New method for preparing roflumilast

A technology of roflumilast and difluoromethoxy, which is applied in the field of improvement of the preparation method of industrially synthesized roflumilast, can solve problems such as poor selectivity, and achieve the effects of low cost, high yield, and simple reaction operation

Inactive Publication Date: 2012-08-01
TIANJIN INSTITUTE OF PHARMA RESEARCH +1
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Problems solved by technology

[0008] The applicant has now developed a new industrial synthesis method, which overcomes the problem of po

Method used

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  • New method for preparing roflumilast
  • New method for preparing roflumilast
  • New method for preparing roflumilast

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Embodiment 14- 2

[0019] The synthesis of embodiment 14-difluoromethoxy-3-hydroxybenzaldehyde (II)

[0020] In a 100mL single-necked bottle, 3-bromo-4-hydroxybenzaldehyde (1.66g, 8.3mmol), sodium chlorodifluoroacetate (1.27g, 8.3mmol), sodium hydroxide (0.48g, 12mmol), DMF ( 15mL) and water (0.3mL), heated at 120°C, reacted for 2 hours, and distilled off the solvent. Add 10mL of hydrochloric acid solution, extract with ethyl acetate, evaporate to dryness, add water, adjust the pH value to about 13-14 with sodium hydroxide, extract with ethyl acetate, dry over magnesium sulfate, filter and evaporate to dryness to obtain a brown oil, which turns white when placed at low temperature 1.90 g of needle-like crystals, yield 91.6%. mp 68-70°C; 1H NMR (400MHZ DMSO): δ7.239(s, 0.2H, CHF2), 7.420(s, 0.5H, CHF2), 7.474-7.495(d, 1H, J=8.4, ArH), 7.601(s, 0.3H, CHF2), 7.933-7.959(q, 1H, J=2, J=8.4, ArH), 8.164-8.169(d, 1H, J=2, ArH), 9.920(s, 1H, CHO), ESI-MS: m / z 251 [M+H]+.

[0021] With reference to t...

Embodiment 23

[0023] Synthesis of Example 23-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde (III)

[0024] In a 100mL single-necked bottle, add 4-difluoromethoxy-3-hydroxybenzaldehyde (0.25g, 1.0mmol), cyclopropylmethanol (0.30g, 4.2mmol), 8-hydroxyquinoline (0.04g, 0.28mmol), cuprous iodide (0.04g, 0.22mmol), potassium carbonate (0.69g, 5.0mmol), DMF (10mL), heated at 140°C, reacted for 20 hours, and evaporated the solvent. Extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 0.15 g of yellow oil with a yield of 62.0%. 1H NMR (400MHZ DMSO): δ0.563-0.609(m, 2H, CH2), 0.912-0.929(m, 2H, CH2), 1.224-1.286(m, 1H, CH), 3.991-4.008(d, 2H, J=6.8, CH2), 7.239(s, 0.2H, CHF2), 7.420(s, 0.5H, CHF2), 7.474-7.495(d, 1H, J=8.4, ArH), 7.601(s, 0.3H, CHF2 ), 7.933-7.959 (q, 1H, J=2, J=8.4, ArH), 8.164-8.169 (d, 1H, J=2, ArH), 9.920 (s, 1H, CHO), ESI-MS: m / z243[M+H]+.

[0025] With reference to the method of Example 2, the experimental conditions ...

Embodiment 33

[0028] Synthesis of Example 33-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (IV)

[0029] In a 100mL single-necked bottle, add 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde (1.54g, 6.4mmol), sulfamic acid (0.90g, 9.3mmol), sodium hypochlorite (1.00g, 11.0mmol), glacial acetic acid (6mL), water (2mL), reacted at room temperature for 1 hour, a solid precipitated, added 30mL of water, filtered, and dried to obtain 1.40g of white crystals, with a yield of 87.5%. mp 129-130°C; 1H NMR (400MHZ DMSO): δ0.563-0.609 (m, 2H, CH2), 0.912-0.929 (m, 2H, CH2), 1.224-1.286 (m, 1H, CH), 3.991- 4.008(d, 2H, J=6.8, CH2), 7.239(s, 0.2H, CHF2), 7.420(s, 0.5H, CHF2), 7.474-7.495(d, 1H, J=8.4, ArH), 7.601( s, 0.3H, CHF2), 7.933-7.959 (q, 1H, J=2, J=8.4, ArH), 8.164-8.169 (d, 1H, J=2, ArH), 12.969 (s, 1H, COOH) , ESI-MS: m / z 259 [M+H]+.

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Abstract

The invention provides a simple method for preparing roflumilast. According to the invention, 3-bromine-4-hydroxy-benzaldehyde (I) is etherified to obtain 4-difluoromethoxy-3-hydroxybenzaldehyde (II), the compound II is subjected to an Ullmann condensation reaction to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde (III), the compound III is oxidized by sodium hypochlorite to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (IV), the compound IV is chloridized to obtain 3-cyclopropylmethoxy-4-difluoromethoxy-benzoyl chloride (V), and the compound V and 3,5-dichloro-4-aminopyridine are acylated to obtain the roflumilast. The method of the invention has the advantages of no need of selective etherification and column chromatography purification in the preparation process, simple reaction operation, simple post-treatment, low cost, high yield, and high purity.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the improvement of the preparation method of industrially synthesized roflumilast. Background technique [0002] Daxas(R) (roflumilast) is an oral, selective phosphodiesterase 4 (PDE4) inhibitor that has demonstrated a novel mode of action associated with chronic obstructive pulmonary disease (COPD) of inflammation. There are several synthetic methods for roflumilast, but the existing methods have disadvantages such as difficult separation and purification, and low yield. For example, the world patent WO9501338A1 reacts 3,4-dihydroxybenzaldehyde with chlorodifluoromethane, then etherifies with cyclopropylmethyl bromide, oxidizes with sodium hypochlorite, chlorates, and acylates to obtain Roflumilast. The selectivity of the first step of the method is low, column chromatography separation is required, and the yield is low, and the price of cyclopropylmethyl bromide is relatively ex...

Claims

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Application Information

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IPC IPC(8): C07D213/76C07C47/575C07C45/64
Inventor 蔡志强徐为人邹美香孙歆慧汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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