Novel synthesis method of bromfenac sodium

Bromfenac sodium, a newly synthesized technology, applied in chemical instruments and methods, sulfonic acid preparation, carboxylic acid amide preparation and other directions, can solve the problems of excessive heavy metal, explosion or personnel poisoning, high toxicity, etc., and achieves low cost, avoidance of The effect of low moisture and high purity

Pending Publication Date: 2021-11-26
山东辰龙药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] This method is also the mainstream synthesis route for the domestic production of bromfenac sodium, but manganese dioxide is used in the synthesis process, which may easily lead to excessive heavy metals in the finished product
Boron trichloride and N-bromosuccinimide (NBS) are also used in the synthesis process, which are high-risk chemicals. N-bromosuccinimide (NBS) has high toxicity and is easy to produce during the preparation process. cause explosion or poisoning

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  • Novel synthesis method of bromfenac sodium
  • Novel synthesis method of bromfenac sodium
  • Novel synthesis method of bromfenac sodium

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specific Embodiment approach

[0046] The new synthetic method of bromfenac sodium is characterized in that the preparation method comprises:

[0047] (1) Preparation of Intermediate I:

[0048] Using o-aminophenylacetic acid as the starting material, the intermediate I, i.e. o-acetamidophenylacetic acid, is obtained through acylation reaction;

[0049]

[0050] specifically:

[0051] Add anthranilic acid into solvent I (dichloromethane or toluene), add acetic anhydride to react at room temperature, and slowly add reaction auxiliary agent (triethylamine) to generate a mixed solution containing intermediate I; the mixed solution of intermediate I is depressurized After concentration, add ethanol and stir evenly, then add purified water to crystallize, filter with suction, and dry with hot air to obtain intermediate I, o-acetaminophenylacetic acid;

[0052] (2) Preparation of Intermediate II;

[0053] Intermediate Ⅰ is subjected to sulfonation reaction to obtain intermediate Ⅱ, namely 2-acetylamino-5 su...

Embodiment 1

[0074] (1) Preparation of Intermediate I:

[0075] ① Add 30g (0.20mol) of anthranilic acid and 300ml of dichloromethane into the reaction flask, start stirring, and slowly add 40.8g (0.4mol) of acetic anhydride at a temperature of 20-30°C, and control the dropping time at 1.5 -2h added;

[0076] ② After adding acetic anhydride dropwise for 30 minutes, add 40.8 g (0.40 mol) of triethylamine dropwise from another feeding port of the reaction bottle;

[0077] ③ After the dropwise addition is completed, keep the temperature for 1 hour;

[0078] 4. After the reaction is completed, distill under reduced pressure until the inside is viscous, stop the decompression, add 90g of ethanol, and stir evenly;

[0079] ⑤ Control the temperature of the reaction solution within 20-30°C, add 720g of purified water, and control the addition time within 1-1.5 hours;

[0080] ⑥ Keep stirring and crystallize for 1 hour, filter with suction, wash the filter cake once with 100ml purified water, and...

Embodiment 2

[0113] 1) Preparation of Intermediate I:

[0114] ①Add 15g (0.1mol) of anthranilic acid and 150ml of dichloromethane into the reaction flask, start stirring, and slowly add 20.4g (0.2mol) of acetic anhydride at a temperature of 20-30°C, and control the dropping time at 1.5 -2h added;

[0115] ②After acetic anhydride was added dropwise for 30 minutes, 20.4 g (0.20 mol) of triethylamine was added dropwise from another feeding port of the reaction flask.

[0116] ③ After the dropwise addition is completed, keep the reaction for 1 hour.

[0117] ④ After the reaction is completed, distill under reduced pressure until the inside is viscous, stop the decompression, add 90g of ethanol, and stir evenly.

[0118] ⑤ Control the temperature of the reaction solution within 20-30°C, add 360g of purified water, and control the addition time within 1-1.5 hours.

[0119] ⑥Insulate, stir and crystallize for 1 hour, filter with suction, wash the filter cake once with 50ml purified water, filt...

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Abstract

The invention discloses a novel synthesis method of bromfenac sodium, which belongs to the technical field of drug synthesis, and is characterized in that the preparation method comprises the following steps of taking o-aminophenylacetic acid as an initial raw material, and obtaining an intermediate I through acylation reaction, performing sulfonation reaction on the intermediate I to obtain an intermediate II, carrying out substitution reaction on the intermediate II and p-bromobenzoyl chloride to obtain an intermediate III, hydrolyzing the intermediate III to obtain bromfenac, and reacting bromfenac with sodium hydroxide to obtain the final product bromfenac sodium. The method has the beneficial effects that the generation of impurities containing indole rings caused by a synthesis method in the prior art is avoided; the problem that in the prior art, phosphoric acid or glacial acetic acid is used for producing acid salt, so that the pH value of a final finished product exceeds the standard is solved, the quality problem that the water content is too low due to the proportion of materials for preparing the bromfenac sodium finished product is solved, and meanwhile, the synthesis method is simple, easy to control and suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of medicine synthesis, and more specifically relates to a new synthesis method of bromfenac sodium. Background technique: [0002] Bromfenac sodium (Bromfenac sodium), the chemical name is 2-amino-3-(4-bromobenzoyl) sodium phenylacetate, its structure is similar to ketoprofen and diclofenac, and it is the most effective cyclooxygenase inhibitor One, it can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, and has strong anti-inflammatory and analgesic effects, and its action strength is 10 times that of other non-steroidal anti-inflammatory drugs. At present, it is mainly used clinically as an eye drop with anti-inflammatory effect for the symptomatic treatment of inflammatory diseases in the outer eye and anterior eye. [0003] [0004] The synthetic route of existing bromfenac sodium mainly contains following several kinds: [0005] Patent CN106957237A disclose...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/02C07C229/42C07C221/00C07C225/22C07C303/06C07C303/22C07C309/52C07C231/02C07C233/33
CPCC07C227/02C07C221/00C07C303/06C07C303/22C07C231/02C07C233/33C07C309/52C07C225/22C07C229/42
Inventor 李兴臣李浩梁祺孔霞董纪贺韩寒寒沈广宾
Owner 山东辰龙药业有限公司
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