Synthesis process of roflumilast intermediate
By preparing the steps of sodium-4--4- (diofluoride oxygen), the problem of large-scale mass production and quality control of Ronofloflzet intermediate mass production was solved, and realized Product stability and efficient production.
Patent Information
- Application Number
- CN202310931168.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-27
- Publication Date
- 2025-01-28
AI Technical Summary
It is difficult for the prior art to achieve efficient and stable mass production of roflustat intermediates.
By preparing the steps to prepare sodium phenyl azhenyate-4- (diofluoride oxygenyl), including the 4-diofloxyoxyl-3-hydroxybenzene formaldehyde and bromide and carbonate 铯 React in DMF, and then reacted in methanol with 30% H2O2 and KOH, and finally collected the precipitation by dilution and regulating the pH value.
The stability of the Ronflont intermediate is good, the process is feasible, it can effectively control the quality of the product, and meet the large -scale mass production and sales needs.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine, and specifically relates to a synthesis process of a roflumilast intermediate. Background Art
[0002] Roflumilast, whose scientific name is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide. This drug is a phosphodiesterase-4 inhibitor. Phosphodiesterase-4 is a major cyclic adenosine monophosphate (cAMP) metabolic enzyme in inflammatory and immune cells, and phosphodiesterase-4 inhibitors have a wide range of anti-inflammatory activities, including inhibiting the release of inflammatory mediators and inhibiting the activation of immune cells. In addition, phosphodiesterase-4 inhibitors have also been shown to have therapeutic effects in animal airway inflammation models. Roflumilast and its main active metabolite, roflumilast-N-oxide, are both potent and selective phosphodiesterase-4 inhibitors, which can inhibit the activation of human immune cells and the release of inflammatory mediators in vitro. Roflumilast became the first phosphodiesterase-4 inhibitor approved for marketing worldwide. Summary of the invention
[0003] The purpose of the present invention is to provide a synthesis process of a roflumilast intermediate, which is conducive to large-scale mass production.
[0004] To achieve the above object, the present invention provides the following technical solutions:
[0005] A synthesis process of a roflumilast intermediate, characterized by comprising:
[0006] Procedure for the preparation of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate.
[0007] The molecular formula of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate is C 12 H 12 F2O4, chemical formula is
[0008]
[0009] The steps of preparing sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate include:
[0010] 4-Difluoromethoxy-3-hydroxybenzaldehyde (1.88 g, 10 mmol), alkyl bromide (20 mmol), and cesium carbonate (6.51 g, 20 mmol) were stirred in DMF (15 mL);
[0011] The mixture was stirred at 65 °C for 1 hour and monitored by TLC. Then, the reaction solution was poured into water and the solid was collected. The obtained reaction intermediate 4-difluoromethoxy-3-alkoxybenzaldehyde precipitate was used for all the following reactions without further purification;
[0012] A mixture of 4-difluoromethoxy-3-alkoxybenzaldehyde (6.25 mmol), 30% H2O2 (1 mL) and KOH (2.8 g, 50 mmol) in methanol (10 ml) was stirred at room temperature for 1 hour and monitored by TLC;
[0013] After the reaction was completed, the reaction mixture was diluted with water (30 mL) and adjusted to pH 2 with concentrated hydrochloric acid; the resulting precipitate was collected by filtration to give pure 4-difluoromethoxy-3-alkoxybenzoic acid.
[0014] Compared with the prior art, the present invention has the following beneficial effects:
[0015] The stability test confirmed that the product prepared by this process has good stability and the process is feasible. It can effectively control the product quality. The stability study showed that this product is stable and can meet the needs of production and sales. DETAILED DESCRIPTION
[0016] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0017] Example.
[0018] A synthesis process of a roflumilast intermediate, characterized by comprising:
[0019] Procedure for the preparation of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate.
[0020] The molecular formula of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate is C 12 H 12 F2O4, chemical formula is
[0021]
[0022] The steps of preparing sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate include:
[0023] 4-Difluoromethoxy-3-hydroxybenzaldehyde (1.88 g, 10 mmol), alkyl bromide (20 mmol), and cesium carbonate (6.51 g, 20 mmol) were stirred in DMF (15 mL);
[0024] The mixture was stirred at 65 °C for 1 hour and monitored by TLC. Then, the reaction solution was poured into water and the solid was collected. The obtained reaction intermediate 4-difluoromethoxy-3-alkoxybenzaldehyde precipitate was used for all the following reactions without further purification;
[0025] A mixture of 4-difluoromethoxy-3-alkoxybenzaldehyde (6.25 mmol), 30% H2O2 (1 mL) and KOH (2.8 g, 50 mmol) in methanol (10 ml) was stirred at room temperature for 1 hour and monitored by TLC;
[0026] After the reaction was completed, the reaction mixture was diluted with water (30 mL) and adjusted to pH 2 with concentrated hydrochloric acid; the resulting precipitate was collected by filtration to give pure 4-difluoromethoxy-3-alkoxybenzoic acid.
Claims
1. A synthesis process of a roflumilast intermediate, characterized in that include: Procedure for the preparation of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate.
2. The synthesis process of the Roflumilast intermediate according to claim 1, characterized in that The molecular formula of sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate is C 12 H 12 F2O4, chemical formula is 3. The synthesis process of the Roflumilast intermediate according to claim 1, characterized in that The steps of preparing sodium 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoate include: 4-Difluoromethoxy-3-hydroxybenzaldehyde (1.88 g, 10 mmol), alkyl bromide (20 mmol), and cesium carbonate (6.51 g, 20 mmol) were stirred in DMF (15 mL); The mixture was stirred at 65 °C for 1 hour and monitored by TLC. Then, the reaction solution was poured into water and the solid was collected. The obtained reaction intermediate 4-difluoromethoxy-3-alkoxybenzaldehyde precipitate was used for all the following reactions without further purification; A mixture of 4-difluoromethoxy-3-alkoxybenzaldehyde (6.25 mmol), 30% H2O2 (1 mL) and KOH (2.8 g, 50 mmol) in methanol (10 ml) was stirred at room temperature for 1 hour and monitored by TLC; After the reaction was completed, the reaction mixture was diluted with water (30 mL) and adjusted to pH 2 with concentrated hydrochloric acid; the resulting precipitate was collected by filtration to give pure 4-difluoromethoxy-3-alkoxybenzoic acid.