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Method for preparing oxazoline insecticide arforaging intermediate

A technology of intermediates and pesticides, applied in the field of pharmaceuticals

Pending Publication Date: 2021-04-20
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the yield reported in the patent literature, the esterification yield is only 35%, and the total yield is 24%.

Method used

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  • Method for preparing oxazoline insecticide arforaging intermediate
  • Method for preparing oxazoline insecticide arforaging intermediate
  • Method for preparing oxazoline insecticide arforaging intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Halogenation reaction

[0060] Preparation of 4-(bromomethyl)-naphthalene-1-carboxylic acid

[0061]

[0062]1) In a 500ml round bottom flask, add acetonitrile 200ml, 4-methyl-naphthalene-1-carboxylic acid 26g (0.14mol), 1,3-dibromo-5,5-dimethylhydantoin 60.04g ( 0.21mol) and then the temperature rose to 50-60°C, and the reaction was continued for 3 hours;

[0063] 2) Concentrate under reduced pressure, extract with dichloromethane, wash the organic layer successively with water and 15% saline, dry over anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure at 45°C to obtain 4-(methyl bromide Base) naphthalene-1-carboxylic acid 32.85g, yield 88.5%.

[0064] MS (m / z): [M-H] + = 264.32. 1 H NMR (400MHz, DMSO-D 6 ): δ5.38 (s, 2H), 7.75 (m, 3H), 8.11 (d, 1H), 8.44 (d, 1H), 8.73 (d, 1H), 13.41 (brd s, 1H).

[0065] Hydrolysis reaction

[0066] Preparation of 4-(hydroxymethyl)-naphthalene-1-carboxylic acid

[0067]

[0068] 3) In a ...

Embodiment 2

[0080] Halogenation reaction

[0081] Preparation of methyl 4-(bromomethyl)-1-naphthoate

[0082]

[0083] 1) In a 500ml round bottom flask, add 240ml of acetonitrile, 14.02g (0.07mol) of methyl 4-methyl-1-naphthoate, and 25.73g of 1,3-dibromo-5,5-dimethylhydantoin (0.09mol) after the temperature rose to 50 ~ 60 ℃, continue to react for 3 hours;

[0084] 2) Concentrate under reduced pressure, extract with dichloromethane, wash the organic layer successively with water and 15% saline, dry over anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure at 45°C to obtain 4-(methyl bromide Base)-1-naphthoic acid methyl ester 17.45g, yield 89.3%.

[0085] MS (m / z): [M-H] + =278.33. 1 H NMR(400MHz, CDCl3): δ:4.14(s,3H),4.88(s,2H),7.76(d,1H),7.57-7.69(m,2H),8.36(d,1H),8.15-8.18 (m,1H),8.89-8.95(m,1H).

[0086] Hydrolysis reaction

[0087] Preparation of 4-(hydroxymethyl)-naphthalene-1-carboxylic acid

[0088]

[0089] 3) In a 500ml round bottom...

Embodiment 3

[0101] Halogenation reaction

[0102] Preparation of 4-(bromomethyl)-naphthalene-1-carboxylic acid

[0103]

[0104] 1) In a 500ml round-bottomed flask, add 310ml of dichloromethane, 20.5g (0.11mol) of 4-methyl-naphthalene-1-carboxylic acid, and 26g (0.16mol) of bromine in sequence, and then the temperature rises to 50-60°C. Continue to react for 2 hours;

[0105] 2) The organic phase layer was washed with water and 15% saline successively, dried over anhydrous sodium sulfate, filtered, and the solution was distilled off under reduced pressure at 45°C to obtain 4-(bromomethyl)naphthalene-1-carboxylic acid 25.5 g, yield 87.5%

[0106] MS (m / z): [M-H] + = 264.32. 1 H NMR (400MHz, DMSO-D 6 ): δ5.38(s,2H),7.75(m,3H),8.11(d,1H),8.44(d,1H),8.73(d,1H),13.41(brds,1H).

[0107] Hydrolysis reaction

[0108] Preparation of 4-(hydroxymethyl)-naphthalene-1-carboxylic acid

[0109]

[0110] 3) In a 500ml round bottom flask, add 300ml of water, 13.3g (0.05mol) of 4-(bromomethyl...

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Abstract

The invention discloses a method for preparing an oxazoline insecticide arfamarin intermediate. The intermediate is 4-formyl-naphthalene-1-carboxylic acid, and compared with a synthesis route of US6613942B1, the synthesis route of the oxazoline insecticide arfamarin is simple. According to the method provided by some embodiments of the invention, through exploration, the reaction steps are shortened from three steps to one step, so the oxazoline insecticide arforlaana intermediate product with qualified purity can be obtained. The intermediate control steps are simplified, meanwhile, the product yield is increased, and industrial production is easier.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a synthesis process of a pharmaceutical intermediate, in particular to a method for preparing an oxazoline insecticide afolana intermediate. Background technique [0002] Afoxolaner, trade name NexGard, is Boehringer Ingelheim's first oral dewormer for dogs that targets both ticks and fleas in China in August 2017 medicine. It belongs to the isoxazoline compound, and its principle of action is to inhibit the GABA chloride ion channel of arthropods, and then the nerves are highly excited and lead to death. At present, the number of pet dogs in China exceeds 62 million. Dogs are active by nature and are susceptible to various parasites, which may cause harm to the health of themselves and their owners. Therefore, a series of measures are needed to drive and kill parasites. Two hours after taking Afurana, the fleas were killed and the fleas could not lay eggs, which avoided environmental ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/373C07C65/30C07C51/367C07C65/11C07C51/363C07C63/72C07C67/307C07C69/76C07C51/09C07D261/04
CPCY02P20/55
Inventor 米俊儒李冰冰姜桥温军贤
Owner LIVZON NEW NORTH RIVER PHARMA
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