CN1429807A - Synthesis of antitumour medicine bexarotene - Google Patents
Synthesis of antitumour medicine bexarotene Download PDFInfo
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- CN1429807A CN1429807A CN 01145585 CN01145585A CN1429807A CN 1429807 A CN1429807 A CN 1429807A CN 01145585 CN01145585 CN 01145585 CN 01145585 A CN01145585 A CN 01145585A CN 1429807 A CN1429807 A CN 1429807A
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- bexarotene
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- tetrahydrochysene
- pentamethyl
- naphthyl
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Abstract
A process for synthesizing the antineoplastic medicine "bexarotene" features use of the nucleophilic addition-dewatering reaction instead of original witting reaction. Its advantages are less consumption of phosphorus compound and no environmental pollution.
Description
Technical field
The present invention relates to organic compound preparation technology and improve, the synthesis technique of the new drug Targretin1 (bexarotene) of more specifically saying so improves.
Background technology
Bexarotene'sChemistry is by name: 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) vinyl] phenylformic acid is that on January 15th, 2000 is in U.S.'s Initial Public Offering by the development of U.S. Ligand drugmaker.Trade(brand)name: Targretin 1.
Tretinoin is used for lung cancer therapy, has expanded traditional drug categories, and steroid/thryoid receptor belongs to same superfamily in its acceptor and the cell.This receptor is the transcription factor that relies on part, is divided into two kinds of subgroups: tretinoin acceptor (RAR) and tretinoin X acceptor (RXR).The medicine bexarotene of Ligand company has the tretinoin acceptor and select to give birth to, and the ratio of its RXR and RAR selectivity is above 50 times.And RXR can form heterodimer with multiple acceptor (as tieing up D acceptor, thryoid receptor, tretinoin acceptor RAR, reaching peroxisome Proliferator-activated receptor PPAR), expression that just can controlling gene after they are activated, thereby control cytodifferentiation and hyperplasia.In experiment in vitro, this medicine can be controlled the growth of some tumor cell line; In the experiment, this medicine can lure that mastadenoma disappears in animal model; In vivo, this medicine plays regulating cell differentiation and propagation, can stop clonal growth, but it is big to be not so good as the effect of RAR specificity tretinoin.These are confirmed in the experiment in vivo and vitro of a kind of thing of xenogenesis of department of human head and neck squama cancer; In addition, clinical preceding experiment shows that also can kill 90% tumour cell to mouse mammary cancer, similar to the effect of tamoxifen, 72% tumour disappears fully; In addition, this medicine also has killing action to the tumour cell of cancer of the stomach.
1997, Miller etc. reported the I phase of the first Application bexartene of solid tumor have been tested, to check clinical the being subjected to property and the pharmacokinetics of relying of this medicine.52 routine patients comprise that 20 routine patients with lung cancer have participated in this oral bexanotene research, and wherein, cutaneous T cell lymphoma curative effect the best has 2 examples that significant curative effect is arranged among the 9 routine patients.Other have two explorations studies show that this medicine to early stage and late period intractable cutaneous T cell lymphoma effective: in first research, after at least two kinds of reactionless early stage cutaneous T cell lymphoma patients that maybe can not tolerate of methods of treatment are taken this medicine 300mg/m2/d, have 15 examples (54%) to obtain all or part of reaction among the 28 routine patients, and more the high dose group reactivity is 10/15 example (67%); In second research, to the invalid cutaneous T cell lymphoma patient in late period of 94 routine at least a systemic treatment methods, 56 examples accept have 25 examples (45%) to obtain reaction behind this medicine 300mg/m2/d, and other 35 examples are accepted higher dosage, have 21 examples (55%) to obtain reaction.
The method of the synthetic bexarotene of bibliographical information (Boehem M.F.Zhang L.et al.J.Med.Chem.1994,37,2930-2941, Dawson et al US5466861), be with 2,5-two chloro-2,5-dimethylhexane 2 and toluene obtain 1,2,3 through Fu-Ke reaction, 4-tetrahydrochysene-1,1,4,4, behind the 6-pentamethyl-naphthalene 3, by another Fu-Ke reaction and right-(methoxycarbonyl) Benzoyl chloride react 4-[(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] methyl benzoate 4, with the Wittig reaction ketone carbonyl is converted into two keys then, ester hydrolysis reaction gets 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) vinyl] phenylformic acid 1 promptly is bexarotene (reaction formula 1 is as follows).
But; the Wittig that wherein relates to reaction, severe reaction conditions is as, strict protection of inert gas; strict anhydrous solvent processing etc.; be difficult to operation in industrialized process, and use triphenyl phosphorus, atom is uneconomical in the reaction; produce a large amount of solid waste; comprise phosphorus compound, during suitability for industrialized production environment is caused very big pollution, this was difficult to accept in today that environment protection comes into one's own day by day.These shortcomings are that this method is difficult to overcome, and therefore, need to develop industrial superior preparation method.
Summary of the invention
The purpose of this invention is to provide one and can reduce environmental pollution, be easy to the convenient road map of the synthetic bexarotene of industrialization operation.
The present invention implements by following steps:
According to literature method (Boehem M.F.Zhang L.et al.J.Med.Chem.1994,37,2930-2941), can prepare compound easily, 4-[(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] phenylformic acid 6 (reaction formula 2 is as follows).
By grignard reagent the ketone carbonyl of compound 6 is carried out nucleophilic addition(Adn), a tertiary alcohol 7, reaction conditions is: temperature-20-20 ℃, preferably 0 ℃; Solvent can be ether, tetrahydrofuran (THF), glycol dimethyl ether; Nucleophilic reagent can be CH
3MgI, CH
3MgBr, CH
3MgCl, CH
3Li; Reaction times is 10-24 hour.Post-treating method: in reaction mixture impouring frozen water, add 20% dilute hydrochloric acid acidifying, with solvent as extractions such as ether, ethyl acetate, methylene dichloride.Na
2SO
4Or the MgSO drying, filtration, concentrated, petroleum ether-ethyl acetate recrystallization get product 7 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid (reaction formula 3 is as follows).
Get compound 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] behind the phenylformic acid 7, to the tertiary alcohol to be dehydrated into the alkene method more, the method of bibliographical information refluxes as: tosic acid-benzene or the ordinary method of 50% sulfuric acid-hexane two-phase dehydration reaction is not fine for our substrate result, our application method: in appropriate solvent, as: benzene, methylene dichloride, chloroform, acetone, wherein, benzene, methylene dichloride is preferred, adds substrate, tosic acid is made dewatering agent, in suitable temperature, as: room temperature-50 ℃, preferred room temperature, stir just can be clean obtain final product 1, i.e. bexarotene.Present method has mild condition, easy handling, yield height, makes things convenient for the economic dispatch advantage.Best condition is: in benzole soln or dichloromethane solution, stirring at room 2 hours gets product.Aftertreatment: filtration, washing, NaCl wash, drying, concentrated; Perhaps direct filtration, concentrate; Petroleum ether-ethyl acetate recrystallization (reaction formula 4 is as follows).
Advantage of the present invention:
The present invention have reaction easy handling, mild condition, atom economy, environmental pollution seldom, the yield height, be convenient to suitability for industrialized production and synthetic route cheaply, the condition that has solved literature method is difficult to control, contaminate environment, shortcoming that cost is high, thereby the novel method of a preparation bexarotene is provided.
Each compound of present method gained, by
1H-NMR, MS, IR, ultimate analysis are identified.The gained final product
1H-NMR, MS, IR, ultimate analysis, fusing point all and bibliographical information 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) vinyl] benzoic analytical data unanimity.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but the present invention is not done any restriction.
Embodiment 1:
The first step: under the nitrogen protection, magnesium rod 6.38 grams inject 110 milliliters of anhydrous diethyl ethers; under the ice bath, drip 16.55 milliliters of methyl iodide, stir; make the magnesium rod dissolving, drip compound 4-[(3,5; 5,8,8-pentamethyl--5; 6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] phenylformic acid 630 grams are dissolved in the solution of 300 milliliters of anhydrous diethyl ethers; back stirred overnight at room temperature; after the TLC detection reaction finished, in reaction mixture impouring frozen water, being acidified to PH with dilute hydrochloric acid was 1-2; layering; water merges organic layer with ethyl acetate or extracted with diethyl ether, washing; again with saturated common salt washing, anhydrous Na
2SO4 or MgSO4 drying are filtered, and after steaming desolventizes, get 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid 7 23 grams.
The data white solid of compound 7,220 ℃ of fusing points.
1HNMR (400MHz): 1.26 (s, 3H), 1.27 (s, 3H), 1.33 (s, 6H), 1.70 (s, 4H), 1.92 (s, 6H), 7.00 (s, 1H), 7.42 (d, J=8.3Hz, 2H), 7.55 (s, 1H), 8.03 (d, J=8.5Hz, 2H) .MS:366 (M-), 351 (base), 333,245,165,149.
Second step: get compound 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid 710 grams, be dissolved in 30 milliliters of dry-out benzene, add tosic acid 3 grams, stirring at room 2-3 hour, after the TLC detection reaction finishes, add ethyl acetate, washing, saturated common salt washing, Na
2SO
4Or MgSO
4Drying is filtered, and after steaming desolventizes, gets product 8 grams.
The data of compound 1: MP:230～232 ℃ (literature value: 234 ℃).1HMNR(400MHz)：1.28(s，6H)，131(s，6H)，1.70(s，4H)，1.95(s，3H)，5.35(s，1H)，5.84(s，1H)，7.09(s，1H)，7.14(s，1H)，7.38(d，J＝7.8Hz，2H)，8.03(d，J＝8.3Hz，2H).MS：348(M+)，333(base)，303，147。
Embodiment 2:
The solvent anhydrous diethyl ether of the first step reaction is changed to anhydrous tetrahydro furan, and other operations are same as embodiment 1.
Embodiment 3:
The solvent dry-out benzene in second step is changed to anhydrous methylene chloride, and other operations are same as embodiment 1.
Embodiment 4:
The solvent dry-out benzene in second step is changed to ethyl acetate, and other operations are same as embodiment 1.
Embodiment 5:
The first step: under the nitrogen protection, compound 4-[(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] phenylformic acid 6 20 grams, be dissolved in 200 milliliters of anhydrous diethyl ethers, under the ice bath, drip CH
3Li reagent, 72 milliliters (diethyl ether solution of 5%) is after dropwising, stirred overnight at room temperature, after the TLC detection reaction finished, in reaction mixture impouring frozen water, being acidified to PH with dilute hydrochloric acid was 1-2, layering, water merges organic layer with ethyl acetate or extracted with diethyl ether, washes with water, again with saturated common salt washing, anhydrous Na
2SO
4Or MgSO
4Drying is filtered, and after steaming desolventizes, gets 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid 716.5 grams.
Second step: be same as embodiment 1 or 3 or 4.
Embodiment 6:
The solvent anhydrous diethyl ether of embodiment 5 the first steps reaction is changed to anhydrous tetrahydro furan, and other operations are same as embodiment 5
Claims (5)
1. one kind by 2,5-two chloro-2, and 5-dimethylhexane and toluene are through Friedel-Crafts reaction, make intermediate 4-[(3,5,5 through a Friedel-Crafts reaction and right-(methoxycarbonyl) Benzoyl chloride reaction again, 8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] synthesis of antitumour medicine bexarotene of phenylformic acid (6), be characterised in that intermediate 4-[(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) carbonyl] phenylformic acid (6) carries out nucleophilic addition(Adn) to its ketone carbonyl by grignard reagent and gets 4-[1-hydroxyl-1-(3,5,5 in the presence of nucleophilic reagent, 8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid (7), compound 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid (7) in the presence of dewatering agent, carry out dehydration reaction in the certain temperature solvent and get bexarotene.
2. synthesis of antitumour medicine bexarotene according to claim 1 is characterized in that grignard reagent is ether, THF, glycol dimethyl ether to the solvent that the ketone carbonyl of (6) carries out nucleophilic addition, and nucleophilic reagent is CH
3MgI, CH
3MgBr, CH
3MgCl, CH
3Li.
3. synthesis of antitumour medicine bexarotene according to claim 1 is characterized in that grignard reagent carries out nucleophilic addition to the ketone carbonyl of (6) temperature for-20-20 ℃, is preferably 0 ℃, and the reaction times is 10-24 hour.
4. synthesis of antitumour medicine bexarotene according to claim 1 is characterized in that compound 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid is in the presence of the tosic acid at dewatering agent, reaction solvent is a benzene, methylene dichloride, chloroform, acetone.
5. synthesis of antitumour medicine bexarotene according to claim 1 is characterized in that compound 4-[1-hydroxyl-1-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] phenylformic acid is in the presence of the tosic acid at dewatering agent, temperature of reaction is a room temperature-50 ℃.
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| CN 01145585 CN1205166C (en) | 2001-12-29 | 2001-12-29 | Synthesis of antitumour medicine bexarotene |
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|---|---|---|---|
| CN 01145585 CN1205166C (en) | 2001-12-29 | 2001-12-29 | Synthesis of antitumour medicine bexarotene |
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| CN1429807A true CN1429807A (en) | 2003-07-16 |
| CN1205166C CN1205166C (en) | 2005-06-08 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100434068C (en) * | 2004-12-30 | 2008-11-19 | 天津药物研究院 | Bexarotene gel and its preparation method |
| WO2011141928A1 (en) * | 2010-05-11 | 2011-11-17 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure bexarotene |
| CN106146313A (en) * | 2015-04-15 | 2016-11-23 | 天津药物研究院有限公司 | The preparation method of bexarotene key intermediate |
| CN106572663A (en) * | 2014-03-10 | 2017-04-19 | 康奈尔大学 | Combination therapy for head and neck cancer |
| CN110105213A (en) * | 2019-06-06 | 2019-08-09 | 唐山师范学院 | The synthetic method of two octenoic acid -8- ester of one kind (E) -2- (naphthalene -1- oxygen methyl) -2- |
-
2001
- 2001-12-29 CN CN 01145585 patent/CN1205166C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100434068C (en) * | 2004-12-30 | 2008-11-19 | 天津药物研究院 | Bexarotene gel and its preparation method |
| WO2011141928A1 (en) * | 2010-05-11 | 2011-11-17 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure bexarotene |
| CN106572663A (en) * | 2014-03-10 | 2017-04-19 | 康奈尔大学 | Combination therapy for head and neck cancer |
| CN106146313A (en) * | 2015-04-15 | 2016-11-23 | 天津药物研究院有限公司 | The preparation method of bexarotene key intermediate |
| CN110105213A (en) * | 2019-06-06 | 2019-08-09 | 唐山师范学院 | The synthetic method of two octenoic acid -8- ester of one kind (E) -2- (naphthalene -1- oxygen methyl) -2- |
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| Publication number | Publication date |
|---|---|
| CN1205166C (en) | 2005-06-08 |
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