Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof

A technology of derivatives and pyrrolidine, which is applied in the production of 3,4-disubstituted pyrrolidine derivatives and its production intermediates, and can solve the problems of reduced optical purity of products

Inactive Publication Date: 2012-09-26
KYORIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since 3-hydroxypiperidine produces 4-fluoropiperidine via rearrangement at the fluorination position, the optical purity of the product is reduced when optically active starting materials are used

Method used

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  • Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof
  • Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof
  • Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof

Examples

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preparation example Construction

[0106] The preparation method of the present invention is shown in Scheme 1.

[0107] [chemical 11]

[0108] plan 1

[0109]

[0110] In Scheme 1, PG in formula (1) and formula (2) and R in formula (1) to formula (3) 1 has the same meaning as above.

[0111] I. Step 1

[0112] Step 1 is to fluorinate 4-hydroxyl-3-(N-substituted aminomethyl)pyrrolidine derivatives or their enantiomers shown in general formula (1) by using sulfur tetrafluoride derivatives to convert the general A step of converting the hydroxyl group of the compound represented by formula (1) or its enantiomer into a fluorine group.

[0113] In Step 1, the sulfur tetrafluoride derivative acts as a fluorinating agent. Examples of "sulfur tetrafluoride derivatives" include (dimethylamino)sulfur trifluoride (Methyl DAST), (diethylamino)sulfur trifluoride (DAST), morpholinosulfur trifluoride (Morpho-DAST ) and bis(2-methoxyethyl)aminosulfur trifluoride (Dexo-Fluor).

[0114] Among them, morpholinosulfur trif...

Embodiment 1

[0169] Benzyl (3S,4R)-3-(cyclopropylaminomethyl)-4-hydroxypyrrolidine-1-carboxylate obtained by the method described in Reference Example was dissolved in a solvent (acetonitrile, 6 times). A fluorinating agent (Deoxo-Fluor, 4 equivalents) was added at an internal temperature of -5 to 5°C, followed by stirring at an internal temperature of -5 to 5°C for 1 hour, increasing the temperature, and then internally Stirred at room temperature for 7 hours and allowed to stand overnight at room temperature (Table 1). The reaction solution was detected by HPLC. The results are listed in Table 7.

Embodiment 2

[0171] Benzyl (3S,4R)-3-(cyclopropylaminomethyl)-4-hydroxypyrrolidine-1-carboxylate obtained by the method described in Reference Example was dissolved in a solvent (acetonitrile, 6 times). Then, an additive (triethylamine pentahydrofluoric acid, 2 equivalents) was added at an internal temperature of -5 to 10°C, followed by stirring at an internal temperature of -5 to 5°C for 0.5 hours. Then, a fluorinating agent (Deoxo-Fluor) was added at an internal temperature of -5 to 5°C, followed by stirring at an internal temperature of -5 to 5°C for 1 hour, and then the temperature was raised, followed by internal Stirred at room temperature for 7 hours, then allowed to stand overnight at room temperature (Table 1). The reaction solution was detected by HPLC. The results are listed in Table 7.

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Abstract

Provided is an inexpensive and industrially advantageous method for preparing (3R,4S)-3-(N-substituted aminomethyl)-4-fluoropyrrolidine or an enantiomer thereof which can be an intermediate for producing pharmaceuticals. It relates to a method for preparing (3R,4S)-3-(N-substituted cyclopropylaminomethyl)-4-fluoropyrrolidine derivative or ait's enantiomer, or their salts, comprising a step of fluorinating a 4-hydroxy-3-(N-substituted aminomethyl)pyrrolidine derivative represented by the general formula (1) or an enantiomer thereof using a sulfur tetrafluoride derivative. [In the formula (1), PG represents a protective group for the amino group, and R1 represents a C1 to C6 alkyl group which may be substituted, or a C3 to C8 cycloalkyl group which may be substituted].

Description

technical field [0001] The present invention relates to a novel process for the preparation of 3-(N-substituted aminomethyl)-4-fluoropyrrolidines in optically active form for the preparation of 7-(3-(N-substituted aminomethyl)-4- Fluoropyrrolidinyl) intermediates of quinolone carboxylic acid derivatives, which are safe, exhibit strong antibacterial activity, and are also effective against resistant bacteria that are difficult for conventional antibacterial agents to take effect. Background technique [0002] Patent Documents 1 and 2 disclose 10-(3-cyclopropylaminomethyl-4-substituted 1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivatives and 7-(3-cyclopropyl Aminomethyl-4-substituted 1-pyrrolidinyl) quinolone carboxylic acid derivatives, which exhibit excellent antibacterial activity against resistant bacteria and are highly safe. [0003] These patent documents disclose methods for preparing a useful intermediate, (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/10
CPCC07D207/10A61P31/04C07D207/09Y02P20/55A61K31/40C07D207/14
Inventor 荒谷一郎织田和雄
Owner KYORIN PHARMA CO LTD
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