CN104693058A - Capryloyl aniline acid methyl ester preparation method - Google Patents
Capryloyl aniline acid methyl ester preparation method Download PDFInfo
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- CN104693058A CN104693058A CN201310648749.2A CN201310648749A CN104693058A CN 104693058 A CN104693058 A CN 104693058A CN 201310648749 A CN201310648749 A CN 201310648749A CN 104693058 A CN104693058 A CN 104693058A
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Abstract
The invention provides a preparation method of capryloyl aniline acid methyl ester. The method is capable of improving preparation of intermediates and products, the method has the advantages of simple treatment, low cost, no high temperature requirement, mild reaction condition, high yield and adaption of industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, be specifically related to a kind of decoyl Phenyl Acetic Acid (Powder） methyl esters preparation method.
Background technology
Vorinostat Vorinostat is the new antitumor drug of first inhibition of histone deacetylase in the world, and on October 6th, 2006, U.S.'s listing, had obvious synergy with other tumour medicine drug combination.Vorinostat has significant antitumor action to multiple solid tumor, at present for the clinical trial well afoot of multinomial indication.
Vorinostat is a histone deacetylase (HDAC) inhibitor.Regulate and control by Cell differentiation inducing activity, blocking-up cell cycle, inducing cell and play a role.Treatment increases the weight of, continue and recur or treat rear invalid cutaneous T cell lymphomas (CTCL, a kind of non-Hodgkin lymphoma) by two kinds of systemic medication.CTCL is a kind of T cell cancer of cutaneous white blood cell types.
In vitro study shows, Vorinostat can suppress HDAC 1, HDAC2 and HDAC 3(I type at nanomolar concentrations (IC50<86nmol/L)) and HDAC 6(II type) enzymic activity.In some cancer cells, suppress excessive HDAC enzyme can activate the gene of normal cell activity.Vorinostat reduces HDAC activity and contributes to the gene activation slowing down or stop growth of cancer cells.
Compound patent WO/1993/007148, discloses Vorinostat compound structure.Its chemical structural formula is:
The multiplex suberic acid of current synthetic method intramolecular dehydration under diacetyl oxide effect generates suberic acid acid anhydride, obtains suberic acid list anilide with aniline in ethyl acetate in 0 DEG C of open loop amidation, then methanol esterification and oxammonium hydrochloride aminolysis, can obtain antitumour drug Vorinostat.
The synthetic route of Vorinostat is more, the synthetic route mainly containing bibliographical information has three: one, Breslow R, Marks PA, Rifkind BA etc. are at Novel potent inducers of terminal differentiation andmethods of use thereof([P] .WO:9307148.1993.04.15) middle report, suberoyl chlorine and aniline, oxammonium hydrochloride and KOH solution, " one kettle way " feeds intake, be separated by chromatographic column afterwards and obtain product, yield only has 15-30%, yield is very low, and cost is higher simultaneously, is not suitable for suitability for industrialized production, they are two years old, Stowell JC, Huot RI, van Voast L etc. are at The synthesis of N-hydroxy-N '-phenyloctanediamide and its inhibitory effecton proliferation of AXC rat prostate cancer cells([J] .J Med Chem, 1995, 38 (9): 1411-1413.) report in, suberic acid first reacts under the high temperature of 190 DEG C with aniline, and then use KOH solution process, obtained suberic acid list anilide, again by ion exchange resin esterification, obtain suberic acid list anilide mono-methyl, again with sodium methylate, oxammonium hydrochloride and methyl alcohol are obtained by reacting product, total recovery nearly 35%, but intermediate reaction touches high temperature (190 DEG C), not be well suited for industrialized production operation, they are three years old, Wang Yi. Yang Jiannan. Chen Lin. Sun Qiang etc. (derive from magazine pharmaceutical synthesis in " synthesis of antitumour drug Vorinostat ", 2011, 188-190.) middle report, mixed acid anhydride is generated with suberic acid and Vinyl chloroformate reaction, suberic acid list anilide is generated again with aniline reaction, generate mixed acid anhydride with reacting with isobutyl chlorocarbonate again, again with oxammonium hydrochloride, triethylamine is obtained by reacting Vorinostat in tetrahydrofuran (THF), but this method uses Vinyl chloroformate and isobutyl chlorocarbonate in operation, there is very strong irritating smell, suitability for industrialized production needs to carry out safe ventilation measure, otherwise are acid tests to the safety of operator.
To sum up in existing technology, preparation method's ubiquity yield of Vorinostat is low, cost is high, smell is strong, reaction high temperature etc. is unfavorable for the problems such as industrialized production.Wherein, the yield of decoyl Phenyl Acetic Acid (Powder） methyl ester intermediate III is the committed step affecting Vorinostat yield.
Summary of the invention
Preparation method's ubiquity yield for Vorinostat in prior art is low, cost is high, smell is strong, reaction high temperature etc. is unfavorable for the problems such as industrialized production, the object of the present invention is to provide a kind of preparation method of decoyl Phenyl Acetic Acid (Powder） methyl esters (intermediate III), it specifically comprises the steps:
Get suberic acid list anilide and tosic acid, be dissolved in methanol solvate, heating reflux reaction, be chilled to room temperature, remove solvent under reduced pressure, in residuum, add water or weak alkaline aqueous solution, with ethyl acetate or dichloromethane extraction, dry, filter, filtrate reduced in volume is to dry, crystallization solvent is added, stirring at room temperature 1h, suction filtration in residue deep yellow oily matter, filter cake is dried, and obtains off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters.
Described crystallization solvent consumption is 2-8 times of suberic acid list anilide quality.
Described crystallization solvent is the mixture of sherwood oil, sherwood oil and ethyl acetate, normal hexane, normal hexane and ethyl acetate mixture, normal heptane, normal heptane and ethyl acetate mixture.
Described crystallization solvent be the mixture of sherwood oil and ethyl acetate, normal hexane and ethyl acetate mixture, normal heptane and ethyl acetate mixture time, the amount of ethyl acetate is the 1/5-1/20 of mixture.
Suberic acid list anilide: tosic acid: methyl alcohol=1g:0.07g:2-20ml,
Suberic acid list anilide: tosic acid: methyl alcohol=1g:0.07g:10ml.
The amount adding water or alkaline aqueous solution after removing solvent under reduced pressure in residuum is 1-4 times of suberic acid list anilide quality.
Extraction solvent for use is ethyl acetate or methylene dichloride.
Extraction solvent for use is ethyl acetate.
Embodiment
Illustrate the present invention and beneficial effect thereof by the following examples, the apparent change that those of ordinary skill in the art do the present invention and modification are also contained within the present invention.
Embodiment 1
Suberic acid list anilide 100g and tosic acid 7g is dissolved in 400ml methyl alcohol, reflux 8h, be chilled to room temperature, remove solvent under reduced pressure, water 100ml is added in residuum, be extracted with ethyl acetate 3 times, each 100ml, combined ethyl acetate layer, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, sherwood oil and ethyl acetate mixtures 600ml is added in residue deep yellow oily matter, the amount of ethyl acetate is 1/10 of sherwood oil and ethyl acetate mixtures, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 87.6%.
Embodiment 2
Suberic acid list anilide 100g and tosic acid 7g is dissolved in 1000ml methyl alcohol, reflux 8h, be chilled to room temperature, remove solvent under reduced pressure, alkaline aqueous solution 300ml is added in residuum, be extracted with ethyl acetate 3 times, each 120ml, combined ethyl acetate layer, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, normal hexane and ethyl acetate mixture 400ml is added in residue deep yellow oily matter, ethyl acetate amount is 1/5 of normal hexane and ethyl acetate mixture, wherein sherwood oil and ethyl acetate mixtures PetroChina Company Limited. ether and ethyl acetate ratio are 10:1, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 89.6%.
Embodiment 3
Suberic acid list anilide 100g and tosic acid 7g is dissolved in 600ml methyl alcohol, reflux 8h, be chilled to room temperature, remove solvent under reduced pressure, alkaline aqueous solution 400ml is added in residuum, with dichloromethane extraction 3 times, each 40ml, merge organic phase, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, normal heptane and ethyl acetate mixture 800ml is added in residue deep yellow oily matter, the amount of ethyl acetate is 1/20 of normal heptane and ethyl acetate mixture, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 88.9%.
Embodiment 4
Be dissolved in 200ml methyl alcohol by suberic acid list anilide 100g and tosic acid 7g, reflux 8h, is chilled to room temperature, remove solvent under reduced pressure, in residuum, add water 400ml, with dichloromethane extraction 3 times, each 150ml, merges organic phase, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, to dry, adds normal heptane 400ml in residue deep yellow oily matter, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 88.5%.
Embodiment 5
Be dissolved in 600ml methyl alcohol by suberic acid list anilide 100g and tosic acid 7g, reflux 8h, is chilled to room temperature, remove solvent under reduced pressure, in residuum, add water 100ml, with dichloromethane extraction 3 times, each 40ml, merges organic phase, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, to dry, adds sherwood oil 800ml in residue deep yellow oily matter, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 88.9%.
Prepared by embodiment 6 Vorinostat
1) preparation of suberic acid acid anhydride (intermediate I)
In 500ml round-bottomed flask, add suberic acid 100g and aceticanhydride 120ml, heating reflux reaction 5h, is chilled to room temperature, remove solvent under reduced pressure, residuum is cooled to 0 DEG C, obtains faint yellow solid, filters, filter cake recrystallized from acetonitrile, obtains white crystals suberic acid acid anhydride, yield about 88.2%.
2) preparation of suberic acid list anilide (intermediate II)
Add in 400ml THF by suberic acid acid anhydride 100g ,-8 DEG C are stirred lower dropping aniline 65g, drip and finish, naturally rise to room temperature, stir 0.5h.Add 10% sodium hydroxide solution, be transferred to pH=12, stirring at room temperature 30min, suction filtration, filtrate is adjusted to pH=4 with 1mol/L hydrochloric acid, suction filtration, and filter cake washes rear drying with water, obtains white solid suberic acid list anilide, yield 80.2%.
3) preparation of decoyl Phenyl Acetic Acid (Powder） methyl esters (intermediate III)
Suberic acid list anilide 100g and tosic acid 7g is dissolved in 400ml methyl alcohol, reflux 8h, be chilled to room temperature, remove solvent under reduced pressure, water 100ml is added in residuum, be extracted with ethyl acetate 3 times, each 100ml, combined ethyl acetate layer, through washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, sherwood oil and ethyl acetate mixtures 600ml is added in residue deep yellow oily matter, the amount of ethyl acetate is 1/10 of sherwood oil and ethyl acetate mixtures, stirring at room temperature 1h, suction filtration, filter cake is dried, obtain off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters, yield 87.6%.
4) preparation of Vorinostat
Hydroxylamine chloride 52.8g adds in 500mL anhydrous methanol, and stirring at room temperature slowly adds sodium methylate 51.3g after dissolving, stir 0.5h, filter, in filtrate, add decoyl Phenyl Acetic Acid (Powder） methyl esters 100g, after 25 DEG C of stirring 16h, with sodium methylate control pH=9, stirring at room temperature 0.5h, suction filtration, filter cake washes with water, and the hydrochloric acid of filter cake 1mol/L is adjusted pH=7, after stirring 0.5h, suction filtration, filter cake washes with water, dry rear ethyl alcohol recrystallization, obtain white crystal, yield 90.5%.
Claims (9)
1. the preparation method of a decoyl Phenyl Acetic Acid (Powder） methyl esters, it is characterized in that, specifically comprise the steps: to get suberic acid list anilide and tosic acid, be dissolved in methanol solvate, heating reflux reaction, is chilled to room temperature, removes solvent under reduced pressure, water or weak alkaline aqueous solution is added in residuum, with ethyl acetate or dichloromethane extraction, dry, filter, filtrate reduced in volume is to dry, crystallization solvent is added, stirring at room temperature 1h, suction filtration in residue deep yellow oily matter, filter cake is dried, and obtains off-white color solid decoyl Phenyl Acetic Acid (Powder） methyl esters.
2. preparation method according to claim 1, is characterized in that, described crystallization solvent consumption be the 2-8 of suberic acid list anilide quality doubly.
3. preparation method according to claim 1 or 2, is characterized in that, described crystallization solvent is the mixture of sherwood oil, sherwood oil and ethyl acetate, normal hexane, normal hexane and ethyl acetate mixture, normal heptane, normal heptane and ethyl acetate mixture.
4. preparation method according to claim 3, it is characterized in that, described crystallization solvent be the mixture of sherwood oil and ethyl acetate, normal hexane and ethyl acetate mixture, normal heptane and ethyl acetate mixture time, the amount of ethyl acetate is the 1/5-1/20 of mixture.
5. preparation method according to claim 1, is characterized in that, suberic acid list anilide: tosic acid: methyl alcohol=1g:0.07g:2-20ml.
6. preparation method according to claim 5, is characterized in that, suberic acid list anilide: tosic acid: methyl alcohol=1g:0.07g:10ml.
7. preparation method according to claim 1, is characterized in that, the amount adding water or alkaline aqueous solution after removing solvent under reduced pressure in residuum be the 1-4 of suberic acid list anilide quality doubly.
8. preparation method according to claim 1, is characterized in that, extraction solvent for use is ethyl acetate or methylene dichloride.
9. preparation method according to claim 1, it is characterized in that, extraction solvent for use is ethyl acetate.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011097166A2 (en) * | 2010-02-02 | 2011-08-11 | Board Of Regents, The University Of Texas System | Combination therapy for treating cancer comprising an igf-1r inhibitor and an hdac inhibitor |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011097166A2 (en) * | 2010-02-02 | 2011-08-11 | Board Of Regents, The University Of Texas System | Combination therapy for treating cancer comprising an igf-1r inhibitor and an hdac inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| 刘连军: "新型组蛋白去乙酰化酶抑制剂前药的设计与合成研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
| 胡杨等: "伏立诺他的合成", 《中国医药工业杂志》 * |
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Application publication date: 20150610 |