Preparation method of (S)-3-hydroxypyrrolidine hydrochloride

A hydroxypyrrolidine hydrochloride and hydroxypyrrolidine technology are applied in the field of preparation of -3-hydroxypyrrolidine hydrochloride, can solve problems such as inability to meet industrialized production, avoid column chromatography purification, reduce risk factor, Guaranteed effect of optical purity

Inactive Publication Date: 2016-06-08
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The third method literature (JournalofLabelledCompoundsandRadiopharmaceuticals.44,31-41(2001), WO2007050522A1) reported that L-hydroxyproline was used as raw material, and finally obtained ( S)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine, although the raw material source of this method is convenient and easy to get, what post-treatment purification adopts is column chromatography purification, can not satisfy suitability for industrialized production

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  • Preparation method of (S)-3-hydroxypyrrolidine hydrochloride
  • Preparation method of (S)-3-hydroxypyrrolidine hydrochloride
  • Preparation method of (S)-3-hydroxypyrrolidine hydrochloride

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[0026] The present invention will be further described below through the examples, but the examples do not limit the protection scope of the present invention.

[0027] 1. Preparation of (R)-1-tert-butoxycarbonyl-3-benzoyloxypyrrolidine (3)

[0028] Dissolve 50g (0.267mol) of (R)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine, 42.4g (0.348mol) of benzoic acid, and 91g (0.348mol) of triphenylphosphine in 200ml of dry tetrahydrofuran, Under nitrogen protection, stir at -10°C. Slowly add 68.4ml (0.384mol) of diisopropyl azodicarboxylate dropwise, and control the internal temperature not to exceed -5°C. The dropwise addition time was about 30 minutes, and after the addition was completed, the temperature was slowly raised to room temperature, and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, 200ml of water was added to the residue, extracted with ethyl acetate (100ml×3), the organic phases were combined, washed with water (50ml×2) a...

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Abstract

The invention relates to the field of chemistry, particularly a preparation method of a key intermediate (S)-3-hydroxypyrrolidine hydrochloride of darifenacin for treating overactive bladder syndrome and an antihypertensive drug barnidipine. The preparation method comprises the following steps: carrying out Mitsunobu reaction on (R)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine so as to be condensed with acid to obtain an upturned-structure ester, hydrolyzing ester bond under alkaline conditions to obtain (S)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine, and removing Boc protecting groups under acidic conditions, thereby finally obtaining the key intermediate. The method is simple and easy to implement, has the advantages of cheap and accessible raw materials, lower cost and high yield, and has potential production value.

Description

Technical field: [0001] The invention relates to a preparation method of (S)-3-hydroxypyrrolidine hydrochloride Background technique: [0002] (S)-3-Hydroxypyrrolidine is an important structural fragment in drug design, and is often used in the structural modification of various drugs. For example, the structures of darfinacin, an overactive bladder treatment, and barnidipine, an antihypertensive drug, contain (S)-3-hydroxypyrrolidine fragments in their structures. Darfenacine is a selective muscarinic M3 receptor antagonist developed by Pfizer, which is clinically used to treat overactive bladder (OAB) such as urge incontinence, urgency, and frequent urination. It selectively acts on M3 The receptor thus greatly reduces the incidence of adverse reactions in the central nervous system and cardiovascular system, and has good curative effect, tolerance and safety, and is the drug of choice for the treatment of OAB. Barnidipine is a new type of long-acting dihydropyridine cal...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12
CPCY02P20/55C07D207/12C07B2200/07
Inventor 薛晓文龙劲节班浩宋志强李嘉宾
Owner CHINA PHARM UNIV
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