CN106008307A - Method for synthesizing D-isoglutamine-D-tryptophan - Google Patents
Method for synthesizing D-isoglutamine-D-tryptophan Download PDFInfo
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- CN106008307A CN106008307A CN201610283054.2A CN201610283054A CN106008307A CN 106008307 A CN106008307 A CN 106008307A CN 201610283054 A CN201610283054 A CN 201610283054A CN 106008307 A CN106008307 A CN 106008307A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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Abstract
The invention relates to a method for synthesizing D-isoglutamine-D-tryptophan. The method comprises the steps that H-D-Glu-OR2 (a compound I) serves as the raw material, trityl or derivatives (Trt') thereof serve as a protecting group, and synthesizing is carried out to obtain the intermediate Trt'-D-Glu-OR2 (a compound III); the intermediate compound II and H-D-Trp-OR3 (a compound IV) are condensed to obtain Trt'-D-Glu(D-Trp-OR3)-OR2 (a compound V); the compound V is subjected to one or two steps of acidolysis, hydrogenolysis and hydrolysis to obtain coarse peptide, and coarse peptide is purified to obtain D-isoglutamine-D-tryptophan. The method has the advantages of being short in synthesizing route, low in technological condition requirement, low in related raw material and reagent cost and high in yield, producing few side products and the like, and is suitable for large-scale production of D-isoglutamine-D-tryptophan.
Description
Technical field
The present invention relates to medicine synthesis field, be specifically related to a kind of method synthesizing H-D-GAMMA-Glu-D-Trp-OH.
Background technology
H-D-GAMMA-Glu-D-Trp-OH, English name is Thymodepressin or referred to as H-D-iGlu-DTrp-
OH (No. CAS: 186087-26-3).It is that the blood of a kind of synthetic adjusts dipeptides, has a following chemical structural formula:
。
Research finds, this dipeptides has multiple physiologically active；These activity can be used to realize related medical purpose.
It can suppress body's immunity as immunosuppressant and alleviate rejection (O. in bone marrow, tissue and organ transplantation
V.Semina, et al. Bulletin of Experimental Biology and Medcinine, 2001, 131
(5), 493-5)；Protect medullary cell and immune system from injury (V. I. Deigin, the et al. of chemotherapy and radiation
US573519; V. I. Deigin, et al. US6103699;V. I. Deigin, et al. US6410515) and control
Treat autoimmune disease, such as psoriasis and atopic dermatitis (S.G. Sapuntsova, et al. Bulletin of
Experimental Biology and Medcinine, 2002, 133(5), 488-90).This dipeptides is not suitable for making sheet
Agent or capsule are by administered in oral forms, and main cause is that bioavailability is the highest.This dipeptides is made into disodium salt at present, passes through
Intravenous injection or nasal administration.This type of medicine is sold in Russia.
The synthesis of H-D-GAMMA-Glu-D-Trp-OH has numerous patents report before this, with lower part to this simple conclusion.
Synthetic method described in WO2008064465 is as follows:
Wherein R1And R2For benzyl or C1～C4 alkyl.
The method that US5736519 describes is with Boc-D-Glu-OH and H-D-Trp-OH as raw material, through DCC condensation and formic acid
The mixture of H-D-Glu-D-Trp-OH and H-D-iGlu-D-Trp-OH is obtained after deprotection.It is then passed through ion exchange chromatography
Obtaining target product after purification, yield is 12.0 %.The method shortcoming is that poor selectivity, by-product are many, the therefore purification of product
Difficulty is big.
Method described in CN102603609 is as follows:
Wherein R1For Fmoc or Cbz, R2For benzyl or C1～C4 alkyl.Spread out as D-isoglutamic acid when using Fmoc or Cbz
During biological amino protecting group, last protection group removing has various problem.
In sum, the method for existing patent report is: protected by Glu and Trp by suitable protection group, then through work
Change, coupling, deprotection and purification, finally obtain H-D-GAMMA-Glu-D-Trp-OH.Wherein the forms of protection of Glu can use formula
R1-Glu-OR2Represent；The forms of protection of Trp can use formula H-Trp (R4)-OR3Represent.R1Protection group selects Boc, Fmoc
Or Cbz；R2Select benzyl, alkyl or do not protect；R3Select benzyl, alkyl or do not protect；R4It is generally selected and does not protect；Wherein alkane
Base is typically chosen phenyl or C1～C4 alkyl.
Using Boc as R1 protection group, its advantage is that deprotection is more convenient；Shortcoming is and ester compared with aromatic ring class protection group
Dissolubility is poor, and therefore in synthesis journey, extracting and washing loss is relatively large, and synthesis yield is relatively low.Additionally, Boc protection group takes off
Produce a large amount of tert-butyl group cation that Trp side chain is had addition during protection, the cacodorous second of a certain amount of tool two need to be added
Mercaptan additive is to suppress this side reaction, and this is unfavorable for large-scale production and has an impact environment.Different using Fmoc or Cbz as D-
The amino protecting group of glutamate derivatives, although during extracting and washing, loss of product is less than Boc protection group, the most there is not guarantor
Side reaction to Trp side chain addition when protecting, but the removing of the two protection group is the most inconvenient.The removing needs of Fmoc have
The solution of certain alkalescence is carried out, after there is racemization risk and deprotection, produces substantial amounts of by-product hexichol fluorenes alkene.Hexichol fluorenes alkene
Liquid phase synthesis remove more difficult and be easily polymerized.The removing of Cbz needs Pd/C catalyst and carries out under an atmosphere of hydrogen,
After using catalyst costly, reaction in course of reaction, Pd/C processes and more bothers and have an impact environment；Additionally hydrogenate
Equipment be there are certain requirements, there is certain potential safety hazard by condition.
The selection of protection group is extremely important to this two peptide symthesis, which determines initiation material cost, intermediate synthesis yield
And technological process.If in whole building-up process, often step reaction all can reach higher yields；And after peptide chain coupling,
All protection groups all can be removed conveniently and efficiently, and by-product is few, and this will be to simplification of flowsheet, reduction production cost and realization
Large-scale production H-D-GAMMA-Glu-D-Trp-OH is significant.
Summary of the invention
The present invention provides a kind of synthesis H-D-GAMMA-Glu-D-Trp-OH method.The method is with H-D-Glu-OR2(chemical combination
Thing I) it is raw material, employing trityl or derivatives thereof (Trt ') as protection group, synthesis obtains Trt '-D-Glu-OR2(change
Compound III).Compound III and H-D-Trp-OR3There is condensation reaction in (compound IV), obtains Trt '-D-Glu (D-
Trp-OR3)-OR2(compound V).(compound V) is according to protection group R2Or R3Difference, can be through the method for one of the following
Process obtains thick peptide 1) acidolysis 2) hydrogenolysis 3) first through acidolysis, then hydrolysis or hydrogenolysis 4) first through hydrolysis, then acidolysis；Thick peptide
H-D-iGlu-D-Trp-OH is obtained after purified.The method has that synthetic route is short, process conditions require raw material low, involved examination
The feature that agent low cost, yield are high, by-product is few and environmental pollution is little.
In order to realize foregoing invention purpose, the present invention provides techniques below scheme.
With H-D-Glu-OR2(compound I) is raw material, first uses R1 3SiX1With organic base process, then be connected with X2Three
Benzyl and derivant (compound II) reaction thereof, obtain Trt '-D-Glu-OR after post processing2Compound III.The latter is in contracting
Close reagent or with under conditions of activating reagent with H-D-Trp-OR3There is condensation reaction in (compound IV), obtains Trt '-D-
Glu(D-Trp-OR3)-OR2(compound V).Compound V is according to its protection group R2Or R3Difference, can be through acidolysis or hydrogenolysis
After directly obtain thick peptide；Also thick peptide can be obtained after acidolysis, hydrolysis or hydrogenolysis；Also thick peptide can be obtained after hydrolysis, acidolysis.Above-mentioned
H-D-iGlu-D-Trp-OH is obtained after the thick peptide of gained is purified.The method has that synthetic route is short, process conditions require low, institute
Relate to source chemicals low cost, yield is high, by-product is few and environmental pollution is little feature.
Reaction scheme figure is as follows:
As preferably, R in described method2Can be hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, 2-fourth
Base, the tert-butyl group, 2 '-propyloxy phenyl base, trityl or, 2-chlorine trityl, trityl, C5～C10 alkyl, C3～C10
One in cycloalkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl, but it is not limited only to this.
As preferably, three R in described method1Group is each independently C1～C10 alkyl, C3～C10 cycloalkyl, benzene
The combination of one or more in base or substituted-phenyl, benzyl or substituted benzyl, but it is not limited only to this.At embodiments of the invention
In, more preferably three R1Group is all methyl.
As preferably, X1For the one in F, Cl, Br, I, CN, SCN and trifluoromethanesulfonic acid ester group, but it is not limited only to this.?
In embodiments of the invention, X1More preferably Cl.
As preferably, organic base used is DIPEA, triethylamine, N-methylmorpholine and 1,8-diaza
One or more in dicyclo (5.4.0) 11-7-alkene (DBU), but it is not limited only to this.In an embodiment of the present invention, more excellent
Elect triethylamine as.
As preferably, Y can be H, OH, SH, NH2；Can be F, Cl, Br, I, CN, SCN or trifluoromethanesulfonic acid ester group；
Can be C1～C10 alkyl, C3～C10 cycloalkyl, phenyl and substituted-phenyl；Can be C1～C10 alkoxyl, C3～C10 ring
Alkoxyl, phenyl and substituted-phenyl epoxide；Can be C1～C10 alkylamino, C3～C10 naphthene amino, phenyl and substituted-phenyl
Amino；On described phenyl ring with substituent group can be the combination of one or more in above-mentioned substituent group；These substituent groups can
With on same phenyl ring or on different phenyl ring, but it is not limited only to this.In an embodiment of the present invention, Y is preferably H.
As preferably, X2For the one in F, Cl, Br, I, CN, SCN and trifluoromethanesulfonic acid ester group, but it is not limited only to this.?
In embodiments of the invention, X2More excellent for Cl.
As preferably, described synthesis Trt '-D-Glu-OR2(compound III) solvent for use is dichloromethane, three chloromethanes
Alkane, carbon tetrachloride, ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane and replacement pentane, hexane and replacement hexane, hexamethylene and
Substituted cyclohexane, normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halogeno-benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide,
Hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl ether, oxolane, Pentamethylene oxide., 1,4-dioxane, alkyl formate, acetic acid alkane
Base ester, alkyl propionates, alkyl butyrate, benzoic acid Arrcostab, nitromethane, nitroethane, nitropropane, acetonitrile, propionitrile,
Butyronitrile, benzene acetonitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl acetamide, N methyl pyrrolidone, Benzoylamide, first sulfur
Ether, ethyl sulfide, thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone and pentanone etc., reaction can be carried out in single solvent, also
Can carry out in the mixed solvent being made up of above-mentioned several solvents, but be not limited only to this.The most more preferably
For chloroform.
As preferably, in described method, condensation reagent is N, N-DIC (DIC), N, N-dicyclohexyl carbon
Diimine (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCIHCl), 2-(7-azo benzo three
Nitrogen azoles)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU)/organic base, O-BTA-tetramethylurea hexafluoro phosphorus
Acid esters (HBTU)/organic base, BTA-1-base epoxide three (dimethylamino) phosphorus hexafluorophosphate (BOP)/organic
Alkali, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP)/organic base and O-BTA-N, N,
N ', N ' one or more in-tetramethylurea Tetrafluoroboric acid ester (TBTU)/organic base.Organic base used is N, N-diisopropyl
One or more in ethamine, triethylamine or N-methylmorpholine, but it is not limited only to this.The most more preferably
For EDCIHCl.
As preferably, in described method, activating reagent is N-hydroxy-succinamide (HOSu), I-hydroxybenzotriazole
(HOBt), 1-hydroxyl-7-azo BTA (HOAt), 3-hydroxyl-1,2,3-phentriazine-4 (3H)-one (HODhBt) or
N-hydroxyl-5-norborene-2, one or more in 3-dicarboximide (HONb), but it is not limited only to this.The present invention's
More preferably HOBt in embodiment.
As preferably, R in described method3Hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, 2-can be selected
Butyl, the tert-butyl group, 2 '-propyloxy phenyl base, trityl or, 2-chlorine trityl, trityl, C5～C10 alkyl, C3～
One in C10 cycloalkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl, but it is not limited only to this.
As preferably, described method synthesizes Trt '-D-Glu (D-Trp-OR3)-OR2Solvent for use is.
Dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane and replacement pentane,
Hexane and replace hexane, hexamethylene and substituted cyclohexane, normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halogeno-benzene, ether,
Propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl ether, oxolane, Pentamethylene oxide., 1,4-bis-
Oxygen six ring, alkyl formate, alkyl acetate, alkyl propionates, alkyl butyrate, benzoic acid Arrcostab, nitromethane, nitro
Ethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl acetamide, N methyl
Ketopyrrolidine, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone, pentanone, water, methanol,
Ethanol, propanol, isopropanol, butanol etc..Reaction can be carried out in single solvent, it is possible to mixed be made up of above-mentioned several solvents
Bonding solvent is carried out, but is not limited only to this.It is more preferably N,N-dimethylformamide in an embodiment of the present invention.
As preferably, in described method, the alkali used by condensation reaction is selected from DIPEA, triethylamine, N-first
Base morpholine, 1,8-diazabicyclo (5.4.0) 11-7-alkene (DBU), sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate,
One or more in cesium carbonate, but it is not limited only to this.As preferably, the acid hydrolysis solution acid hydrolysis solution that in described method, acidolysis uses is
The mixed solution of following component composition: a) selected from formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, fluohydric acid gas, hydrogen chloride, bromination
Hydrogen or one or more compounds of hydrogen iodide；B) selected from thioanisole, methyl phenyl ethers anisole, dithioglycol, tri isopropyl silane, phenol,
One or more compounds in indole；And c) selected from dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,2-bis-chloroethene
Alkane, chloropropane, pentane and replacement pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane, normal heptane, toluene, diformazan
Benzene, Nitrobenzol, various halogeno-benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl
Ether, oxolane, Pentamethylene oxide., 1,4-dioxane, alkyl formate, alkyl acetate, alkyl propionates, butanoic acid alkyl
Ester, benzoic acid Arrcostab, nitromethane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-dimethyl
Methanamide, N, N '-dimethyl acetamide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, dimethyl sulfoxide,
The mixing of dimethylsulfone, acetone, butanone, pentanone, water, formic acid, acetic acid, propanoic acid and one or more solvents benzoic composition is molten
Agent, but it is not limited only to this.
As preferably, in described method, hydrogenolysis is 20 ~ 100oC, hydrogen is pressed under 2 ~ 5 atmospheric pressure, at catalyst
Effect under carry out；Also can be in one or more reagent of cyclohexene, formic acid, ammonium formate or tetrahydronaphthalene and the effect of catalyst
Under carry out.Described catalyst is Pd/C, Pd/BaSO4、PdCl2、Pd(OH)2、Raney Ni、Pt、Pt/C、PtO2、(Ph3P)3·
RhCl、(Ph3P)3·RuCl2In one or more, but be not limited only to this.
As preferably, the mixed solution a) that hydrolyzed solution is following component composition hydrolyzing use in described method is selected from
NaOH, KOH, LiOH, CsOH, 1,8-diazabicyclo (5.4.0) 11-7-alkene (DBU), K2CO3、Cs2CO3In one or
Several, b) water, and c) selected from dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane
With replacement pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane, normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halogen
For benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl ether, oxolane, tetrahydrochysene
Pyrans, 1,4-dioxane, alkyl formate, alkyl acetate, alkyl propionates, alkyl butyrate, benzoic acid Arrcostab, nitre
Methylmethane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl
Acetamide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone and
One or more in pentanone, but it is not limited only to this.
As preferably, in described method, purification uses chromatography of ions, C18 or C8 high-efficient liquid phase reversed phase chromatography, or by
H2The mixed solvent of one or more solvents composition in O, acetonitrile, formic acid, phosphoric acid, methanol, ethanol, isopropanol and acetone is heavily tied
Crystalline substance is carried out, but is not limited only to this.It is more preferably chromatography of ions in an embodiment of the present invention thick peptide is purified.
The method has the advantage that 1 compared with method described in patent before) process conditions require low.Institute in this method
The most required mild condition to equipment without particular/special requirement；2) yield is high.Due to trityl and derivant thereof and Boc, Fmoc
Or Cbz compares ester dissolubility more preferably, therefore corresponding raw material or intermediate are protected compared with rear several radical protections by Trt ', and each step is instead
Answering and lose relatively smaller in last handling process, yield is higher；3) production cost is low.The all raw materials related in this method and reagent
The most large-scale commercial, simple and easy to get and price is relatively low；4) side reaction is few.Trt protection group is produced triphen after removing
Base cation is preferable without addition side reaction and ester dissolubility to Trp side chain.Owing to the water solublity of product is preferable, therefore by-product is permissible
Remove easily.
Accompanying drawing explanation
Fig. 1: Trt-Glu-OtBu1H NMR spectra.
Fig. 2: H-D-GAMMA-Glu-D-Trp-OH1H NMR spectra.
Fig. 3: H-D-GAMMA-Glu-D-Trp-OH HPLC spectrogram.
Fig. 4: H-D-GAMMA-Glu-D-Trp-OH mass spectrum.
Detailed description of the invention
The present invention is open has a kind of method synthesizing H-D-GAMMA-Glu-D-Trp-OH.Those skilled in the art are permissible
Use for reference present invention, be suitably modified technological parameter and realize.Special needs to be pointed out is, all similar replacements and change are to this
Will be apparent from for skilled person, they are considered as being included in the present invention.The method of the present invention has been led to
Crossing preferred embodiments to be described, related personnel substantially can not be to institute in this paper in without departing from present invention, spirit and scope
State methods and applications to be modified, suitably change and combine and realize and apply the technology of the present invention.
Below in conjunction with embodiment, the present invention is expanded on further.
Embodiment 1.
1.1:Trt-Glu-O t The synthesis of Bu.
500 ml three-necked bottles add H-D-Glu-O t Bu (10.0 g, 49.2 mmol), then evacuation, nitrogen charging
Gas is repeatedly for three times；Be sequentially added under nitrogen atmosphere chloroform (150 ml), trim,ethylchlorosilane (25.0 ml, 197
And triethylamine (61.7 ml, 443 mmol) mmol)；After gained mixture is stirred at room temperature 15 minutes, under nitrogen atmosphere
Add chlorotrityl (13.7 g, 49.2 mmol)；After gained solution is stirred at room temperature overnight, add methanol (10
And be stirred at room temperature 30 minutes ml).Solution in three-necked bottle is poured in 1000 ml separatory funnels, with the phosphoric acid of 10%
(200 ml) washs three times, and saturated aqueous common salt (200 ml) washed once, isolated organic facies.It is dried with anhydrous sodium sulfate
Gained organic facies 30 minutes.After solids removed by filtration, gained filtrate concentrates and is evaporated, and obtaining white solid is Trt-D-Glu-O t
Bu (20.47 g, yield 89.9%；1H NMR (Fig. 1, CDCl3) δ7.378-7.397 (6H, m), 7.180-7.216
(6H, m), 7.103-7.139 (3H, m), 3.396-3.418 (1H, t, J = 4.4 Hz), 2.425-2.485
(1H, m), 2.215-2.292 (1H, m), 1.830-1.860 (2H, t, J = 6.0 Hz), 1.144 (9H, s);
HPLC purity: 96.3%).
1.2:Trt-D-Glu (D-Trp-O t Bu)-O t The synthesis of Bu.
500 ml single port flasks add and is sequentially added into DMF (200 ml), Trt-Glu-O t Bu (10.36 g, 22.4
Mmol, purity 96.3%), H-D-Trp-O t Bu (5.83 g, 22.4 mmol) and HOBt (3.03 g, 22.4
mmol).Stir to gained solution clarify after, add EDCIHCl (4.29 g, 22.4 mmol) and triethylamine (3.12 ml,
22.4 mmol).After gained solution is stirred overnight at ambient temperature, reaction solution is poured in 1000 ml water, in a large number white
Precipitation.Gained precipitation water and ether washing final vacuum are dried, and obtaining pale solid is Trt-D-Glu (D-Trp-O t
Bu)-O t Bu(15.7 g, yield 86.8%；HPLC purity: 85.2%).
The synthesis of the thick peptide of 1.3:H-D-Glu (D-Trp-OH)-OH.
500 ml single port flask bottles add Trt-D-Glu (D-Trp-O t Bu)-O t Bu (10.0 g, 12.4
Mmol, purity 85.2%), ethyl acetate (150 ml), dithioglycol (1.5 ml) and H2O (0.5 ml).Stirring is to completely
After dissolving, being slowly passed in solution by HCl gas, a large amount of solids separate out.Stirring and ventilation is stopped after 30 minutes, solution is dense
Contracting, obtains yellow oil (HPLC purity: 72.3%).
1.4:D-isoglutamine-D-trp.
Above-mentioned yellow oil Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects after loading
And merge fraction.After gained fraction lyophilization, obtain white powder H-D-GAMMA-Glu-D-Trp-OH (3.43 g,
Yield 83.0%).1H NMR (Fig. 2, CD3OD) δ 7.541-7.560 (1H, d,J = 7.8 Hz), 7.307-7.327
(1H, d, J = 7.8 Hz), 6.987-7.095 (3H, m), 4.698-4.984 (1H, m), 3.775-3.806
(1H, t, J = 6 Hz), 3.351-3.338 (1H, m), 3.120-3.178 (1H, m), 2.397-2.463 (1H,
m), 1.198-2.102 (1H, m);HPLC purity (Fig. 3): 99.4 %;Mass spectrum (Fig. 4): ESI m/z, 334.2(M++H,
100)。
Embodiment 2.
The synthesis of 2.1:Trt-Glu-OMe.
Adding H-D-Glu-OMe (10.0 g, 62.1 mmol) in 500 ml three-necked bottles, then evacuation, inflated with nitrogen are anti-
Multiple three times；It is sequentially added into chloroform (200 ml), trim,ethylchlorosilane (31.4 ml, 248 mmol) under nitrogen atmosphere
With triethylamine (77.9 ml, 559 mmol)；After gained mixture is stirred at room temperature 15 minutes, add under nitrogen atmosphere
Chlorotrityl (17.3 g, 62.1 mmol)；After gained solution is stirred at room temperature overnight, add methanol (10 ml)
And it is stirred at room temperature 30 minutes.Solution in three-necked bottle is poured into the phosphoric acid (200 in 1000 ml separatory funnels, with 10%
Ml) washing three times, saturated aqueous common salt (200 ml) washed once, isolated organic facies.It is dried gained with anhydrous sodium sulfate to have
Machine 30 minutes mutually.After solids removed by filtration, gained filtrate concentrates and is evaporated, and the white solid obtained is Trt-D-Glu-OMe
(22.5 g, yield: 85.7%).1H NMR (CDCl3)δ7.397-7.416 (6H, m), 7.146-7.201 (6H, m),
7.103-7.121 (3H, m), 3.359-3.389 (1H, t, J = 6.0 Hz), 3.098 (3H, s), 2.441-
2.484 (1H, m), 2.307-2.387 (1H, m), 1.973-2.026 (2H, m);HPLC purity: 95.4 %.
The synthesis of 2.2:Trt-D-Glu (D-Trp-OMe)-OMe.
In 250 ml single port flasks add be sequentially added into DMF (200 ml), Trt-Glu-OMe (9.43 g, 22.3
Mmol, purity 95.4%), H-D-Trp-OMe (4.87g, 22.3 mmol), HOBt (3.01 g, 22.3 mmol) and
DMF (80.0 ml).After the agitated clarification of gained solution, add EDCIHCl (4.27 g, 22.3 mmol) and triethylamine
(3.11 ml, 22.3 mmol).After gained solution is stirred overnight at ambient temperature into, reaction solution is poured 1000 ml water
In, a large amount of white precipitates separate out.Gained precipitation water and ether washing final vacuum are dried, and the white solid obtained is Trt-D-
Glu (D-Trp-OMe)-OMe (12.9 g, yield: 81.2%, HPLC purity: 84.8%).
The synthesis of 2.3:H-D-Glu (D-Trp-OMe)-OMe.
100 ml single port flasks add Trt-D-Glu (D-Trp-OMe)-OMe (6.37 g, 8.95 mmol, purity
84.8%), ethyl acetate (40.0 ml), H2HCl gas, to after being completely dissolved, is slowly passed into molten by O (0.15 ml) stirring
In liquid, a large amount of solids separate out.Stop stirring and ventilation after 30 minutes, after being concentrated by solution, obtain white-yellowish solid.This solid is used
It is vacuum dried again after petroleum ether, obtains white solid.(3.39 g, yield: 98.1%;HPLC purity: 93.6%).
The synthesis of the thick peptide of 2.4:H-D-Glu (D-Trp-OH)-OH.
100 ml single port flasks add H-D-Glu (D-Trp-OMe)-OMe (3.00 g, 7.77 mmol, purity
93.6%) and 2MNaOH aqueous solution (20 ml), it is completely dissolved after being stirred at room temperature 10 minutes.It is little that gained solution at room temperature reacts 2
Shi Hou, reacting liquid pH value is transferred to 2 ~ 3 with 20% phosphate aqueous solution, and (HPLC is pure to obtain white solid after gained solution lyophilization
Degree: 88.4%).
2.5:D-isoglutamine-D-trp.
Above-mentioned white solid Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects also after loading
Merge fraction.After gained fraction lyophilization, obtain H-D-GAMMA-Glu-D-Trp-OH (2.24 g, the receipts of white powder
Rate: 86.5 %, HPLC purity: 99.5%).
Embodiment 3.
The synthesis of 3.1:Trt-D-Glu (D-Trp-OMe)-OMe is identical with 2.2.
The synthesis of 3.2:Trt-D-Glu (D-Trp-OH)-OH.
In 100 ml single port flasks add Trt-D-Glu (D-Trp-OMe)-OMe (6.37 g, 8.95 mmol, pure
Degree: 84.8%), methanol (40.0 ml) and 2M NaOH aqueous solution (10.0 ml).After being stirred at room temperature 15 minutes, solid is the most molten
Solve.After gained solution at room temperature reacts 4 hours, reacting liquid pH value is transferred to 2 ~ 3 with 5% phosphate aqueous solution.Then by reaction solution
Concentrate, add water (50.0 ml).By ethyl acetate (150.0 ml) aqueous phase extracted three times, combined ethyl acetate is the most afterwards with saturated
NaCl.Gained organic facies anhydrous sodium sulfate is dried, filter, obtain after concentration yellow solid (5.01 g, yield:
80.9%, HPLC purity: 83.2%).
The synthesis of 3.3:H-D-Glu (D-Trp-OH)-OH.
In 100 ml single port flasks add Trt-D-Glu (D-Trp-OH)-OH (5.01 g, 7.24 mmol, purity:
83.2%) and ethyl acetate (60 ml) and H2O (0.2 ml).Stir to after being completely dissolved, HCl gas is slowly passed into
In solution, a large amount of solids separate out.Stopping stirring and ventilation after 30 minutes, concentrated by solution, (HPLC is pure to obtain yellow oil
Degree: 78.3%).
3.4:D-isoglutamine-D-trp.
Above-mentioned yellow oil Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects after loading
And merge fraction.After gained fraction lyophilization, obtain white powder H-D-GAMMA-Glu-D-Trp-OH (1.99 g,
Yield: 82.5%, HPLC purity: 99.5%).
Embodiment 4.
The synthesis of 4.1:Trt-Glu-OBzl.
500 ml three-necked bottles add H-D-Glu-OBzl (10.0 g, 42.1 mmol), then evacuation, inflated with nitrogen
Repeatedly for three times；Be sequentially added under nitrogen atmosphere chloroform (200 ml), trim,ethylchlorosilane (21.3 ml, 168
And triethylamine (52.8 ml, 379 mmol) mmol)；After gained mixture is stirred at room temperature 15 minutes, under nitrogen atmosphere
Add chlorotrityl (11.7 g, 42.1 mmol)；After gained solution is stirred at room temperature overnight, add methanol (10
And be stirred at room temperature 30 minutes ml).Solution in three-necked bottle is poured in 1000 ml separatory funnels, with the phosphoric acid of 10%
(200 ml) washs three times, and saturated aqueous common salt (200 ml) washed once, isolated organic facies.It is dried with anhydrous sodium sulfate
Gained organic facies 30 minutes.After solids removed by filtration, gained filtrate concentrates and is evaporated, and obtains the Trt-D-Glu-OBzl of white solid
(17.8 g, yield: 85.4%,1H NMR (CDCl3)δ7.157-7.334 (7H, m), 7.004-7.157 (13H, m),
4.468-4.499 (1H, d, J = 12.4 Hz), 4.252-4.283 (1H, d, J = 12.4 Hz), 3.343-
3.372 (1H, t, J = 5.6 Hz), 2.297-2.358 (1H, m), 2.181-2.226 (1H, m), 1.891-
1.910 (2H, m);HPLC purity: 96.9 %.
The synthesis of 4.2:Trt-Glu (D-Trp-OBzl)-OBzl.
Addition Trt-D-Glu-OBzl (9.30 g, 18.8 mmol, purity: 96.9 %) in 250 ml single port flasks,
H-D-Trp-OBzl (5.53g, 18.8 mmol), HOBt (2.54 g, 18.8 mmol) and DMF (80.0 ml)；Gained
After the agitated clarification of solution, add EDCIHCl (3.60 g, 18.8 mmol) and triethylamine (2.62 ml, 18.8
mmol)；After gained solution is stirred overnight at ambient temperature, being poured into by reaction solution in 1000 ml water, a large amount of white precipitates are analysed
Go out.Gained precipitation water and ether washing final vacuum are dried, and obtain Trt-D-Glu (the D-Trp-OBzl)-OBzl of white solid
(13.6 g, yield: 84.0%, HPLC purity: 87.8%).
The synthesis of 4.3:H-Glu (D-Trp-OBzl)-OBzl.
In 100 ml single port flasks add Trt-Glu (D-Trp-OBzl)-OBzl (6.0g, 6.97mmol, purity:
87.8%), ethyl acetate (40.0 ml), H2O (0.15 ml), stirs to after being completely dissolved, is slowly passed into by HCl gas
In solution, a large amount of solids separate out.Stop stirring and ventilation after 30 minutes, after being concentrated by solution, obtain white-yellowish solid.This solid
It is vacuum dried again after petroleum ether, obtains white solid (4.05g, yield: 94.0%, HPLC purity: 83.1%).
The synthesis of 4.4:H-Glu (D-Trp-OH)-OH.
In 100 ml single port flasks add H-D-Glu (D-Trp-OBzl)-OBzl (2.03 g, 3.28 mmol, pure
Degree: 83.1%) and 2M NaOH aqueous solution (30 ml), it is completely dissolved after being stirred at room temperature 10 minutes.Gained solution at room temperature reacts
After 2 hours, reacting liquid pH value is transferred to 2 ~ 3 with 20% phosphate aqueous solution, obtains white solid (HPLC after gained solution lyophilization
Purity: 78.4%).
4.5:D-isoglutamine-D-trp.
Above-mentioned white solid Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects also after loading
Merge fraction.After gained fraction lyophilization, obtain H-D-GAMMA-Glu-D-Trp-OH (0.791 g, the receipts of white powder
Rate: 72.3%, HPLC purity: 99.4%).
Embodiment 5.
The synthesis of 5.1:H-D-Glu (D-Trp-OBzl)-OBzl is identical with 4.3.
The synthesis of the thick peptide of 5.2:H-D-Glu (D-Trp-OH)-OH.
In 50 ml single port flasks add H-D-Glu (D-Trp-OBzl)-OBzl (2.025 g, 3.40 mmol, pure
Degree: 83.1%) and methanol (25.0 ml), until being completely dissolved after being stirred at room temperature 5 minutes；Then add in this settled solution
200mg Pd/C, reactant mixture is stirred overnight under the nitrogen atmosphere of 2 atmospheric pressure；Then reaction system being filtered, filtrate is dense
White solid (HPLC purity: 61.5%) is obtained after contracting.
5.3:D-isoglutamine-D-trp.
Above-mentioned white solid Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects also after loading
Merge fraction.After gained fraction lyophilization, obtain H-D-GAMMA-Glu-D-Trp-OH (0.835 g, the receipts of white powder
Rate: 73.7%, HPLC purity: 99.4%).
Embodiment 6.
The synthesis of 6.1:Trt-D-Glu (D-Trp-OBzl)-OBzl is identical with 4.2.
The synthesis of the thick peptide of 6.2:H-D-Glu (D-Trp-OH)-OH.
In 100 ml single port flasks add Trt-Glu (D-Trp-OBzl)-OBzl (6.0g, 6.97mmol, purity:
87.8%), methanol (60.0 ml), stir to after being completely dissolved, in this settled solution, add 600mg Pd/C, reaction mixing
Thing is stirred overnight under the nitrogen atmosphere of 2 atmospheric pressure；Then reaction system being filtered, filtrate obtains white solid after concentrating
(HPLC purity: 26.2%).
6.3:D-isoglutamine-D-trp.
Above-mentioned white solid Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects also after loading
Merge fraction.After gained fraction lyophilization, obtain H-D-GAMMA-Glu-D-Trp-OH (1.92 g, the receipts of white powder
Rate: 82.6%;HPLC purity: 99.5%).
Embodiment 7.
The synthesis of 7.1:Trt-D-Glu-OH.
Adding H-D-Glu-OH (10.0 g, 68.0 mmol) in 500 ml three-necked bottles, then evacuation, inflated with nitrogen are anti-
Multiple three times；It is sequentially added into chloroform (200 ml), trim,ethylchlorosilane (34.5 ml, 272 mmol) under nitrogen atmosphere
With triethylamine (85.3 ml, 612 mmol)；After gained mixture is stirred at room temperature 5 minutes, add chlorine under nitrogen atmosphere
For trityl (37.9 g, 136 mmol)；After gained solution is stirred at room temperature overnight, add methanol (20 ml) and
Stir 30 minutes under room temperature.Being poured into by solution in three-necked bottle in 1000 ml separatory funnels, the phosphoric acid (200 ml) with 10% is washed
Washing three times, saturated aqueous common salt (200 ml) washed once, isolated organic facies.It is dried gained organic facies with anhydrous sodium sulfate
30 minutes.After solids removed by filtration, gained filtrate concentrate be evaporated, the white solid obtained be Trt-D-Glu-OH (22.9 g,
Yield: 82.6%,1H NMR (CDCl3)δ7.456-7.475 (6H, m), 7.250-7.339 (9H, m), 3.627-
3.633 (1H, t, J = 5.8 Hz), 2.541-2.556 (1H, m), 2.474-2.497 (1H, m), 2.031-
2.100 (2H, m);HPLC purity: 95.5%).
The synthesis of 7.2:Trt-D-Glu (D-Trp-OH)-OH.
250 ml single port flasks add Trt-D-Glu-OH (10.5 g, 25.7 mmol, purity: 95.5%), H-D-
Trp-OH (5.25 g, 25.7 mmol), HOBt (3.47 g, 25.7 mmol) and DMF (80.0 ml);Gained solution
After agitated clarification, add EDCIHCl (4.93 g, 25.7 mmol) and triethylamine (3.58 ml, 25.7 mmol)；Institute
After solution is stirred overnight at ambient temperature, reaction solution is poured in 1000 ml water, a large amount of white precipitates separate out.Gained
Precipitation water and ether washing final vacuum are dried, and obtaining white solid is Trt-D-Glu (D-Trp-OH)-OH and Trt-D-Glu-
(its ratio is 2.32/1 to the mixture of D-Trp-OH for 14.1g, yield: 82.6%;HPLC purity: 86.7%).
The synthesis of the thick peptide of 7.3:H-D-Glu (D-Trp-OH)-OH.
100 ml single port flasks add the mixing of Trt-D-Glu (D-Trp-OH)-OH and Trt-D-Glu-D-Trp-OH
Thing (7.05g, 10.6 mmol, HPLC purity: 86.7%), is subsequently adding ethyl acetate (50 ml), H2O (0.15 ml)。
Stirring to after being completely dissolved, be slowly passed in solution by HCl gas, a large amount of solids separate out.Stop stirring after 30 minutes and lead to
Gas, concentrates solution, obtains yellow oil, wherein comprise H-D-Glu (D-Trp-OH)-OH's and H-D-Glu-D-Trp-OH
Mixture (HPLC purity: 75.3%;Both ratios are 2.32/1).
7.4:D-isoglutamine-D-trp.
Above-mentioned white solid Dowex 50WX2 cation exchange resin purification, uses gradient elution, collects also after loading
Merge fraction.After gained fraction lyophilization, obtain H-D-GAMMA-Glu-D-Trp-OH (1.85 g, the receipts of white powder
Rate: 52.4%, HPLC purity: 99.2%).
Claims (19)
1. the method synthesizing H-D-GAMMA-Glu-D-Trp-OH, it is characterised in that comprise the following steps:
A) with H-D-Glu-OR2(compound I) is raw material, uses R1 3SiX1With Trt ' X after processing with organic base2(compound II)
Reaction, obtains intermediate Trt '-D-Glu-OR2(compound III);
B) (condensation reagent, activating reagent and alkali), compound III and H-D-Trp-OR under condensation condition3(compound IV) contracts
Close, obtain the dipeptides Trt '-D-Glu (D-Trp-OR of band protection group3)-OR2(compound V)；
C) by obtaining thick peptide after the method process compound V of one of the following: 1) acidolysis, 2) hydrogenolysis, 3) first through acidolysis, then water
Solve or hydrogenolysis, 4) first through hydrolysis, then acidolysis；
D) H-D-iGlu-D-Trp-OH is obtained after the thick peptide of step c) acquisition is purified；
Wherein, R2For hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, 2-butyl, the tert-butyl group, 2 '-propyloxy phenyl
Base, 2-chlorine trityl, trityl, C5～C10 alkyl, C3～C10 cycloalkyl, phenyl or substituted-phenyl, benzyl or replacement
Benzyl；Three R1Group is each independently C1～C10 alkyl, C3～C10 cycloalkyl, phenyl or substituted-phenyl, benzyl or takes
For benzyl；X1For F, Cl, Br, I, CN, SCN or trifluoromethanesulfonic acid ester group；Trt ' be carry on trityl group or phenyl ring substituted
The trityl group of base；X2For F, Cl, Br, I, CN, SCN or trifluoromethanesulfonic acid ester group；R3For hydrogen, methyl, ethyl, propyl group, isopropyl
Base, normal-butyl, isobutyl group, 2-butyl, the tert-butyl group, 2 '-propyloxy phenyl base, 2-chlorine trityl, trityl, C5～C10 alkane
Base, C3～C10 cycloalkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl.
Method the most according to claim 1, it is characterised in that organic base used by step a) selected from DIPEA,
One or more in triethylamine, N-methylmorpholine and 1,8-diazabicyclo (5.4.0) 11-7-alkene (DBU).
3. according to method described in claim 1 to 2 any one, it is characterised in that with the triphen of substituent group on described phenyl ring
Methyl, its substituent group can be H, OH, SH, NH2；Can be F, Cl, Br, I, CNSCN and trifluoromethanesulfonic acid ester group；Can be C1
～C10 alkyl, C3～C10 cycloalkyl, phenyl and substituted-phenyl；Can be C1～C10 alkoxyl, C3～C10 cycloalkyloxy, benzene
Base and substituted-phenyl epoxide；Can be C1～C10 alkylamino, C3～C10 naphthene amino, phenyl and substituted-phenyl amino；Described
On phenyl ring with substituent group can be the combination of one or more in above-mentioned substituent group；These substituent groups can be same
On phenyl ring or on different phenyl ring.
4. according to method described in claims 1 to 3 any one, it is characterised in that synthetic intermediate Trt '-D-Glu-OR2(change
Compound III) reaction in use solvent can carry out in single solvent, it is possible to molten in the mixing being made up of multi-solvents
Agent is carried out.
Method the most according to claim 4, it is characterised in that synthetic intermediate Trt '-D-Glu-OR2(compound III's)
The solvent used in reaction is: dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane
With replacement pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane, normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halogen
For benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl ether, oxolane, tetrahydrochysene
Pyrans, 1,4-dioxane, alkyl formate, alkyl acetate, alkyl propionates, alkyl butyrate, benzoic acid Arrcostab, nitre
Methylmethane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl
Acetamide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone and
Pentanone；Reaction can be carried out in single solvent, it is possible to carries out in the mixed solvent being made up of above-mentioned multi-solvents.
6. according to method described in claim 1 to 5 any one, it is characterised in that in described method, condensation reagent is N, N-bis-
Diisopropylcarbodiimide (DIC), N, N-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl carbon two Asia
Amine hydrochlorate (EDCI HCl), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU)/
Organic base, O-BTA-tetramethylurea hexafluorophosphoric acid ester (HBTU)/organic base, BTA-1-base epoxide three (two
Methylamino) phosphorus hexafluorophosphate (BOP)/organic base, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus
(PyBOP)/organic base and O-BTA-N, N, N ', in N '-tetramethylurea Tetrafluoroboric acid ester (TBTU)/organic base
Plant or multiple；Organic base in condensation reagent be the one in N, N-diisopropylethylamine, triethylamine or N-methylmorpholine or
Multiple.
7. according to method described in claim 1 to 6 any one, it is characterised in that described activating reagent is N-hydroxysuccinimidyl acyl
Imines (HOSu), I-hydroxybenzotriazole (HOBt), 1-hydroxyl-7-azo BTA (HOAt), 3-hydroxyl-1,2,3-benzene
And the one or many in triazine-4 (3H)-one (HODhBt) or N-hydroxyl-5-norborene-2,3-dicarboximide (HONb)
Kind.
8. according to method described in claim 1 to 7 any one, it is characterised in that condensation reaction is carried out in a solvent, used molten
Agent can be single solvent, it is also possible to be the mixed solvent of multi-solvents composition.
Method the most according to claim 8, it is characterised in that solvent for use be dichloromethane, chloroform, carbon tetrachloride,
Ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane and replacement pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane,
Normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halogeno-benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl-tert
Butyl ether, alkyl phenyl ether, oxolane, Pentamethylene oxide., 1,4-dioxane, alkyl formate, alkyl acetate, propanoic acid alkane
Base ester, alkyl butyrate, benzoic acid Arrcostab, nitromethane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene second
Nitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl acetamide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide,
Thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone, pentanone, water, methanol, ethanol, propanol, isopropanol and butanol；Reaction can be
Single solvent is carried out, it is possible to carry out in the mixed solvent being made up of above-mentioned multi-solvents.
10. according to method described in claim 1 to 9 any one, it is characterised in that the alkali used by condensation reaction is selected from N, N-
Diisopropylethylamine, triethylamine, N-methylmorpholine, 1,8-diazabicyclo (5.4.0) 11-7-alkene (DBU), sodium carbonate,
One or more in sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate.
11. according to method described in claim 1 to 10 any one, it is characterised in that the acidolysis that in described method, acidolysis uses
Liquid is the mixed solution of following component composition: a) selected from formic acid, acetic acid, trifluoroacetic acid, in trifluoromethanesulfonic acid or hydrogen halides
Plant or multiple compounds；B) one in thioanisole, methyl phenyl ethers anisole, dithioglycol, tri isopropyl silane, phenol, indole
Or several compound；And c) selected from a kind of or mixed solvent of polar solvent composition.
12. according to method described in claim 11, it is characterised in that described hydrogen halides be fluohydric acid gas, hydrogen chloride, hydrogen bromide or
Hydrogen iodide；Described solvent be dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,2-dichloroethanes, chloropropane, pentane and
Replace pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane, normal heptane, toluene, dimethylbenzene, Nitrobenzol, various halo
Benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkyl phenyl ether, oxolane, tetrahydrochysene pyrrole
Mutter, 1,4-dioxane, alkyl formate, alkyl acetate, alkyl propionates, alkyl butyrate, benzoic acid Arrcostab, nitro
Methane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-dimethyl Methanamide, N, N '-dimethyl second
Amide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, dimethyl sulfoxide, dimethylsulfone, acetone, butanone, penta
Ketone, water, formic acid, acetic acid, propanoic acid and benzoic acid.
13. according to method described in claim 1 to 12 any one, it is characterised in that in described method, hydrogenolysis is 20 ~ 100oC,
Hydrogen pressure is 2 ~ 5 atmospheric pressure, carries out under the effect of catalyst；Also can be in the one of cyclohexene, formic acid, ammonium formate or tetrahydronaphthalene
Or carry out under the effect of several reagent and catalyst.
14. according to method described in claim 13, it is characterised in that described catalyst is Pd/C, Pd/BaSO4、PdCl2、Pd
(OH)2、Raney Ni、Pt、Pt/C、PtO2、(Ph3P)3·RhCl、(Ph3P)3·RuCl2In one or more.
15. according to method described in claim 1 to 14 any one, it is characterised in that hydrolyze the hydrolysis of use in described method
Liquid is the mixed solution of following component composition: a) selected from NaOH, KOH, LiOH, CsOH, 1,8-diazabicyclo (5.4.0) ten
One-7-alkene (DBU), K2CO3、Cs2CO3In one or more, b) water, and c) one or more groups in the polar solvent
The mixed solvent become.
16. according to method described in claim 15, described solvent be dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, 1,
2-dichloroethanes, chloropropane, pentane and replacement pentane, hexane and replacement hexane, hexamethylene and substituted cyclohexane, normal heptane, first
Benzene, dimethylbenzene, Nitrobenzol, various halogeno-benzene, ether, propyl ether, diisopropyl ether, butyl ether, isoamyl oxide, hexyl ether, methyl tertiary butyl ether(MTBE), alkane
Base phenyl ether, oxolane, Pentamethylene oxide., 1,4-dioxane, alkyl formate, alkyl acetate, alkyl propionates, butanoic acid
Arrcostab, benzoic acid Arrcostab, nitromethane, nitroethane, nitropropane, acetonitrile, propionitrile, butyronitrile, benzene acetonitrile, N, N '-two
Methylformamide, N, N '-dimethyl acetamide, N methyl pyrrolidone, Benzoylamide, methyl sulfide, ethyl sulfide, thiophene, diformazan are sub-
Sulfone, dimethylsulfone, acetone, butanone and pentanone.
17. according to method described in claim 1 to 16 any one, it is characterised in that in described method, purification uses ion color
Spectrum, C18 or C8 high-efficient liquid phase reversed phase chromatography, or by H2In O, acetonitrile, formic acid, phosphoric acid, methanol, ethanol, isopropanol and acetone
One or more solvents composition mixed solvent recrystallization carry out.
18. 1 kinds of polypeptide intermediate, its chemical formula is Trt '-D-Glu-OR2(compound III), wherein, R2For hydrogen, methyl, second
Base, propyl group, isopropyl, normal-butyl, isobutyl group, 2-butyl, the tert-butyl group, 2 '-propyloxy phenyl base, 2-chlorine trityl, triphen first
Base, C5～C10 alkyl, C3～C10 cycloalkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；Trt ' be trityl group or
With the trityl group of substituent group on phenyl ring.
19. intermediate according to claim 18, it is characterised in that on described phenyl ring with substituent group can be H,
OH, SH, NH2；Can be F, Cl, Br, I, CN, SCN and trifluoromethanesulfonic acid ester group；Can be C1～C10 alkyl, C3～C10 ring
Alkyl, phenyl and substituted-phenyl；Can be C1～C10 alkoxyl, C3～C10 cycloalkyloxy, phenyl and substituted-phenyl epoxide；Can
To be C1～C10 alkylamino, C3～C10 naphthene amino, phenyl and substituted-phenyl amino；On described phenyl ring with substituent group can
To be the combination of one or more in above-mentioned substituent group；These substituent groups can be on same phenyl ring or different phenyl ring
On.
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