Iguratimod intermediate and synthesis method thereof

A synthesis method and a technology for intermediates, applied in the field of chemical drug synthesis, can solve the problems of low purity, excessively long reaction steps, low yield and the like, and achieve the effects of simplified reaction steps, low cost and high yield

Inactive Publication Date: 2019-05-03
NANJING REDWOOD FINE CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The prior art uses 4-chloro-3-nitroanisole as a raw material, through etherification, nitro reduction, and mesylation to obtain the desired intermediate (5-methoxyl-2phenoxyl-benzenesulfonamide ), the method uses 4-chloro-3-nitroanisole as a raw material, the reaction steps are too long, the final product purity and yield (79%) are not high, and the overall cost is too high, which is not conducive to industrial produ

Method used

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  • Iguratimod intermediate and synthesis method thereof
  • Iguratimod intermediate and synthesis method thereof
  • Iguratimod intermediate and synthesis method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Such as figure 1 As shown, this embodiment 1 provides a synthetic method of the key intermediate of Alamod, including:

[0025] Step S1, reduction, that is, using 4-methoxy-2 nitrophenol to prepare 2-amino-4-methoxyphenol;

[0026] Step S2, Ullmann reaction, that is, the preparation of 3-amino-4-phenoxy-anisole through 2-amino-4-methoxyphenol; and

[0027] Step S3, mesylation, that is, preparing 5-methoxy-2-phenoxy-benzenesulfonamide through 3-amino-4-phenoxy-anisole.

[0028] As an optional implementation of reduction.

[0029] The reduction method includes: dissolving 4-methoxy-2 nitrophenol in a mixed solution of 70% ethanol and 4N HCl, raising the temperature of the reaction solution to 65-75°C; then adding iron powder evenly in three batches within 20 minutes into the reaction solution; stir the reaction quickly, and control until there is no raw material; after the reaction is completed, add a saturated solution of sodium carbonate to adjust the pH to 8-9 to ob...

Embodiment 2

[0040] On the basis of Example 1, this Example 2 provides a key intermediate of iguratimod, which is suitable for being prepared by the aforementioned synthesis method.

[0041] For the composition and content of the key intermediates of iguratimod and the specific implementation process, please refer to the relevant discussion in Example 1, which will not be repeated here.

Embodiment 3

[0043] (1) Dissolve 169g of 4-methoxy-2 nitrophenol in a mixed solution of 1500ml 70% ethanol and 40ml 4N HCl, and heat up the reaction solution to 65°C; add 140g iron powder evenly in three batches within 20min In the reaction solution, the reaction was stirred rapidly, and controlled until there was no raw material; after the reaction was completed, a saturated solution of sodium carbonate was added to adjust the pH to 8 to obtain 2-amino-4-methoxyphenol.

[0044] (2) Add 67.2g of powdered potassium hydroxide to the 2-amino-4-methoxyphenol prepared in (1), stir, and heat at 150°C for 2.5 hours, until the reaction is complete to obtain dry salt; Add 0.63g of copper powder and 157g of bromobenzene in sequence, stir at 160°C until the color changes, then raise the temperature to 190°C, and heat for 1.5 hours. After cooling, pour 1200ml of water and 300ml of ether, and distill to obtain 3-amino-4-phenoxy-anisole.

[0045](3) Dissolve the 3-amino-4-phenoxy-anisole prepared in (2...

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Abstract

The invention belongs to the technical field of chemical drug synthesis, and particularly relates to an Iguratimod key intermediate and a synthesis method thereof. The synthesis method comprises the following steps: carrying out reduction on 4-methoxy-2-nitrophenol, and carrying out an Ullmann reaction and methyl sulfonylation to finally obtain 5-methoxy-2-phenoxy-benzenesulfonamide. The syntheticmethod has the advantages of simple process operation, environmental friendliness and mild reaction conditions, purity of the final product is up to 99.6%, the yield is up to 93.93%, and the method is very suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a key intermediate of iguratimod and a synthesis method thereof. Background technique [0002] Iguratimod (Iguratimod, T 614) is a non-steroidal anti-inflammatory drug (NSAIDs), the chemical name is 3-carboxamido-7-methylsulfonamido-6-phenoxy-4H-1-benzopyran- 4-ketone is a new type of disease-modifying drug (DMARDs) jointly developed by Japan Toyama and Eisai Pharmaceutical Co., Ltd. for the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA). Compared with previous DMARDs, it has a rapid effect, and its curative effect is equal to that of highly effective antirheumatic drugs (SAP, MTX), but its toxicity is low. [0003] 5-Methoxy-2phenoxy-benzenesulfonamide is a key intermediate in the synthesis process of iguratimod. The prior art uses 4-chloro-3-nitroanisole as a raw material, through etherification, nitro reduction, and mesylation to obtain the de...

Claims

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Application Information

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IPC IPC(8): C07C311/08C07C303/38
Inventor 高仰哲吴法浩李钢邵明忠
Owner NANJING REDWOOD FINE CHEM CO LTD
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