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Montelukast sodium intermediate and its preparation method and application

A technology of montelukast sodium and its synthesis method, which is applied to the key intermediate of montelukast sodium and its preparation. Cyclization, easy elimination and other problems, to achieve the effect of stable chemical properties, high optical purity, and mild conditions

Active Publication Date: 2018-09-21
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] In summary, the preparation methods of montelukast sodium in the prior art generally have side reactions such as unstable chemical properties of intermediates, easy elimination, intramolecular cyclization, etc., harsh reaction conditions, unfavorable for industrial production, and anti-asthma In the technical field of preparation of the drug montelukast sodium, it is necessary to develop a more mature and stable process route

Method used

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  • Montelukast sodium intermediate and its preparation method and application
  • Montelukast sodium intermediate and its preparation method and application
  • Montelukast sodium intermediate and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Embodiment 1: the synthesis of intermediate IIIa

[0061]

[0062] The formula IVa compound (50g, 109.2mmol) was dissolved in 500mL of dichloromethane, triethylamine (22.1g, 218.4mmol) was added, and diphenyl chlorophosphate (44g, 163.8mmol) was added dropwise. Stir at 30° C. for 3 h, and TLC detects that the reaction of the raw materials is complete. Pour the reaction liquid into 500mL of 1mol / L dilute hydrochloric acid, extract and separate the organic phase, wash with saturated sodium bicarbonate solution and brine successively and collect the organic phase, dry and decolorize, then concentrate under reduced pressure to obtain 74.5g of oily formula Compound IIIa, the yield was 99%. MS:690[M+H]

[0063] 1 H-NMR (400MHz, DMSO-d 6 ),ppm:8.42-8.40(d,J=8.8Hz,1H),8.04(d,J=1.6Hz,1H),8.02-7.99(d,J=8.8Hz,1H),7.93-7.91(d, J=8.8Hz,1H),7.90-7.86(d,J=16.4Hz,1H),7.82(s,1H),7.80-7.78(d,J=7.2Hz,1H),7.75-7.73(d,J =6.8Hz,1H),7.61-7.59(dd,J=8.4Hz,1.6Hz,1H),7.51-7.50(d,J=16.4Hz...

Embodiment 2

[0064] Embodiment 2: the synthesis of intermediate IIIb

[0065]

[0066] The compound of formula IVb (50g, 105.9mmol) was dissolved in 500mL ethyl acetate, triethylamine (32.1g, 317.7mmol) was added, diphenyl chlorophosphate (56.9g, 211.8mmol) was added dropwise, after the dropwise addition was completed, Raised to 50°C and stirred for 2 h, TLC detected that the reaction of raw materials was complete. Pour the reaction solution into 500mL of 1mol / L dilute hydrochloric acid, extract and separate the organic phase, wash with saturated sodium bicarbonate solution and brine successively and collect the organic phase, dry and decolorize, then concentrate under reduced pressure to obtain 72.3g of oil The compound of formula IIIb has a yield of 97%. MS:704[M+H]

Embodiment 3

[0067] Embodiment 3: the synthesis of intermediate IIIc

[0068]

[0069] Dissolve the compound of formula IVb (30g, 63.6mmol) in 300mL of toluene, cool down to 0°C, add N,N-diisopropylethylamine (41.1g, 317.8mmol), drop diethyl chlorophosphate (54.8g , 317.8mmol), after the dropwise addition was completed, it was raised to 100° C. and stirred for 1 h, and TLC detected that the reaction of the raw materials was complete. Pour the reaction solution into 300mL of 1mol / L dilute hydrochloric acid, add 300mL of ethyl acetate for extraction, wash the organic phase with saturated sodium bicarbonate solution and brine successively and collect the organic phase, then dry, decolorize and concentrate under reduced pressure. That is, 38 g of the oily compound of formula IIIc was obtained, with a yield of 98%. MS:608[M+H]

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Abstract

The present invention relates to a series of novel compounds having the following general formula (III) and their preparation methods. The present invention also relates to the application of the novel compound of general formula (III) in the synthesis of montelukast sodium. The compound of general formula (Ⅲ) is a key intermediate in the synthesis process of montelukast sodium, which plays a vital role in the synthesis of the final target compound, has stable chemical properties, mild reaction conditions in the preparation process, high yield, and optical purity High, suitable for mass production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a key intermediate of Montelukast sodium and a preparation method thereof, and further relates to the application of the intermediate in the synthesis of Montelukast Sodium. Background technique [0002] Montelukast sodium is an anti-asthma drug developed by Merck & Co. of the United States, which was approved by the U.S. Food and Drug Administration (FDA) on February 20, 1998. The trade name is It went on the market in Finland and Mexico in February 1998, went on sale in the United States in October 1998, and then went on the market in Britain, Canada, Italy, France, Germany and other countries. As a selective leukotriene receptor antagonist, montelukast sodium can selectively bind to leukotriene receptors in the respiratory tract, competitively block the action of allergic mediators, and then block the organ's ability to leukotriene receptors...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/60C07D215/18
CPCC07B2200/07C07D215/18C07F9/60
Inventor 甄宜战陈敬金赵显栋张志强邱欣
Owner SHANDONG BESTCOMM PHARMA CO LTD
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