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Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone

A technology of methoxyacetophenone and methanesulfonamide, which is applied in the field of preparing anti-inflammatory drug 3--7--6--4H-1-benzopyran-4-one, can solve the complicated after-treatment, Problems such as low reaction yield and high toxicity are not suitable for large-scale synthesis

Inactive Publication Date: 2003-12-24
YANGTZE RIVER PHARM GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Such as industrial production, the method also has the following problems: the raw material 4-phenoxy-3 nitrophenol cannot be purchased from the market; the yield of phenol into ether reaction is low, and column chromatography separation and purification are required; Low, complex post-treatment; Bromination reaction uses bromine as raw material, high toxicity, not suitable for large-scale synthesis

Method used

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  • Preparation of 3-(formamide)-7-(methylsulfonyl amine)-6-(phenoxy)-4H-1-(benzopyran)-4-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Example 1: Preparation of 2-acetyl-4-phenoxy-5-methanesulfonamidophenol (compound 2)

[0014] 54L acetonitrile, 3.0kg anhydrous AlCl 3 Add 3.7kg of compound 1 into the reaction kettle, add 1.9kg of sodium iodide at 0-5°C, react at room temperature for 3 hours, after the reaction is complete, add 1% sodium thiosulfate under ice water cooling, filter, add water to the filtrate to precipitate a solid , filtered, and vacuum-dried to obtain 2-acetyl-4-phenoxy-5-methanesulfonamide phenol (compound 2), yield: 86%.

[0015] 1 H NMR (300MHz, CDCl 3 )δ: 2.45 (3H, s), 3.10 (3H, s), 6.94-7.40 (m, 10), 12.44 (1H, s);

[0016] EI-Ms (m / z, int.%): 321 (M + , 100), 242(21.54), 306(20.60), 199(18.80), 322(18.34), 144(16.65), 200(16.33), 43(15.33).IR(υ KBr max ): 3254, 1634, 1600, 1569, 1504, 1493, 1430, 1409cm -1 .

Embodiment 2

[0017] Example 2: Preparation of 7-(methylsulfonamide)-6-(phenoxy)-4H-1-benzopyran-4-one (compound 3)

[0018] Suspend compound 23.05Kg in triethyl orthoformate, add 2.5L perchloric acid at room temperature, react for 1-24h, after the reaction is complete, filter, boil in water for 1-3h, and drain to obtain compound 7-(methanesulfonamide)- 6-phenoxy-4H-1-benzofuran-4-one (compound 3), yield: 85%.

[0019] 1 H NMR (300MHz, CDCl 3 )δ: 3.18(3H, s), 6.28(1H, d), 7.05(2H, d), 7.26-7.27(2H, m), 7.44(2H, m), 7.57(1H, s), 7.77(1H ,s), 7.83(1H,d).

[0020] EI-Ms (m / z, int.%): 3 31 (M + , 100), 251(95.56), 332(20.10), 252(18.23), 168(16.15), 154(15.28), 149(15.07), 196(13.66).IR(υ KBr max ): 3027, 1625, 1594, 1567, 1473, 1444, 1325, 1305cm -1 .

Embodiment 3

[0021] Example 3: Preparation of 7-(methylsulfonamide)-6-(phenoxy)-4H-1-(benzo-2,3-dihydrofuran)-4-one (compound 4)

[0022] Add the mixed solution of 2.72kg compound 3, 30L tetrahydrofuran and methanol into the reaction kettle, stir to make compound 3 dissolve completely, and 2 Under protection, 0.79 kg of palladium carbon was fully wetted with ethanol and added to the reaction kettle, and then 13.44 kg of ammonium formate was added in batches at room temperature, reacted for 2-3 hours, filtered, concentrated, and dried to obtain compound 4, yield: 90 %.

[0023] 1 H NMR (300MHz, CDCl 3 )δ: 2.75 (2H, t), 3.13 (3H, s), 4.52 (2H, t), 6.97-7.37 (m, 7H);

[0024] EI-Ms (m / z, int.%): 333 (M + , 100), 254 (72.42), 198 (43.58), 144 (23.82), 170 (21.56), 77 (19.16), 334 (16.6).

[0025] IR(υ KBr max): 3254, 1674, 1618, 1578, 1497, 1450, 1394, 1322, 1270, 1219, 1166, 1140.

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Abstract

A process for preparing 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one as an anti-inflammatory from 3-phenoxy-4-methylsulfonylamine-6- methoxyacetophenone includes demethylation, cyclization, catalytic hydrogenation, bromination, vinylog and amination.

Description

technical field [0001] The invention relates to a preparation of anti-inflammatory drug 3-(formamide)-7-(methylsulfonamide)-6-(phenoxy base)-4H-1-benzopyran-4-one method. Background technique [0002] 3-(formamide)-7-(methylsulfonamide)-6-phenoxy-4H-1-benzopyran-4-one (code: T-614, English name: Iguratimod, Chinese drug name: Ai Lamod) is a novel drug for the treatment of osteoarthritis and rheumatoid arthritis. It can not only selectively inhibit cyclooxygenase COX-II, but also regulate T-cells. The side effects are small, the effect is rapid, and it is effective for patients who have no effect on other drugs. The results of clinical trials show that: T-614 can significantly reduce inflammatory reactions, and can inhibit the production of inflammatory cytokines, tumor necrosis factor, lymphocytes and immunoglobulins. 3-(formamide)-7-(methylsulfonamide)-6-(phenoxy)-4H-1-(benzopyran)-4-one will be a new specific drug for treating arthritis. The in-depth study of this comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/22
Inventor 王进义李旭东林国强张正艮王林卢文芽
Owner YANGTZE RIVER PHARM GRP CO LTD
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