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CN-122010697-A - Preparation method of adapalene key intermediate

CN122010697ACN 122010697 ACN122010697 ACN 122010697ACN-122010697-A

Abstract

The invention discloses a preparation method of adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane, which is characterized in that p-bromophenol and 1-adamantanol are subjected to Friedel-crafts reaction methylation reaction to obtain the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane. The preparation method provided by the invention has the advantages of cheap and easily obtained raw materials, avoidance of high-base toxicity reagent, simplicity and safety in operation, high yield, low cost, high product purity and yield and the like, is very friendly to the environment, and is suitable for industrial amplification.

Inventors

  • HE QIU
  • WANG DAOSHENG
  • Zi Dong
  • DING HAN

Assignees

  • 江苏联环药业股份有限公司

Dates

Publication Date
20260512
Application Date
20260203

Claims (10)

  1. 1. The preparation method of the adapalene key intermediate is characterized in that 2- (1-adamantyl) -4-bromophenol (AD-a) is used as a raw material, and the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane (AD-b) is obtained through methylation reaction, wherein a low-toxicity methylation reagent is adopted in the methylation reaction, and the molar ratio of the low-toxicity methylation reagent to the AD-a is (1.25-4.00): 1, preferably 1.5:1.
  2. 2. The preparation method according to claim 1, wherein a phase transfer catalyst is further added into the reaction system, and the mass ratio of the addition amount of the phase transfer catalyst to the AD-a is (0.02-0.05): 1, preferably 0.02:1.
  3. 3. The method according to claim 1, wherein the low-toxicity methylation reagent is one or more selected from the group consisting of methyl p-toluenesulfonate, methyl benzenesulfonate and methyl formate.
  4. 4. The preparation method according to claim 1, wherein the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride and benzyltriethylammonium chloride.
  5. 5. The preparation method according to claim 1, characterized by comprising the following steps: step 1, adding an alkali reagent, water and AD-a into a reaction bottle, stirring and heating to 50 ℃, and reacting for 10 min-3 hours; Step 2, adding an acetone solution of a methylation reagent, optionally adding a phase transfer catalyst, and reacting for 30 minutes to 3 hours; step 3, cooling, separating liquid to remove water phase, washing the organic phase twice, and concentrating to dryness; And 4, adding alcohol, heating to 50 ℃, adding water, controlling the temperature to 20-30 ℃, stirring for 1h, filtering, and drying a filter cake by blowing at 45-55 ℃ for 6h to obtain the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane.
  6. 6. The preparation method according to claim 1, wherein the alkali agent is one or more selected from sodium hydroxide, sodium carbonate and potassium carbonate, and the molar ratio of the alkali agent to the AD-a is (1.1-1.5): 1, preferably 1.2:1.
  7. 7. The preparation method of claim 1, wherein the water addition amount in the step 1 is 5-10 times of the mass-volume ratio of the AD-a, the acetone addition amount in the step 2 is 2.5-5 times of the mass-volume ratio of the AD-a, and the volume ratio of the water to the acetone is 1.5-2.5:1.
  8. 8. The preparation method according to claim 1, wherein the alcohol is used in the step 4 in an amount of 1.5 to 2.5 times the mass-to-volume ratio of AD-a, the added water is in an amount of 1.5 to 2.5 times the mass-to-volume ratio of AD-a, and the alcohol-to-water ratio in the step 4 is 1:1.
  9. 9. The method according to claim 1, wherein the alcohol in step 4 is methanol, ethanol, preferably methanol.
  10. 10. The process according to claim 1, wherein the yield of 1- (5-bromo-2-methoxyphenyl) adamantane (AD-b) is greater than 90%.

Description

Preparation method of adapalene key intermediate Technical Field The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a key intermediate of adapalene. Background Adapalene (ADAPALENE), chemical name 6[3(1Adamantyl group4Methoxyphenyl ]2Naphthoic acid with molecular formula of C 28H28O3 is white or white-like crystal powder at normal temperature, and is insoluble in water or ethanol and slightly soluble in tetrahydrofuran. The medicine belongs to 3 rd generation vitamin A acid medicines, regulates the differentiation of epidermal cells by selectively combining RAR beta and RAR gamma receptors, has the effects of inhibiting follicular keratosis, dissolving acne and resisting inflammation, and is clinically mainly used for treating light and medium acne vulgaris which is mainly represented by acne, pimple and pustule on the face, chest and back, and the common dosage form is 0.1% gel. The product is named as "Dafu", is marketed in France for the first time in 1996, is approved by the FDA in the United states in 7 th year, is marketed as an over-the-counter drug (OTC) for the first time in the United states in 11 th year, has anti-inflammatory effect in the process of treating acne, and can effectively improve dermatitis skin lesions, so that the product is widely applied clinically. In recent years, there are reports on a variety of methods for synthesizing adapalene in the literature, and patent or literature reports on the method for synthesizing adapalene by performing Friedel-crafts reaction and hydrolysis on 6- (4-methoxyphenyl) -2-naphthoate and 1-adamantanol as described in China patent CN111333496A, but the method uses a second solvent such as dichloroethane and an expensive catalyst such as bis (triphenylphosphine) nickel chloride in the reaction process, so that solvent residue, metal residue control and personnel protection are high in the production process of bulk drugs. The mainstream production processes include the techniques described in US4717720a and chinese CN104003838a, both involving the key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane. However, the methylating agents used in the above patents are dimethyl sulfate, methyl iodide and the like, which are highly genotoxic impurities, and increase higher risks in terms of labor protection and post-treatment in the production process. Therefore, there is a need to develop a high-efficiency and low-cost preparation method of adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane. Disclosure of Invention In order to solve the technical problems, the invention provides a preparation method for efficiently producing the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane with low cost, which can avoid a high genotoxic reagent and a two-class solvent in the process of alkylation as far as possible, and has the advantages of simple process, easily available raw materials, high yield and low cost, and the quality of the adapalene can reach a satisfactory level. The invention is realized by the following technical scheme: the preparation method of the adapalene key intermediate takes 2- (1-adamantyl) -4-bromophenol (AD-a) as a raw material, and the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane (AD-b) is obtained through methylation reaction, wherein a low-toxicity methylation reagent is adopted in the methylation reaction, and the molar ratio of the low-toxicity methylation reagent to the AD-a is (1.25-4.00): 1, preferably 1.5:1. As a preferred embodiment, a phase transfer catalyst is further added to the reaction system, wherein the mass ratio of the addition amount of the phase transfer catalyst to AD-a is (0.02-0.05): 1, preferably 0.02:1. As a preferred embodiment, the low-toxicity methylation reagent is selected from one or more of methyl p-toluenesulfonate, methyl benzenesulfonate and methyl formate. As a preferred embodiment, the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium fluoride, benzyltriethylammonium chloride. As a preferred embodiment, the preparation method specifically comprises the following steps: step 1, adding an alkali reagent, water and AD-a into a reaction bottle, stirring and heating to 50 ℃, and reacting for 10 min-3 hours; Step 2, adding an acetone solution of a methylation reagent, optionally adding a phase transfer catalyst, and reacting for 30 minutes to 3 hours; step 3, cooling, separating liquid to remove water phase, washing the organic phase twice, and concentrating to dryness; And 4, adding alcohol, heating to 50 ℃, adding water, controlling the temperature to 20-30 ℃, stirring for 1h, filtering, and drying a filter cake by blowing at 45-55 ℃ for 6h to obtain the adapalene key intermediate 1- (5-bromo-2-methoxyphenyl) adamantane. In a preferred embodiment, the alkali agent is one or more selected from sodium hydroxide, sodium carbonate and pot