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The synthetic method of (s)-3-aminopyrrolidine 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: 2016-12-14
SHANGHAI INST OF PHARMA IND CO LTD +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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  • The synthetic method of (s)-3-aminopyrrolidine dihydrochloride
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  • The synthetic method of (s)-3-aminopyrrolidine dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of (R)-3-hydroxypyrrolidine hydrochloride (II)

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

[0043] Yield: 80.0%

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

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

Embodiment 2

[0058] Preparation of (R)-3-hydroxypyrrolidine hydrochloride (II)

[0059] Trans-4-hydroxy-L-proline (10.0g, 0.75mol), cyclohexanol (50.0ml) and 2-cyclohexen-1-one (1.0ml, 0.11mol) were mixed well and heated to 150 ℃, heat preservation reaction for 3h, after cooling to room temperature, add toluene (50ml), cool to about 0 ℃ in ice-water bath, pass dry hydrogen chloride gas to pH 2~3, stir at about 5 ℃ for 1h, filter to obtain solid , recrystallized with isopropanol (30ml) to give light pink crystalline solid II (7.7g, 82.1%), mp: 104~107℃

[0060] Yield: 82.1%

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

[0062] The light pink crystalline solid II (62.1g, 0.50mol) was placed in a solution of dichloromethane (800ml), cooled to 0°C, triethylamine (90.0ml, 0.65mol) was added, and after stirring uniformly, ( Boc) 2 A solution of O (110.0g, 0.50mol) in dichloromethane (400ml) was reacted at 0°C for 3h, then triethylamine (80.0ml, 0.55...

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Abstract

The invention relates to a chiral synthesis method of (S)-3-aminopyrrolidine dihydrochloride, which uses trans-4-hydroxyl-L-proline as a raw material, first undergoes a decarboxylation reaction, and then performs N-tert-butyl Oxycarbonyl protection, hydroxyl sulfonylation, and then SN2 reaction with sodium azide, configuration inversion, after triphenylphosphine reduction of azido group to amino group, directly remove N-Boc protection with concentrated hydrochloric acid, a total of A four-step chain reaction yields the target product. The raw materials used in the inventive method are cheap and easy to obtain, the reaction conditions are mild, the aftertreatment is simple and convenient, and the yield of the obtained product is relatively high.

Description

technical field [0001] The invention relates to the technical field of chiral drug preparation, in particular to a method for preparing a chiral drug intermediate (S)-3-aminopyrrolidine dihydrochloride. Background technique [0002] 3-Aminopyrrolidine dihydrochloride and its optical isomers are key intermediates in the synthesis of a large number of chiral drugs. 3-aminopyrrolidine 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), its synthetic route report mainly contains the following five kinds: [0004] [0005] Chinese Journal of Pharmaceutical Industry (29(9): 429-431), reported the route of using N-benzyl-3-pyrroline as raw material, first with (+)-diisosporin borane [(+)- Ipc 2 BH] undergoes hydroboration, and then oxidizes to (3S)-3-hydroxyl compound, which is then sulfonylated, SN 2 The reac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/14
Inventor 蒋旭东袁哲东罗颖黄雨俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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