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A kind of preparation method of pharmaceutical intermediate optically pure cyclopentenol

A technology of pure cyclopentenol and intermediates, applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, can solve the problems of expensive reagents and high requirements for reaction conditions, and achieve low price, simple operation, and high reaction efficiency. The effect of mild conditions

Active Publication Date: 2021-10-22
HUBEI GRAND LIFE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the synthetic route has only two steps, the reagents used are expensive and the reaction conditions are demanding, so finding a more convenient synthetic method is always a challenge

Method used

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  • A kind of preparation method of pharmaceutical intermediate optically pure cyclopentenol
  • A kind of preparation method of pharmaceutical intermediate optically pure cyclopentenol
  • A kind of preparation method of pharmaceutical intermediate optically pure cyclopentenol

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Experimental program
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Effect test

Embodiment 1

[0035] The preparation of embodiment 1 (2R, 3S)-3-hydroxyl-2-vinylhex-5-ene-1-aldehyde

[0036] (S)-proline (14.9 mg, 0.13 mmol) was added to a stirred solution of 3-butenal (150 mg) in 1 ml of tetrahydrofuran, stirred at 25°C for 20 h, and the reaction solution was concentrated with petroleum The mixture of ether and ethyl acetate was separated by liquid column chromatography to obtain 100 mg of (2R,3S)-3-hydroxy-2-vinylhex-5-en-1-al. Yield 67%, 1 H NMR (DMSO-d 6 )δ:1.95(brs,1H),2.11(m,2H),3.11(m,1H),3.51(m,1H),4.97(d,1H),5.03(d,1H),5.17(d,1H ), 5.19(d,1H), 5.70(dd,1H), 5.97(dd,1H), 9.72(s,1H).

Embodiment 2

[0037] The preparation of embodiment 2 (2R, 3S)-3-hydroxyl-2-vinylhex-5-en-1-alcohol

[0038] 2 mmol (222 mg) of calcium chloride, 1 mmol (140 mg) (2R, 3S)-3-hydroxyl-2-vinylhex-5-en-1-aldehyde were added to a 50-mL one-necked flask, Add 5 ml of methanol and stir at 25°C for 30 minutes. 1.2 mmol (50 mg) of sodium borohydride was dissolved in a solution prepared by 1 ml of methanol and 1 ml of 1% sodium hydroxide, and the sodium borohydride solution was added dropwise under ice-cooling and stirring. After the dropwise addition, the stirring reaction was continued at 25° C. for 30 minutes, and then 1 ml of 4M hydrochloric acid solution was added to decompose the solid that appeared. Most of the methanol was removed under reduced pressure, cooled to 25°C, 10 ml of ice water was added, extracted three times with dichloromethane, the organic phases were combined, dried and concentrated, and separated by column chromatography to obtain (2R,3S)-3-hydroxy-2- Vinylhex-5-en-1-ol 120 m...

Embodiment 3

[0039] The preparation of embodiment 3 (3R, 4S)-3-benzyloxymethylhepta-1,6-dien-4-ol

[0040] 142 mg of (2R,3S)-3-hydroxy-2-vinylhex-5-en-1-ol (1.0 mmol) was added to 200 mg of sodium hydride in 2 ml of DMF under cooling at 0 °C, then 342 mg (2 mmol) of benzyl bromide was added with stirring. After the addition, continue to stir at 25°C for 30 minutes. After no raw material spots are detected by thin-plate chromatography, the reaction solution is poured into 50 grams of ice, extracted three times with dichloromethane, and the extracts are combined, dried, concentrated, and purified by column chromatography. 205 mg of (3R,4S)-3-benzyloxymethylhept-1,6-dien-4-ol was obtained with a yield of 88%. 1 H NMR (DMSO-d 6)δ:2.00(brs,1H),2.11(m,2H),2.56(m,1H),3.28(m,1H),3.37(m,2H),4.63(m,2H),4.97(m,2H ), 5.02(m,2H), 5.70(m,2H), 7.19-7.40(m,5H).

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Abstract

The present invention relates to a kind of preparation method of optically pure cyclopentenol of pharmaceutical intermediate, and this method is to use 3-butenal and its 3-position or 4-position derivative as raw material, in catalytic amount (S)-proline Synthesized in the presence of optically pure aldol condensation products, the aldehyde group was reduced to a hydroxyl group and then protected with benzyl bromide, and then obtained through a high-efficiency double bond metathesis ring-closure reaction (1 S ,2 R )-2-benzyloxymethylcyclopent-3-en-1-alcohol, the method provided by the invention has mild reaction conditions, cheap raw materials and reagents, high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic chemical industry, in particular to a method for preparing a pharmaceutical intermediate optically pure cyclopentenol. Background technique [0002] (1S,2R)-2-Benzyloxymethylcyclopent-3-en-1-ol is an important pharmaceutical intermediate for the synthesis of carbocyclic nucleosides (Abdallah Ezzitouni, Pamela Russ, and Victor E. Marquez. J. Org. Chem. 1997, 62, 4870-4873), such as entecavir (GS Bisacchi et al, Bioorg Med Chem Lett, 1997, 7(2), 127-132). [0003] Regarding the synthesis of (1S,2R)-2-benzyloxymethylcyclopent-3-en-1-ol, mainly using sodium cyclopentadiene as a raw material, the synthetic route is as follows: [0004] [0005] Sodium cyclopentadiene reacts with benzyl chloride methyl ether to obtain 5-benzyloxymethyl cyclopentadiene, and then carries out hydroboration reaction with dipinyl borane, and after oxidation, the target product (1S,2R)-2- Benzyloxymethylcyclopent-3-en-1-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C41/18C07C43/178
CPCC07B2200/07C07C29/143C07C41/16C07C41/18C07C45/72C07C43/1788C07C43/1787C07C33/02C07C47/263
Inventor 孙华君杨尚金钱志强熊先胜谢国范何本斌朱毅郭晨
Owner HUBEI GRAND LIFE SCI & TECH CO LTD
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