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Synthesis method of (S)-3-amino pyrrolidine dihydrochloride

A technology of aminopyrrolidine dihydrochloride and hydroxypyrrolidine hydrochloride, which is applied in the field of preparation of chiral drugs, can solve the problems of difficult recovery of solvent THF and cumbersome operation, and achieve low cost, readily available raw materials, and mild reaction conditions Effect

Active Publication Date: 2012-07-04
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction yield is high, but the operation is cumbersome, and the solvent THF used is not easy to recover

Method used

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  • Synthesis method of (S)-3-amino pyrrolidine dihydrochloride
  • Synthesis method of (S)-3-amino pyrrolidine dihydrochloride
  • Synthesis method of (S)-3-amino pyrrolidine dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (R)-3-hydroxypyrrolidine hydrochloride (II) preparation

[0042] Mix trans-4-hydroxyl-L-proline (100.0g, 0.75mol), cyclohexanol (500.0ml) and 2-cyclohexen-1-one (10.0ml, 0.11mol) and heat to 154°C, heat preservation reaction for 5h, after cooling to room temperature, add toluene (500ml), cool in an ice-water bath to about 0°C, pass in dry hydrogen chloride gas until the pH value is 2-3, stir at about 5°C for 1h, and filter to obtain a solid , recrystallized from isopropanol (300ml) to give light pink crystalline solid II (75.0g, 80.0%), mp: 104~107°C

[0043] Yield: 80.0%

[0044] Preparation of (R)-1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (III)

[0045] Light pink crystalline solid II (12.4g, 0.10mol) was placed in dichloromethane (200ml) solution, cooled to 0°C, triethylamine (18.0ml, 0.13mol) was added, after stirring evenly, dropwise added ( Boc) 2 O (22.0g, 0.10mol) in dichloromethane (100ml) solution, reacted at 0°C for 3h, then added triethylamin...

Embodiment 2

[0058] (R)-3-hydroxypyrrolidine hydrochloride (II) preparation

[0059] Mix trans-4-hydroxyl-L-proline (10.0g, 0.75mol), cyclohexanol (50.0ml) and 2-cyclohexen-1-one (1.0ml, 0.11mol) and heat to 150°C, heat preservation reaction for 3h, after cooling to room temperature, add toluene (50ml), cool in an ice-water bath to about 0°C, pass in dry hydrogen chloride gas until the pH value is 2-3, stir at about 5°C for 1h, and filter to obtain a solid , recrystallized from isopropanol (30ml) to give light pink crystalline solid II (7.7g, 82.1%), mp: 104~107°C

[0060] Yield: 82.1%

[0061] Preparation of (R)-1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (III)

[0062] Put light pink crystalline solid II (62.1g, 0.50mol) in dichloromethane (800ml) solution, cool to 0°C, add triethylamine (90.0ml, 0.65mol), stir evenly, add dropwise ( Boc) 2 O (110.0g, 0.50mol) in dichloromethane (400ml) solution, reacted at 0°C for 3h, then added triethylamine (80.0ml, 0.55mol), then added ...

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Abstract

The invention relates to a chiral synthesis method of (S)-3-amino pyrrolidine dihydrochloride. Trans-4-hydroxyl-L-proline is taken as raw materials, is first subjected to decarboxylation and then subjected to N-tert-butoxycarbonyl (N-Boc) protection and hydroxyl sulfonylurea acylation, and is then subjected to an SN2 reaction with sodium azide and configuration reversal. After azido is changed to amino through reduction by triphenylphosphine, concentrated hydrochloric acid is directly used for removal of N-Boc protection, and target products are obtained through a total of four steps of chain reactions. Raw materials of the chiral synthesis method are easy to obtain, reaction conditions are mild, post-processing is simple and convenient, and product yield is high.

Description

technical field [0001] The invention relates to the technical field of chiral drug preparation, in particular to a preparation method of a chiral drug intermediate (S)-3-aminopyrrolidine dihydrochloride. Background technique [0002] 3-aminopyrrolidine dihydrochloride and its optical isomers are key intermediates for the synthesis of a large number of chiral drugs. Through 3-aminopyrrolidine, it can be used to synthesize a series of drugs such as carbapenem antibiotics, quinolone antibacterial agents, and chemokine regulators. [0003] At present, (S)-3-aminopyrrolidine dihydrochloride, as shown in formula (I), mainly contains following five kinds of its synthetic route report: [0004] [0005] Chinese Journal of Pharmaceutical Industry (29 (9): 429-431), has reported the route with N-benzyl-3-pyrroline as raw material, earlier with (+)-diisopine camphene borane [(+)- Ipc 2 BH] undergoes hydroboration, and then oxidizes (3S)-3-hydroxyl, and then undergoes sulfonylatio...

Claims

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Application Information

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IPC IPC(8): C07D207/14
Inventor 蒋旭东袁哲东罗颖黄雨俞雄
Owner SHANGHAI INST OF PHARMA IND
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