the dry glycylglycine that gets; Or
Get ethylene glycol mother liquor, glycine, mix and stir, be warming up to 170-175 ℃ of reaction, after reacting completely, be cooled to room temperature, the centrifugal crude product that gets, crude product adds the 2N lithium hydroxide aqueous solution in 30-40 ℃ of insulation 30-60 minute, with in the hydrochloric acid and PH5.5-6.0, add the refining decolouring of activated carbon, add alcohol filter the glycylglycine crude product, water recrystallization again, add alcohol, filtration washing, the dry glycylglycine that gets.
3. the synthetic method of four peptidylglycines as claimed in claim 1 is characterized in that, the concrete steps of described synthetic three peptidylglycines are, water, glycine are mixed, keep PH=9-10 with the 4N aqueous sodium hydroxide solution, keep 5-10 ℃ of temperature, be added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC again, in 25-30 ℃ of reaction, react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid, splash in glycylglycine, water, the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, use in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-three peptidylglycines; Again Z-three peptidylglycines, ethyl acetate, Pa/C are mixed, stir down and feed hydrogen, the 0.1-0.Mpa that keep-ups pressure is in 30-40 ℃ of hydrogenolysis, treat that hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving, filtered and recycled Pa/C, filtrate concentrates, and adds alcohol, filter three peptidylglycines; Or
Water, glycine are mixed, aqueous sodium hydroxide solution with 4N is kept PH=9-10, keeps 5-10 ℃ of temperature, is added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC, in 25-30 ℃ of reaction, originally react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid; Splash into three peptidylglycines, water, in the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, use in the hydrochloric acid and PH=2.2-2.5, stir the centrifugal Z-gly-gly-gly-OH of getting, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-three peptidylglycines, with Z-three peptidylglycines, ethyl acetate, Pa/C mixes, and stirs to feed hydrogen down, 0.1-0.Mpa keep-ups pressure, in 30-40 ℃ of hydrogenolysis, hydrogenolysis is complete, filter three peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving, filtered and recycled Pa/C, filtrate concentrates, add alcohol, filter three peptidylglycines.
4. the synthetic method of as claimed in claim 1 four sweet ammonia phthaleins is characterized in that, the concrete steps of described synthetic four peptidylglycines are, water, glycine are mixed, keep PH=9-10 with the aqueous sodium hydroxide solution of 4N, keep 5-10 ℃ of temperature, be added dropwise to chloromethyl ester benzyl ester, drip the natural temperature reaction in back, react completely to chloroformic acid benzyl ester, add ethyl acetate, with in the hydrochloric acid and PH2.2-2.5, stirred crystallization, centrifuge washing, dry the Z-glycine; Add ethyl acetate, HOSU, DCC, in 25-30 ℃ of reaction, react completely to carbobenzoxyglycine, filter out solid and get the Z-GLY-OSU/ acetic acid ethyl fluid; This Z-GLY-OSU/ acetic acid ethyl fluid is splashed into three peptidylglycines, water, in the sodium bicarbonate mixed solution, in room temperature reaction, to Z-GLY-OSU reaction more than 98%, tell ethyl acetate layer at reaction end, use ethyl acetate extraction upper strata diamicton again, with in the hydrochloric acid and PH=2.2-2.5, stir centrifugal Z-gly-gly-gly-gly-OH, with ethyl acetate/normal hexane recrystallization, dry the pure product of Z-three peptidylglycines, with Z-three peptidylglycines, ethyl acetate, Pa/C mixes, and stirs down and feeds hydrogen, and 0.1-0.Mpa keep-ups pressure, in 30-40 ℃ of hydrogenolysis, hydrogenolysis fully after, filter three peptidylglycines and Pa/C mixture, this mixture adds water, rising temperature for dissolving filtered and recycled Pa/C, filtrate concentrates, and adds alcohol, filter four peptidylglycines.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110143896A (en) * | 2019-06-14 | 2019-08-20 | 南京博源医药科技有限公司 | A kind of preparation method of N- benzyloxycarbonyl group-L- glycoleucine |
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| CN101759767A (en) * | 2008-10-23 | 2010-06-30 | 湖州来色生物基因工程有限公司 | Method for synthesizing glycylglycine |
| CN101906150A (en) * | 2010-06-28 | 2010-12-08 | 上海昂博生物技术有限公司 | Preparation method of Bivalirudin |
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| CN101759767A (en) * | 2008-10-23 | 2010-06-30 | 湖州来色生物基因工程有限公司 | Method for synthesizing glycylglycine |
| CN101906150A (en) * | 2010-06-28 | 2010-12-08 | 上海昂博生物技术有限公司 | Preparation method of Bivalirudin |
Non-Patent Citations (1)
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110143896A (en) * | 2019-06-14 | 2019-08-20 | 南京博源医药科技有限公司 | A kind of preparation method of N- benzyloxycarbonyl group-L- glycoleucine |
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Application publication date: 20130717 |