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Preparation method of alpha-aza toroid drug template

A technology for azaspirocycles and drugs, which is applied in the field of preparation of spirocyclic drug templates, can solve the problems of low yield and many reaction steps in the synthesis method, and achieve the effects of high yield, easy industrial operation, and mild conditions

Active Publication Date: 2012-05-09
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The purpose of the present invention is to provide a synthetic method of an α-azaspiro drug template with high efficiency, mild conditions and large-scale preparation value. The technical problem to be solved is: the original synthetic method has many reaction steps and the yield Low

Method used

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  • Preparation method of alpha-aza toroid drug template
  • Preparation method of alpha-aza toroid drug template
  • Preparation method of alpha-aza toroid drug template

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]

[0043] 1. Synthesis of tert-butyl 2-formyl-pyrrole-1-carboxylate

[0044] Dissolve pyrrole-1,2-dicarboxylic acid-1-tert-butyl ester (10.75g, 0.05mol) and triethylamine (22.5g, 0.225mol) in dichloromethane (50ml), cool to -30°C and add chlorine Ethyl formate (10.8 g, 0.1 mol), NH was added after 30 min 3 .H 2 O (11 ml, 0.15 mol). The system was raised to room temperature and reacted overnight. The reaction system was washed with water, and the organic phase was washed with Na 2 SO 4 Drying and solvent removal gave tert-butyl 2-formyl-pyrrole-1-carboxylate (6.4 g, 60%).

[0045] 1 H-NMR (400MHz, CDCl 3 ): 5.50-7.01(m, 2H), 4.87(m, 1H), 4.35(m, 1H), 3.44(m, 2H), 1.75-1.99(m, 4H), 1.43(s, 9H); MS( m / z): 215 (M+1)

[0046] 2. Synthesis of tert-butyl 2-cyano-pyrrole-1-carboxylate

[0047] 2-Formyl-pyrrole-1-carboxylic acid tert-butyl ester (10.7 g, 0.05 mol) was dissolved in CH 2 Cl 2 (300ml) and Et 3 N (30.3g, 0.3mol), trifluoroacetic anhydride (20.1g, 0.1m...

Embodiment 2

[0056]

[0057] Refer to Example 1 for the synthesis of tert-butyl 2-cyano-pyrrole-1-carboxylate.

[0058] 1. Synthesis of tert-butyl 2-(3-chloro-propyl)-2-cyano-pyrrole-1-carboxylate

[0059] At -78°C, a THF (30ml) solution of 2-cyano-pyrrole-1-carboxylic acid tert-butyl ester (4.9g, 0.025mol) was added to a THF solution of LDA (0.0375mol), and the reaction was continued for 45min. At -78°C, 1,3-dichloropropane (2.8 g, 0.025 mol) was added, the system was raised to room temperature, and reacted overnight. NH 4 The Cl solution was quenched, extracted with EtOAc, and the organic phase was dried and stripped to obtain the crude product tert-butyl 2-(3-chloro-propyl)-2-cyano-pyrrole-1-carboxylate (6.9 g). The product was subjected to column chromatography to obtain tert-butyl 2-(3-chloro-propyl)-2-cyano-pyrrole-1-carboxylate (5.1 g, 75%).

[0060] 1 H-NMR (400MHz, CDCl 3 ): 3.31-3.75(m, 4H), 2.35-2.51(m, 2H), 1.70-2.25(m, 6H), 1.51(s, 9H); MS(m / z): 295(M+23)

[0061] 2.1...

Embodiment 3

[0065]

[0066] 1. Synthesis of tert-butyl 2-formyl-piperidine-1-carboxylate

[0067] Dissolve 1-tert-butyl piperidine-1,2-dicarboxylate (11.45g, 0.05mol) and triethylamine (40.4g, 0.4mol) in dichloromethane (50ml), cool to -20°C and add chlorine Isopropyl formate (6.1 g, 0.05 mol), NH was added after 30 min 3 .H 2 O (18ml, 0.25mol). The system was raised to room temperature and reacted overnight. The reaction system was washed with water, and the organic phase was washed with Na 2 SO 4 Drying and solvent removal gave tert-butyl 2-formyl-piperidine-1-carboxylate (6.8 g, 60%).

[0068] 1 H-NMR (400MHz, CDCl 3 ): 6.12(m, 2H), 4.70(m, 1H), 4.11(m, 1H), 2.70(m, 1H), 2.25(m, 1H), 1.46(s, 9H), 1.38-1.70(m, 5H); MS (m / z): 229 (M+1)

[0069] 2. Synthesis of tert-butyl 2-cyano-piperidine-1-carboxylate

[0070] tert-butyl 2-formyl-piperidine-1-carboxylate (11.4 g, 0.05 mol) was dissolved in CH 2 Cl 2 (300ml) and Et 3 N (25.3g, 0.25mol), trifluoroacetic anhydride (50.0g, ...

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Abstract

The present invention relates to a process for synthesizing alpha-aza spirocyclic medicine template. The improved technological process prepares the alpha-aza spirocyclic medicine template (target compound I) with proline (m=1) or 2-nipecotic acid (m=2) derivative carrying protecting amido group and through four reaction steps, including amidation, oxidation, alkylation and hydrogenation. The structural formula of the alpha-aza spirocyclic medicine template is as below, wherein m=1 or 2, n=1, 2 or 3, here m and n may be the same or different; PG1 and PG2 are substituent groups on the nitrogen atom, for example hydrogen atom (H), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn) and so on, here the PG1 and the PG2 may be the same or different. The method has less reaction steps, high yield and mild condition and is a synthesizing method of the alpha-aza spirocyclic medicine template having large-scale preparation value.

Description

Technical field: [0001] The invention relates to a preparation method of a spirocyclic drug template, in particular to a preparation method of an α-azaspirocyclic drug template. Background technique: [0002] α-Azaspirocyclic drug templates, such as [5.5], [5.6], [6.5], [6.6], [5.7] and [6.7], etc., can be used as Type II β-turn analogues, which have been widely used Proved to have a variety of physiological activities, the following are examples of several compounds that have been disclosed in some patents or literature and are closely related to the technology of the present invention: [0003] [0004] In addition, in the literature J.Med.Chem.1990, (33), it has been reported in 2270 that compound 7 is an antibiotic with excellent performance, as norfloxacin, spafloxacin, enoxacin and ciprofloxacin Derivatives such as quinolone antibiotics, the introduction of α-azaspiro substituents can significantly improve the physiological activity. [0005] α-Azaspirocyclic drug...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/10C07D471/10
CPCY02P20/55
Inventor 唐飞宇曲立强徐艳马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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