CN112479918A - Synthetic method of retinoid derivative Am580 - Google Patents
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Abstract
The invention discloses a synthesis method of a retinoid derivative Am580, which comprises the following steps: stirring a solution of 2, 5-dimethylhexane-2, 5-diol 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 an intermediate 3, wherein the product is a white solid, and dissolving 2, 5-dichloro-2, 5-dimethylhexane in an organic solventIn the agent, AlCl is added3Adding the 2, 5-dichloro-2, 5-dimethylhexane and AlCl into the solution3Is 1:0.1-1:0.2, is heated to 100 ℃ and 120 ℃, is stirred for 16h, is quenched by 3M HCl, is extracted by normal hexane, and is decompressed and distilled to remove the solvent to obtain a product, namely a colorless oily intermediate 4. The invention has the beneficial effects that: the method has the advantages of high yield in each step, simple post-treatment and easy industrial production; the invention optimizes the reaction conditions and solvent system aiming at the Friedel-crafts reaction and the 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 a retinoid derivative Am580, and belongs to the technical field of medicine and health.
Background
The research on vitamin A metabolism pathway and action receptors in human body finds a series of lead compounds with biological activity, such as Retinoic acid (Retinoic acid) and Retinoic acid derivatives, and the like, 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 closer 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 of the all-trans retinoic acid limit the wide-range clinical use of the all-trans retinoic acid.
Since Am580 was synthesized by Kagechika et al in 1986, Am580 has received much attention from researchers due to its excellent and wide range of biological activities, such as treating skin diseases, psoriasis, modulating immune system, anticancer activity, and reducing the risk of cardiovascular and cerebrovascular diseases. At present, more scientific researchers focus on the work of further modification and activity evaluation of Am580, and the specific synthetic process route of Am580 is only rarely reported, so that the exploration of an efficient and reliable Am580 synthetic route has great significance for research and development and large-scale production of new drugs. The existing synthesis route is investigated, the original synthesis process is further improved and optimized, and reference is provided for large-scale production.
Am580 with the chemical name of 4- [ [ (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) carbonyl ] amino ] benzoic acid (1) and the structural formula thereof
Literature (arch. pharm. chem. life sci.2006,339,193-200.) and patents EP,1541549, WO,2019/169270 starting from 1,2,3, 4-tetrahydro-1, 1,4,4,6 pentamethylnaphthalene (4) by KMnO4Oxidizing, reacting with thionyl chloride to generate acyl chloride, condensing with methyl p-aminobenzoate, and removing methanol to obtain the product. 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 document (Chinese. J. chem.2010,28,1951-1956.) which reports that 2, 5-dimethyl-2, 5-hexanediol (2) is used as a raw material, and reacts with HCl under an acidic condition to produce 2, 5-dimethyl-2, 5-dichlorohexane (3), and then the 2, 5-dimethyl-2, 5-dichlorohexane is subjected to Friedel-crafts reaction with benzene to obtain a raw material (4), and then the above steps are repeated to obtain Am 580. The method has the advantages of simple and easily obtained raw materials, low yield and long reaction time when Friedel-crafts reaction and oxidation are carried out to generate the 5,5,8, 8-tetramethyl-5.6.7.8-tetrahydronaphthalene-2-carboxylic acid (5), and industrial production needs to be further optimized.
Disclosure of Invention
The invention aims to solve the problems, and provides a synthesis method of a retinoid derivative Am580, which avoids the complex post-treatment in the prior art and the use of a high-cost cyclization reaction catalyst; simplifies the post-treatment method, particularly optimizes the catalytic system of the cyclization reaction, improves the reaction yield, reduces the environmental pollution, saves the production cost and is more beneficial to industrialized mass production.
The purpose of the invention can be realized by the following technical scheme: a method for synthesizing a retinoid derivative Am580, comprising the following steps:
the method comprises the following steps: chlorination reaction
Stirring a solution of 2, 5-dimethylhexane-2, 5-diol 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, 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 AlCl3Adding the 2, 5-dichloro-2, 5-dimethylhexane and AlCl into the solution3The molar ratio of the intermediate to the intermediate is 1:0.1-1:0.2, the mixture is heated to 100 ℃ and 120 ℃, stirred for 16h, quenched by 3M HCl, extracted by normal hexane, and decompressed and distilled to remove the solvent to obtain a product, namely a colorless oily intermediate 4;
step three: oxidation reaction
Adding an organic solvent, water and a base into a reaction vessel, and sequentially adding the intermediate 4 and the KMnO4Said intermediate 4 with a base and KMnO4The molar ratio of the intermediate to the intermediate is 1:1.5:3-1:2.5:5, heating to 90-110 ℃, stirring for reaction for 16 hours, cooling the reaction system to 10 ℃ by using an ice water bath, adding HCl, adjusting the pH value of the system to 1, extracting the product by using ethyl acetate, and distilling under reduced pressure to obtain a white solid intermediate 5;
step four: amidation reaction
Intermediate 5 was dissolved in SOCl at 0 deg.C2In (1), the SOCl2The volume amount of (1) is 10 times of the mass of the intermediate 5, 0.05-0.1ml DMF is added, the mixture is stirred for 0.5h, and SOCl is removed in vacuum2Dissolving crude acyl chloride in organic solvent, adding 4-ethyl aminobenzoate and DMAP, wherein the molar ratio of DMAP to 4-ethyl aminobenzoate is 1:10-1:12, heating the mixture at 60 ℃ for 2h under stirring, extracting with organic solvent, sequentially adding HCl and saturated NaHCO into an organic layer3Washing with saturated NaCl, drying, filtering, vacuum distillingObtaining 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 15h under reflux, cooling to room temperature, distilling under reduced pressure to remove the solvent, adding the following organic solvent and water, adjusting the pH value 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 retinoid derivative Am 580;
the specific synthetic route of the retinoid derivative Am580 is as follows:
preferably, the organic solvent in step three 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, the acid solution in the fifth step is any one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid solution.
Preferably, in the fifth step, the organic solvent 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 high yield in each step, simple post-treatment, mild reaction conditions and easy industrial production.
2. The invention optimizes the reaction conditions and solvent system aiming at the Friedel-crafts reaction and the oxidation reaction, and is more beneficial to industrial production.
Drawings
In order to facilitate understanding for those skilled in the art, the present invention will be further described with reference to the accompanying drawings.
FIG. 1 is a liquid chromatogram of retinoid derivative Am580 according to the invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: synthesis of Compound 3
Chlorination reaction
A solution of 2, 5-dimethylhexane-2, 5-diol (2) (14.6g, 0.10mol) in concentrated HCl was stirred for 30 min. Then HCl gas is introduced into the system for reaction for 3 hours. Then stirred until the system became a two phase mixture, cooled to room temperature, filtered to give a light pink solid, washed with water, recrystallized from methanol and filtered to give compound 3 as a white solid (17.02g, 93.1%).
Example 2: preparation of Compound 4
Friedel-crafts reaction
2, 5-dichloro-2, 5-dimethylhexane (3) (3g, 0.016mol) was dissolved in dry toluene (80 mL). Mixing AlCl3(0.22g, 1.64mmol) was added to the solution, heated to 110 deg.C, stirred for 16h, quenched with 3M HCl (10mL), extracted with hexane (50 mL. times.3), combined organic phases and washed with saturated brine, anhydrous Na2SO4Drying and removal of the solvent by distillation under reduced pressure gave the product as a colourless oil (3.06g, 92.6%).
Example 3: preparation of Compound 5
Oxidation reaction
Chlorobenzene (80ml), H, was added to a three-necked round bottom flask (250ml)2O (20ml) and NaOH (1.2 g, 29.6 mmol). Compound 4(3.00g, 14.8mmol) and KMnO were added in this order4(9.36g, 59.2 mmol). Heating and stirring at 100 deg.C for 16h, cooling to 10 deg.C in ice-water bath, adding HCl (6N, 100mL) to adjust pH to 1, extracting with ethyl acetate (3X 100mL), and adding Na2SO4Drying, filtering, and distilling under reduced pressure to obtain white pigmentColor solid 5(2.17g, 63.3%).
Example 4: process for producing Compound 6
Amidation reaction
Compound 5(2.0g, 8.6mmol) was dissolved in SOCl at 0 deg.C2(20 mL). A few drops of DMF were added, stirred for 0.5h and SOCl removed in vacuo2And the crude acid chloride was dissolved in pyridine (50 mL). Ethyl 4-aminobenzoate (1.5g, 9.9mmol) and DMAP (0.10mg, 0.86mmol) were added and the mixture was heated at 60 ℃ for 2h with stirring. Then quenched with water, extracted with ethyl acetate, and the organic layer was successively washed with HCl (2mol/L), saturated NaHCO3Washed with saturated NaCl and then with anhydrous Na2SO4Drying, filtration and distillation under reduced pressure gave a white solid (2.45g, 78.0%).
Example 5: process for producing Compound 1
Hydrolysis reaction
A round-bottom flask was charged with Compound 6(1.0g, 2.74mmol), MeOH (40mL), and KOH (0.62g, 11 mmol). The reaction mixture was stirred under reflux for 15h, cooled to room temperature, the solvent was distilled off under reduced pressure, ethyl acetate (30ml) and water (20ml) were added, the pH was adjusted to acidity with HCl (6N) solution, the organic phase was separated, washed successively with saturated brine, Na2SO4Dried, filtered and the solvent distilled off under reduced pressure to give a white solid (0.78g, 81.2%);
the specific synthetic route of the retinoid derivative Am580 is as follows:
test example 1
The carbon spectrum of the NMR spectrum of Am580 obtained in example 5 was measured as follows:
1H 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 measured liquid phase data for Am580 obtained in example 5 are as follows:
liquid phase purity: 96.7 percent.
Note: chromatographic conditions
A chromatographic column: waters X Bridge C18 reverse phase chromatography column: 50mm 4.6mm 3.5 um; mobile phase: a: water (0.01mol/L NH4HCO3) B: acetonitrile; elution gradient: b: 0-1.6min, 5% -95%, 1.6-2.5min, 95%; flow rate: 2 ml/min; column temperature: at 40 ℃.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise forms 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 utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (6)
1. A synthetic method of a retinoid derivative Am580 is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: chlorination reaction
Stirring a solution of 2, 5-dimethylhexane-2, 5-diol 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, 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 the solution to 100 ℃ and 120 ℃, stirring the solution for 16 hours, quenching the reaction by using 3M HCl, extracting the solution by using n-hexane, and removing the solvent by reduced pressure distillation to obtain a product, namely a colorless oily intermediate 4, wherein the molar ratio of the 2, 5-dichloro-2, 5-dimethylhexane to the AlCl3 is 1:0.1-1: 0.2;
step three: oxidation reaction
Adding an organic solvent, water and a base into a reaction vessel, and sequentially adding the intermediate 4 and the KMnO4Said intermediate 4 with a base and KMnO4The molar ratio of the intermediate to the intermediate is 1:1.5:3-1:2.5:5, heating to 90-110 ℃, stirring for reaction for 16 hours, cooling the reaction system to 10 ℃ by using an ice water bath, adding HCl, adjusting the pH value of the system to 1, extracting the product by using ethyl acetate, and distilling under reduced pressure to obtain a white solid intermediate 5;
step four: amidation reaction
Intermediate 5 was dissolved in SOCl at 0 deg.C2In (1), the SOCl2The volume of (2) is 10 times of the mass of the intermediate 5, 0.05ml-0.1ml DMF is added, the mixture is stirred for 0.5h and SOCl is removed in vacuum2Dissolving crude acyl chloride in organic solvent, adding 4-ethyl aminobenzoate and DMAP, wherein the molar ratio of DMAP to 4-ethyl aminobenzoate is 1:10-1:12, heating the mixture at 60 ℃ for 2h under stirring, extracting with organic solvent, sequentially adding HCl and saturated NaHCO into an organic layer3Washing 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 15h under reflux, cooling to room temperature, distilling under reduced pressure to remove the solvent, adding an organic solvent and water, adjusting the pH value to be acidic by using an acid solution, separating the organic phase, and distilling under reduced pressure to remove the solvent to obtain a white solid target product 1, namely a retinoid derivative Am 580;
the specific synthetic route of the retinoid derivative Am580 is as follows:
2. the synthesis method of the retinoid Am580 according to claim 1, wherein the organic solvent in step III is one of toluene, chlorobenzene, chloroform and dichloromethane.
3. The method for synthesizing the retinoid Am580 according to claim 2, wherein the base in step three is one of sodium hydroxide, potassium hydroxide, ammonia water, potassium carbonate and sodium carbonate.
4. The method for synthesizing the retinoid derivative Am580 according to claim 1, wherein the reaction temperature in step two is 110 ℃.
5. The method for synthesizing the retinoid 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.
6. The method for synthesizing the retinoid Am580 according to claim 1, wherein the organic solvent in step five is any one of tetrahydrofuran, ethyl acetate, dichloromethane, trichloromethane and toluene.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115646505A (en) * | 2022-11-10 | 2023-01-31 | 天和药业股份有限公司 | Method for preparing aminomethylbenzoic acid by catalytic oxidation of nano-carrier |
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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Patent 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115646505A (en) * | 2022-11-10 | 2023-01-31 | 天和药业股份有限公司 | Method for preparing aminomethylbenzoic acid by catalytic oxidation of nano-carrier |
| CN115646505B (en) * | 2022-11-10 | 2023-12-15 | 天和药业股份有限公司 | Method for preparing aminomethylbenzoic acid by catalytic oxidation of nano-carrier |
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