Preparation method of otilonium bromide

A technology for octilonium bromide and a compound is applied in the field of preparation of octilonium bromide, can solve problems such as being unsuitable for large-scale industrial production, unsuitable for large-scale industrial production, and difficult in industrial operation, and achieves fast and convenient preparation process, High recyclability and the effect of shortening production time

Inactive Publication Date: 2015-11-11
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Route 4 is to react compound (2) with ethyl p-aminobenzoate to obtain compound (5), and then react compound (5) with diethylaminoethanol to obtain compound (6). This route needs to use sodium metal, industrial operation It is difficult and the yield is low, so it is not suitable for large-scale industrial production
[0008] The four routes all adopt 2-octyloxyb

Method used

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  • Preparation method of otilonium bromide
  • Preparation method of otilonium bromide
  • Preparation method of otilonium bromide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of 4-(2-octyloxybenzamido) benzoic acid

[0044]

[0045] Dissolve (50g, 0.2mol) o-octyloxybenzoic acid in 500ml of dichloromethane, add (50.6g, 0.5mol) triethylamine under stirring, cool down to 0-5°C, keep the temperature below 10°C, add dropwise (23g, 0.212mol) of ethyl chloroformate, after the dropwise reaction was completed, the temperature was kept at 0-5°C for 1h. At the end of the heat preservation, (28.6g, 0.209mol) p-aminobenzoic acid was added and reacted at 20-25°C for 18h. Add 200ml of water, stir, separate the organic layer, concentrate to dryness under reduced pressure, add 1L of water, adjust the pH to 2-3 with dilute hydrochloric acid, stir and crystallize, filter with suction, dry, and recrystallize from absolute ethanol to obtain an off-white solid product 58.5g. The yield is 80%, and the HPLC purity is greater than 98%.

[0046] end product from 1 HNMR and mass spectral characterization.

[0047] ESI-MS(m / z): 371...

Embodiment 2

[0051] Example 2: Preparation of N,N-diethyl-2-[4-(2-octyloxybenzamido)benzoyloxy]ethylamine

[0052]

[0053] (45g, 0.122mol) 4-(2-octyloxybenzamido) benzoic acid was dissolved in 600ml of acetone, and (19.8g, 0.146mol) diethylaminochloroethane and (84g, 0.609 mol) potassium carbonate, warming up to reflux for 3h. Cool to room temperature, filter, and concentrate the filtrate to dryness under reduced pressure. The concentrate is dissolved in 350 ml of petroleum ether, washed with water, dried over anhydrous sodium sulfate, filtered, cooled to crystallize, filtered with suction, and vacuum-dried at room temperature to obtain 52.6 g of a white solid product. The yield was 92%, and the HPLC purity was greater than 99%.

[0054] end product from 1 HNMR and mass spectral characterization.

[0055] ESI-MS(m / z): 470[M+H] + .

[0056] 1 HNMR (400MHz, DMSO) δ: 10.39 (s, 1H, NH), 7.92 (d, 2H, Ar-H), 7.84 (d, 2H, Ar-H), 7.65 (s, 1H, Ar-H), 7.49(s,1H,Ar-H), 7.16(s,1H,Ar-H), 7.0...

Embodiment 3

[0059] Embodiment 3: the preparation of otilonium bromide

[0060]

[0061] Add 800ml of acetone to a 1L four-neck flask, cool down to 5-10°C, and introduce (120g, 1.26mol) methyl bromide gas. After completion, add (40g, 0.085mol) N,N-diethyl-2-[4 -(2-octyloxybenzamido)benzoyloxy]ethylamine, react at 10-15°C for 12 hours, filter with suction, and dry to obtain 42 g of white crystals. The yield was 87%, and the HPLC purity was greater than 99%.

[0062] end product from 1 HNMR and mass spectral characterization.

[0063] ESI-MS (m / z): 483 [M-80] + , 484[M+H-80] + ;

[0064]

[0065] 1 HNMR (400MHz, DMSO) δ: 10.46 (s, 1H, NH), 7.98 (d, 2H, Ar-H), 7.88 (d, 2H, Ar-H), 7.64 (d, 1H, Ar-H), 7.62(d, 1H, Ar-H), 7.19(d, 1H, Ar-H), 7.07(s, 1H, Ar-H), 4.67(t, 2H, OC H 2 CH 2 N), 4.10(t,2H,OC H 2 (CH 2 ) 6 CH 3 ), 3.76(t,2H,OCH 2 C H 2 N), 3.45(q,4H,NC H 2 CH 3 ), 3.09 (s,3H,NCH 3 ), 1.74 (m,2H,OCH 2 C H 2 (CH 2 ) 5 CH 3 ), 1.38(m,2H,O(CH 2 ) 2 C H 2 )...

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Abstract

The invention provides a preparation method of otilonium bromide, belonging to the technical field of medicine production. The method comprises the following steps: reacting o-octanoxy benzoic acid serving as a raw material and chloroformate to obtain a product; then, carrying out condensation on the product and p-aminobenzoic acid to obtain 4-(2-octanoxybenzoylamino)benzoic acid; reacting 4-(2-octanoxybenzoylamino)benzoic acid and diethylaminoethyl chloride to obtain N,N-diethyl-2-[4-(2-octanoxybenzoylamino)benzoyloxy]ethylamine; and reacting N,N-diethyl-2-[4-(2-octanoxybenzoylamino)benzoyloxy]ethylamine and bromomethane to generate otilonium bromide. The preparation method has the advantages of simple process, low reaction byproduct content, high yield, simplicity and convenience in operation, economical efficiency, environmental friendliness and high industrial popularization value so as to be suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine manufacture, in particular to a preparation method of otilonium bromide. Background technique [0002] Otilonium bromide (otilonium bromide) is developed and produced by Menarini Company in Italy, and its trade name is Spasmomen (Spasmomen). It was imported to my country in 2000. This product has the functions of inhibiting the influx of calcium ions in intestinal smooth muscle cells, antagonizing muscarinic receptors and tachykinin NK2 receptors, and has high selectivity and strong antispasmodic effect on digestive tract smooth muscle. Clinically, as a specific antispasmodic agent for intestinal smooth muscle, it is widely used in the treatment of irritable bowel syndrome (IBS). [0003] The chemical name of otilonium bromide is: N,N-diethyl-N-methyl-2-[[4[[2-(octyl)benzoyl]amino]benzoyl]oxy]ethane ammonium bromide. Has the structural formula of formula I: [0004] [0005] The existing r...

Claims

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Application Information

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IPC IPC(8): C07C235/64C07C231/12
Inventor 贾春祥王涛黄锋陈文斌盛景新黄晓飞
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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