CN101219970A - Method for synthesizing N-fluorene methoxycarbonyl-N-trityl-D-glutamine - Google Patents
Method for synthesizing N-fluorene methoxycarbonyl-N-trityl-D-glutamine Download PDFInfo
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- CN101219970A CN101219970A CNA2007100362680A CN200710036268A CN101219970A CN 101219970 A CN101219970 A CN 101219970A CN A2007100362680 A CNA2007100362680 A CN A2007100362680A CN 200710036268 A CN200710036268 A CN 200710036268A CN 101219970 A CN101219970 A CN 101219970A
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- glutamine
- carbobenzoxy
- trityl
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- benzyl
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a synthetic method of N-fluorenylmethoxycarbonyl-N- triphenylmethyl-D-glutamine to solve the current problems of the shortage of D-Gln raw materials and high cost of synthesizing products from the D-Gln. The synthesis includes the following steps: a. D-glutamate and a carbobenzoxy chloride are reacted to get the N-carbobenzoxy-D-glutamate; in an organic solvent N and N-dimethylformamide with the existence of a triethylamine and bromomethyl-benzene, the N-carbobenzoxy-D-glutamate selectively protects an Alpha-carboxyl to get an N-benzyloxycarbonyl-D-benzyl L-glutamate; b. the triethylamine, ethyl chloroformate and ammonia are added to N- benzyloxycarbonyl-D- benzyl L-glutamate organic solvent with a molar ratio of 1:1:2 to 6; after reacted for 6 to 24 hours under a temperature of -20 to 20 DEG C, an N- benzyloxycarbonyl-D-glutaminebenzylester is gotten; c. the product of b, acetate liquor is reacted with a triphenylmethanol under a catalysis of concentrated sulfuric acid, and N- benzyloxycarbonyl-N-triphenylmethyl-D-glutaminebenzylester can be gotten after reacted for 8 to 24 hours under a temperature of 40 to 60 DEG C; d. benzyloxycarbonyl and benzyl are detracted from the product of c to get the N-triphenylmethyl-D-glutamine; e. the product of d is protected by an Fmoc group to get the N-fluorenylmethoxycarbonyl-N-triphenylmethyl-D- glutamine.
Description
Technical field:
The present invention relates to a kind of N-fluorene methoxycarbonyl-N-trityl-D-glutamine (synthetic method of Fmoc-D-Gln (Trt)-OH).
Background technology:
The N-fluorene methoxycarbonyl-N-trityl-D-glutamine is that solid phase connects reagent commonly used in the peptide, and we can be that initial feed is synthesized (ref:Tetrahedron Lett with the D-glutamine by simpler method; EN; 32; 6; 1991; 739-742), promptly Z-D-Gln-OH obtains product through three-step reaction, but because the lower and D-Gln market price of raw material costliness of productivity ratio, the D-Glu price is then relatively cheap a lot, so we have researched and developed this synthetic method from this angle.Fmoc-Gln (Trt)-OH structural formula is:
Summary of the invention:
The synthesis method that the purpose of this invention is to provide a kind of N-fluorene methoxycarbonyl-N-trityl-D-glutamine.Solve and adopt the synthetic cost problem of higher of D-glutamine at present.Technical scheme specifically comprises the steps:
1.D-L-glutamic acid and Z-Cl (Carbobenzoxy Chloride) reaction obtains Z-D-Glu-OH (N-carbobenzoxy-(Cbz)-D-L-glutamic acid); Z-D-Glu-OH is at organic solvent N; in the dinethylformamide; at triethylamine; under the existence of bromobenzyl; optionally protect α-carboxyl, obtain Z-D-Glu-OBzl (N-carbobenzoxy-(Cbz)-D-benzyl glutamate).
2.Z-D-Glu-OBz l in organic solvent, adds triethylamine, Vinyl chloroformate, ammoniacal liquor (mol ratio: 1: 1: 2 ~ 6), obtain Z-D-Gln-OBzl (N-carbobenzoxy-(Cbz)-D-glutamine benzyl ester)-20 ~ 20 ℃ of reactions after 6 ~ 24 hours.Organic solvent is tetrahydrofuran (THF) or ethyl acetate;
3.Z-D-Gln-OBzl acetum under sulphuric acid catalysis with trityl alcohol reaction, obtained Z-D-Gln (Trt)-OBzl (N-carbobenzoxy-(Cbz)-N-trityl-D-glutamine benzyl ester) in 8 ~ 24 hours 45 ~ 60 ℃ of reactions;
4.Z-D-Gln (Trt)-OBzl hydrogenation sloughs Z group and Bzl group, obtains D-Gln (Trt)-OH (N-trityl-D-glutamine).Slough a kind of with in a kind of and hydrogen in 10% palladium carbon, the 5% palladium carbon, the tetrahydrobenzene of Z-, Bzl-protection;
5.D-Gln (Trt)-the last Fmoc protecting group of OH obtains Fmoc-D-Gln (Trt)-OH (N-fluorene methoxycarbonyl-N-trityl-D-glutamine).With Fmoc-Cl (fluorenes methoxy dicarbonyl chloride) or Fmoc-Osu (fluorenes methoxy carbonyl acyl succinimide) as last protection reagent.
Some abbreviations commonly used have following implication among the present invention:
Fmoc: fluorenylmethyloxycarbonyl
Z-: carbobenzoxy-(Cbz)
Trt-: trityl
BrBzl: bromobenzyl
OBzl: benzyl ester
Glu: L-glutamic acid
Gln: glutamine
DMF:N, dinethylformamide
ClCOOEt: Vinyl chloroformate
Et
3N: triethylamine
NH
3.H
2O: ammoniacal liquor
Pd/C: palladium/carbon
Z-D-Glu-OH:N-carbobenzoxy-(Cbz)-D-L-glutamic acid
Z-D-Glu-OBzl:N-carbobenzoxy-(Cbz)-D-benzyl glutamate
Z-D-Gln (Trt)-OBzl:N-carbobenzoxy-(Cbz)-N-trityl-D-glutamine benzyl ester
D-Gln (Trt)-OH:N-trityl-D-glutamine
Fmoc-D-Gln (Trt)-OH:N-fluorene methoxycarbonyl-N-trityl-D-glutamine
Synthetic route is as follows:
a)Z-Cl/NaOH，0℃→rt，35h90％；
b)Et
3N，BrBzl，DMF，rt，24h
(ref：Recl.Trav.Chim.Pays-Bas；EN；83；1964；199-207)
c)ClCOOEt/ET
3N，NH
3.H
2O，THF，-20~25℃
The invention has the beneficial effects as follows: utilize low price raw material D-L-glutamic acid to synthesize D-glutamine derivative, can reduce production costs more greatly.
Embodiment:
The present invention is described in further detail hereinafter with reference to example, but the invention is not restricted to these specific exampless.
Embodiment 1, and with reference to synthetic route, L-glutamic acid and Z-Cl obtain Z-D-Glu-OH 0-15 ℃ of reaction in sodium hydroxide solution.Z-D-Glu-OH is dissolved in DMF, adds the reaction of triethylamine and bromobenzyl and obtains Z-D-Glu-OBzl in 24 hours.10mmolZ-D-Glu-OBzl is dissolved among the 100mlTHF, adds 10mmolET
3N adds 10mmolClCOOEt at-10 ~-20 ℃, adds ammoniacal liquor 60mmol behind the 15-30min, room temperature reaction 6hr, and aftertreatment obtains product 3, and productive rate is 62%.With 10mmol compound 3, the 20mmol trityl alcohol is dissolved in 300mlHAc, adds 1mmol sulfuric acid, 20mmol acetic anhydride, and at 60 ℃ of reaction 8hr, aftertreatment gets product 4, and productive rate is 50%.10mmol compound 4 is dissolved in methyl alcohol, adds 0.3g10%Pd/C, logical hydrogen reaction 24hr, handle product 5, productive rate is 92%.10mmol compound 5 is dissolved in saturated sodium bicarbonate and dioxane, adds 10mmolFmoc-Osu, reacted 6 hours, aftertreatment obtains product 6, productive rate 85%, and HPLC98.0%,
Embodiment 2, and 10mmolZ-D-Glu-OBzl is dissolved among the 100mlTHF, add 10mmolET
3N adds 10mmolClCOOEt at-10 ~-20 ℃, adds 40mmol ammoniacal liquor behind the 15-30mi n, room temperature reaction 16hr, and aftertreatment obtains product 3, and productive rate is 60.5%.With 10mmol compound 3, the 20mmol trityl alcohol is dissolved in 300mlHAc, adds 1mmol sulfuric acid, 20mmol acetic anhydride, and at 50 ℃ of reaction 24hr, aftertreatment gets product 4, and productive rate is 48%.10mmol compound 4 is dissolved in methyl alcohol, adds 0.6g5%Pd/C, logical hydrogen reaction 36hr, handle product 5, productive rate is 91.5%.All the other are identical with embodiment 1.
Embodiment 3, and 10mmolZ-D-Glu-OBzl is dissolved in the 100ml ethyl acetate, add 10mmolET
3N adds 10mmolClCOOEt at-10 ~-20 ℃, adds 20mmol ammoniacal liquor behind the 15-30min, room temperature reaction 24hr, and aftertreatment obtains product 3, and productive rate is 60%.With 10mmol compound 3, the 20mmol trityl alcohol is dissolved in 300mlHAc, adds 1mmol sulfuric acid, 20mmol acetic anhydride, and at 45 ℃ of reaction 24hr, aftertreatment gets product 4, and productive rate is 47%.10mmol compound 4 is dissolved in methyl alcohol, adds 0.6g10%Pd/C, adds the 10ml tetrahydrobenzene and refluxes 8 hours, and aftertreatment gets product 5, and productive rate is 90%.10mmol compound 5 is dissolved in saturated sodium bicarbonate and dioxane, adds 10mmolFmoc-Cl, reacted 4 hours, aftertreatment obtains product 6.All the other are identical with embodiment 1.
Claims (4)
1. the synthesis method of a N-fluorene methoxycarbonyl-N-trityl-D-glutamine may further comprise the steps:
A.D-L-glutamic acid and Carbobenzoxy Chloride reaction obtain N-carbobenzoxy-(Cbz)-D L-glutamic acid, and N-carbobenzoxy-(Cbz)-D-L-glutamic acid is at organic solvent N, in the dinethylformamide, at triethylamine, under the existence of bromobenzyl, optionally protect α-carboxyl, obtain N-carbobenzoxy-(Cbz)-D-benzyl glutamate;
B.N-carbobenzoxy-(Cbz)-D-benzyl glutamate changes N-carbobenzoxy-(Cbz)-D-glutamine benzyl ester into: add triethylamine in the organic solvent of N-carbobenzoxy-(Cbz)-D-benzyl glutamate, Vinyl chloroformate, ammoniacal liquor, its mol ratio is 1: 1: 2 ~ 6, obtains N-carbobenzoxy-(Cbz)-D-glutamine benzyl ester-20 ~ 20 ℃ of reactions after 6 ~ 24 hours;
The acetum of c.N-carbobenzoxy-(Cbz)-D-glutamine benzyl ester reacts with trityl alcohol under sulphuric acid catalysis, obtains N-carbobenzoxy-(Cbz)-N-trityl-D-glutamine benzyl ester in 8 ~ 24 hours 45 ~ 60 ℃ of reactions;
D.N-carbobenzoxy-(Cbz)-N-trityl-D-glutamine benzyl ester sloughs carbobenzoxy-(Cbz) and benzyl obtains N-trityl-D-glutamine;
E.N-trityl-D-glutamine obtains the N-fluorene methoxycarbonyl-N-trityl-D-glutamine with the Fmoc radical protection.
2. the synthesis method of a kind of N-fluorene methoxycarbonyl-N-trityl-D-glutamine according to claim 1 is characterized in that: organic solvent is tetrahydrofuran (THF) or ethyl acetate among the step b.
3. the synthesis method of a kind of N-fluorene methoxycarbonyl-N-trityl-D-glutamine according to claim 1 is characterized in that: slough a kind of with in a kind of and hydrogen in 10% palladium carbon, the 5% palladium carbon, the tetrahydrobenzene of Z-protection in the steps d;
4. the synthesis method of a kind of N-fluorene methoxycarbonyl-N-trityl-D-glutamine according to claim 1 is characterized in that: step e uses fluorenes methoxy dicarbonyl chloride or fluorenes methoxy carbonyl acyl succinimide as last protection reagent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924332A (en) * | 2011-08-10 | 2013-02-13 | 浙江九洲药业股份有限公司 | Improvement of synthetic technology of N-P-dual-acid amino acid monoester |
| CN103242200A (en) * | 2013-04-10 | 2013-08-14 | 吉尔生化（上海）有限公司 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nepsilon-acetyl-lysine |
| CN108383757A (en) * | 2018-04-12 | 2018-08-10 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of N ε-tertbutyloxycarbonyl-N α-fluorenylmethyloxycarbonyl-N ε-methyl-lysine |
| CN110933946A (en) * | 2017-07-20 | 2020-03-27 | 百时美施贵宝公司 | Process for the preparation of N- ((1R,2S,5R) -5- (tert-butylamino) -2- ((S) -3- (7-tert-butylpyrazolo [1,5-a ] [1,3,5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide |
| CN112557572A (en) * | 2020-12-31 | 2021-03-26 | 成都普康生物科技有限公司 | Method for detecting isomer content in Cbz-Glu |
| CN113979886A (en) * | 2021-10-25 | 2022-01-28 | 成都市科隆化学品有限公司 | Protected amino acid with amide side chain and preparation method thereof |
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2007
- 2007-01-09 CN CN200710036268A patent/CN100593536C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924332A (en) * | 2011-08-10 | 2013-02-13 | 浙江九洲药业股份有限公司 | Improvement of synthetic technology of N-P-dual-acid amino acid monoester |
| CN102924332B (en) * | 2011-08-10 | 2015-12-16 | 浙江九洲药业股份有限公司 | The improvement in synthesis of N-P-bisgallic acid amino acid monoesters |
| CN103242200A (en) * | 2013-04-10 | 2013-08-14 | 吉尔生化（上海）有限公司 | Preparation method of Nalpha-fluorenylmethoxycarbonyl-Nepsilon-acetyl-lysine |
| CN110933946A (en) * | 2017-07-20 | 2020-03-27 | 百时美施贵宝公司 | Process for the preparation of N- ((1R,2S,5R) -5- (tert-butylamino) -2- ((S) -3- (7-tert-butylpyrazolo [1,5-a ] [1,3,5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide |
| CN108383757A (en) * | 2018-04-12 | 2018-08-10 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of N ε-tertbutyloxycarbonyl-N α-fluorenylmethyloxycarbonyl-N ε-methyl-lysine |
| CN112557572A (en) * | 2020-12-31 | 2021-03-26 | 成都普康生物科技有限公司 | Method for detecting isomer content in Cbz-Glu |
| CN113979886A (en) * | 2021-10-25 | 2022-01-28 | 成都市科隆化学品有限公司 | Protected amino acid with amide side chain and preparation method thereof |
| CN113979886B (en) * | 2021-10-25 | 2024-05-24 | 成都市科隆化学品有限公司 | Protective amino acid with side chain being amide and preparation method thereof |
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