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A key intermediate of 6,7,8,9-tetrahydro-5h-pyrido[2,3-d]azepine and its preparation method

A compound and a range of technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of relatively high requirements on reaction conditions and unsuitability for industrial production, and achieve the effects of stable process, mild conditions and convenient purification

Active Publication Date: 2021-02-26
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preparation of compound XIII: using AlCl 3 / LiAlH 4 Ring-closing reaction at -78°C requires relatively high reaction conditions and is not suitable for industrial production

Method used

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  • A key intermediate of 6,7,8,9-tetrahydro-5h-pyrido[2,3-d]azepine and its preparation method
  • A key intermediate of 6,7,8,9-tetrahydro-5h-pyrido[2,3-d]azepine and its preparation method
  • A key intermediate of 6,7,8,9-tetrahydro-5h-pyrido[2,3-d]azepine and its preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]Synthesis of compound III:

[0044]

[0045]Trimethylsilyl cyanide (140.88g, 1.42mol, 5.0eq) was dissolved in acetonitrile (300mL), compound II (50.00g, 0.284mol, 1.0eq) was added dropwise to it at 10°C, and finally at 30°C The reaction was stirred for 15 hours. LC-MS shows that the reaction is complete, spin dry the reaction solution, pour the residue into water, stir well, separate the liquids, extract the aqueous phase with DCM, combine the organic phases, wash with saturated NaCl solution, and separate the organic phase with anhydrous Mg2SO4After drying, the solvent was evaporated under reduced pressure to obtain 40.00 g of compound III as a brown solid, yield: 89.6%.

[0046]Synthesis of compound I:

[0047]

[0048]Compound III (40.00g, 0.254mol, 1.0e.q.) was dissolved in methanol (400mL), and SOCl was added dropwise2(151.32g, 1.27mol, 5.0e.q.), after the dropping is completed, the reaction is stirred at 40°C for 12 hours. TLC shows that the reaction is complete, the reaction solution ...

Embodiment 2

[0050]Synthesis of compound III:

[0051]

[0052]Trimethylsilyl cyanide (56.35g, 0.568mol, 2.0eq) was dissolved in acetonitrile (400mL), compound II (50.00g, 0.284mol, 1.0eq) was added dropwise to it at 10℃, and finally at 70℃ The reaction was stirred for 16 hours. LC-MS shows that the reaction is complete, spin dry the reaction solution, pour the residue into water, stir well, separate the liquids, extract the aqueous phase with DCM, combine the organic phases, wash with saturated NaCl solution, and separate the organic phase with anhydrous Mg2SO4After drying, the solvent was evaporated under reduced pressure to obtain 35.84 g of compound III as a brown solid, with a yield of 80.3%.

[0053]Synthesis of compound I:

[0054]

[0055]Compound III (35.84g, 0.228mo, 1.0e.q.) was dissolved in ethanol (500mL), and concentrated H was added dropwise2SO4(167.58g, 1.71mol, 7.5e.q.), after dripping, the reaction was stirred at 60°C for 14 hours. TLC shows that the reaction is complete, the reaction solutio...

Embodiment 3

[0057]Synthesis of compound III:

[0058]

[0059]Trimethylsilyl cyanide (281.76g, 2.84mol, 10.0eq) was dissolved in acetonitrile (400mL), compound II (50.00g, 0.284mol, 1.0eq) was added dropwise to it at 10°C, and finally at 10°C The reaction was stirred for 18 hours. LC-MS shows that the reaction is complete, spin dry the reaction solution, pour the residue into water, stir well, separate the liquids, extract the aqueous phase with DCM, combine the organic phases, wash with saturated NaCl solution, and separate the organic phase with anhydrous Mg2SO4After drying, the solvent was evaporated under reduced pressure to obtain 24.82 g of compound III as a brown solid, yield: 55.6%.

[0060]Synthesis of compound I-1:

[0061]

[0062]Compound III (24.82g, 0.158mol, 1.0e.q.) was dissolved in methanol (300mL), and SOCl was added dropwise2(189.15g, 1.59mol, 10.0e.q.), after the dropping is completed, the reaction is stirred at 60°C for 16 hours. TLC shows that the reaction is complete, the reaction solut...

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Abstract

The invention discloses a key intermediate (compound I) of 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine and its preparation method and application, comprising the following steps: Using 2,3-bis(chloromethyl)pyridine (compound II) as raw material, compound III was first obtained through cyanation reaction; then compound I was obtained through hydrolysis and esterification. Compound I is reduced to obtain compound IV; then reacted with acid chloride to obtain compound V; ring-closing reaction occurs between compound V and ammonia reagent to obtain 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine Zhuo (Compound VI).

Description

Technical field[0001]The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to an intermediate of 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine and its preparation method and application.Background technique[0002]6,7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepine is an important intermediate in pharmaceutical synthesis. It can be used to prepare metabotropic glutamate receptor antagonists of pyrazolopyrimidine derivatives, and to prepare substituted 1,2,4-triazole derivatives as allosteric modulators of mGluR5 receptors. Therefore, 6,7, 8,9-Tetrahydro-5H-pyrido[2,3-d]azepine is a very potential pharmaceutical intermediate.[0003]Gottschling, Dirk et al. reported in WO2013144172A the synthesis method of 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azazepine:[0004][0005](a) Et3N, Pd / C, MeOH, room temperature, 6h, yield 99%.[0006]WO2008009125 reports the synthesis method of compound XVI:[0007][0008]Reagents and conditions: (b) 1,3-acetone dicarboxylate diethyl ester, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/55C07D471/04
CPCC07D213/55C07D471/04
Inventor 张锋余善宝李辉杨民民
Owner PHARMABLOCK SCIENCES (NANJING) INC