Synthesis method of trifarotene intermediate
Synthesis of trifarotene intermediates under mild conditions by base-induced radical coupling method, solving the high cost and complex operation problems of the borication step in the prior art, and achieving a simplified synthesis process and efficient yield.
Patent Information
- Application Number
- CN202410601126.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-15
- Publication Date
- 2024-12-31
AI Technical Summary
In the existing trifarotene synthesis method, the borolation step requires the use of organic lithium reagent or palladium catalysis under ultra-low temperature conditions, resulting in high cost and harsh operation.
The alkali-induced radical coupling method was adopted to introduce borate esters, avoiding the use of metal catalysts and ultra-low temperature reaction conditions, and mild borylation reaction was carried out through the mixing of alkali and organic solvents, followed by decompression distillation, washing and recrystallization. The trifarotene intermediate was obtained.
The gentle reaction conditions are achieved, operation is simplified, cost is reduced, and the use of protective groups and metal catalysts is successfully avoided, improving synthesis efficiency and safety.
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Figure CN119219679A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for synthesizing an intermediate of an anti-inflammatory drug trefarotene. Background Art
[0002] Trifarotene, a retinoid drug developed by Aklief Pharmaceuticals for the treatment of acne vulgaris, was first approved for marketing in the United States in October 2019. Its chemical name is 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid, and its molecular formula is C 29 H 33 NO4, molecular weight is 459.58, its structural formula is as follows:
[0003] The currently reported method for preparing trefarotene (reference: CN101087752B) is to use 2-tert-butylaniline as the raw material, and then undergo para-bromination, alkylation and boration (the boration step involves ultra-low temperatures: -70 ~ -78 o C) The aromatic boronic acid intermediate (I) is obtained in three steps; the intermediate (III) is obtained by one-step O-alkylation using biphenol (II) as the raw material; (I) and (III) are further subjected to Suzuki coupling to obtain (IV), and finally the two ester groups are hydrolyzed step by step to obtain the product (V).
[0004]
[0005] The method disclosed in reference document CN113816925 is to obtain intermediate (I) through Miyaura borylation reaction, and then obtain trefarotene through Suzuki coupling.
[0006]
[0007] In the prior art, the borylation step is carried out using an organic lithium reagent under harsh conditions of ultra-low temperature, or using palladium catalysis to introduce a boronic acid functional group, which has the problem of high cost. Summary of the invention
[0008] In order to solve the above problems in the prior art, the purpose of the present invention is to provide a method for synthesizing a trefarotene intermediate (1-(2-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine). The method introduces boric acid ester by alkali-induced free radical coupling, has mild reaction conditions, simple operation, and successfully avoids the harsh reaction conditions of introducing protective groups, using metal catalysts, and ultra-low temperatures. The steps are as follows:
[0009] The synthesis method of trofarotene is characterized by comprising the following steps: Step 1: Mix compound 1, a base and an organic solvent, then lower the temperature to 0°C, add a boronating reagent (compound 2), keep the temperature for 2 hours, then naturally raise the temperature to room temperature and stir for 8 hours.
[0010] Step 2: After the reaction is completed, the solvent is removed by vacuum distillation, ethyl acetate is added to the residue, stirred and diluted, washed twice with sodium chloride aqueous solution, and the organic phase is collected. The filtrate is concentrated to obtain a brown solid, which is then recrystallized in n-heptane to obtain an off-white solid (compound of formula 3).
[0011] Step 3: The filter cake was recrystallized in methanol, filtered, washed with n-heptane, collected, and vacuum dried at 45 °C for 12 h to obtain compound 3.
[0012] Furthermore, the organic solvent is selected from one of methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
[0013] Furthermore, the base is selected from one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, sodium methoxide, potassium methoxide, and lithium methoxide. The molar ratio of compound 1 to the base is 1:1-10.
[0014] Furthermore, the boronation reagent is bis(pinacol)diboron.
[0015] Furthermore, the molar ratio of compound 1 to the boronating agent is 1:1-10.
[0016] Furthermore, the boronation reaction temperature is -10~110°C. DETAILED DESCRIPTION
[0017] In order to make the technical solutions and beneficial effects of the present invention more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs. Example
[0018] Under nitrogen protection, add the compound of formula I (10.0g, 35.4 mmol), methanol (100ml), potassium tert-butoxide (11.9g, 106.3mmol) to the reaction bottle, reduce the temperature to 0℃, add B2pin2 (26.9g, 106.3mmol), and keep warm for 24h. After the reaction is completed, remove the solvent by vacuum distillation, add ethyl acetate (300ml) to the concentrate to dilute, and then wash twice with saturated sodium chloride (2×100ml). Collect the organic phase and concentrate under reduced pressure. Add 100ml of n-heptane to the concentrate and stir for 10h, filter, collect the filter cake, and vacuum dry (-0.08MPa, 50℃) for 4h to obtain 9.2g of compound of formula II with a yield of 79.1%. 1 HNMR(400 MHz, CDCl3) δH = 7.83 (1H, d, J = 1.5 Hz), 7.69 (1H, dd, J = 7.8, 1.5Hz), 7.37 (1H, d, J = 7.8 Hz), 3.03–2.90 (4H, m), 1.98–1.85 (4H, m), 1.45(9H, s), 1.34 (12H, s). 11 B NMR (128 MHz, CDCl3) δB = 31.2; 13 C NMR (101 MHz, CDCl3) δC = 155.1 (C), 148.2 (C), 133.7 (CH), 133.2 (CH), 126.1 (CH), 83.6 (2×C), 56.1 (2×CH2), 35.5 (2×C), 31.1 (3×CH3), 24.8 (4×CH3), 24.7 (2×CH2). Example
[0019] Under nitrogen protection, add the compound of formula I (10.0g, 35.4 mmol), methanol (100ml), potassium methoxide (7.5g, 106.3mmol) to the reaction bottle, reduce the temperature to 0℃, add B2pin2 (26.9g, 106.3 mmol), and keep warm for 24h. After the reaction is completed, remove the solvent by vacuum distillation, add ethyl acetate (300ml) to the concentrate to dilute, and then wash twice with saturated sodium chloride (2×100ml). Collect the organic phase and concentrate under reduced pressure. Add 100ml of n-heptane to the concentrate and stir for 10h, filter, collect the filter cake, and vacuum dry (-0.08MPa, 50℃) for 4h to obtain 8.7g of compound of formula II with a yield of 74.2%. 1HNMR (400MHz, CDCl3) δH = 7.83 (1H, d, J = 1.5 Hz), 7.69 (1H, dd, J = 7.8, 1.5 Hz),7.37 (1H, d, J = 7.8 Hz), 3.03–2.90 (4H, m), 1.98–1.85 (4H, m), 1.45 (9H, s),1.34 (12H, s). 11 B NMR (128 MHz, CDCl3) δB = 31.2; 13 C NMR (101 MHz, CDCl3) δC= 155.1 (C), 148.2 (C), 133.7 (CH), 133.2 (CH), 126.1 (CH), 83.6 (2×C), 56.1(2×CH2), 35.5 (2×C), 31.1 (3×CH3), 24.8 (4×CH3), 24.7 (2×CH2)。
Claims
1. The present invention discloses a method for synthesizing a trefarotene intermediate, characterized in that: Compound 1 Under the action of base, it is coupled with a boronating reagent (compound 2) in an organic solvent to obtain compound 3.
2. The method for synthesizing a trefarotene intermediate according to claim 1, characterized in that: The organic solvent is selected from one of methanol, ethanol, propanol, isopropanol, butanol and tert-butanol.
3. The method for synthesizing a trefarotene intermediate according to claim 1, characterized in that: The base is one or more of sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
4. The method for synthesizing a trefarotene intermediate according to claim 1, characterized in that: The molar ratio of the compound 1 to the base is in the range of 1:1 to 10.
5. The method for synthesizing a trefarotene intermediate according to claim 1, characterized in that: The reaction temperature ranges from -10 to 100°C.