CN112479933A - Preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester - Google Patents
Preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester Download PDFInfo
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- CN112479933A CN112479933A CN202011445114.9A CN202011445114A CN112479933A CN 112479933 A CN112479933 A CN 112479933A CN 202011445114 A CN202011445114 A CN 202011445114A CN 112479933 A CN112479933 A CN 112479933A
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- benzyl ester
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- alanine benzyl
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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Abstract
The invention relates to a preparation method of N-fluorenylmethyloxycarbonyl-3-chloro-alanine benzyl ester, which mainly solves the problems of too long reaction steps, low yield, narrow product application range and the like of the existing synthetic method. The technical scheme of the invention is as follows: a preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester comprises the following steps: taking N-fluorenylmethoxycarbonyl-serine-benzyl ester as an initial raw material, reacting with a chlorinating reagent in an organic solvent under the heating condition, and carrying out post-treatment to obtain the N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester. The product of the invention is used as an important starting material and has important application in the field of polypeptide drugs.
Description
Technical Field
The invention relates to a preparation method of alanine derivatives, in particular to a preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester.
Background
The Fmoc-3-chloro-alanine benzyl ester is an important starting point for synthesizing various unnatural amino acids which are difficult to obtain by a common synthetic method, and the Fmoc-3-chloro-alanine benzyl ester is taken as a starting point, so that various special amino acids can be synthesized by a metal organic method, such as: polyoxy-substituted phenylalanines, angiotensin converting enzyme inhibitor fragments, HIV-1 protease inhibitors, puromycin precursors, 3, 4-dihydroxyphenylalanine (precursor of dopamine capable of treating Parkinson). Journal of the British chemical society (1, 2001, 1876) -1884) discloses the "direct synthesis of Fmoc-protected amino acids using organozinc chemistry: the N-fluorenylmethoxycarbonyl-3-chloro-alanine tert-butyl ester is prepared by taking serine as an initial raw material through multi-step reaction, and the N-fluorenylmethoxycarbonyl-3-chloro-alanine tert-butyl ester is used as a raw material to synthesize some special unnatural amino acids. This route has two disadvantages, firstly, the procedure is too long, which leads to a low yield of the final product, and secondly, the t-butyl ester of t-butyl N-fluorenylmethoxycarbonyl-3-chloro-alanine is easily removed under acidic conditions, which leads to a narrow range of applications.
Disclosure of Invention
The invention aims to provide a preparation method of N-fluorenylmethyloxycarbonyl-3-chloro-alanine benzyl ester, which mainly solves the problems of too long existing route and narrow product application range.
The technical scheme of the invention is as follows: a preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester,
the method comprises the following steps: taking N-fluorenylmethoxycarbonyl-serine-benzyl ester as an initial raw material, reacting with a chlorinating reagent in an organic solvent under the heating condition, and carrying out post-treatment to obtain the N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester.
The chlorinating agent is thionyl chloride or oxalyl chloride.
The organic solvent is one of dioxane, tetrahydrofuran or dichloromethane.
The serine is one of L-serine, DL-serine or D-serine.
The heating condition and the reaction temperature are preferably 55 ℃.
The invention has the beneficial effects that: the invention provides a preparation method of N-fluorenylmethyloxycarbonyl-3-chloro-alanine benzyl ester, which avoids acidic removal of a product and avoids the problems of long synthesis steps and narrow application range in the original method.
Drawings
FIG. 1 is an infrared spectrum of a product of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of the product of the invention.
Detailed Description
Example 1:
14.2g (0.034 mol) of Fmoc-L-serine-benzyl ester were dissolved in 80ml of tetrahydrofuran until clear. And (3) cooling to 10 ℃ under an ice water bath, slowly dripping 11.6ml (0.137 mol) of oxalyl chloride, removing the ice water bath, slowly heating to 25 ℃, stirring for 1 hour, heating to 55 ℃, and keeping the temperature for reaction overnight. The next day, the raw material N-fluorenylmethyloxycarbonyl-L-serine-benzyl ester is completely reacted through thin-layer chromatography analysis and can be treated. And (3) treatment: cooling the reaction system, slowly adding the reaction solution into 500ml of ice water, stirring, adding 300ml of ethyl acetate, stirring, layering, retaining the oil phase, discarding the water phase, washing the oil phase once with water, washing once with saturated sodium bicarbonate solution, washing twice with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a liquid, evaporating to dryness to separate out a solid, adding a mixture of 150ml of petroleum ether and 15ml of ethyl acetate, and stirring for dispersing. And (3) performing suction filtration to obtain a crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester, and pulping the crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester once by using a mixture of 150ml of petroleum ether and 15ml of ethyl acetate to obtain a refined product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester with the dry weight of 10.8g and the yield of 72.6 percent. The infrared spectrum and nuclear magnetic spectrum are shown in figure 1 and figure 2.
Example 2:
14.2g (0.034 mol) of Fmoc-L-serine-benzyl ester were dissolved in 80ml of dioxane until clear. Cooling to 10 ℃ in ice water bath, slowly dripping 10ml (0.137 mol) of thionyl chloride, finishing dripping the thionyl chloride, removing the ice water bath, slowly heating to 25 ℃, stirring for 1 hour, then heating to 55 ℃, and keeping the temperature for reaction overnight. The next day, the raw material N-fluorenylmethyloxycarbonyl-L-serine-benzyl ester is completely reacted through thin-layer chromatography analysis and can be treated. And (3) treatment: cooling the reaction system, slowly adding the reaction solution into 500ml of ice water, stirring, adding 300ml of ethyl acetate, stirring, layering, retaining the oil phase, discarding the water phase, washing the oil phase once with water, washing once with saturated sodium bicarbonate solution, washing twice with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a liquid, evaporating to dryness to separate out a solid, adding a mixture of 150ml of petroleum ether and 15ml of ethyl acetate, and stirring for dispersing. And (3) performing suction filtration to obtain a crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester, and pulping the crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester once by using a mixture of 150ml of petroleum ether and 15ml of ethyl acetate to obtain a refined product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester with the dry weight of 11.3g and the yield of 76%.
Example 3:
14.2g (0.034 mol) of Fmoc-L-serine-benzyl ester were dissolved in 80ml of dichloromethane until clear. Cooling to 10 ℃ in ice water bath, slowly dripping 10ml (0.137 mol) of thionyl chloride, finishing dripping the thionyl chloride, removing the ice water bath, slowly heating to 25 ℃, stirring for 1 hour, then heating to 55 ℃, and keeping the temperature for reaction overnight. The next day, the raw material N-fluorenylmethyloxycarbonyl-L-serine-benzyl ester is completely reacted through thin-layer chromatography analysis and can be treated. And (3) treatment: cooling the reaction system, slowly adding the reaction solution into 500ml of ice water, stirring, adding 300ml of ethyl acetate, stirring, layering, retaining the oil phase, discarding the water phase, washing the oil phase once with water, washing once with saturated sodium bicarbonate solution, washing twice with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a liquid, evaporating to dryness to separate out a solid, adding a mixture of 150ml of petroleum ether and 15ml of ethyl acetate, and stirring for dispersing. And (3) performing suction filtration to obtain a crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester, and pulping the crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester once by using a mixture of 150ml of petroleum ether and 15ml of ethyl acetate to obtain a refined product of the N-fluorenylmethyloxycarbonyl-3-chloro-L-alanine benzyl ester with the dry weight of 9.8g and the yield of 66%.
Example 4:
14.2g (0.034 mol) of Fmoc-D-serine-benzyl ester were dissolved in 80ml of tetrahydrofuran until clear. Cooling to 10 ℃ in ice water bath, slowly dripping 10ml (0.137 mol) of thionyl chloride, finishing dripping the thionyl chloride, removing the ice water bath, slowly heating to 25 ℃, stirring for 1 hour, then heating to 55 ℃, and keeping the temperature for reaction overnight. The next day, the raw material N-fluorenylmethyloxycarbonyl-L-serine-benzyl ester is completely reacted through thin-layer chromatography analysis and can be treated. And (3) treatment: cooling the reaction system, slowly adding the reaction solution into 500ml of ice water, stirring, adding 300ml of ethyl acetate, stirring, layering, retaining the oil phase, discarding the water phase, washing the oil phase once with water, washing once with saturated sodium bicarbonate solution, washing twice with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a liquid, evaporating to dryness to separate out a solid, adding a mixture of 150ml of petroleum ether and 15ml of ethyl acetate, and stirring for dispersing. And (3) performing suction filtration to obtain a crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-D-alanine benzyl ester, and pulping the crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-D-alanine benzyl ester once by using a mixture of 150ml of petroleum ether and 15ml of ethyl acetate to obtain a refined product of the N-fluorenylmethyloxycarbonyl-3-chloro-D-alanine benzyl ester with the dry weight of 11.5g and the yield of 77 percent.
Example 5:
14.2g (0.034 mol) of Fmoc-DL-serine-benzyl ester were dissolved in 80ml of tetrahydrofuran until clear. And (3) cooling to 10 ℃ under an ice water bath, slowly dripping 11.6ml (0.137 mol) of oxalyl chloride, removing the ice water bath, slowly heating to 25 ℃, stirring for 1 hour, heating to 55 ℃, and keeping the temperature for reaction overnight. The next day, the raw material N-fluorenylmethyloxycarbonyl-DL-serine-benzyl ester is completely reacted and can be treated through thin-layer chromatography analysis. And (3) treatment: cooling the reaction system, slowly adding the reaction solution into 500ml of ice water, stirring, adding 300ml of ethyl acetate, stirring, layering, retaining the oil phase, discarding the water phase, washing the oil phase once with water, washing once with saturated sodium bicarbonate solution, washing twice with saturated saline solution, drying with anhydrous sodium sulfate, filtering to obtain a liquid, evaporating to dryness to separate out a solid, adding a mixture of 150ml of petroleum ether and 15ml of ethyl acetate, and stirring for dispersing. And (3) performing suction filtration to obtain a crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-DL-alanine benzyl ester, and pulping the crude product of the N-fluorenylmethyloxycarbonyl-3-chloro-DL-alanine benzyl ester once by using a mixture of 150ml of petroleum ether and 15ml of ethyl acetate to obtain a refined product of the N-fluorenylmethyloxycarbonyl-3-chloro-DL-alanine benzyl ester with the dry weight of 10.9g and the yield of 73.3 percent.
Claims (5)
1. A preparation method of N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester is characterized by comprising the following steps: the method comprises the following steps: taking N-fluorenylmethoxycarbonyl-serine-benzyl ester as an initial raw material, reacting with a chlorinating reagent in an organic solvent under the heating condition, and carrying out post-treatment to obtain the N-fluorenylmethoxycarbonyl-3-chloro-alanine benzyl ester.
2. The method for preparing Fmoc-3-chloro-alanine benzyl ester according to claim 1, characterized in that: the chlorinating agent is thionyl chloride or oxalyl chloride.
3. The method for preparing Fmoc-3-chloro-alanine benzyl ester according to claim 1, characterized in that: the organic solvent is one of dioxane, tetrahydrofuran or dichloromethane.
4. The method for preparing Fmoc-3-chloro-alanine benzyl ester according to claim 1, characterized in that: the serine is one of L-serine, DL-serine or D-serine.
5. The method for preparing Fmoc-3-chloro-alanine benzyl ester according to claim 1, characterized in that: the heating condition is that the reaction temperature is 55 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080253997A1 (en) * | 2007-03-27 | 2008-10-16 | Perscitus Biosciences, Llc | Compositions and methods for protecting cells from toxic exposures |
| CN106459148A (en) * | 2014-03-21 | 2017-02-22 | 生物梅里埃公司 | Antimicrobial compounds |
| CN109251155A (en) * | 2017-07-14 | 2019-01-22 | 广东东阳光药业有限公司 | Alpha-aminoamide derivatives and application thereof |
| WO2020095983A1 (en) * | 2018-11-07 | 2020-05-14 | 中外製薬株式会社 | O-substituted serine derivative production method |
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2020
- 2020-12-11 CN CN202011445114.9A patent/CN112479933A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080253997A1 (en) * | 2007-03-27 | 2008-10-16 | Perscitus Biosciences, Llc | Compositions and methods for protecting cells from toxic exposures |
| CN106459148A (en) * | 2014-03-21 | 2017-02-22 | 生物梅里埃公司 | Antimicrobial compounds |
| CN109251155A (en) * | 2017-07-14 | 2019-01-22 | 广东东阳光药业有限公司 | Alpha-aminoamide derivatives and application thereof |
| WO2020095983A1 (en) * | 2018-11-07 | 2020-05-14 | 中外製薬株式会社 | O-substituted serine derivative production method |
Non-Patent Citations (2)
| Title |
|---|
| HIROMITSU SAITO 等: "SYNTHETIC APPROACH TO QUINOCARCIN", 《TETRAHEDRON LETTERS》 * |
| SYLWIA BOLEK 等: "Ring opening reactions of cyclic sulfamidates. Synthesis of β-fluoroaryl alanines and derivatives of 4,4-difluoroglutamic acid", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
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Application publication date: 20210312 |