CN110054574B - Synthesis method of fluorenylmethyloxycarbonyl-2, 3-dehydro-valine - Google Patents
Synthesis method of fluorenylmethyloxycarbonyl-2, 3-dehydro-valine Download PDFInfo
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- CN110054574B CN110054574B CN201910289616.8A CN201910289616A CN110054574B CN 110054574 B CN110054574 B CN 110054574B CN 201910289616 A CN201910289616 A CN 201910289616A CN 110054574 B CN110054574 B CN 110054574B
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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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- C07—ORGANIC CHEMISTRY
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Abstract
The invention relates to a method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine. Mainly solves the technical problem of lack of an effective synthesis method. The synthesis method comprises the following steps: carrying out HWE reaction on Boc-alpha-phosphonoglycine trimethyl ester and acetone in a dichloromethane solution under the catalysis of DBU to generate a compound 1; heating compound 1 and sodium hydroxide in a mixed solution of methanol and water for hydrolysis to generate compound 2; removing a protecting group from the compound 2 in dichloromethane solution of trifluoroacetic acid to generate a compound 3; the compound 3, 9-fluorenylmethyl-N-succinimidyl carbonate and sodium bicarbonate react in a mixed solution of tetrahydrofuran and water to generate a target compound 4. The fluorenylmethyloxycarbonyl-2, 3-dehydro-valine serving as an amino acid derivative is mainly used as a medical intermediate, the synthesis of polypeptide and the like.
Description
Technical Field
The invention relates to a method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine.
Background
Fluorenylmethoxycarbonyl-2, 3-dehydro-valine (CAS: 198546-38-2) is used as an amino acid derivative, mainly used as a medical intermediate, the synthesis of polypeptide and the like, and has wide application, but the synthesis method is not reported in the publication so far.
In this regard, we searched and studied the synthetic scheme of the compound with similar structure. In 2014, Ma, Zhiwei et al reported a method for synthesizing (Z) -2- (2- (((benzyloxy) carbonyl) amino) acetamido) -3-methylpent-2-enoic acid ethyl ester in chloroform at 50 ℃ by using (2S, 3R) -2- (2- (((benzyloxy) carbonyl) amino) acetamido) -3-hydroxy-3-methylpentanoic acid ethyl ester as a raw material and Martins sulfurane as a dehydrating agent in Organic Letters, wherein expensive Martins sulfurane is used in the method, and the dehydrating agent is not suitable for scale-up production; in 2000, Nagano, Tanemasa et al in Bulletin of the Chemical Society of Japan reported a method of synthesizing ethyl α -N-t-butoxycarbonyl- α, β -dihydrovaleric acid ester using ethyl tert-butoxycarbonylamino (toluene-4-sulfonyl) acetate and 2-nitropropane as raw materials and tetrahydrofuran as a solvent under the catalysis of DBU, in which ethyl tert-butoxycarbonylamino (toluene-4-sulfonyl) acetate was not easily available and is inconvenient to produce. Therefore, the problem to be solved is to provide a reliable and economic solution for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine (CAS: 198546-38-2).
Disclosure of Invention
The invention aims to provide a method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine, which mainly solves the technical problem of lack of an effective synthesis method.
The technical scheme of the invention is as follows: a method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine is characterized by comprising the following steps: in a first step, Boc- α -phosphonoglycine trimethyl ester and acetone in Dichloromethane (DCM) are catalyzed by DBU (1, 8-diazabicycloundec-7-ene) to produce compound 1 via a horner-Watts-Eimers reaction (HWE reaction); secondly, heating and hydrolyzing the compound 1 and sodium hydroxide in a mixed solution of methanol and water to generate a compound 2; thirdly, removing a protecting group from the compound 2 in Dichloromethane (DCM) solution of trifluoroacetic acid (TFA) to generate a compound 3; fourthly, reacting the compound 3, 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-Osu) and sodium bicarbonate in a mixed solution of tetrahydrofuran and water to generate a target compound 4.
The synthesis route is as follows:
in the first step, the dosage of DBU is 10 equivalents, and the reaction is carried out overnight at room temperature; the second step is that the reaction temperature is 70-80 ℃ and the reaction time is 1 hour; the third step, the volume ratio of the trifluoroacetic acid to the dichloromethane is 1: 3; the amount of 9-fluorenylmethyl-N-succinimidyl carbonate used in the fourth reaction stage was 1.1 equivalents.
The invention has the beneficial effects that: cheap and easily available compounds are used as raw materials, a final compound 4 is obtained through a simple and easily-operated chemical reaction, a simple and convenient synthetic method suitable for large-scale production of fluorenylmethoxycarbonyl-2, 3-dehydro-valine (CAS: 198546-38-2) is obtained, and the HWE reaction condition is simple and convenient to operate; the hydrolysis reaction is carried out at 70-80 ℃, so that the reaction time is greatly shortened; the mixed system of trifluoroacetic acid and dichloromethane is used for removing protecting groups, and the post-treatment is simple and convenient; the target product with high purity and high yield can be obtained by pulping.
Detailed Description
Example 1:
step 1:
to a 250 mL single-neck flask were added Boc- α -phosphonoglycine trimethyl ester (10.0 g, 33.6 mmol), dichloromethane (100 mL), DBU (51.1g, 336mmol) and acetone (19.5 g, 336mmol) in that order, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to no liquid and dropped to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain high purity compound 1 (3.8 g, 16.6mmol, 49%). LC-MS (ESI) M/z 252.1 [ M + Na ]]+；
Step 2:
a100 mL single-neck flask was charged with Compound 1 (2.85 g, 12.4 mmol), methanol (30 mL), water (6 mL) and sodium hydroxide (1 g, 24.8 mmol), warmed to 70-80 deg.C, and stirred for 1 hour. Concentrate under reduced pressure to remove most of the methanol, add 20 mL of water, extract with dichloromethane (10 mL x 3), discard the dichloromethane phase; the aqueous phase was adjusted to pH =3 with 1M hydrochloric acid, a solid precipitated, filtered, and the cake was washed 2 times with water and dried to obtain high purity compound 2 (0.8 g, 3.7 mmol, 29.8%).1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.08 (d, J = 70.8 Hz, 1H)，1.93 (d, J = 16.4 Hz, 3H), 1.71 (s, 3H), 1.37 (d, J = 22.4 Hz, 9H).
LC-MS (ESI): m/z 238.1 [M+Na]+；
And step 3:
to a 50 mL one-neck flask were added compound 2 (0.8 g, 3.7 mmol), dichloromethane (6 mL) and trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 1.5 hours. Inverse directionThe reaction solution is concentrated under reduced pressure until no liquid drips to obtain a crude compound 3 which is directly used for the next reaction. LC-MS (ESI) M/z 116.1 [ M +1 ]]+；
And 4, step 4:
to crude compound 3 was added tetrahydrofuran (8 mL), water (8 mL), 9-fluorenylmethyl-N-succinimidyl carbonate (1.4 g, 4.1 mmol), and excess sodium bicarbonate was added to adjust the reaction pH =9 and stirred at room temperature overnight. Most of tetrahydrofuran was removed by concentration under reduced pressure, the remaining aqueous phase was adjusted to pH =3 with 1M hydrochloric acid, a solid was precipitated, filtered, and the filter cake was washed with dichloromethane slurry 3 times and dried to obtain the objective compound 4 (0.9 g, 2.7 mmol, 73.0%). LC-MS (ESI) M/z 359.6 [ M + Na ]]+；
1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.67 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.81 – 7.55 (m, 2H), 7.49 – 7.38 (m, 2H), 7.34 (td, J = 7.6, 1.2 Hz, 2H), 4.40 – 4.01 (m, 3H), 2.01 (s, 3H), 1.75 (s, 3H)。
Claims (6)
1. A method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine is characterized by comprising the following steps: the method comprises the following steps: carrying out a Horner-Wtzwars-Emonts reaction on Boc-alpha-phosphonoglycine trimethyl ester and acetone in a dichloromethane solution under the catalysis of 1, 8-diazabicycloundecen-7-ene to generate a compound 1; heating the compound 1 and sodium hydroxide in a mixed solution of methanol and water to 70-80 ℃ for hydrolysis to generate a compound 2; removing a protecting group from the compound 2 in dichloromethane solution of trifluoroacetic acid to generate a compound 3; reacting a compound 3, 9-fluorenylmethyl-N-succinimidyl carbonate and sodium bicarbonate in a mixed solution of tetrahydrofuran and water, filtering, pulping and washing a filter cake for 3 times by using dichloromethane, and drying to generate a target compound 4; the synthesis route is as follows:
2. the method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine according to claim 1, wherein the method comprises the following steps: the amount of 1, 8-diazabicycloundecen-7-ene added in the first step was 10 equivalents of Boc- α -phosphonoglycine trimethyl ester.
3. The method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine according to claim 1, wherein the method comprises the following steps: the first step was carried out overnight at room temperature.
4. The method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine according to claim 1, wherein the method comprises the following steps: the second reaction time was 1 hour.
5. The method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine according to claim 1, wherein the method comprises the following steps: the volume ratio of the trifluoroacetic acid to the dichloromethane in the third step is 1: 3.
6. The method for synthesizing fluorenylmethyloxycarbonyl-2, 3-dehydro-valine according to claim 1, wherein the method comprises the following steps: the fourth step 9-fluorenylmethyl-N-succinimidyl carbonate was added in an amount of 1.1 equivalents based on compound 3.
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| CN110627686A (en) * | 2019-09-11 | 2019-12-31 | 上海吉奉生物科技有限公司 | Synthesis method of fluorenylmethyloxycarbonyl-O-trityl-L-threonine |
| CN110642753A (en) * | 2019-09-25 | 2020-01-03 | 成都奥达生物科技有限公司 | Amino acid derivative |
| CN112062693A (en) * | 2020-09-23 | 2020-12-11 | 上海吉奉生物科技有限公司 | Synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791693A (en) * | 2009-12-30 | 2012-11-21 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN109369460A (en) * | 2018-11-06 | 2019-02-22 | 康化（上海）新药研发有限公司 | The synthetic method of one kind (2S) -2-N- fluorenylmethyloxycarbonyl amino -2,4- dimethyl valeric acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791693A (en) * | 2009-12-30 | 2012-11-21 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN109369460A (en) * | 2018-11-06 | 2019-02-22 | 康化（上海）新药研发有限公司 | The synthetic method of one kind (2S) -2-N- fluorenylmethyloxycarbonyl amino -2,4- dimethyl valeric acid |
Non-Patent Citations (4)
| Title |
|---|
| "Customizable" Units in Di- and Tripeptides: Selective Conversion into Substituted Dehydroamino Acids;Carlos J. Saavedra et al;《Organic Letters》;20121231;第14卷(第14期);3788-3791 * |
| Diastereoselective Formation of (Z)-Didehydroamino Acid Esters;Ulrich Schmidt et al;《Synthesis》;19921231;第1992卷(第5期);487-490 * |
| Fmoc系列保护氨基酸的制备研究;杜秀敏;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20050315(第1期);B014-73 * |
| α,β-脱氢氨基酸衍生物的合成及还原方法研究;孙云;《中国博士学位论文全文数据库 工程科技I辑》;20090815(第8期);B014-19 * |
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Effective date of registration: 20211020 Address after: 200000 floors 1-4, A2, building a, No. 688 Qiushi Road, Jinshanwei Town, Jinshan District, Shanghai Patentee after: SHANGHAI JIFENG BIOTECHNOLOGY Co.,Ltd. Patentee after: Jill peptide biopharmaceutical (Dalian) Co.,Ltd. Address before: A2, building a, 688 Qiushi Road, Jinshanwei Town, Jinshan District, Shanghai, May 12, 2015 Patentee before: SHANGHAI JIFENG BIOTECHNOLOGY Co.,Ltd. |