CN103232370B - A kind of preparation method of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester - Google Patents
A kind of preparation method of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester Download PDFInfo
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- CN103232370B CN103232370B CN201310169364.8A CN201310169364A CN103232370B CN 103232370 B CN103232370 B CN 103232370B CN 201310169364 A CN201310169364 A CN 201310169364A CN 103232370 B CN103232370 B CN 103232370B
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- otbu
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- aspartic acid
- butyl ester
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Abstract
The invention discloses a kind of preparation method of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, comprise Asp (OtBu)
2preparation, Asp (OtBu)
2cu [Asp (OtBu)] is obtained through the mantoquita selectively removing 1-tert-butyl ester
x(x=1 ~ 2), then through decopper(ing), obtain Asp (OtBu), then be obtained by reacting Fmoc-Asp (OtBu) with Fmoc-Osu or Fmoc-Cl; The method is by arranging the Cu in mantoquita
2+to Asp (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.
Description
Technical field
The present invention relates to Peptides Synthesis, be specifically related to the preparation method of a kind of aspartame and the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester.
Background technology
In prior art, the synthetic route of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is that Asp and Z-osu reaction generates Z-Asp, Z-Asp and acetic anhydride altogether heat generate Z-Asp acid anhydrides, Z-Asp acid anhydrides is dissolved in ether and phenylcarbinol, ice bath drips hexahydroaniline and obtains Z-Asp-OBzl.DCHA crystallization, removes DCHA and obtains Z-Asp-OBzl, then generates Z-Asp (OtBu) OBzl through acid catalysis and iso-butylene addition, Z-Asp (OtBu) OBzl, again through Pd catalysis, leads to H
2hydrogenolysis obtains Asp (OtBu), last and Fmoc-OSu is obtained by reacting target product Fmoc-Asp (OtBu), and it is comparatively loaded down with trivial details that aforesaid method or similar approach produce Fmoc-Asp (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-Asp in prior art (OtBu); a kind of preparation method of the fluorenes methoxy carbonyl acyl aspartic acid-4-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 aspartic acid-4-tert-butyl ester, is characterized in that, comprise the following steps:
(1) Asp is prepared into Asp (OtBu)
2;
(2) by Asp (OtBu)
2mix with mantoquita, obtain Cu [Asp (OtBu)]
x, x=1 ~ 2;
(3) again at Cu [Asp (OtBu)]
xin add decopper(ing) agent decopper(ing), obtain Asp (OtBu); Then add the protection reagent mix of Fmoc group at Asp (OtBu), obtain Fmoc-Asp (OtBu), be i.e. the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester.
Describedly Asp is prepared into Asp (OtBu)
2concrete steps be: Asp is mixed with tert-butyl acetate, under the katalysis of perchloric acid, carries out transesterification reaction, then through extraction, alkali cleaning, obtain Asp (OtBu)
2; Wherein, Asp, 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 Asp and tert-butyl acetate react is 10 ~ 20 DEG C, and the reaction times is 24 ~ 48 hours.
Describedly Asp is prepared into Asp (OtBu)
2concrete steps be: Asp is mixed with iso-butylene, under the katalysis of anhydrous tosic acid, carries out addition reaction, obtain Asp (OtBu)
2; Wherein, Asp, 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 Asp and isobutene reaction is-10 ~-5 DEG C, and the reaction times is 48 ~ 72 hours.
Described Asp (OtBu)
2mix according to the ratio that mol ratio is 1 ~ 2:1 with mantoquita, react 12 ~ 16 hours at 30 ~ 50 DEG C, obtained Cu [Asp (OtBu)]
x, its synthetic route is as follows:
Described mantoquita is CuSO
4, Cu (NO
3)
2, CuCl
2or Cu
2(OH)
2cO
3.
At Cu [Asp (OtBu)]
xin add decopper(ing) agent and solvent according to certain ratio, the pH value of regulator solution is 8 ~ 9, obtains Asp (OtBu); In Asp (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 aspartic acid-4-tert-butyl ester; Wherein, described decopper(ing) agent and Cu [Asp (OtBu)]
xmol ratio be 1:1; The mol ratio of solvent and Cu [Asp (OtBu)] x (x=1-2) is 3 ~ 10:1; Described Asp (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 Asp (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 aspartic acid-4-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 133g aspartic acid, stir, drip 96.5mL perchloric acid, react 48 hours at 10 DEG C, be cooled to 0 DEG C, then add 700mL water, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=7, separatory, concentrating under reduced pressure tert-butyl acetate layer, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by.
Gained mixture is proceeded to 3000mL there-necked flask, adds 125gCuSO
45H
2o, regulates pH to be 3 with concentrated hydrochloric acid, stirs and is warming up to 50 DEG C, react 12 hours, obtained Cu [Asp (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 116.2g Tetramethyl Ethylene Diamine and 300mL dioxane, then regulate pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 82g Fmoc-OSu again, maintaining pH is 8 ~ 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, the obtained 85g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, yield 20.7%.
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.2%, and specific rotation is-23.5, and fusing point is 147.9 ~ 149.5, and content of isomer is 0.18%.
Embodiment 2
In 3000mL there-necked flask, add 1162g tert-butyl acetate and 133g aspartic acid, stir, drip 130mL perchloric acid, react 30 hours at 15 DEG C, be cooled to 0 DEG C, then add 1200mL water, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=7, separatory, concentrating under reduced pressure tert-butyl acetate layer, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by.
Gained mixture proceeds to 3000mL there-necked flask, adds 241.6gCu (NO
3)
23H
2o, regulates pH to be 3 with concentrated hydrochloric acid, stirs and is warming up to 40 DEG C, react 16 hours, obtained Cu [Asp (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 372.5g Na
2eDTA2H
2o and 450mL dioxane, then regulate pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 100g Fmoc-OSu again, maintaining pH is 8 ~ 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, the obtained 105g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, yield 25.5%.
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.97%, and specific rotation is-23.7, and fusing point is 148.8 ~ 150.1, and content of isomer is 0.07%.
Embodiment 3
In 5000mL there-necked flask, add 2324g tert-butyl acetate and 133g aspartic acid, stir, drip 160.8mL perchloric acid, react 24 hours at 20 DEG C, be cooled to 0 DEG C, then add 1200mL water, extraction (remaining tert-butyl acetate is as solvent extraction), uses Na
2cO
3be neutralized to pH=7, separatory, concentrating under reduced pressure tert-butyl acetate layer, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by.
Gained mixture proceeds to 3000mL there-necked flask, adds 135g CuCl
2, regulate pH to be 3 with concentrated hydrochloric acid, stir and be warming up to 30 DEG C, react 16 hours, obtained Cu [Asp (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 232.4g Tetramethyl Ethylene Diamine and 450mL dioxane, regulate pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 118g Fmoc-OSu again, maintaining pH is 8 ~ 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, the obtained 124g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, yield 30.2%.
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.35%, and specific rotation is-24.6, and fusing point is 146.8 ~ 148.0, and content of isomer is 0.18%.
Embodiment 4
In 3000mL there-necked flask, add methylene dichloride 1000mL, cool to-5 DEG C, add the anhydrous tosic acid of 344g and 133g aspartic acid, pass into 448g iso-butylene, react 50 hours at maintaining-5 DEG C; Use 10%Na again
2cO
3the aqueous solution adjusts pH to be 7, separatory, and water layer is stand-by, evaporated under reduced pressure, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by, and yield is 58.4%.
Gained mixture proceeds to 3000mL there-necked flask, adds 125gCuSO
45H
2o, regulates pH to be 3 with concentrated hydrochloric acid, stirs and is warming up to 40 DEG C, react 16 hours, obtained Cu [Asp (OtBu)]
x(x=1 ~ 2); Drop to room temperature again, add 186.3g Na
2eDTA2H
2o and 400mL dioxane, regulates pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 200g Fmoc-OSu again, maintaining pH is 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, and the obtained 205g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, yield is 49.9%.
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.64%, and specific rotation is-23.7, and fusing point is 148.5 ~ 149.8, and content of isomer is 0.21%.
The implication of the abbreviation used in the present invention or English full name is listed in the table below:
| Asp | Aspartic 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-Asp(OtBu) | The fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester |
| Asp(OtBu) 2 | The two tert-butyl ester of aspartic acid |
| Asp(OtBu) | Aspartic acid-4-the tert-butyl ester |
| Z-Asp | Benzene methoxy carbonyl acyl L-glutamic acid |
| Z-Asp-OBzl | Benzene methoxy carbonyl acyl aspartic acid-1-benzyl ester |
| Z-Asp(OtBu)-OBzl | The benzene methoxy carbonyl acyl aspartic acid-1-benzyl ester-4-tert-butyl ester |
| tert-butylacetate | Tert-butyl acetate |
| 2-methylpropene | Iso-butylene |
| 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 (2)
1. a preparation method for the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, is characterized in that, comprise the following steps:
In 5000mL there-necked flask, add 2324g tert-butyl acetate and 133g aspartic acid, stir, drip 160.8mL perchloric acid, react 24 hours, be cooled to 0 DEG C, then add 1200mL water at 20 DEG C, extraction, uses Na
2cO
3be neutralized to pH=7, separatory, concentrating under reduced pressure tert-butyl acetate layer, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by;
Gained mixture proceeds to 3000mL there-necked flask, adds 135g CuCl
2, regulate pH to be 3 with concentrated hydrochloric acid, stir and be warming up to 30 DEG C, react 16 hours, obtained Cu [Asp (OtBu)]
x, x=1 ~ 2; Drop to room temperature again, add 232.4g Tetramethyl Ethylene Diamine and 450mL dioxane, regulate pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 118g Fmoc-OSu again, maintaining pH is 8 ~ 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, the obtained 124g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, yield 30.2%;
Described Asp (OtBu)
2for the two tert-butyl ester of aspartic acid; Described Asp (OtBu) and Asp-OtBu is respectively the aspartic acid-4-tert-butyl ester and the aspartic acid-1-tert-butyl ester; Described Cu [Asp (OtBu)]
xfor aspartic acid many tert-butyl esters mantoquita; Described Fmoc-OSu is fluorenes methoxy carbonyl acyl succinimide;
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.35%, and specific rotation is-24.6, and fusing point is 146.8 ~ 148.0, and content of isomer is 0.18%.
2. a preparation method for the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, is characterized in that, comprise the following steps:
In 3000mL there-necked flask, add methylene dichloride 1000mL, cool to-5 DEG C, add the anhydrous tosic acid of 344g and 133g aspartic acid, pass into 448g iso-butylene, react 50 hours at maintaining-5 DEG C; Use 10%Na again
2cO
3the aqueous solution adjusts pH to be 7, separatory, and water layer is stand-by, evaporated under reduced pressure, obtained Asp (OtBu)
2, Asp (OtBu) and Asp-OtBu oily matter mixture, oily matter and water layer merge stand-by, and yield is 58.4%;
Gained mixture proceeds to 3000mL there-necked flask, adds 125gCuSO
45H
2o, regulates pH to be 3 with concentrated hydrochloric acid, stirs and is warming up to 40 DEG C, react 16 hours, obtained Cu [Asp (OtBu)]
x, x=1 ~ 2; Drop to room temperature again, add 186.3g Na
2eDTA2H
2o and 400mL dioxane, regulates pH to be 8 ~ 9 with triethylamine, obtained Asp (OtBu); In Asp (OtBu), add 200g Fmoc-OSu again, maintaining pH is 9, reacts 8 hours, then through extraction into ethyl acetate, acidifying, washing, underpressure distillation, crystallization, dries, the obtained 205g fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester, and yield is 49.9%;
Described Asp (OtBu)
2for the two tert-butyl ester of aspartic acid; Described Asp (OtBu) and Asp-OtBu is respectively the aspartic acid-4-tert-butyl ester and the aspartic acid-1-tert-butyl ester; Described Cu [Asp (OtBu)]
xfor aspartic acid many tert-butyl esters mantoquita; Described Fmoc-OSu is fluorenes methoxy carbonyl acyl succinimide;
Analyzed the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester by HPLC, the purity of the fluorenes methoxy carbonyl acyl aspartic acid-4-tert-butyl ester is 99.64%, and specific rotation is-23.7, and fusing point is 148.5 ~ 149.8, and content of isomer is 0.21%.
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| CN105237420B (en) * | 2015-11-06 | 2017-09-12 | 安徽赛诺制药有限公司 | L threonine synthesis techniques |
| 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 |
| CN106008271B (en) * | 2016-05-27 | 2018-06-19 | 成都郑源生化科技有限公司 | A kind of preparation method of glutamic 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 |
| CN109265371A (en) * | 2018-10-12 | 2019-01-25 | 吉尔生化（上海）有限公司 | A kind of N α-[(9H- fluorenes -9- ylmethoxy) carbonyl]-N ε-acetyl group-L-lysine preparation method |
| 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 |
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| CN1532191A (en) * | 2003-03-19 | 2004-09-29 | 四川三高生化股份有限公司 | Process for producing Ne-teriary butoxy carbonyl lysine |
| CN101284803B (en) * | 2008-06-06 | 2012-01-04 | 吉尔生化（上海）有限公司 | Synthetic method of N-fluorenylmethoxycarbonyl-O-tert-butyl serine |
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