CN112479918B - Synthesis method of retinoic acid derivative Am580 - Google Patents
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- CN112479918B CN112479918B CN202011457051.9A CN202011457051A CN112479918B CN 112479918 B CN112479918 B CN 112479918B CN 202011457051 A CN202011457051 A CN 202011457051A CN 112479918 B CN112479918 B CN 112479918B
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Abstract
The invention discloses a synthesis method of a retinoic acid derivative Am580, which comprises the following steps: stirring 2, 5-dimethylhexane-2, 5-diol solution in concentrated HCl for 30min, introducing HCl gas into the system for reaction for 3h, stirring until the system becomes a two-phase mixture, cooling to room temperature, filtering to obtain a light pink solid, washing with water, recrystallizing in methanol, filtering to obtain intermediate 3 as white solid, dissolving 2, 5-dichloro-2, 5-dimethylhexane in organic solvent, dissolving AlCl into the solvent, and concentrating to obtain a solid 3 Adding into the solution, and adding the 2, 5-dichloro-2, 5-dimethylhexane and AlCl 3 The molar ratio of (2) is 1:0.1-1:0.2, heating to 100-120 ℃, stirring for 16h, quenching the reaction with 3M HCl, extracting the reaction product with n-hexane, and distilling the solvent under reduced pressure to obtain a colorless oily intermediate 4. The beneficial effects of the invention are as follows: the invention has higher yield per step, simple post-treatment and easy industrialized production; the method optimizes the reaction conditions and the solvent system aiming at Friedel-crafts reaction and oxidation reaction, and is more beneficial to industrial production.
Description
Technical Field
The invention relates to a drug synthesis process, in particular to a synthesis method of retinoic acid derivative Am580, and belongs to the technical field of medicine and health.
Background
The search for lead compounds from in vivo metabolites has been an important idea for scientific researchers to complete new drug development, and from the discovery of vitamin a for over one hundred years, people have discovered a series of lead compounds with biological activity such as Retinoic acid (Retinoic acid) and Retinoic acid derivatives through the research of metabolic pathways, action receptors and the like of vitamin a in human bodies, and many lead compounds are used for treating cancers and skin diseases (such as acne, psoriasis and the like). Although natural all-trans retinoic acid (all-trans retinoic acid) has good biological activity, the effective dose is relatively close to the toxic dose, the treatment window is small, tolerance can be generated after long-term use, and the defects of side effects such as teratogenesis, allergy and the like limit the wide clinical application range.
Since Kagechika et al in 1986 synthesized Am580, am580 has been receiving extensive attention from researchers due to its good and broad biological activity, such as the treatment of skin diseases, psoriasis, modulation of immune system, anticancer activity and the ability to reduce the risk of cardiovascular and cerebrovascular diseases. At present, more scientific researchers focus on the work of Am580 on the aspects of further modification and activity evaluation, and specific synthetic process routes of Am580 are freshly reported, so that the exploration of a high-efficiency and reliable synthetic route of Am580 has great significance for the research and development of new drugs and large-scale production. The method further improves and optimizes the original synthesis process through researching the existing synthesis route, and provides reference for large-scale production.
Am580, chemical name 4- [ [ (5, 6,7, 8-tetrahydro-5, 8-tetramethyl-2-naphtyl) carbonyl ] amino ] benzoic acid (1), its structural formula is
Literature (Arch. Pharm. Chem. Life Sci.2006,339, 193-200.) and patent EP 1541549, WO,2019/169270 starting from 1,2,3, 4-tetrahydro-1,1,4,4,6 pentamethylnaphthalene (4) via KMnO 4 Oxidizing, reacting with thionyl chloride to generate acyl chloride and then reacting with p-aminobenzeneAnd (3) condensing methyl formate and removing methanol. The raw materials used in the method are expensive, the cost of large-scale production is increased, and the method is not suitable for industrial production. There is also a literature (chi. J. Chem.2010,28, 1951-1956.) reporting that Am580 is obtained by starting from 2, 5-dimethyl-2, 5-hexanediol (2), reacting with HCl under acidic conditions to form 2, 5-dimethyl-2, 5-dichlorohexane (3), reacting with benzene to give starting material (4), and repeating the above steps. The method has the advantages of simple and easily obtained raw materials, lower yield and longer reaction time when the Friedel-crafts reaction and oxidation generate 5, 8-tetramethyl-5.6.7.8-tetrahydronaphthalene-2-carboxylic acid (5), and the industrial production needs to be further optimized.
Disclosure of Invention
The invention aims to solve the problems, and provides a synthesis method of a retinoic acid derivative Am580, which avoids complex post-treatment in the prior art and uses a cyclization reaction catalyst with higher cost; the post-treatment method is simplified, the catalytic system of the cyclization reaction is optimized, the reaction yield is improved, the environmental pollution is reduced, the production cost is saved, and the industrial mass production is facilitated.
The aim of the invention can be achieved by the following technical scheme: a synthesis method of a retinoic acid derivative Am580, which comprises the following steps:
step one: chlorination reaction
Stirring a solution of 2, 5-dimethylhexane-2, 5-diol in concentrated HCl for 30min, introducing HCl gas into a system for reaction for 3h, stirring until the system becomes a two-phase mixture, cooling to room temperature, filtering to obtain a light pink solid, washing with water, recrystallizing in methanol, and filtering to obtain an intermediate 3, wherein the product is a white solid;
step two: friedel-crafts reaction
Dissolving 2, 5-dichloro-2, 5-dimethylhexane in organic solvent, and dissolving AlCl 3 Adding into the solution, and adding the 2, 5-dichloro-2, 5-dimethylhexane and AlCl 3 The molar ratio of (2) is 1:0.1-1:0.2, heating to 100-120 ℃, stirring for 16h, quenching the reaction by using 3M HCl, extracting the reaction product by using n-hexane, and removing the solvent by reduced pressure distillation to obtain a colorless oily intermediate 4;
step three: oxidation reaction
Adding organic solvent, water, and alkali into a reaction vessel, and sequentially adding intermediate 4 and KMnO 4 Intermediate 4 is combined with alkali, KMnO 4 The molar ratio of (2) is 1:1.5:3-1:2.5:5, then the temperature is raised to 90-110 ℃ and the mixture is stirred for reaction for 16 hours, the reaction system is cooled to 10 ℃ by ice water bath, HCl is added, the pH=1 of the system is regulated, the product is extracted by ethyl acetate, and a white solid intermediate 5 is obtained after reduced pressure distillation;
step four: amidation reaction
Dissolving intermediate 5 in SOCl at 0deg.C 2 In the SOCl 2 10 times the mass of intermediate 5, 0.05-0.1ml DMF was added, stirred for 0.5h and then SOCl was removed in vacuo 2 Dissolving crude acyl chloride in an organic solvent, adding 4-ethyl aminobenzoate and DMAP, wherein the mol ratio of the DMAP to the 4-ethyl aminobenzoate is 1:10-1:12, heating the mixture at 60 ℃ for 2 hours under stirring, extracting with the organic solvent, and sequentially extracting an organic layer with HCl and saturated NaHCO 3 Washing with saturated NaCl, drying, filtering, and distilling under reduced pressure to obtain a white solid intermediate 6;
step five: hydrolysis reaction
Dissolving an intermediate 6 and KOH in methanol, wherein the molar ratio of the intermediate 6 to the KOH is 1:3-1:5, stirring for 15 hours under reflux, cooling to room temperature, distilling under reduced pressure to remove the solvent, adding the following organic solvent and water, regulating pH to be acidic by using an acid solution, separating an organic phase, and distilling under reduced pressure to remove the solvent to obtain a white solid target product 1, namely a retinoic acid derivative Am580;
the specific synthetic route of the retinoic acid derivative Am580 is as follows:
preferably, the organic solvent in the third step is one of toluene, chlorobenzene, chloroform and dichloromethane.
Preferably, the alkali in the third step is one of sodium hydroxide, potassium hydroxide, ammonia water, potassium carbonate and sodium carbonate.
Preferably, the reaction temperature in step two is 110 ℃.
Preferably, in the fifth step, the acid solution is any one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid solution.
Preferably, the organic solvent in the fifth step is any one of tetrahydrofuran, ethyl acetate, dichloromethane, chloroform and toluene.
Compared with the prior art, the invention has the beneficial effects that:
1. the method has the advantages of higher yield per step, simple post-treatment, mild reaction conditions and easy industrialized production.
2. The method optimizes the reaction conditions and the solvent system aiming at Friedel-crafts reaction and oxidation reaction, and is more beneficial to industrial production.
Drawings
The present invention is further described below with reference to the accompanying drawings for the convenience of understanding by those skilled in the art.
FIG. 1 is a liquid chromatogram of retinoic acid derivative Am580 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: synthesis of Compound 3
Chlorination reaction
A solution of 2, 5-dimethylhexane-2, 5-diol (2) (14.6 g,0.10 mol) in concentrated HCl was stirred for 30min. And then HCl gas is introduced into the system to react for 3 hours. After stirring until the system became a two-phase mixture, cooling to room temperature, filtering to give a pale pink solid, washing with water, recrystallizing in methanol, and filtering to give compound 3 as a white solid (17.02 g, 93.1%).
Example 2: preparation of Compound 4
Friedel-crafts reaction
2, 5-dichloro-2, 5-dimethylhexane (3) (3 g,0.016 mol) was dissolved in toluene (80 mL) obtained by drying. AlCl is added 3 (0.22 g,1.64 mmol) was added to the solution, heated to 110deg.C and stirred for 16h, quenched with 3M HCl (10 mL), extracted with hexane (50 mL. Times.3), the combined organic phases were washed with saturated brine, anhydrous Na 2 SO 4 Drying and distillation under reduced pressure gave the product as a colourless oil (3.06 g, 92.6%).
Example 3: preparation of Compound 5
Oxidation reaction
Chlorobenzene (80 ml), H, was charged to a three-necked round bottom flask (250 ml) 2 O (20 ml) and NaOH (1.2 g,29.6 mmol). Compound 4 (3.00 g,14.8 mmol) and KMnO were added sequentially 4 (9.36 g,59.2 mmol). The reaction was heated and stirred at 100deg.C for 16h, then cooled to 10deg.C with ice-water bath, HCl (6N, 100 mL) was added to adjust pH=1, the product was extracted with ethyl acetate (3X 100 mL) and taken over Na 2 SO 4 Drying, filtration and distillation under reduced pressure gave white solid 5 (2.17 g, 63.3%).
Example 4: process for the preparation of Compound 6
Amidation reaction
Compound 5 (2.0 g,8.6 mmol) was dissolved in SOCl at 0deg.C 2 (20 mL). A few drops of DMF was added and after stirring for 0.5h SOCl was removed in vacuo 2 And the crude acid chloride was dissolved in pyridine (50 mL). Ethyl 4-aminobenzoate (1.5 g,9.9 mmol) and DMAP (0.10 mg,0.86 mmol) were added and the mixture was heated at 60℃for 2h with stirring. After water quenching, ethyl acetate extraction, the organic layer was successively quenched with HCl (2 mol/L), saturated NaHCO 3 Washing with saturated NaCl and then with anhydrous Na 2 SO 4 Drying, filtration and distillation under reduced pressure gave a white solid (2.45 g, 78.0%).
Example 5: process for the preparation of compound 1
Hydrolysis reaction
In a round bottom flask was charged compound 6 (1.0 g,2.74 mmol), meOH (40 mL) and KOH (0.62 g,11 mmol). The reaction mixture was stirred at reflux for 15h and cooled to room temperature before subtractionThe solvent was distilled off under pressure, ethyl acetate (30 ml) and water (20 ml) were added, the pH was adjusted to be acidic with HCl (6N) solution, and then the organic phase was separated, washed with saturated brine, na 2 SO 4 Drying, filtration and distillation under reduced pressure gave a white solid (0.78 g, 81.2%);
the specific synthetic route of the retinoic acid derivative Am580 is as follows:
test example 1
The nmr hydrogen spectrum and carbon spectrum of Am580 obtained in example 5 were measured as follows:
1 H NMR(600MHz,DMSO-d6)δ10.39(s,1H),7.95(d,J＝10.3Hz,2H),7.91(d,J＝10.3Hz,2H),7.88(d,J＝2.2Hz,1H),7.70(dd,J＝9.6,2.2Hz,1H),7.43(d,J＝9.6Hz,1H),4.29(q,J＝7.0Hz,2H),1.69(s,4H),1.31(t,J＝7.1Hz,3H),1.30(s,6H),1.27(s,6H)。
test example 2
The liquid phase data for Am580 obtained in example 5 were determined as follows:
purity of liquid phase: 96.7%.
Note that: chromatographic conditions
Chromatographic column: waters X Bridge C18 reverse phase chromatography column: 50mm 4.6mm 3.5um; mobile phase: a: water (0.01 mol/L NH4HCO 3) B: acetonitrile; elution gradient: b:0-1.6min,5% -95%,1.6-2.5min,95%; flow rate: 2ml/min; column temperature: 40 ℃.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
Claims (6)
1. A synthesis method of a retinoic acid derivative Am580 is characterized in that: the method comprises the following steps:
step one: chlorination reaction
Stirring a solution of 2, 5-dimethylhexane-2, 5-diol in concentrated HCl for 30min, introducing HCl gas into a system for reaction for 3h, stirring until the system becomes a two-phase mixture, cooling to room temperature, filtering to obtain a light pink solid, washing with water, recrystallizing in methanol, and filtering to obtain an intermediate 3, wherein the product is a white solid;
step two: friedel-crafts reaction
Dissolving 2, 5-dichloro-2, 5-dimethylhexane in an organic solvent, adding AlCl3 into the solution, heating to 100-120 ℃ and stirring for 16 hours, then quenching the solution by using 3M HCl, extracting the solution by using n-hexane, and removing the solvent by reduced pressure distillation to obtain a colorless oily intermediate 4;
step three: oxidation reaction
Adding organic solvent, water, and alkali into a reaction vessel, and sequentially adding intermediate 4 and KMnO 4 Intermediate 4 is mixed with alkali, KMnO 4 The molar ratio of (2) is 1:1.5:3-1:2.5:5, then the temperature is raised to 90-110 ℃ and the mixture is stirred for reaction for 16 hours, the reaction system is cooled to 10 ℃ by ice water bath, HCl is added, the pH=1 of the system is regulated, the product is extracted by ethyl acetate, and a white solid intermediate 5 is obtained after reduced pressure distillation;
step four: amidation reaction
Dissolving intermediate 5 in SOCl at 0deg.C 2 In the SOCl 2 10 times the mass of intermediate 5, 0.05ml-0.1ml DMF was added, stirred for 0.5h and then SOCl was removed in vacuo 2 Dissolving crude acyl chloride in an organic solvent, adding 4-ethyl aminobenzoate and DMAP, wherein the mol ratio of the DMAP to the 4-ethyl aminobenzoate is 1:10-1:12, heating the mixture at 60 ℃ for 2 hours under stirring, extracting with the organic solvent, and sequentially extracting an organic layer with HCl and saturated NaHCO 3 Washing with saturated NaCl, drying, filtering, and distilling under reduced pressure to obtain a white solid intermediate 6;
step five: hydrolysis reaction
Dissolving an intermediate 6 and KOH in methanol, wherein the molar ratio of the intermediate 6 to the KOH is 1:3-1:5, stirring for 15 hours under reflux, cooling to room temperature, removing the solvent by reduced pressure distillation, adding an organic solvent and water, adjusting pH to be acidic by an acid solution, separating an organic phase, and removing the solvent by reduced pressure distillation to obtain a white solid target product 1, namely a retinoic acid derivative Am580;
the specific synthetic route of the retinoic acid derivative Am580 is as follows:
2. the method for synthesizing retinoic acid derivative Am580 according to claim 1, wherein the organic solvent in step three is one of toluene, chlorobenzene, chloroform and dichloromethane.
3. The method for synthesizing retinoic acid derivative Am580 according to claim 2, wherein the alkali in the third step is one of sodium hydroxide, potassium hydroxide, ammonia water, potassium carbonate and sodium carbonate.
4. The method for synthesizing retinoic acid derivative Am580 according to claim 1, wherein the reaction temperature in the second step is 110 ℃.
5. The method for synthesizing retinoic acid derivative Am580 according to claim 2, wherein the acid solution in the fifth step is any one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid solution.
6. The method for synthesizing retinoic acid derivative Am580 according to claim 1, wherein the organic solvent in the fifth step is any one of tetrahydrofuran, ethyl acetate, dichloromethane, chloroform and toluene.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661259A1 (en) * | 1994-01-03 | 1995-07-05 | Bristol-Myers Squibb Company | Substituted (5,6)-dihydronaphthalenyl compounds having retinoid-like activity |
| EP1541549A1 (en) * | 2003-12-12 | 2005-06-15 | Exonhit Therapeutics S.A. | Tricyclic hydroxamate and benzaminde derivatives, compositions and methods |
| US7321064B1 (en) * | 2007-03-08 | 2008-01-22 | Cedarburg Pharmaceuticals, Inc. | Preparation of amides of retinoic acid via mixed anhydride and mixed carbonate intermediates |
| WO2019169270A1 (en) * | 2018-03-01 | 2019-09-06 | Dawn Scientific Pharmaceuticals, Llc | Bexarotene derivatives and their use in treating cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661259A1 (en) * | 1994-01-03 | 1995-07-05 | Bristol-Myers Squibb Company | Substituted (5,6)-dihydronaphthalenyl compounds having retinoid-like activity |
| EP1541549A1 (en) * | 2003-12-12 | 2005-06-15 | Exonhit Therapeutics S.A. | Tricyclic hydroxamate and benzaminde derivatives, compositions and methods |
| US7321064B1 (en) * | 2007-03-08 | 2008-01-22 | Cedarburg Pharmaceuticals, Inc. | Preparation of amides of retinoic acid via mixed anhydride and mixed carbonate intermediates |
| WO2019169270A1 (en) * | 2018-03-01 | 2019-09-06 | Dawn Scientific Pharmaceuticals, Llc | Bexarotene derivatives and their use in treating cancer |
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