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Octahydro cyclopenteno [c] pyrroletetrazole derivative and preparation thereof

A technology of octahydrocyclopentene and pyrrole carboxylic acid, applied in the production of bulk chemicals, organic chemistry, etc., can solve problems such as unsatisfactory, and achieve the effect of easy industrial operation and simple process

Inactive Publication Date: 2009-06-24
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problem that the current amino acid bicyclic structure still cannot meet the diverse needs of different drugs or biological systems for drug metabolism, distribution, and biomacromolecule interaction performance changes

Method used

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  • Octahydro cyclopenteno [c] pyrroletetrazole derivative and preparation thereof
  • Octahydro cyclopenteno [c] pyrroletetrazole derivative and preparation thereof
  • Octahydro cyclopenteno [c] pyrroletetrazole derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of (1S, 3aR, 6aS)-2-benzyloxycarbonyl-5-oxoctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester

[0032]

[0033] Step 1: Preparation of (S)-4-methylmercapto-2-(prop-2-ynylamino)butanoic acid methyl ester

[0034] Reaction formula:

[0035]

[0036] Steps:

[0037]Add No. 4 molecular sieves (240g) and lithium hydroxide monohydrate (41.7g, 993mmol) into N,N-dimethylformamide (460mL), stir at 0°C for 20 minutes; add (S)-4-form Mercapto-butyric acid methyl ester hydrochloride (92 g, 460 mmol), continued stirring at 0° C. for 45 minutes; 3-bromopropyne was added dropwise. The reaction mixture was stirred at room temperature for 28 hours, then filtered, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the product with a yield of 60%.

[0038] 1 H NMR (400MHz, CDCl 3 )δ: 1.85-2.03(m, 2H), 2.10(s, 3H), 2.23(dd, J=2.4, 2.4Hz, 1H), 2.36(br...

Embodiment 2

[0068] Preparation of (1S, 3aS, 6aR)-2-benzyloxycarbonyl-5-oxoctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester

[0069] The first step reaction: the preparation of (S)-2-benzyloxycarbonyl-5-oxoctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester

[0070] Reaction formula:

[0071]

[0072] (S)-methyl 2-((benzyloxycarbonyl)(propargyl)-amine)butene-3-carboxylate (1 g, 3.48 mmol) and cobalt carbonyl (0.16 g, 0.47 mmol) were dissolved in tetrahydrofuran ( 20 mL), carbon monoxide was introduced to maintain a pressure of 0.7 MPa, and the mixture was stirred at 135°C for 24 hours. After filtration, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain the product with a yield of 30%.

[0073] 1 H NMR (400MHz, CDCl 3 )δ: 2.24(br, 1H), 3.60(br, 2H), 3.75(br, 3H), 4.20(br, 1H), 5.20(br, 2H), 5.38(m, 2H), 6.14(ddd, J = 6.2, 10.3, 17.0 Hz, 1H), 7.34-7.36 (m,...

Embodiment 3

[0083] Preparation of (1S, 3aR, 5S, 6aS)-2-benzyloxycarbonyl-5-hydroxyoctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester

[0084] Reaction formula:

[0085]

[0086] Steps:

[0087]Dissolve methyl (1S,3aR,6aS)-2-benzyloxycarbonyl-5-oxoctahydrocyclopenta[c]pyrrole-1-carboxylate (0.111 g, 0.35 mmol) in anhydrous methanol (5 mL) , added sodium borohydride (0.013 g, 0.35 mmol), under nitrogen protection, and stirred at 0° C. for 30 minutes. Add saturated ammonium chloride aqueous solution (10 mL) to stop the reaction, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the product with a yield of 95%.

[0088] 1 H NMR (400MHz, CDCl 3 )δ: 7.36-7.28 (m, 5H), 5.14-5.01 (m, 2H), 4.36-4.34 (m, 1H), 4.23 (m, 1H), 3.91-3.89 (m, 1H), 3.71-3.59 ( m, 7H), 2.69(br, 2H), 2.28-2.15(m, 2H), 1.68-1.62(m, 1H), 1.42-1.49(m, 1H), 1.30-1.28(m, 1H)

[0089] MS(ESI)m / e(M+H + ): 3...

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Abstract

The invention relates to an octahydro cyclopentenopyridine (c) carboxylic acid derivative and a preparing method thereof, providing basis for designing and preparing compounds with different biological activities. A chemical structural formula is shown in the fight formula, wherein, R1 is one of alkoxy, bydroxy and amine. R2 and R3 are one of bydroxy, fluorine and hydrogen. N protecting group is tertbutyloxycarbonyl, benzyloxycarbonyl or benzyl. The compounds are optically pure. Starting from natural methionine ester or hydrochloride thereof, the compound of (S)-2-((benzyloxycarbonyl)(propargyl)-amine)butane-3-carboxylic ester (5) is obtained through substitution, oxidation and elimination. After reactions of cobalt carbonyl catalytic cyclization, and the like, (S)-2-benzyloxycarbonyl-5-octahydro cyclopentenopyridine (c)-1- carboxylic ester is obtained. Series of deritative compounds are obtained through reduction of carbonyl, fluorination, chiral separation, hydrolysis and condensation.

Description

Technical field: [0001] The invention relates to an octahydrocyclopenta[c]pyrrole carboxylic acid derivative and a preparation method thereof, in particular to an optically pure 5-oxo (or fluoro) octahydrocyclopenta[c]pyrrole-1-carboxylic acid derivative method of preparation. technical background: [0002] Monocyclic proline is the only amino acid that can divert peptide bonds, but it is easily hydrolyzed by peptidases in the human body and cannot exist stably. Monocyclic proline compounds retain the function of redirecting peptide bonds. Compound formulas 1 to 5 are all monocyclic proline compounds reported in the literature, but these compounds are easily hydrolyzed by peptidases in the human body And can not exist stably, resulting in poor bioavailability. [0003] [0004] Merged ring structures are widely used in medicines, and the core structures containing merged rings are very common in marketed drugs. Compounds of formulas 6-8 are acyclic compounds that have ...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 梁宏艳杜峰吴颢胡斌唐飞宇董径超陈曙辉李革
Owner 上海药明康德新药开发有限公司
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