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A kind of preparation method of bromfenac sodium intermediate

An intermediate, phosphoric acid technology, applied in organic chemistry methods, organic chemistry and other directions, can solve problems such as affecting yield and post-processing, and achieve the effects of improving purity, simplifying production procedures, and not easy to decompose

Active Publication Date: 2022-03-04
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when preparing the intermediate shown in formula II, it is generally hydrolyzed by ethylene glycol monomethyl ether and phosphoric acid system, and a large amount of brick red by-products will be produced in the reaction process, which will affect the yield and post-treatment, and the obtained intermediate II Contains a large amount of impurity X

Method used

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  • A kind of preparation method of bromfenac sodium intermediate
  • A kind of preparation method of bromfenac sodium intermediate
  • A kind of preparation method of bromfenac sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0027] Preparation Example 1 Preparation of 3-bromo-7-p-bromobenzoyl indole (intermediate III):

[0028] Add 90g of 7-(4-bromobenzoyl)indole into 4500mL of dichloromethane, lower the temperature to -10℃~-5℃, dissolve 55.8g of NBS in 2000mL of dichloromethane solution, and then Add it dropwise to the above solution at 10~-5°C. After the dropwise addition, keep at -5~0°C to continue the reaction for 2 hours. After the reaction is completed, add cold water to quench the reaction, wash the organic layer with purified water, collect the organic layer, and add Dry with sulfuric acid in water for 2-3 hours, filter, remove the desiccant, concentrate dichloromethane to obtain a solid, add 200 mL of cold ethyl acetate to make a slurry, then filter with suction, dry at 40-50°C for 2 hours to obtain intermediate III, the yield is 91.29% .

[0029] 1 H-NMR (400MHz, CDCl 3 )δ10.377(s,1H), 7.890~7.870(m,1H), 7.680~7.603(m,5H), 7.403~7.397(m,1H), 7.263~7.224(m,1H); MS(m / z):[M-H] - 377.9...

Embodiment 1

[0030] Example 1 Preparation of 7-p-bromobenzoyl-1,3-dihydro-2H-indol-2-one (intermediate II)

[0031] Add 100g of Intermediate III to 450mL of glacial acetic acid, heat to 90-95°C, then add 1800mL of phosphoric acid, react at 120-125°C for 6 hours, cool down to 80-85°C, add 1700mL of purified water to the reaction solution to cool down and analyze crystallized, filtered, washed, and dried to obtain the crude product of intermediate II, and its HPLC was as follows: figure 2 As shown; the obtained Intermediate II crude product was added to 250 mL of ethyl acetate and stirred for 0.5-2 hours, filtered and dried to obtain 75.2 g of Intermediate II product with a total yield of 90.2%. After testing, the X-RPD collection of illustrative plates of gained intermediate II product is as follows figure 1 As shown, its HPLC spectrum is as image 3 As shown, the HPLC purity was 99.2%, and impurity X was not detected.

[0032] 1 H-NMR (400MHz, CDCl 3 )δ9.520(s,1H), 7.660~7.586(m,4H),...

Embodiment 2

[0034] Example 2 Preparation of 7-p-bromobenzoyl-1,3-dihydro-2H-indol-2-one (intermediate II)

[0035] Add 100g of intermediate III to a mixed solvent composed of 450mL of glacial acetic acid and 1800mL of phosphoric acid, react at 120-125°C for 5h, cool down to 80-85°C, add 1600mL of purified water to the reaction solution to cool down and crystallize, filter and wash , dried, added 250mL ethyl acetate and stirred for 0.5-2h, filtered and dried to obtain 70.43g of intermediate II with a yield of 84.51%; the X-RPD pattern of the obtained intermediate II is as follows figure 1 As shown, its HPLC spectrum is as image 3 As shown, the HPLC purity was 99.3%, and impurity X was not detected.

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of bromfenac sodium and an intermediate thereof. The method adopts a new solvent system to prepare the intermediate, avoids the generation of brick-red by-products, greatly reduces the impurity content in the intermediate, and improves the purity and yield of the intermediate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of bromfenac sodium and an intermediate thereof. The method adopts a new solvent system to prepare intermediate II, which greatly reduces the generation of brick-red by-products and impurity X, and improves product purity and yield. Background technique [0002] Bromfenac sodium is one of 2-amino-3-benzoylphenylacetic acid derivatives, and its chemical name is 2-amino-3-(4-bromobenzoyl) sodium phenylacetic acid, which has the following properties as shown in formula I Its chemical structure can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, and it is an effective cyclooxygenase inhibitor with strong anti-inflammatory and analgesic effects. [0003] [0004] U.S. Patents US4126635 and US4182774 use 2-amino-4-bromobenzophenone and ethyl 2-methylthioacetate as raw materials, use aluminum chloride as a ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34
CPCC07D209/34C07B2200/13
Inventor 潘雷张贵岭周晓东田振平范传文
Owner QILU PHARMA CO LTD
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