CN106146313A - The preparation method of bexarotene key intermediate - Google Patents

The preparation method of bexarotene key intermediate Download PDF

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Publication number
CN106146313A
CN106146313A CN201510180812.3A CN201510180812A CN106146313A CN 106146313 A CN106146313 A CN 106146313A CN 201510180812 A CN201510180812 A CN 201510180812A CN 106146313 A CN106146313 A CN 106146313A
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pentamethyl
chloride
bexarotene
reaction
yield
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赵世明
李玲
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Abstract

The present invention is the preparation method of key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalene) methoxyl group] essence of Niobe (5) about PTS bexarotene.The method of the present invention is with intermediate 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (4) directly with chlorinating agent, aluminum chloride and the dichloromethane equal solvent such as commercially available industrial chemicals terephthalic acid monomethyl ester, thionyl chloride or oxalyl chloride, single step reaction i.e. obtains intermediate (5).

Description

The preparation method of bexarotene key intermediate
Technical field
The present invention relates to the preparation method of a kind of PTS bexarotene key intermediate
Technical background
Bexarotene (Bexarotene) is the new antitumor drug developed by Ligand drugmaker of the U.S., its Trade nameObtain FDA approval in January, 2000 to list in the U.S..Calendar year 2001 is in Europe city Field is approved listing.
This medicine optionally combines and activates retinoid X receptor (RXR), promotes RXR and multiple receptor [such as: retinoid receptor (RAR), vitamin D receptor (VDR) and peroxisome proliferator-activated Receptor (PPAR) etc.] form heterodimer, thus controlling gene is expressed and the differentiation hypertrophy of cell.At present, This medicine is mainly used in treating recalcitrant dermal T-cell lymphoma clinically.
The chemical structural formula of bexarotene:
Chemical name: 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl-2-naphthyl) vinyl] benzoic acid
Patent US5466861 and document J.Med.Chem.1994 abroad, 37 (18): 2930～2941, J.Med.Chem.1995, all reports the synthetic method of bexarotene in 38 (17): 3368～3383.With 2,5- Dimethyl-2,5-hexanediol 2 is initiation material, through chlorination reaction generate 2,5-bis-chloro-2,5-dimethylhexane 3, Carry out Friedel-Crafts alkylated reaction with toluene, obtain 1, Isosorbide-5-Nitrae, 4,6-pentamethyl-1,2,3,4-tetra- Hydrogenated naphthalene 4,4 with methoxycarbonyl group Benzenecarbonyl chloride. condensation reaction is obtained 4-[(3,5,5,8,8-pentamethyls -5,6,7,8-tetrahydrochysene-2-naphthalenes) methoxyl group] essence of Niobe 5, then obtained by Wittig reaction 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalenes) vinyl] essence of Niobe 6, then by hydrolysis Reaction obtains 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl-2-naphthyl) vinyl] benzoic acid 1 (shellfish Bimbisara spit of fland).
In document J.Org.Chm.2001,66 (17): 5772～5782 synthetic route reported, only centerings Method when mesosome 5 prepares 6 changes, and uses methyl grignard reagent, by intermediate 5 methoxy acyl group Chelation, then by benzene methanesulfonic acid dehydration obtain 6.Other reactions steps are unchanged.
The route of Chinese patent CN1429807A is will abroad to report the last two step exchange orders of route, first will Intermediate 5 hydrolysis obtains 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalene) carbonyl] benzoic acid first Acid, then form dehydration after the tertiary alcohol with form reagent reacting and obtain end product bexarotene.
In above three synthetic routes, the synthetic method as key intermediate 5 all uses intermediate 4 with right Methoxycarbonyl group Benzenecarbonyl chloride. condensation reaction prepares.
And very active to methoxycarbonyl group Benzenecarbonyl chloride. chemical property, should not place for a long time, therefore without commercially available product Product, general employing is now used existing system, terephthalic acid monomethyl ester is prepared by chlorination reactions such as toxic articles phosphorus pentachlorides.
Due to very active to the chemical property of methoxycarbonyl group Benzenecarbonyl chloride., process after the reaction or Long contact time Causing decomposition rotten during air, side reaction when making intermediate 4 prepare 5 is more, not only reaction yield low (70%), And the purity difference of product 5.As can be seen here, literature method not only needs to increase by a step to methoxycarbonyl group Benzenecarbonyl chloride. Preparation, and reaction yield is low, product purity is poor, so the production cost of bexarotene and refined can be increased The difficulty of purification, is unfavorable for that industry is big and produces.
Summary of the invention
The present invention is directed to bexarotene key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2- Naphthalene) methoxyl group] problem present in essence of Niobe 5 preparation technology, through substantial amounts of test and improvement repeatedly Research, achieves and is surprisingly found that, it was found that a kind of raw material is easy to get, process route is simple, it is adaptable to industrialization Big production prepares 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalene) methoxyl group] essence of Niobe 5 Method.
The method of the present invention is by direct for intermediate 4 and commercially available industrial chemicals terephthalic acid monomethyl ester, thionyl chloride (SOCl2) or oxalyl chloride ((COCl)2) etc. chlorinating agent, aluminum chloride and dichloromethane equal solvent, a step is anti- Should i.e. obtain bexarotene key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalene) first Epoxide] essence of Niobe 5.
The method of the present invention not only simplify reactions steps, raw material is easy to get, reaction condition gentle, and reacts receipts Rate is up to 95% (former literature method yield 70%), product purity >=98%, has also sliced off in literature method for surely Determine the chemical reagent nitromethane hypertoxic, explosive of reactant.Reduce production cost, simplify production technology, It is particularly suitable for industrialized great production.
The chlorinating agent used in the inventive method can be thionyl chloride (SOCl2), oxalyl chloride ((COCl)2) etc..
The solvent used in the inventive method can be dichloromethane, chloroform, dichloroethanes, toluene, second Acetoacetic ester etc..
In the inventive method, the charge ratio (mol ratio) of each reactant is intermediate 4: terephthalic acid monomethyl ester: Chlorinating agent: aluminum chloride=1:0.8-1.5:0.8-1.5:1-4, preferably 1:1:1.2:2.7.
In the inventive method, reaction temperature is 0～100 DEG C, preferably 20～50 DEG C.
In the inventive method, the response time is 1～10 hour, preferably 3～5 hours.
Specific embodiment:
The present invention being explained in more detail with example below, the present invention is not limited in the content of following instance.
Example 1
By terephthalic acid monomethyl ester 120.0g (0.666mol), thionyl chloride 58.0ml (0.799mol), two Chloromethanes 1500ml and 134.5g (0.666mol) intermediate 4 adds in reaction bulb, stirs, then Add aluminum chloride 239.6g (1.798mol), add rear room temperature (20 DEG C) stirring reaction 1 hour.Then It is heated to reflux 3 hours, after concentrating under reduced pressure reactant liquor, cools down and be slowly added into frozen water stirring and dissolving, add acetic acid second Ester extracts, and separates organic layer, washes secondary, is dried with anhydrous sodium sulfate.Methanol is used after organic layer evaporated under reduced pressure Recrystallization, filters, is dried to obtain white crystalline powder 231.0g, fusing point: 141-143 DEG C, yield 95.3% (literary composition Offer J.Med.Chem.1994,37 (18): 2930～2941 report fusing points: 142-143 DEG C, yield: 72%).1H-NMR(CDCl3) δ: 1.29 (6H, s, CH3×2)；1.31 (6H, s, CH3×2)；1.72 (4H, S, CH2×2)；3.95 (3H, s, COCH3)；7.29 (1H, d, J=8Hz, aromatic H)；7.46 (1H, d-d, J=2and 8Hz, aromatic H)；(7.64 1H, d, J=2Hz, aromatic H)； 8.00 (2H, d, J=8Hz, aromatic H)；8.13 (2H, d, J=8Hz, aromatic H).
Example 2
By terephthalic acid monomethyl ester 180.0g (0.999mol), oxalyl chloride 85.2ml (0.999mol), trichlorine Methane 1500ml and 134.5g (0.666mol) intermediate 4 adds in reaction bulb, stirs, then adds Enter aluminum chloride 355.2g (2.664mol), in 30 DEG C of stirring reactions 1 hour after adding.Then it is heated to reflux 5 hours, after concentrating under reduced pressure reactant liquor, cool down and be slowly added into frozen water stirring and dissolving, add ethyl acetate extraction, Separate organic layer, wash secondary, be dried with anhydrous sodium sulfate.By recrystallizing methanol after organic layer evaporated under reduced pressure, Filter, be dried to obtain white crystalline powder 217.0g, fusing point: 141-143 DEG C, yield 89.5% (document J.Med.Chem.1994,37 (18): 2930～2941 report fusing points: 142-143 DEG C, yield: 72%).1H-NMR(CDCl3) δ: 1.29 (6H, s, CH3×2)；1.31 (6H, s, CH3×2)；1.72 (4H, S, CH2×2)；3.95 (3H, s, COCH3)；7.29 (1H, d, J=8Hz, aromatic H)；7.46 (1H, d-d, J=2and 8Hz, aromatic H)；(7.64 1H, d, J=2Hz, aromatic H)； 8.00 (2H, d, J=8Hz, aromatic H)；(8.13 2H, d, J=8Hz, aromatic H).
Example 3
By terephthalic acid monomethyl ester 96.3g (0.533mol), thionyl chloride 38.7ml (0.533mol), first Benzene 1500ml and 134.5g (0.666mol) intermediate 4 adds in reaction bulb, stirs, is subsequently adding Aluminum chloride 88.8g (0.666mol), in 50 DEG C of stirring reactions 1 hour after adding.Then 8 it are heated to reflux Hour, cool down and be slowly added into frozen water stirring and dissolving after concentrating under reduced pressure reactant liquor, add ethyl acetate extraction, point Go out organic layer, wash secondary, be dried with anhydrous sodium sulfate.By recrystallizing methanol after organic layer evaporated under reduced pressure, mistake Filter, be dried to obtain white crystalline powder 170.4g, fusing point: 141-143 DEG C, yield 70.3% (document J.Med.Chem.1994,37 (18): 2930～2941 report fusing points: 142-143 DEG C, yield: 72%).1H-NMR(CDCl3) δ: 1.29 (6H, s, CH3×2)；1.31 (6H, s, CH3×2)；1.72 (4H, S, CH2×2)；3.95 (3H, s, COCH3)；7.29 (1H, d, J=8Hz, aromatic H)；7.46 (1H, d-d, J=2and 8Hz, aromatic H)；(7.64 1H, d, J=2Hz, aromatic H)； 8.00 (2H, d, J=8Hz, aromatic H)；(8.13 2H, d, J=8Hz, aromatic H).
Example 4
By terephthalic acid monomethyl ester 120.0g (0.666mol), thionyl chloride 58.0ml (0.799mol), two Ethyl chloride 1500ml and 134.5g (0.666mol) intermediate 4 adds in reaction bulb, stirs, then Add aluminum chloride 239.6g (1.798mol), add rear room temperature (25 DEG C) stirring reaction 1 hour.Then It is heated to reflux 10 hours, after concentrating under reduced pressure reactant liquor, cools down and be slowly added into frozen water stirring and dissolving, add acetic acid Ethyl ester extracts, and separates organic layer, washes secondary, is dried with anhydrous sodium sulfate.First is used after organic layer evaporated under reduced pressure Alcohol recrystallization, filters, is dried to obtain white crystalline powder 224.5g, fusing point: 141-143 DEG C, yield 92.6% (document J.Med.Chem.1994,37 (18): 2930～2941 report fusing points: 142-143 DEG C, yield: 72%).
1H-NMR(CDCl3) δ: 1.29 (6H, s, CH3×2)；1.31 (6H, s, CH3×2)；1.72 (4H, S, CH2×2)；3.95 (3H, s, COCH3)；7.29 (1H, d, J=8Hz, aromatic H)；7.46 (1H, d-d, J=2 and 8Hz, aromatic H)；7.64 (1H, d, J=2Hz, aromatic H)； (8.00 2H, d, J=8Hz, aromatic H)；8.13 (2H, d, J=8Hz, aromatic H).

Claims (6)

1. prepare bexarotene key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrochysene-2-naphthalene) for one kind Methoxyl group] method of essence of Niobe (5), it is characterized in that with intermediate 1, Isosorbide-5-Nitrae, 4,6-pentamethyl-1,2,3,4- Tetrahydronaphthalene (4) is raw material, with commercially available industrial chemicals terephthalic acid monomethyl ester, chlorinating agent, aluminum chloride, Solvent, single step reaction i.e. obtain bexarotene key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetra- Hydrogen-2-naphthalene) methoxyl group] essence of Niobe (5),
Method the most according to claim 1, it is characterised in that described chlorinating agent is selected from thionyl chloride, grass Acyl chlorides.
Method the most according to claim 1, it is characterised in that described solvent is selected from dichloromethane, trichlorine Methane, dichloroethanes, toluene, ethyl acetate.
Method the most according to claim 1, it is characterised in that the charge ratio (mol ratio) of each reactant is Intermediate 4: terephthalic acid monomethyl ester: chlorinating agent: aluminum chloride=1:0.8-1.5:0.8-1.5:1-4, is preferably 1:1:1.2:2.7。
Method the most according to claim 1, it is characterised in that reaction temperature is 0～100 DEG C, is preferably 20～50 DEG C.
Method the most according to claim 1, it is characterised in that the response time is 1～10 hour, is preferably 3～5 hours.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994012880A2 (en) * 1992-11-25 1994-06-09 La Jolla Cancer Research Foundation Rxr homodimer formation and bridged bicyclic aromatic compounds and their use in modulating gene expression
CN1429807A (en) * 2001-12-29 2003-07-16 中国科学院上海药物研究所 Synthesis of antitumour medicine bexarotene
US7655699B1 (en) * 1992-04-22 2010-02-02 Eisai Inc. Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
WO2011103321A1 (en) * 2010-02-19 2011-08-25 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Novel bexarotene analogs
WO2011141928A1 (en) * 2010-05-11 2011-11-17 Ind-Swift Laboratories Limited Process for the preparation of highly pure bexarotene

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7655699B1 (en) * 1992-04-22 2010-02-02 Eisai Inc. Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
WO1994012880A2 (en) * 1992-11-25 1994-06-09 La Jolla Cancer Research Foundation Rxr homodimer formation and bridged bicyclic aromatic compounds and their use in modulating gene expression
CN1429807A (en) * 2001-12-29 2003-07-16 中国科学院上海药物研究所 Synthesis of antitumour medicine bexarotene
WO2011103321A1 (en) * 2010-02-19 2011-08-25 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Novel bexarotene analogs
WO2011141928A1 (en) * 2010-05-11 2011-11-17 Ind-Swift Laboratories Limited Process for the preparation of highly pure bexarotene

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Title
陈笑宇: "贝萨罗汀的合成研究", 《中国优秀硕士学位论文 医药卫生科技辑》 *
魏玮等: "蓓萨罗丁的合成及优化", 《化学研究与应用》 *

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