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Vilanterol intermediate, preparation method and application thereof

A compound and solvent technology, applied in the field of preparation of vilanterol and its key intermediate -5--1,3 oxazolidin-2-one, can solve the problems of low atom utilization, high price and high cost , to achieve the effect of increasing yield and atom utilization, low cost and high yield

Active Publication Date: 2016-06-08
SHANGHAI INST OF PHARMA IND +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route uses salicylaldehyde as a raw material, and the final intermediate is synthesized through seven steps, but there is a one-step reaction, 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxane En-6-yl) ethyl ketone and di-tert-butyl iminodicarboxylate reaction, productive rate is lower, only 58%; Simultaneously the price of di-tert-butyl iminodicarboxylate and cesium carbonate is more expensive, and cost is lower High; and the next step is to acidify a tert-butoxycarbonyl group, and the atom utilization rate is relatively low

Method used

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  • Vilanterol intermediate, preparation method and application thereof
  • Vilanterol intermediate, preparation method and application thereof
  • Vilanterol intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: Preparation of 5-(2-bromoacetyl)-2-hydroxybenzaldehyde 4

[0049] Under nitrogen protection, under an ice bath, disperse 164g (5eq) of aluminum trichloride into 600mL (20 times the amount) of DCM, and slowly add 99.4g (2eq) of bromoacetyl bromide dropwise. After 20min, the temperature rises to room temperature, and the reaction 1h, 30g of salicylaldehyde was added dropwise to the mixture, and the dropwise addition was completed in 20min, and the reaction was carried out overnight at 35°C. Ice water was added to the reaction solution, and the organic layer was separated, washed with water, dried, and then concentrated to dryness in vacuo. Recrystallize with DCM and n-hexane, and filter to obtain 36.5 g of the product, with a yield of about 61%. 1 HNMR (400MHz, CDCl 3 ): δ11.52(s, 1H), 9.99(s, 1H), 8.30(s, 1H), 8.17(d, 1H, J=8Hz), 7.10(d, 1H, J=8Hz), 4.39(s , 2H); MS (-ESI) m / z 240 [M-H] -

Embodiment 2

[0050] Example 2: Preparation of 2-bromo-1-[4-hydroxyl-3-(hydroxymethyl)-phenylethan-1-one 5

[0051] 40.0 g of compound 4 was dissolved in 400 mL of acetic acid (10 times the amount), and 6.8 g (1.1 eq) of sodium borohydride was added in batches under ice cooling. After the addition was complete, the reaction was carried out at room temperature for 1 h, and TLC showed that the reaction was complete. Concentrate in vacuo to remove most of the acetic acid, dilute with water, neutralize with sodium bicarbonate, extract with EA, wash the organic phase with water and brine in turn, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain the crude off-white powder. After reflux washing with DCM, 32 g of white powder was obtained, and the yield was 80%.

[0052] 1 HNMR (400MHz, DMSO-d6): δ10.53(s, 1H), 7.99(s, 1H), 7.79(d, 1H, J=8Hz), 6.87(d, 1H, J=8Hz), 4.75(s , 2H), 4.50(s, 2H); MS(+ESI) m / z 267[M+Na] +

Embodiment 3

[0053] Example 3: Preparation of hydrochloride (6) of 2-amino-1-[4-hydroxyl-3-(hydroxymethyl)-phenylethan-1-one

[0054] 10.0 g of compound 5 was added to 200 mL of ethyl acetate, 6.2 g of urotropine (1.1 eq) was added, and the reaction was carried out at room temperature for 1 h. TLC showed that the reaction was complete. After filtering, the filter cake was vacuum-dried to 15.6 g of white powder. Dissolve the above white powder in 150mL of ethanol, add 17.5mL of concentrated hydrochloric acid (5eq), react at room temperature overnight, and concentrate the reaction solution in vacuo to obtain 16.0g of off-white powder (mixture), which is directly used in the next step.

[0055] 1 HNMR (400MHz, DMSO-d6): δ10.89(s, 1H), 8.40(s, 2H), 7.98(d, 1H, J=2Hz), 7.70(dd, 1H, J=8Hzand2Hz), 7.02(d , 1H, J=8Hz), 4.49(s, 2H), 4.43(s, 2H); MS(+ESI) m / z 182[M+H] +

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PUM

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Abstract

The invention provides a new Vilanterol intermediate compound 2. According to the invention, primary amino is introduced into a compound 5 through Delepine reaction, then di-tert-butyl dicarbonate is employed for amino protection, and the strategy greatly improves the yield and atom utilization rate. On the other hand, cheap and easily available urotropin is adopted in the invention to lower the cost, thus being easy for industrial large-scale production. Compared with the prior art, the yield of the method involved in the invention is increased to 65% by three-step reaction, also use of expensive di-tert-butyl iminodicarboxylate and cesium carbonate is avoided, the cost is reduced, the operation is simple, and the conditions are mild. Therefore, the method is suitable for industrial preparation of Vilanterol and its key intermediate (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3 oxazolidine-2-one. (formula of compound 2).

Description

technical field [0001] The present invention relates to vilanterol and its key intermediate (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxine-6-yl)-1,3 The preparation method of oxazolidin-2-one technical field. Background technique [0002] β2-adrenergic receptor agonists are the most widely used drugs in the treatment of asthma and chronic obstructive pulmonary disease. The longest duration of action of currently available β2-adrenoceptor agonists on the market is 12 hours, which results in the need for twice daily dosing. In the past ten years, the development of β2-adrenoceptor agonists with high potency, high selectivity, fast onset, long duration of action, and once-a-day administration has attracted great attention from the pharmaceutical industry. Vilanterol triphenylacetate is a new type of ultra-long-acting β2-adrenoceptor agonist developed by Glaxo Group Co., Ltd., which has bronchodilation effect. [0003] The chemical name of vilanterol is 4-{(1R)-2-[(6-{2-[(2,6-dichl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/18C07C269/04C07D413/04
Inventor 季宗德杨玉雷蒋慧娟莫利英朱雪焱
Owner SHANGHAI INST OF PHARMA IND
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