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Industrial compounding method of mule (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic

A synthetic method and the technology of piperidone, applied in the field of industrial synthesis of spiro[benzo[e][1,3]oxazine-2,4'-piperidin]4(3H)-one, to achieve easy reaction , low preparation cost, reasonable reaction process selection

Active Publication Date: 2012-07-04
上海药明康德新药开发有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The technical problem to be solved in the present invention is: to solve the existing synthetic spiro[benzo[e][1,3]oxazine-2,4'-piperidin]-4(3H)-ketone with many impurities and needs Purification by column chromatography, the problem of being unable to scale up production

Method used

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  • Industrial compounding method of mule (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add methyl 4-aminosalicylate (700g) to a 10L autoclave, add methanol (3.5L) and concentrated ammonia water (3.5L), seal and heat, stir at 100°C for 20 hours, cool down, and concentrate to dryness. Dichloromethane (3.5 L) was added, heated to reflux for 30 minutes, and cooled to room temperature. Filtration and washing of the filter cake with dichloromethane (200 mL) yielded 550 g of product. 1 H NMR (400MHz, DMSO-d 6 ): δ13.22(s, 1H, OH), 7.75(s, 1H, NH), 7.46(d, J=8.8Hz, 1H), 7.25(s, 1H, NH), 6.02(dd, J=8.4 Hz, 1H), 5.91(d, J=2.0 Hz, 1H), 5.71(s, 2H, NH)); Ms(M + +1, 153.1).

[0021] Synthesis of 7-aminospiro[benzo[e][1,3]-2,4'-Boc-piperidin]-4(3H)-one

[0022] 4-amino salicylamide (400 grams) joins in the there-necked flask of 10L, then adds N,N-dimethylformamide (1.3L), toluene (5L), N-Boc-4-piperidone ( 1050 g) and morpholine (230 g). Heated to 115°C, carried water through toluene, and heated to reflux for 20 hours. Cool down and concentrate to remove tolue...

Embodiment 2

[0027] 4-Amino salicylamide (30 grams) was added into a 2L there-necked flask, then N, N-dimethylformamide (200mL), toluene (400mL), p-toluenesulfonic acid (47.3 grams), N- Boc-4-piperidone (1050 g) and 4 Molecular sieves (10 g). Heated to 115°C, carried water through toluene, and heated to reflux for 48 hours. The temperature was lowered, and the pH was adjusted to 9 with ammonia methanol solution. Filter and concentrate the filtrate to dryness. Acetonitrile (200 mL) was added, filtered, and the filter cake was washed with acetonitrile to obtain 16 g of product with a yield of 32%. Its test data is as shown in above-mentioned embodiment 1.

[0028] Example 3

[0029] Synthesis of 4-aminomethyl salicylate

[0030] Add methanol (3L) to 4-aminosalicylic acid (300g), stir for 15 minutes, cool to 0-10°C, slowly add thionyl chloride (300g), return to room temperature, stir overnight, filter, and add acetic acid to the obtained solid Ethyl ester (3000mL) and water (3000m...

Embodiment 3

[0032] Add 4-aminosalicylic acid methyl ester (270g) to a 10L autoclave, add tetrahydrofuran (3L) and concentrated ammonia water (3L), seal and heat, stir at 100°C for 20 hours, cool down, and concentrate to dryness. Dichloromethane (3.5 L) was added, heated to reflux for 30 minutes, and cooled to room temperature. Filtration and washing of the filter cake with dichloromethane (200 mL) yielded 240 g of crude product. Its test data is as shown in above-mentioned embodiment 1.

[0033] Synthesis of 7-aminospiro[benzo[e][1,3]-2,4'-Boc-piperidin]-4(3H)-one

[0034] Add 4-amino salicylamide (200 grams) into a 10L three-necked flask, then add N,N-dimethylformamide (0.7L), toluene (2.5L), N-Boc-4-piperidone (500 grams) and piperidine (230 grams). Heated to 115°C, passed through toluene with water, and heated to reflux for 40 hours. Cool down and concentrate to remove toluene. Acetonitrile (2.5 L) was added, filtered, and the filter cake was washed with acetonitrile to obtain 2...

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Abstract

The invention relates to an industrial preparation method of spiral (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic, which uses economical, easily-obtained and scale-produced salicylic acid (and various para-orientation salicylic acids) and N-protecting piperidone (including Boc, Cbz, acyl groups and alkyl group protection) as raw materials, and spiral (benzo (e) (1,3) oxazine-2, 4'-piperidine)-4(3H)-ketonic is obtained after methyl esterification, aminolysis and the close under the catalysis of piperidine or morpholino. The invention solves the problems of complex reaction, low purity and yield, and the like in the prior art, does not need column chromatography purification and can realize scale industrial production.

Description

Technical field: [0001] The present invention relates to a kind of synthetic method of spiro[benzo[e][1,3]oxazine-2,4'-piperidin]-4(3H)-ketone, in particular to an effective method of using salicylic acid and N-protected piperidinone is an industrial method for base-catalyzed synthesis of spiro[benzo[e][1,3]oxazin-2,4'-piperidin]-4(3H)-one as a raw material. Background technique: [0002] Spiral compounds are a very important class of pharmaceutical intermediates, which often contain such structures in natural products and often have high pharmaceutical activity, but artificial synthesis is usually difficult. Spiro[benzo[e][1,3]oxazine-2,4'-piperidin]-4(3H)-ones are a representative class of spiro compounds, but they have not been prepared so far Industrial processes for this class of compounds are reported. [0003] Most of the reports are obtained by acid catalysis, that is, salicylamide and piperidone are cyclized under hydrochloric acid or p-toluenesulfonic acid catal...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/10
Inventor 罗扬神小明施峰顾虹唐苏翰李革
Owner 上海药明康德新药开发有限公司
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