Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid

A technology of cyclopropylmethoxy and cyclopropylcarbinol is applied in the preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and the synthesis field of pharmaceutical intermediates, which can solve the problem of high equipment requirements. , incomplete reaction, many by-products, etc., to achieve the effect of high purity, avoiding pollution and low cost

Inactive Publication Date: 2012-09-26
SHANGHAI TONGYUAN BIOTECH
View PDF6 Cites 10 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The technical problem to be solved by this invention is to overcome the incomplete reaction, poor selectivity, many by-products and high requirements for equipment in the method for synthesizing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid in the prior art Defects, provide an economical and environmentally friendly synthetic method suitable for industrial production with mild reaction conditions, good selectivity, high yield, and high purity

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid
  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid
  • Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the synthesis of 3-cyclopropylmethoxy-4-hydroxybenzaldehyde

[0045] Under nitrogen protection, add 100ml of dimethyl sulfoxide to a 250ml four-neck flask, control the temperature at 10-15°C, add 10.08g of 3-chloro-4-hydroxybenzaldehyde, 3.9g of sodium hydride and 5.13g of cyclopropanol, After stirring for 0.5 hours, the temperature was raised to 110° C. and stirred for 10 hours. The reaction system was adjusted to pH 2 with 0.2N hydrochloric acid, extracted 3 times with ethyl acetate (100ml), washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 11.42g of an oily product with a yield of 91%. , HPLC purity 95%.

Embodiment 2

[0046] Embodiment 2: the synthesis of 3-cyclopropylmethoxy-4-hydroxybenzaldehyde

[0047] Under nitrogen protection, add 130ml of acetone to a 250ml four-neck flask, control the temperature at 10-15°C, add 13.08g of 3-bromo-4-hydroxybenzaldehyde, 4.6g of potassium hydride and 3.6g of cyclopropanol, and stir for 0.5 hours. The temperature was raised to 70°C and stirred for 15 hours. The reaction system was adjusted to pH 2 with 0.2N hydrochloric acid, extracted three times with ethyl acetate (100ml), washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 10.04g of an oily product with a yield of 80%. HPLC purity 92.5%.

Embodiment 3

[0048] Embodiment 3: the synthesis of 3-cyclopropylmethoxy-4-hydroxybenzaldehyde

[0049] Under nitrogen protection, add 100ml of N,N-dimethylformamide to a 250ml four-neck flask, control the temperature at 10-15°C, add 14.56g of 3-iodo-4-hydroxybenzaldehyde and 7.8g of sodium hydride, and stir for 0.5 Hour. Dissolve 5.13g of cyclopropanol in 20ml of N,N-dimethylformamide, slowly drop into the above system, raise the temperature to 130°C, and stir for 12 hours. The reaction system was adjusted to pH 2 with 0.2N hydrochloric acid, extracted three times with ethyl acetate (100ml), washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 10.04g of an oily product with a yield of 80%. HPLC purity 85.6%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid shown in the formula I. The preparation method comprises the following step that 3-halogeno-4-hydroxybenzaldehyde shown in the formula II and cyclopropylmethanol undergo a reaction in the presence of one or more alkalis to produce a compound shown in the formula III; the compound shown in the formula III and chlorodifluoroacetic acid or its derivative shown in the formula IV undergo a reaction in the presence of one or more alkalis to produce 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde; and the 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde further undergoes an oxidation reaction to produce 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid shown in the formula I. The preparation method has good reaction selectivity and a high reaction yield, adopts reagents having low costs, allows mild reaction conditions, and has safe and controllable processes. In the whole reaction process, highly toxic reagents and solvents are not used and thus the preparation method satisfies environmental protection requirements and is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to the synthesis of pharmaceutical intermediates, more specifically to the preparation of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Background technique [0002] Phosphodiesterase 4 (PDE4) is a major enzyme involved in cAMP metabolism in immune, inflammatory, and airway smooth muscle cells. Since cAMP can lead to bronchial smooth muscle relaxation and lung inflammation, inhibition of PDE4 can reduce the release of inflammatory mediators, thereby inhibiting the damage to lung tissue caused by respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. There are two isoenzymes of PDE4, namely H-PDE4 and L-PDE4, the inhibition of the former can lead to gastrointestinal adverse reactions, while the inhibition of the latter can produce the expected therapeutic effect. [0003] Recently, the inhibition of PDE4 has been identified as a new target for ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/72C07C51/285C07C51/16
Inventor 熊龙启
Owner SHANGHAI TONGYUAN BIOTECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap