CN112062693A - Synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid - Google Patents
Synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid Download PDFInfo
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- CN112062693A CN112062693A CN202011006073.3A CN202011006073A CN112062693A CN 112062693 A CN112062693 A CN 112062693A CN 202011006073 A CN202011006073 A CN 202011006073A CN 112062693 A CN112062693 A CN 112062693A
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- methyl
- methoxycarbonylamino
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- C—CHEMISTRY; METALLURGY
- 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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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
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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Abstract
The invention relates to a synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid. Mainly solves the technical problem that the prior method for amplifying and producing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid is lacked. The synthesis method comprises the following steps: in methyl tert-butyl ether cooled in an ice bath, acidifying calcium 3-methyl-2-oxybutyrate with concentrated hydrochloric acid to generate a compound 1; in toluene heated and refluxed, the compound 1 and fluorenylmethyloxycarbonyl amide are subjected to dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a target compound 2. 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid, which is used as a medical intermediate and a dehydroamino acid derivative, is widely used in the fields of synthesis of peptide active substances and protein engineering.
Description
Technical Field
The invention relates to a synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid (CAS: 198546-38-2).
Background
In recent years, with the development of biomedicine, polypeptide compounds have been studied more and more intensively in the field of biomedicine as macromolecular substances having biological activity. Traditional polypeptides are susceptible to conformational changes in structure, limiting the use of polypeptides in drug therapy and immunization.
Alpha, beta-dehydro amino acids, which are natural amino acids, are widely present in microorganisms and animals and plants, and are condensed to form a peptide chain containing three rigid groups at the alpha-carbon, thereby limiting the conformation of the peptide compound main chain and generating a specific peptide secondary structure. The alpha, beta-dehydro amino acid is applied to polypeptide synthesis, so that the change of the alpha, beta-dehydro amino acid in conformation can be limited, and the design and synthesis of drugs and bioactive substances of the polypeptide are greatly enriched.
2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid, which is a kind of alpha, beta dehydroamino acid, is increasingly studied in the aspects of polypeptide drugs and immunologically active compounds. Up to now, no technical method for the amplified production of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid has been reported.
Disclosure of Invention
The invention mainly aims to provide a synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid. Mainly solves the technical problem that the prior method for amplifying and producing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid is lacked.
The technical scheme of the invention is as follows: a synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid is characterized by comprising the following steps: step one, in methyl tert-butyl ether cooled by an ice bath, acidifying calcium 3-methyl-2-oxybutyrate with concentrated hydrochloric acid to generate a compound 1; and secondly, in the toluene heated and refluxed, the compound 1 and the fluorenylmethoxycarbonyl amide are subjected to dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a target compound 2. The synthesis route is as follows:
in the first step, calcium 3-methyl-2-oxybate is acidified by 12M concentrated hydrochloric acid; in the first step of reaction, after dropwise adding of concentrated hydrochloric acid is finished, stirring is carried out for 10 minutes at room temperature; the second dehydration condensation reaction is carried out under the catalysis of 0.1 equivalent of p-toluenesulfonic acid; the second reaction was heated to reflux in toluene for 2 hours. After the second reaction, the crude product was purified by stirring at room temperature in a mixture of dichloromethane and water.
Abbreviation definition: MTBE-methyl tert-butyl ether; PTSA-p-toluenesulfonic acid; Fmoc-NH2Fluorenylmethoxycarbonylamide.
The invention has the beneficial effects that: the invention reports a method for synthesizing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid by using 3-methyl-2-oxobutyrate calcium salt and fluorenylmethoxycarbonylamide as raw materials. The reaction raw materials are cheap, the intermediate product and the target compound do not need to be purified by a chromatographic column, the target compound with high chemical purity and chiral purity can be obtained, and the problem of the large-scale production of the 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid is solved.
Detailed Description
Step 1:
A20L reaction flask was charged with calcium 3-methyl-2-oxybutyrate (4.14 kg, 15.3 mol) and methyl tert-butyl ether (MTBE, 10L), and concentrated hydrochloric acid (12M, 2.8L, 33.6 mol) was added dropwise under cooling in an ice bath, and after completion of the addition, the mixture was stirred at room temperature for 10 minutes, after separation of the liquids, the aqueous phase was extracted with MTBE (1L x 3), and after the organic phases were combined, the mixture was washed with saturated brine (1L) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a yellow oil, compound 1 (3.42 kg, 29.5 mol, 96%) as crude product which was used directly in the next reaction. LC-MS (ESI) M/z 115.12 [ M-H ]]-。
Step 2:
toluene (50L), a compound 1 (3.42 kg, 29.5 mol), fluorenylmethoxycarbonylamide (7.0 kg, 29.5 mol) and p-toluenesulfonic acid (0.51 kg, 2.95 mol) are added into a 100L glass reaction kettle, heating is carried out at 130 ℃, water flows out of a water separator, after 2 hours of reaction, heating is stopped, the reaction kettle is gradually cooled to room temperature, and a large amount of white solid is precipitated. Dichloromethane (20L) was added and stirred for 1 hour. The separation was filtered and the solid was washed with dichloromethane (10L x 3), then added to dichloromethane (25L), water (10L) was added and stirred at room temperature overnight. After filtration, the solid was dried at 50 ℃ to give the title compound 2 (HPLC purity 99.4%, 4.5 kg, 13.4 mol, 45%) as a white solid.1H NMR (400 MHz, DMSO-d6) 12.37 (s, 1H), 8.67 (s, 0.8H), 8.25 (s, 0.2H), 7.90-7.92 (m, 2H), 7.73-7.75 (m, 1.6H), 7.60-7.62 (m, 0.4H), 7.40-7.45 (m, 2H), 7.32-7.36 (m, 2H), 4.14-4.31 (3H), 2.10 (s, 0.6H), 2.01 (s, 2.4H), 1.75 (s,3H)；LC-MS (ESI): m/z 360.45 [M+Na]+。
Claims (5)
1. A synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid is characterized by comprising the following steps: the method comprises the following steps: step one, in methyl tert-butyl ether cooled by an ice bath, acidifying calcium 3-methyl-2-oxybutyrate with concentrated hydrochloric acid to generate a compound 1; secondly, in toluene heated and refluxed, the compound 1 and fluorenylmethoxycarbonylamide are subjected to dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a target compound 2; the synthesis route is as follows:
2. the method for synthesizing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid according to claim 1, wherein the method comprises the following steps: the calcium 3-methyl-2-oxybate salt of the first reaction was acidified with 12M concentrated hydrochloric acid.
3. The method for synthesizing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid according to claim 1, wherein the method comprises the following steps: in the second reaction, 0.1 equivalent of p-toluenesulfonic acid was added as a catalyst.
4. The method for synthesizing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid according to claim 1, wherein the method comprises the following steps: the second reaction time was 2 hours.
5. The method for synthesizing 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid according to claim 4, wherein the method comprises the following steps: after the second reaction, the crude product was purified by stirring overnight at room temperature in a mixture of dichloromethane and water.
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| CN202011006073.3A CN112062693A (en) | 2020-09-23 | 2020-09-23 | Synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid |
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| CN202011006073.3A CN112062693A (en) | 2020-09-23 | 2020-09-23 | Synthetic method of 2- (9H-fluorene-9-methoxycarbonylamino) -3-methyl-2-butenoic acid |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59164749A (en) * | 1983-03-09 | 1984-09-17 | Seitetsu Kagaku Co Ltd | Preparation of alpha-keto acid and/or its salt |
| DE10212322A1 (en) * | 2002-03-20 | 2003-10-02 | Degussa | Production of alkali salts of alpha-keto-carboxylic acids, for use e.g. in special diets, involves adding sodium carbonate to an aqueous suspension of the calcium salt and removing calcium carbonate by filtration |
| CN105121433A (en) * | 2012-12-14 | 2015-12-02 | 韩国化学研究院 | Novel compound, pharmaceutically acceptable salt or optical isomer thereof, method for preparing same, and pharmaceutical composition for prevention or treatment of viral diseases containing same as active ingredient |
| CN110054574A (en) * | 2019-04-11 | 2019-07-26 | 上海吉奉生物科技有限公司 | A kind of synthetic method of fluorenylmethyloxycarbonyl -2,3- dehydrogenation-valine |
| CN110642753A (en) * | 2019-09-25 | 2020-01-03 | 成都奥达生物科技有限公司 | Amino acid derivative |
-
2020
- 2020-09-23 CN CN202011006073.3A patent/CN112062693A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59164749A (en) * | 1983-03-09 | 1984-09-17 | Seitetsu Kagaku Co Ltd | Preparation of alpha-keto acid and/or its salt |
| DE10212322A1 (en) * | 2002-03-20 | 2003-10-02 | Degussa | Production of alkali salts of alpha-keto-carboxylic acids, for use e.g. in special diets, involves adding sodium carbonate to an aqueous suspension of the calcium salt and removing calcium carbonate by filtration |
| CN105121433A (en) * | 2012-12-14 | 2015-12-02 | 韩国化学研究院 | Novel compound, pharmaceutically acceptable salt or optical isomer thereof, method for preparing same, and pharmaceutical composition for prevention or treatment of viral diseases containing same as active ingredient |
| CN110054574A (en) * | 2019-04-11 | 2019-07-26 | 上海吉奉生物科技有限公司 | A kind of synthetic method of fluorenylmethyloxycarbonyl -2,3- dehydrogenation-valine |
| CN110642753A (en) * | 2019-09-25 | 2020-01-03 | 成都奥达生物科技有限公司 | Amino acid derivative |
Non-Patent Citations (1)
| Title |
|---|
| VIJAY KUMAR GOEL等: "Design of peptides with α,β-dehydro-residues: synthesis and crystal structure of a tripeptide N-benzyloxycarbonyl-ΔVal-ΔPhe-L-Ala-OCH3", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
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Application publication date: 20201211 |