CN103232369B - Preparation method of fmoc chloride glutamic acid-5-tert-butyl ester - Google Patents
Preparation method of fmoc chloride glutamic acid-5-tert-butyl ester Download PDFInfo
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- CN103232369B CN103232369B CN201310169361.4A CN201310169361A CN103232369B CN 103232369 B CN103232369 B CN 103232369B CN 201310169361 A CN201310169361 A CN 201310169361A CN 103232369 B CN103232369 B CN 103232369B
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- tert
- otbu
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Abstract
The invention discloses a preparation method of fmoc chloride glutamic acid-5-tert-butyl ester. The preparation method comprises the following steps of: preparing Glu(OtBu)2; selectively removing 1-tert-butyl ester of the Glu(OtBu)2 through copper salt to obtain Cu[Glu(OtBu)]x (x is equal to 1-2); removing copper to obtain Glu(OtBu); and reacting the Glu(OtBu) with the Fmoc-Osu or the Fmoc-Cl to obtain Fmoc-Glu(OtBu). The preparation method of the fmoc chloride glutamic acid-5-tert-butyl ester can be used for selectively removing the 1-tert-butyl ester of the Glu(OtBu)2 by setting the Cu<2+> in the copper salt, and is capable of greatly simplifying the process route and lowering the cost and is applicable to large-scale production. According to the preparation method of the fmoc chloride glutamic acid-5-tert-butyl ester, the fmoc chloride glutamic acid-5-tert-butyl ester is prepared under the special process condition by setting the special process route, so that the yield is high and the product quality is greatly improved.
Description
Technical field
The present invention relates to Peptides Synthesis, be specifically related to the preparation method of a kind of glutamic acid derivatives and the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester.
Background technology
In prior art, the synthetic line of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is that Glu and Z-OSu reaction generates Z-Glu, Z-Glu and acetic anhydride altogether heat generate Z-Glu acid anhydrides, Z-Glu acid anhydrides is dissolved in ether and phenylcarbinol, and ice bath drips hexahydroaniline and obtains Z-Glu-OBzlDCHA, through crystallization, remove DCHA and obtain Z-Glu-OBzl, Z-Glu (OtBu)-OBzl, Z-Glu (OtBu)-OBzl is generated again through Pd catalysis again, logical H through acid catalysis and iso-butylene addition
2hydrogenolysis obtains Glu (OtBu), last and Fmoc-OSu is obtained by reacting target product Fmoc-Glu (OtBu), and it is comparatively loaded down with trivial details that aforesaid method or similar approach produce Fmoc-Glu (OtBu), and yield is low, cost is high, is not suitable for the large production of commercialization.
Summary of the invention
The object of the invention is to overcome the problem that complicated process of preparation, cost are high, yield is low of Fmoc-Glu in prior art (OtBu); a kind of preparation method of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is provided; the method is simple, and cost is low, is suitable for large-scale production.
In order to reach foregoing invention object, the technical solution used in the present invention is: the preparation method providing a kind of fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester, is characterized in that, comprise the following steps:
(1) Glu is prepared into Glu (OtBu)
2;
(2) by Glu (OtBu)
2mix with mantoquita, obtain Cu [Glu (OtBu)]
x, x=1 ~ 2;
(3) again at Cu [Glu (OtBu)]
xin add decopper(ing) agent decopper(ing), obtain Glu (OtBu); Then add the protection reagent mix of Fmoc group at Glu (OtBu), obtain Fmoc-Glu (OtBu), be i.e. the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester;
Describedly Glu is prepared into Glu (OtBu)
2concrete steps be: Glu is mixed with tert-butyl acetate, under the katalysis of perchloric acid, carries out transesterification reaction, then through extraction, alkali cleaning, obtain Glu (OtBu)
2; Wherein, Glu, tert-butyl acetate are 1:5 ~ 20:1.2 ~ 2 with the amount of substance ratio of perchloric acid; Its synthetic route is as follows:
Temperature when described Glu and tert-butyl acetate react is 10 ~ 20 DEG C, and the reaction times is 24 ~ 48 hours.
Describedly Glu is prepared into Glu (OtBu)
2concrete steps be: Glu is mixed with iso-butylene, under the katalysis of anhydrous tosic acid, carries out addition reaction, obtain Glu (OtBu)
2; Wherein, Glu, iso-butylene are 1:3 ~ 10:1.2 ~ 2 with the amount of substance ratio of anhydrous tosic acid, and its synthetic route is as follows:
Temperature when described Glu and isobutene reaction is-10 ~-5 DEG C, and the reaction times is 48 ~ 72 hours.
Described Glu (OtBu)
2mix according to the ratio that mol ratio is 1 ~ 2:1 with mantoquita, react 12 ~ 16 hours at 30 ~ 60 DEG C, obtained Cu [Glu (OtBu)]
x, x=1 ~ 2, its synthetic route is as follows:
Described mantoquita is CuSO
4, Cu (NO
3)
2, CuCl
2or Cu
2(OH)
2cO
3.
At Cu [Glu (OtBu)]
xin add decopper(ing) agent and solvent according to certain ratio, the pH value of regulator solution is 8 ~ 9, obtains Glu (OtBu); In Glu (OtBu), add the protection reagent of Fmoc group again, the pH value of regulator solution is 8 ~ 9, reacts 7 ~ 10 hours, then through acidifying, extraction, crystallization, obtains the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Wherein, described decopper(ing) agent and Cu [Glu (OtBu)]
xmol ratio be 1:1; Solvent and Cu [Glu (OtBu)]
xmol ratio be 3 ~ 10:1; Described Glu (OtBu) is 1:1 with the mol ratio of the protection reagent of Fmoc group, and its synthetic route is as follows:
Described decopper(ing) agent is Na
2eDTA, Na
2s or Tetramethyl Ethylene Diamine; Described solvent is ethanol, methyl alcohol, acetone, tetrahydrofuran (THF), dioxane or methylene dichloride.
The protection reagent of described Fmoc group is Fmoc-OSu or Fmoc-Cl.
In sum, preparation method of the present invention is by arranging the Cu in mantoquita
2+to Glu (OtBu)
2the 1-tert-butyl ester tertiary butyl carry out selectively removing, enormously simplify operational path, reduce cost, be applicable to scale operation; The present invention is by arranging unique operational path, and under distinctive processing condition, prepare the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester, yield is high, and quality product is also greatly enhanced.
Embodiment
Below in conjunction with embodiment, the present invention is described in detail, but they are not to further restriction of the present invention.
Embodiment 1
In 2000mL there-necked flask, add 581g tert-butyl acetate and 147g L-glutamic acid, stir, drip 96.5mL perchloric acid, react 48 hours, be cooled to 0 DEG C, then add 600mL water at 20 DEG C, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=8, separatory, then use 400mL1%Na
2cO
3the aqueous solution washes three times, concentrating under reduced pressure tert-butyl acetate layer, obtains 60g oily matter Glu (OtBu)
2, yield is 23.2%.
60g Glu (OtBu) is added in 1000mL there-necked flask
2, then add 600mL water and 57.9gCuSO
45H
2o, stirs, is warming up to 50 DEG C, reacts 12 hours, obtained Cu [Glu (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 86g Na
2eDTA2H
2o and 100mL dioxane, then regulate pH to be 8 ~ 9 with triethylamine, obtained Glu (OtBu); In Glu (OtBu), add 74g Fmoc-OSu again, regulate pH to be 8 ~ 9, react 8 hours, the obtained thick product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Again by the HCl acidifying of this crude product, be extracted with ethyl acetate, concentrating under reduced pressure crystallization, filter, dry, the obtained 88g fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester.
Analyzed the product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is 99.2%, and specific rotation is-8.5, and fusing point is 88.3 ~ 90.5, and content of isomer is 0.12%.
Embodiment 2
In 3000mL there-necked flask, add 1162g tert-butyl acetate and 147g L-glutamic acid, stir, drip 130mL perchloric acid, react 30 hours, be cooled to 0 DEG C, then add 800mL water at 15 DEG C, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=8, separatory, then use 400mL1%Na
2cO
3the aqueous solution washes three times, concentrating under reduced pressure tert-butyl acetate layer, obtains 71g oily matter Glu (OtBu)
2, yield is 27.4%.
71g Glu (OtBu) is added in 1000mL there-necked flask
2, then add 700mL water and 66.2gCu (NO
3)
2.3H
2o, stirs, is warming up to 40 DEG C, reacts 16 hours, obtained Cu [Glu (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 63.6g Tetramethyl Ethylene Diamine and 150mL dioxane, then regulate pH to be 8 with triethylamine, obtained Glu (OtBu); In Glu (OtBu), add 83g Fmoc-OSu again, regulate pH to be 8, react 8 hours, the obtained thick product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Again by the HCl acidifying of this crude product, be extracted with ethyl acetate, concentrating under reduced pressure crystallization, filter, dry, the obtained 94g fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester.
Analyzed the product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is 99.7%, and specific rotation is-8.4, and fusing point is 89.5 ~ 91.6, and content of isomer is 0.07%.
Embodiment 3
In 3000mL there-necked flask, add 2324g tert-butyl acetate and 73.5g L-glutamic acid, stir, drip 160.8mL perchloric acid, react 48 hours, be cooled to 0 DEG C, then add 1000mL water at 10 DEG C, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=8 ~ 9, separatory, then use 400mL1%Na
2cO
3the aqueous solution washes three times, concentrating under reduced pressure tert-butyl acetate layer, obtains 42g oily matter Glu (OtBu)
2, yield is 32.4%.
42g Glu (OtBu) is added in 1000mL there-necked flask
2, then add 400mL water and 11g CuCl
2, be warming up to 50 DEG C, react 12 hours, obtained Cu [Glu (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 19g Tetramethyl Ethylene Diamine and 100mL dioxane, then regulate pH to be 8 ~ 9 with triethylamine, obtained Glu (OtBu); In Glu (OtBu), add 48g Fmoc-OSu again, regulate pH to be 8 ~ 9, react 10 hours, the obtained thick product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Again by the HCl acidifying of this crude product, be extracted with ethyl acetate, concentrating under reduced pressure crystallization, filter, dry, the obtained 55g fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester.
Analyzed the product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is 99.4%, and specific rotation is-8.8, and fusing point is 88.7 ~ 91.2, and content of isomer is 0.12%.
Embodiment 4
In 3000mL there-necked flask, add 1000mL methylene dichloride, cool to-10 DEG C, add the anhydrous tosic acid of 344g and 147g L-glutamic acid, pass into 448g iso-butylene, react 72 hours at maintaining-10 DEG C; Use 10%Na again
2cO
3the aqueous solution regulates pH to be 8 ~ 9, separatory, 1%Na
2cO
3wash 3 times, each 400mL, evaporated under reduced pressure, obtained 160g Glu (OtBu)
2, yield is 61.8%.
The implication of the abbreviation used in the present invention or English full name is listed in the table below:
| Glu | L-glutamic acid |
| Fmoc-OSu | Fluorenes methoxy carbonyl acyl succinimide |
| Z-OSu | Benzene methoxy carbonyl acyl succinimide |
| Na 2EDTA | Disodium ethylene diamine tetraacetate |
| DCHA | Dicyclohexyl amine |
| Fmoc-Glu(OtBu)·H 2O | Fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester monohydrate |
| Glu(OtBu) 2 | The two tert-butyl ester of L-glutamic acid |
| Glu(OtBu)） | L-glutamic acid-5-the tert-butyl ester |
| Z-Glu | Benzene methoxy carbonyl acyl L-glutamic acid |
| Z-Glu-OBzl | Benzene methoxy carbonyl acyl L-glutamic acid-1-benzyl ester |
| Z-Glu(OtBu)-OBzl | The benzene methoxy carbonyl acyl L-glutamic acid-1-benzyl ester-5-tert-butyl ester |
| tert-butylacetate | Tert-butyl acetate |
| 2-methylpropene | Iso-butylene |
| 1，4-dioxane | Dioxane |
| Triethylamine | Triethylamine |
| Tos-OH | Tosic acid |
Although describe in detail the specific embodiment of the present invention in conjunction with specific embodiments, it is not the restriction to this patent protection domain.In claims limited range, the various amendment that those skilled in the art can make without creative work or adjustment are still by the protection of this patent.
Claims (1)
1. a preparation method for the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester, is characterized in that, comprise the following steps:
In 3000mL there-necked flask, add 1162g tert-butyl acetate and 147g L-glutamic acid, stir, drip 130mL perchloric acid, react 30 hours, be cooled to 0 DEG C, then add 800mL water at 15 DEG C, extraction, uses Na
2cO
3being neutralized to pH value is 8, separatory, then uses 400mL 1%Na
2cO
3the aqueous solution washes three times, concentrating under reduced pressure tert-butyl acetate layer, obtains 71g oily matter Glu (OtBu)
2, yield is 27.4%; Described Glu (OtBu)
2for the two tert-butyl ester of L-glutamic acid;
71g Glu (OtBu) is added in 1000mL there-necked flask
2, then add 700mL water and 66.2g Cu (NO
3)
2.3H
2o, stirs, is warming up to 40 DEG C, reacts 16 hours, obtained Cu [Glu (OtBu)]
x, x=1 ~ 2; Drop to room temperature again, add 63.6g Tetramethyl Ethylene Diamine and 150mL dioxane, then be 8 by triethylamine adjust ph, obtained Glu (OtBu); In Glu (OtBu), add 83g Fmoc-OSu again, adjust ph is 8, reacts 8 hours, the obtained crude product fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Again by described crude product HCl acidifying, be extracted with ethyl acetate, concentrating under reduced pressure crystallization, filter, dry, the obtained 94g fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester; Described Cu [Glu (OtBu)]
xfor L-glutamic acid many tert-butyl esters mantoquita, described Glu (OtBu) is the L-glutamic acid-5-tert-butyl ester;
Analyzed the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl L-glutamic acid-5-tert-butyl ester is 99.7%, and specific rotation is-8.4, and fusing point is 89.5 ~ 91.6, and content of isomer is 0.07%.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045883B (en) * | 2016-05-27 | 2018-06-22 | 成都郑源生化科技有限公司 | A kind of preparation method of aspartic acid -1- tert-butyl ester derivatives |
| CN109232320A (en) * | 2018-09-14 | 2019-01-18 | 成都市科隆化学品有限公司 | A kind of Fmoc-Asp(oBut)-OH preparation method |
| CN109180533A (en) * | 2018-09-25 | 2019-01-11 | 四川什邡市三高生化实业有限公司 | A kind of N-9- fluorenylmethyloxycarbonyl-D-ASP -4- tert-butyl ester |
| CN110746323B (en) * | 2019-11-20 | 2022-03-08 | 常州吉恩药业有限公司 | Industrial production method of efficient Fmoc-Glu (Otbu) -OH |
| CN113896657A (en) * | 2021-11-16 | 2022-01-07 | 山东盛安贝新能源有限公司南京分公司 | Synthesis method and purification method of somaglutide protected amino acid |
| CN115504893B (en) * | 2022-11-18 | 2023-03-10 | 成都普康生物科技有限公司 | Synthesis method of L-glutamic acid-alpha-tert-butyl ester |
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| US20040030177A1 (en) * | 2002-08-09 | 2004-02-12 | Behrendt L. Kirk | Hydrolysis of amino acid diesters |
| CN101544576A (en) * | 2008-03-26 | 2009-09-30 | 丹阳吉尔生化有限公司 | Method for preparing fluorenylmethyloxycarbonyl-aspartate-alpha-allyl ester |
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