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Process for preparation of substituted nicotinamides

A technology of dimethylamino and methoxymethyl, applied in the field of preparation of substituted nicotinamide, which can solve the problems of cumbersome steps and low yield

Active Publication Date: 2022-07-22
SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] is used in the prior art to prepare N-isopropyl-6-(((3-(5-(methoxymethyl)isoxazole-3 -yl)-[1,2,4]triazol[3,4-a]phthalazin-6-yl)oxy)methyl)nicotinamide has low yield and complicated steps

Method used

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  • Process for preparation of substituted nicotinamides
  • Process for preparation of substituted nicotinamides
  • Process for preparation of substituted nicotinamides

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Experimental program
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Embodiment 1

[0031] step 1:

[0032]At room temperature, add 31.73kg of acetonitrile in the reactor, add 2.00kg 1,4-dichlorophthalazine I and 1.81kg 5-(methoxymethyl)isoxazole-3-carbonyl hydrazide II under stirring, stir The temperature was raised to reflux (80°C) and reacted for 2 hours. The system was cooled to below 40 ℃, 31.73 kg of acetonitrile, 1.77 kg of 6-(hydroxymethyl) nicotinic acid methyl ester IV were added, stirred for 15-30 minutes, 8.53 kg of potassium phosphate was added, the temperature was raised to 45-55 ℃ and stirred for 20-24 hours, add water, stir, filter, and place the filter cake in an oven at 50-60 °C to dry to obtain 3.85 kg of 6-((((3-(5-(methoxymethyl)isoxazol-3-yl) -[1,2,4]Triazolo[3,4-a]oxazin-6-yl)oxy)methylnicotinate methyl V, yield 85.9%. 1H NMR (400 MHz, CHLOROFORM-d )δppm 3.39 (s, 3 H) 3.89(s, 3H), 4.71 (s, 2 H) 5.81 (s, 2 H) 7.15 (s, 1 H) 7.89(d, J=8.00 Hz, 1 H) 7.98 – 8.05 (m, 1 H) 8.10 –8.18 (m, 1 H) 8.35 (dd, J=7.83, 1.96 Hz, 1 H) 8.39 (d, J=7.83 ...

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Abstract

The invention relates to a method for preparing substituted nicotinamide of a formula (1), which comprises the following steps: step 1): 1, 4-dichlorophthalazine of a formula (I), a compound of a formula (II) and a compound of a formula (IV) are used as starting raw materials to react, and a compound of a formula (V) is obtained by a one-pot method; the preparation method comprises the following steps of 1, carrying out a saponification reaction on a compound shown in a formula (V) to obtain a compound shown in a formula (VI), and 2, carrying out a saponification reaction on the compound shown in the formula (V) to obtain a compound shown in a formula (VI), and 3, carrying out a reaction on the compound shown in the formula (VI) and isopropylamine in the presence of a condensing agent to obtain N-isopropyl-6-(((3-(5-(methoxymethyl) isoxazole-3-yl)-[1, 2, 4] triazole [3, 4-a] phthalazin-6-yl) oxygen) methyl) nicotinamide shown in a formula (1).

Description

technical field [0001] The present invention relates to N-isopropyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazo[3,4-a] ] phthalazin-6-yl) oxy) methyl) nicotinamide synthesis process. Background technique [0002] N-isopropyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazine -6-yl)oxy)methyl)nicotinamide is an antagonist of the α5-GABAA receptor and is described in Chinese patent application CN2019101857359. [0003] Antagonists of α5-GABAA receptors were recently identified as useful in the treatment of pain, particularly neuropathic pain (WO), and N-isopropyl-6-(((3-(5-(methoxymethyl) Isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methyl)nicotinamide was identified as a candidate drug whose structure is shown in formula (1 ) as shown: [0004] [0005] For the preparation of N-isopropyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazole[3 in the prior art ,4-a]phthalazin-6-yl)oxy)methyl)nicotinamide method has low yie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 孙勇尹宝权李垣新
Owner SHANGHAI SIMR BIOTECHNOLOGY CO LTD
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