CN105254710A - Liquid phase synthesis method of antithrombotic compound BNW - Google Patents
Liquid phase synthesis method of antithrombotic compound BNW Download PDFInfo
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- CN105254710A CN105254710A CN201510833547.4A CN201510833547A CN105254710A CN 105254710 A CN105254710 A CN 105254710A CN 201510833547 A CN201510833547 A CN 201510833547A CN 105254710 A CN105254710 A CN 105254710A
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Abstract
The invention discloses a liquid phase synthesis method of an antithrombotic compound BNW. The liquid phase synthesis method comprises the steps that tryptophan and methyl alcohol perform esterification reaction to generate 2-Amino-3-(1H-indol-3-yl)-propionic acid methyl ester; 2-tert-butoxyacylamino asparagine and 2-Amino-3-(1H-indol-3-yl)-propionic acid methyl ester are condensed to generate 2-(2-tert-Butoxycarborylamino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl) propionic acid methyl ester, then the tert-Butoxycarborylamino of the 2-(2-tert-Butoxycarborylamino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl) propionic acid methyl ester is removed to obtain 2-(2-Amino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester; pyroglutamic acid and the 2-(2-Amino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester are condensed to generate 2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionic acid methyl ester; the 2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionic acid methyl ester is hydrolyzed to generate 2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionic acid, and then the 2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionic acid and aniline are condensed to generate the BNW. The liquid phase synthesis method is high in yield and low in cost and is suitable for technologized production.
Description
Technical field
The present invention relates to the synthesis of polypeptide derivative, particularly relate to the liquid-phase synthesis process of a kind of antithrombotic compound BNW.
Background technology
Along with the aging of population, the increase of cardiovascular disease incidence rate, existing antithrombotic standard drug can not adapt to and meet existing demand, and the market capacity of such medicine is still in continuous increase.Current antithrombotic reagent fail to meet active good, drug effect is measurable, can oral, rapid-action, the requirement such as side effect is little.
Thus, in view of the market opportunity is larger and each defectiveness of existing medicine, find safety, novel medicine for treating thrombus thing has become the study hotspot of domestic and international the world of medicine easily, meanwhile, for the innovative research of this type of medicine, particularly to polypeptide and can be oral small molecules class peptide or the research of compound also just there are more importantly meaning and market outlook.
BNW is a kind of compound with antithrombotic acitivity, the chmice acute lung thrombosis that can suppress electricity irritation rat carotid artery thrombosis, suppress ADP to bring out, thus plays antithrombotic effect.BNW is Pyrrolidonecarboxylic acid-Asn-Trp-aniline, and molecular weight is 504, and chemical structural formula is:
But current BNW building-up process exists, and yield is low, high in cost of production problem.
Summary of the invention
Goal of the invention: for the problems of the prior art, the invention provides the liquid-phase synthesis process of a kind of antithrombotic compound BNW, yield is high, is applicable to technology and produces.
The liquid-phase synthesis process of antithrombotic compound BNW of the present invention, comprising:
(1) tryptophane and methyl alcohol carry out esterification, generate tryptophan methyl ester;
(2) with HOBT and EDCI for condensing agent, 2-tertiary fourth oxanamide base l-asparagine and described tryptophan methyl ester carry out condensation reaction and generate 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate;
(3) slough the amino protecting group of described 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate with HCl, obtain 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate;
(4) with HOBT and EDCI for condensing agent, Pyrrolidonecarboxylic acid and described 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate carry out condensation reaction and generate Pyrrolidonecarboxylic acid-Asn-Trp methyl esters;
(5), under alkaline condition, Pyrrolidonecarboxylic acid-Asn-Trp methyl esters hydrolysis generates Pyrrolidonecarboxylic acid-Asn-Trp;
(6) with HOBT and EDCI for condensing agent, described Pyrrolidonecarboxylic acid-Asn-Trp and aniline carry out condensation reaction and generate Pyrrolidonecarboxylic acid-Asn-Trp-aniline.
Concrete, step (1) comprising: by tryptophane and methanol mixed, and control temperature is 0 ~ 5 DEG C, drips sulfur oxychloride, is warming up to 40 DEG C and reacts after dropping terminates, and after reaction terminates, from reaction solution, separation and purification obtains tryptophan methyl ester; The mol ratio of described tryptophane and sulfur oxychloride is 1:2.Tryptophane and methyl alcohol carry out esterification, generate tryptophan methyl ester, unaffected in subsequent reactions with the carboxyl of sematic color propylhomoserin.
Concrete, step (2) comprising: tertiary for 2-fourth oxanamide base l-asparagine and HOBT, solvent is even, control temperature is 0 DEG C, add EDCI, after stirring reaction 30min, then add described tryptophan methyl ester and triethylamine, stirring at room temperature is reacted, after reaction terminates, from reaction solution, separation and purification obtains 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate; The mol ratio of described 2-tertiary fourth oxanamide base l-asparagine and HOBT, EDCI, tryptophan methyl ester and triethylamine is 1:1:1:(0.9 ~ 1): 3.In this step, solvent can be methylene dichloride, tetrahydrofuran (THF), N, N-dimethylamino methane amide etc.Using triethylamine as acid binding agent; with HBOT and EDCI for condensing agent, 2-tertiary fourth oxanamide base l-asparagine and described tryptophan methyl ester carry out condensation reaction and generate 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate.Separation and purification can adopt the column chromatography method of this area routine to carry out.
Concrete; step (3) comprising: mixed with ethyl acetate by described 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate; control temperature is 0 ~ 5 DEG C; pass into HCl gas; stirring reaction; after reaction terminates, from reaction solution, separation and purification obtains 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate.Tertbutyloxycarbonyl is as the protecting group of l-asparagine amino, and make amino unaffected, do not participate in reaction, this step sloughs the amino protecting group of l-asparagine by HCl.
Concrete, step (4) comprising: by Pyrrolidonecarboxylic acid, HOBT and solvent, control temperature is 0 DEG C, add EDCI, after stirring reaction 30min, then add described 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate and triethylamine, stirring at room temperature is reacted, after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp methyl esters; The mol ratio of described Pyrrolidonecarboxylic acid and HOBT, EDCl, 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate and triethylamine is 1:1:1:1:3.Using triethylamine as acid binding agent; with HBOT and EDCI for condensing agent, Pyrrolidonecarboxylic acid and described 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate carry out condensation reaction and generate Pyrrolidonecarboxylic acid-Asn-Trp methyl esters.In this step, solvent can be methylene dichloride, tetrahydrofuran (THF), N, N-dimethylamino methane amide etc.Separation and purification can adopt the column chromatography method of this area routine to carry out.
Concrete, step (5) comprising: by Pyrrolidonecarboxylic acid-Asn-Trp methyl esters, alkali, water, tetrahydrofuran (THF) and methanol mixed, control temperature is 40 DEG C and reacts, and after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp; The mol ratio of described Pyrrolidonecarboxylic acid-Asn-Trp methyl esters and alkali is 1:2.Described alkali can be sodium hydroxide, lithium hydroxide etc.
Concrete, step (6) comprising: by aniline, HOBT and solvent, control temperature is 0 DEG C, add EDCI, after stirring reaction 30min, then add described Pyrrolidonecarboxylic acid-Asn-Trp and triethylamine, stirring at room temperature is reacted, after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp-aniline; The mol ratio of described aniline and HOBT, EDCI, Pyrrolidonecarboxylic acid-Asn-Trp and triethylamine is 1:1:1:1:(0.9 ~ 1): 3.Using triethylamine as acid binding agent, with HBOT and EDCI for condensing agent, aniline and described Pyrrolidonecarboxylic acid-Asn-Trp condensation reaction generate Pyrrolidonecarboxylic acid-Asn-Trp-aniline.In this step, solvent can be methylene dichloride, tetrahydrofuran (THF), N, N-dimethylamino methane amide etc.Separation and purification can adopt the column chromatography method of this area routine to carry out.
Compared with prior art, beneficial effect of the present invention is:
The invention provides the synthesis technique of a kind of new compd B NW, first tryptophane and methyl alcohol are carried out esterification, generate tryptophan methyl ester, unaffected in subsequent reactions with the carboxyl of sematic color propylhomoserin.Again by condensation reaction, deprotection reaction, hydrolysis reaction, generate Pyrrolidonecarboxylic acid-Asn-Trp, last Pyrrolidonecarboxylic acid-Asn-Trp and aniline reaction generate target compound BNW of the present invention.Synthetic method of the present invention, cost is low, is applicable to technology and produces, and the yield of compd B NW improves, and yield can reach 48.9%.
Accompanying drawing explanation
Fig. 1 is the synthetic route of antithrombotic compound BNW of the present invention.
Embodiment
Below in conjunction with specific embodiment, illustrate the present invention further, these embodiments should be understood only be not used in for illustration of the present invention and limit the scope of the invention, after having read the present invention, the amendment of those skilled in the art to the various equivalent form of value of the present invention has all fallen within the application's claims limited range.
The corresponding chemical name of the part shortenings adopted in the present invention is as follows:
Compound 1: tryptophane
Compound 2: tryptophan methyl ester, C
12h
14n
2o
2
Compound 3:2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate, C
21h
28n
4o
6
Compound 4:2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate, C
16h
20n
4o
4
Compound 5: Pyrrolidonecarboxylic acid-Asn-Trp methyl esters, C
21h
25n
5o
6
Compound 6: Pyrrolidonecarboxylic acid-Asn-Trp
Compound 7: Pyrrolidonecarboxylic acid-Asn-Trp-aniline
HOBT:1-hydroxybenzotriazole
EDCI:1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, also known as carbodiimide
Boc: tertbutyloxycarbonyl
TLC: thin-layer chromatography
HRMS: high resolution mass spectrum
Embodiment 1
Fig. 1 is the synthetic route of antithrombotic compound BNW of the present invention.
The liquid-phase synthesis process of antithrombotic compound BNW is specific as follows:
1, synthetic compound 2: tryptophan methyl ester [2-Amino-3-(1H-indol-3-yl)-propionicacidmethylester]
By 10.0g (0.0490mol) tryptophane, 160ml methyl alcohol adds in the three-necked bottle of 500ml, control temperature about 0 DEG C, and slowly drip 7ml (0.0980mol) sulfur oxychloride, 20min drips complete.Be warming up to 40 DEG C of reactions to spend the night, TLC detects (developping agent is the mixed solution of vinyl alcohol and methyl alcohol, ethyl acetate (v): methyl alcohol (v)=3:1) raw material and disappears.Be spin-dried for, dissolve, then to be spin-dried for, stir 4 hours by 150ml ethyl acetate with 100ml toluene, filter, dry gray solid 10.0g, is compound 2, yield 90.4%.
HRMS (FAB) (m/z): C
12h
14n
2o
2calculated value be 219.1124 (M+H)
+, test data is 219.1056.
2, synthetic compound 3:2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate
[2-(2-tert-Butoxycarbonylamino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl)-propionicacidmethylester]
By 6.26g (0.0276mol) 2-tertiary fourth oxanamide base l-asparagine, 3.90g (0.0276mol) HOBT, 20ml methylene dichloride adds in 100ml three-necked bottle respectively, stir, control temperature 0 DEG C, add 5.50g (0.0276mol) EDCI again, stirring reaction 30min, add 6.80g (0.0270mol) compound 2 again, 13.5ml (0.0810mol) triethylamine, stirring at room temperature reaction is spent the night, and TLC detects (developping agent is the mixed solution of vinyl alcohol and methyl alcohol, ethyl acetate (v): methyl alcohol (v)=1:1) raw material and disappears.Be spin-dried for and be dissolved in 10ml water, extract by ethyl acetate (20ml × 3), merge organic layer, (developping agent is the mixed solution of ethyl acetate and sherwood oil to column chromatography, ethyl acetate (v): sherwood oil (v)=2:1) obtain brown oil 5.20g, be compound 3, yield 40.9%.
HRMS (FAB) (m/z): C
21h
28n
4o
6calculated value be 433.2013 (M+H)
+, test data is 433.2024.
3, synthetic compound 4:2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate
[2-(2-Amino-3-carbamoyl-propionylamino)-3-(1H-indol-3-yl)-propionicacidmethylester]
By 5.00g (0.0110mol) compound 3,30ml ethyl acetate adds in 100ml three-necked bottle, control temperature about 0 DEG C, pass into dry HCl gas, stirring reaction 8 hours, TLC detects (developping agent is the mixed solution of vinyl alcohol and methyl alcohol, ethyl acetate (v): methyl alcohol (v)=1:1) raw material and disappears.Stopped reaction, concentrated being spin-dried for obtains yellow solid 3.40g, is compound 4, yield 90.5%.
HRMS (FAB) (m/z): C
16h
20n
4o
4calculated value be 333.1514 (M+H)
+, test data is 333.1505.
4, synthetic compound 5: Pyrrolidonecarboxylic acid-Asn-Trp methyl esters
[2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionicacidmethylester]
By 0.971g (0.00753mol) Pyrrolidonecarboxylic acid, 1.01g (0.00753mol) HOBT, 20ml methylene dichloride adds in 100ml three-necked bottle respectively, stir, control temperature 0 DEG C, add 1.43g (0.00753mol) EDCI again, stirring reaction 30min, add 2.49g (0.00750mol) compound 4 again, 3.78ml (0.0225mol) triethylamine, stirring at room temperature reaction is spent the night, and TLC detects (ethyl acetate: methyl alcohol=1:1) raw material and disappears.Be spin-dried for and be dissolved in 10ml water, extract by ethyl acetate (20ml × 3), merge organic layer, (developping agent is the mixed solution of vinyl alcohol and methyl alcohol to column chromatography, ethyl acetate (v): methyl alcohol (v)=10:1) obtain brown oil 1.53g, be compound 5, yield 44.6%.
HRMS (FAB) (m/z): C
21h
25n
5o
6calculated value 444.1876 (M+H)
+, test data is 444.1856
5, synthetic compound 6: Pyrrolidonecarboxylic acid-Asn-Trp
(2-{3-Carbamoyl-2-[(5-oxo-tetrahydro-furan-2-carbonyl)-amino]-propionylamino}-3-(1H-indol-3-yl)-propionicacid)
By 1.00g (0.00225mol) compound 5,0.180g (0.00451mol) sodium hydroxide, 2ml water, 8ml tetrahydrofuran (THF), 3ml methyl alcohol adds in 50ml three-necked bottle, control temperature 40 DEG C, and stirring reaction spends the night, TLC detects (developping agent is the mixed solution of vinyl alcohol and methyl alcohol, ethyl acetate (v): methyl alcohol (v)=1:1) raw material and disappears.Be spin-dried for organic phase, drip the hydrochloric acid of 6mol/L at 0 DEG C, adjust pH to 2 ~ 3, have solid to separate out, filter, dry, obtain gray solid 0.530g, be compound 6, yield 53.6%.
HRMS (FAB) (m/z): the test data of compound 6 conforms to calculated value.
6, synthetic compound 7: Pyrrolidonecarboxylic acid-Asn-Trp-aniline
By 0.0626g (0.000276mol) aniline, 0.0390g (0.000276mol) HOBT, 2ml methylene dichloride adds in 50ml three-necked bottle respectively, stir, control temperature 0 DEG C, add 0.550g (0.000276mol) EDCI again, stirring reaction 30min, add 0.116g (0.000270mol) compound 6 again, 0.135ml (0.000810mol) triethylamine, stirring at room temperature reaction is spent the night, and TLC detects (developping agent is the mixed solution of vinyl alcohol and methyl alcohol, ethyl acetate (v): methyl alcohol (v)=1:1) raw material and disappears.Be spin-dried for and be dissolved in 10ml water, extract by ethyl acetate (20ml × 3), merge organic layer, (developping agent is the mixed solution of vinyl alcohol and sherwood oil to column chromatography, ethyl acetate (v): sherwood oil (v)=2:1) obtain brown oil 0.0320g, be target compound 7 of the present invention, yield 48.9%.
HRMS (FAB) (m/z): the test data of compound 7 conforms to calculated value.
Comparative example
Prepare and hold N end to carry out one by one from C.Take 5gBoc-Trp, 1.6g aniline, 2.3gHOBt and 4gDCC, dissolve with DMF after mixing, afterwards consoluet mixed solution is added reactor reaction overnight.Point plate confirms to react completely (chloroform: methyl alcohol: Glacial acetic acid=90:8:2).After reacting completely, suction filtration, and extract with EA, add water stratification, put plate afterwards again and confirm that extraction is completely.Respectively wash 2 times by aqueous citric acid solution and saturated NaCl solution afterwards, and then use anhydrous Na
2sO
4drying, concentrated after 20min, add 2mol/LHCl/C after concentrated
4h
4o
2slough Boc, put after 2h plate detection reaction completely after, concentrated dry to the greatest extent, add diethyl ether and separate out solid (Trp-aniline HCl), suction filtration post-drying is stand-by.Then take 5gFomc-Asn (Trt)-OH, 4gTrp-aniline HCl, 1.8gHOBt, 2mlDIEA and 2.6gDCC, dissolve with DMF after mixing, add reaction overnight after reactor.Point plate confirms to react completely (chloroform: methyl alcohol: Glacial acetic acid=90: 8: 2).After reacting completely, suction filtration, and extract with EA, add water stratification, put plate afterwards again and confirm that extraction is completely.Use NaHCO
3, aqueous citric acid solution and saturated NaCl solution respectively wash 2 times, and then use anhydrous Na
2sO
4drying, concentrated after 30min, be concentrated into oily matter, take off and add DCM and dissolve, to be dissolved completely after, add 20mlEDA and react more than 4h, some plate confirms to react completely (chloroform: methyl alcohol: Glacial acetic acid=90:8:2).Concentrated dry to the greatest extent, add Pet and wash 3 times, incline and fall Pet acquisition oily matter, continue concentrated dry, stand-by to the greatest extent.Then take 3gPyr, 3gHOSU, 5.5gDCC, and carry out mixed dissolution using THF as solvent, add reactor reaction overnight afterwards.Point plate confirms to react completely (chloroform: methyl alcohol: Glacial acetic acid=85:10:5).After reacting completely, suction filtration falls solid, takes off a layer liquid, stirs.Then by the equimolar NaOH aqueous dissolution of Asn (Trt)-Trp-aniline, add in reaction solution, put plate after reaction 2h and confirm to react completely.After reacting completely, wash reaction solution 2 times with Pet, when adjusting PH=2-3, use EA extracted products, and wash 2 times with the NaCl aqueous solution, concentrated dry to the greatest extent after dry.Add cutting liquid TFA; H
2o; TIS (95:2:3) stirs 2h.Suction filtration, adds the ice ether of 10 times of volumes in filtrate, fully leaves standstill 30min after concussion.Drain, vacuum-drying, obtain the thick peptide of BNW.The thick peptide of BNW obtains target compound BNW after column chromatography, and yield is 40.2%.
Claims (8)
1. a liquid-phase synthesis process of antithrombotic compound BNW, is characterized in that, comprising:
(1) tryptophane and methyl alcohol carry out esterification, generate tryptophan methyl ester;
(2) with HOBT and EDCI for condensing agent, 2-tertiary fourth oxanamide base l-asparagine and described tryptophan methyl ester carry out condensation reaction and generate 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate;
(3) slough the amino protecting group of described 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate with HCl, obtain 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate;
(4) with HOBT and EDCI for condensing agent, Pyrrolidonecarboxylic acid and described 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate carry out condensation reaction and generate Pyrrolidonecarboxylic acid-Asn-Trp methyl esters;
(5), under alkaline condition, Pyrrolidonecarboxylic acid-Asn-Trp methyl esters hydrolysis generates Pyrrolidonecarboxylic acid-Asn-Trp;
(6) with HOBT and EDCI for condensing agent, described Pyrrolidonecarboxylic acid-Asn-Trp and aniline carry out condensation reaction and generate Pyrrolidonecarboxylic acid-Asn-Trp-aniline.
2. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1, it is characterized in that, step (1) comprising: by tryptophane and methanol mixed, control temperature is 0 ~ 5 DEG C, drip sulfur oxychloride, be warming up to 40 DEG C after dropping terminates to react, after reaction terminates, from reaction solution, separation and purification obtains tryptophan methyl ester; The mol ratio of described tryptophane and sulfur oxychloride is 1:2.
3. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1, it is characterized in that, step (2) comprising: tertiary for 2-fourth oxanamide base l-asparagine and HOBT, solvent is even, control temperature is 0 DEG C, add EDCI, after stirring reaction 30min, add described tryptophan methyl ester and triethylamine again, stirring at room temperature is reacted, after reaction terminates, from reaction solution, separation and purification obtains 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate; The mol ratio of described 2-tertiary fourth oxanamide base l-asparagine and HOBT, EDCI, tryptophan methyl ester and triethylamine is 1:1:1:(0.9 ~ 1): 3.
4. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1; it is characterized in that; step (3) comprising: mixed with ethyl acetate by described 2-(2-tertbutyloxycarbonyl-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate; control temperature is 0 ~ 5 DEG C; pass into HCI gas; stirring reaction; after reaction terminates, from reaction solution, separation and purification obtains 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate.
5. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1, it is characterized in that, step (4) comprising: by Pyrrolidonecarboxylic acid, HOBT and solvent, control temperature is 0 DEG C, add EDCI, after stirring reaction 30min, add described 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate and triethylamine again, stirring at room temperature is reacted, after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp methyl esters; The mol ratio of described Pyrrolidonecarboxylic acid and HOBT, EDCl, 2-(2-amino-3-formamyl propionamido)-3-(1H-indol-3-yl)-methyl propionate and triethylamine is 1:1:1:1:3.
6. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1, it is characterized in that, step (5) comprising: by Pyrrolidonecarboxylic acid-Asn-Trp methyl esters, alkali, water, tetrahydrofuran (THF) and methanol mixed, control temperature is 40 DEG C and reacts, after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp; The mol ratio of described Pyrrolidonecarboxylic acid-Asn-Trp methyl esters and alkali is 1:2.
7. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 6, it is characterized in that, described alkali is sodium hydroxide or lithium hydroxide.
8. the liquid-phase synthesis process of antithrombotic compound BNW as claimed in claim 1, it is characterized in that, step (6) comprising: by aniline, HOBT and solvent, control temperature is 0 DEG C, adds EDCI, after stirring reaction 30min, add described Pyrrolidonecarboxylic acid-Asn-Trp and triethylamine again, stirring at room temperature is reacted, and after reaction terminates, from reaction solution, separation and purification obtains Pyrrolidonecarboxylic acid-Asn-Trp-aniline; The mol ratio of described aniline and HOBT, EDCI, Pyrrolidonecarboxylic acid-Asn-Trp and triethylamine is 1:1:1:1:(0.9 ~ 1): 3.
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