CN112174854A - Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid - Google Patents

Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid Download PDF

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CN112174854A
CN112174854A CN202011106180.3A CN202011106180A CN112174854A CN 112174854 A CN112174854 A CN 112174854A CN 202011106180 A CN202011106180 A CN 202011106180A CN 112174854 A CN112174854 A CN 112174854A
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generate
room temperature
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徐红岩
马敬祥
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Shanghai Jifeng Biotechnology Co ltd
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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
    • C07C269/04—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 from amines with formation of carbamate groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • 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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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a preparation method of (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo pentanoic acid. Mainly solves the technical problems of higher raw material cost and more three wastes generated in the existing synthesis method. The synthesis method comprises the following steps: in a sodium bicarbonate solution, reacting L-glutamic acid with 9-fluorenylmethyl-N-succinimidyl carbonate at room temperature to generate a compound 1; in toluene heated and refluxed, a compound 1 and paraformaldehyde undergo a dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a compound 2; in an ethyl acetate solution, carrying out acylation reaction on the compound 2, ammonium carbonate, pyridine and di-tert-butyl dicarbonate at room temperature to generate a compound 3; in a dichloromethane solution, the compound 3 reacts with triethylsilane and trifluoroacetic acid at room temperature to produce the target compound 4. The product of the invention is used for synthesizing Callipeltin series natural products with effective cytotoxicity and anti-HIV activity, and is also an important intermediate for synthesizing various peptide active substances.

Description

Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid
Technical Field
The invention relates to a synthesis method of (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo pentanoic acid (CAS: 910056-51-8).
Background
In recent years, the biological activity of natural products of the Callipeltin series has been studied intensively. Callipeltin A and B, which are cyclic depsipeptides, are reported to have anti-HIV and anti-fungal activities as well as cytotoxicity against several cancer cells of the human body. In 2002, the D' Auria team successfully isolated calipepeltin E, a noncyclic hexapeptide, from the marine sponge Latrunculia sp. In 2006, 2 isomers 1 and 5 of Callipeltin E were obtained by solid phase synthesis using Fmoc-amino acids as intermediates by the university of Prion chemist.
Figure DEST_PATH_IMAGE002
As an amino acid derivative, (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxopentanoic acid is an important intermediate for synthesizing Callipelten series natural products, and the following synthetic methods have been reported:
Figure DEST_PATH_IMAGE004
。
the method has high cost of raw materials, and three wastes are generated in the large-scale production.
Disclosure of Invention
The invention mainly aims to provide a synthesis method of (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo pentanoic acid. Mainly solves the technical problems of higher raw material cost and more three wastes generated in the existing synthesis method.
The technical scheme of the invention is as follows: a preparation method of (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo-pentanoic acid is characterized by comprising the following steps: firstly, in a sodium bicarbonate solution, reacting L-glutamic acid with 9-fluorenylmethyl-N-succinimidyl carbonate at room temperature to generate a compound 1; secondly, in toluene heated and refluxed, the compound 1 and paraformaldehyde undergo dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a compound 2; thirdly, in ethyl acetate solution, carrying out acylation reaction on the compound 2, ammonium carbonate, pyridine and di-tert-butyl dicarbonate at room temperature to generate a compound 3; and fourthly, reacting the compound 3 with triethylsilane and trifluoroacetic acid in a dichloromethane solution at room temperature to generate a target compound 4. The synthesis route is as follows:
Figure DEST_PATH_IMAGE006
。
the first step is reaction overnight; and the fourth step, reacting the compound 3 with triethylsilane and excess trifluoroacetic acid.
Abbreviation definition: Fmoc-Osu: 9-fluorenylmethyl-N-succinimidyl carbonate; PA: paraformaldehyde; PTSA: p-toluenesulfonic acid; (Boc)2O: di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; TES: triethylsilane.
The invention has the beneficial effects that: the present invention reports a method for synthesizing (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxopentanoic acid using L-glutamic acid and 9-fluorenylmethyl-N-succinimidyl carbonate as raw materials. The reaction raw materials are cheap, the intermediate product does not need to be purified by a chromatographic column, and more choices are provided for synthesizing (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo-pentanoic acid and derivatives thereof.
Detailed Description
Step 1:
adding L-glutamic acid (10.0 g, 68.0 mmol), water (100 mL) and acetone (100 mL) into a 500 mL reaction bottle, adding sodium bicarbonate (14.3 g, 170.0 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (25.2 g, 74.8 mmol) respectively under cooling in an ice bath, stirring overnight at room temperature, adding water (100 mL) into the reaction solution for dilution, extracting with ethyl acetate (3 × 100 mL), separating, adjusting the pH of the aqueous phase to be 2-3 by using 6M hydrochloric acid, and simultaneously precipitating a large amount of white solid; filtration followed by drying at 50 ℃ gave compound 1 as a white solid (23.1 g, 62.6 mmol, 92%). LC-MS (ESI) M/z 368.15 [ M-H ]]-。
Step 2:
a150 mL reaction flask was charged with Compound 1 (30.0 g, 81.2 mmol), paraformaldehyde (5.0 g, 166.7 mmol) and p-toluenesulfonic acid (2.0 g, 11.6 mmol), warmed to 130 deg.C, and heated at reflux for 3 hours until water was separatedNo water can flow out of the container. After cooling to room temperature, the reaction mixture was washed with water (100 mL), a saturated sodium bicarbonate solution (100 mL) and a saturated brine (100 mL), dried over anhydrous sodium sulfate, and then the organic phase was concentrated under reduced pressure to give a pale yellow solid, compound 2 (30.5 g, 80.0 mmol, 98%). LC-MS (ESI) M/z 404.10 [ M + Na [)]+。
And step 3:
ethyl acetate (500 mL), Compound 2 (146.0 g, 383.2 mmol), di-tert-butyl dicarbonate (100.3 g, 460.1 mmol) and pyridine (36.3 g, 459.5 mmol) were charged to a 1L reaction flask, and after stirring at room temperature for 1 hour, ammonium carbonate (55.2 g, 575.0 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1M hydrochloric acid (500 mL), water (500 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 3 (139.8 g, 367.9 mmol, 96%) as a pale yellow solid. LC-MS (ESI) M/z 381.05 [ M + H [ ]]+。
And 4, step 4:
a500 mL reaction flask was charged with dichloromethane (200 mL), compound 3 (46.0 g, 121.0 mmol) and triethylsilane (46.0 g, 396.6 mmol), and trifluoroacetic acid (150 g, 1.31 mol) was slowly added dropwise and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by chromatography (silica gel, dichloromethane: methanol =20: 1) to obtain target compound 4 (HPLC purity 98.4%, 41.8 g, 110.1 mmol, 91%) as a white solid.1H NMR (400 MHz, DMSO-d6) 12.30 (br s, 1H), 7.80-7.95 (m, 2H), 7.55-7.73 (m, 2H), 7.30-7.45 (m, 4H), 6.95 (br s, 2H), 4.50-4.65 (m, 1H), 4.25-4.35 (m, 3H), 2.80 (s, 3H), 2.05-2.10 (m, 3H), 1.85-1.93 (m, 1H)；LC-MS (ESI): m/z 383.20 [M+H]+。

Claims (3)

1. A preparation method of (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxo-pentanoic acid is characterized by comprising the following steps: the method comprises the following steps: firstly, in a sodium bicarbonate solution, reacting L-glutamic acid with 9-fluorenylmethyl-N-succinimidyl carbonate at room temperature to generate a compound 1; secondly, in toluene heated and refluxed, the compound 1 and paraformaldehyde undergo dehydration condensation reaction under the catalytic action of p-toluenesulfonic acid to generate a compound 2; thirdly, in ethyl acetate solution, carrying out acylation reaction on the compound 2, ammonium carbonate, pyridine and di-tert-butyl dicarbonate at room temperature to generate a compound 3; fourthly, in a dichloromethane solution, reacting the compound 3 with triethylsilane and trifluoroacetic acid at room temperature to generate a target compound 4; the synthesis route is as follows:
Figure DEST_PATH_IMAGE001
。
2. the process for producing (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxopentanoic acid according to claim 1, wherein: the first step was carried out overnight.
3. The process for producing (S) -2- ((9H-fluorene-9-methoxycarbonyl) methylamino) -5-amino-5-oxopentanoic acid according to claim 1, wherein: and the fourth step, reacting the compound 3 with triethylsilane and excess trifluoroacetic acid.
CN202011106180.3A 2020-10-16 2020-10-16 Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid Withdrawn CN112174854A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645833A (en) * 2021-01-29 2021-04-13 上海吉奉生物科技有限公司 Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid
CN115385891A (en) * 2022-09-06 2022-11-25 上海药坦药物研究开发有限公司 Preparation method of remazolam intermediate

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Publication number Priority date Publication date Assignee Title
CN101274958A (en) * 2008-05-17 2008-10-01 中国海洋大学 Bioactive peptide, preparation thereof and application thereof
CN101605790A (en) * 2007-01-05 2009-12-16 瑟维尔实验室 New amino-pyrroles is also [1,6-a] indole derivatives, their preparation method and the pharmaceutical composition that comprises them of [1,2-a] indoles and amino pyridazine also
CN111423432A (en) * 2020-05-11 2020-07-17 河南大学 (S) -4/5-phenyl-2- (pyrrolidine-2-yl) thiazole TRPV1 antagonist and preparation and application thereof

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN101605790A (en) * 2007-01-05 2009-12-16 瑟维尔实验室 New amino-pyrroles is also [1,6-a] indole derivatives, their preparation method and the pharmaceutical composition that comprises them of [1,2-a] indoles and amino pyridazine also
CN101274958A (en) * 2008-05-17 2008-10-01 中国海洋大学 Bioactive peptide, preparation thereof and application thereof
CN111423432A (en) * 2020-05-11 2020-07-17 河南大学 (S) -4/5-phenyl-2- (pyrrolidine-2-yl) thiazole TRPV1 antagonist and preparation and application thereof

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Title
ROGER M ET AL: "Synthesis of 9-fluorenylmethyloxycarbonyl-protected N-alkyl amino acids by reduction of oxazolidinones", 《J. ORG. CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645833A (en) * 2021-01-29 2021-04-13 上海吉奉生物科技有限公司 Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid
CN115385891A (en) * 2022-09-06 2022-11-25 上海药坦药物研究开发有限公司 Preparation method of remazolam intermediate

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