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【结 构 式】 
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【分子编号】12890 【品名】Toluene 【CA登记号】108-88-3 |
【 分 子 式 】C7H8 【 分 子 量 】92.14052 【元素组成】C 91.25% H 8.75% |
合成路线1
该中间体在本合成路线中的序号：(I)The Friedel-Crafts condensation of toluene (I) with itaconic anhydride (2-methylenesuccinic anhydride) (II) by means of AlCl3 in methylene chloride or 1,2-dichloroethane gives 3-(4-methylbenzoyl)-2-methylenepropionic acid (III), which is then treated with thioacetic acid (IV) and K2CO3 in DMF/water.
| 【1】 Onodera, A.; Tomisawa, K.; Noguchi, T.; Yokomori, S.; A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (Part 1). Chem Pharm Bull 2002, 50, 10, 1407. |
| 【2】 Mealy, N.; Castaner, J.; KE-298. Drugs Fut 1996, 21, 7, 691. |
| 【3】 Tomisawa, K.; Kameo, K.; Matsunaga, T.; Saito, S.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Benzoylpropionic acid derivs., their use and pharmaceutical compsns. EP 0164101; ES 8603818; JP 1985258160 . |
| 【4】 Tomisawa, K.; Kameo, K.; Matsunaga, Y.; Saito, H.; Sodu, H. (Taisho Pharmaceutical Co., Ltd.); 2-Acylthiomethyl-3-benzoylpropionic acid derivs. JP 1987132825 . |
| 【5】 Kameo, K.; Ogawa, K.; Takeshita, K.; Nakaike, S.; Tomisawa, K.; Sota, K.; Studies on antirheumatic agents: 3-Benzoylpropionic acid derivatives. Chem Pharm Bull 1988, 36, 6, 2050-60. |
合成路线2
该中间体在本合成路线中的序号：(II)Friedel-Crafts acylation of toluene (II) with 3-methoxybenzoyl chloride (I) gave benzophenone (III). Subsequent methyl group oxidation using KMnO4 afforded carboxylic acid (IV), which was further converted to amide (V) by activation with SOCl2, followed by treatment with diethylamine. Reduction of the keto group of (V) by means of NaBH4 yielded alcohol (VI). The required benzhydryl chloride (VII) was then prepared by treatment of alcohol (VI) with concentrated HCl.
| 【1】 Evans, S.M.; Lenz, G.R.; Probes of receptor mediated phenomena 19. Synthesis of (+)-4-[(alphaR)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. Chemtracts - Org Chem 1994, 7, 6, 395. |
| 【2】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena: 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80). J Med Chem 1997, 40, 5, 695. |
| 【3】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. J Med Chem 1994, 14, 37, 2125. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16760 | 3-methoxybenzoyl chloride | 1711-05-3 | C8H7ClO2 | 详情 | 详情 |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 56245 | (3-methoxyphenyl)(4-methylphenyl)methanone | C15H14O2 | 详情 | 详情 | |
| (IV) | 56246 | 4-(3-methoxybenzoyl)benzoic acid | C15H12O4 | 详情 | 详情 | |
| (V) | 56247 | N,N-diethyl-4-(3-methoxybenzoyl)benzamide | C19H21NO3 | 详情 | 详情 | |
| (VI) | 56248 | N,N-diethyl-4-[hydroxy(3-methoxyphenyl)methyl]benzamide | C19H23NO3 | 详情 | 详情 | |
| (VII) | 56249 | 4-[chloro(3-methoxyphenyl)methyl]-N,N-diethylbenzamide | C19H22ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Treatment of 2,5-dimethyl-2-5-hexanediol (I) with dry hydrogen chloride in EtOH gives rise to the dichloro compound (II). Subsequent Friedel-Crafts condensation of dichloride (II) with toluene (III) in the presence of AlCl3 affords the tetrahydronaphthalene derivative (IV) (1). This is then condensed with mono-methyl terephthalic acid chloride (V) to produce ketone (VI). Wittig reaction of (VI) with methylene triphenylphosphorane leads to olefin (VII). Finally, alkaline hydrolysis of the methyl ester group of (VII) furnishes the target carboxylic acid
| 【1】 Zhang, L.; Badea, B.A.; Enyeart, D.; Berger, E.M.; Mais, D.E.; Boehm, M.F.; Syntheses of isotopically labeled 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid X receptor-selective ligand. J Label Compd Radiopharm 1995, 36, 7, 701. |
| 【2】 Boehm, M.F.; Heyman, R.A.; Zhi, L. (Ligand Pharmaceuticals, Inc.); Cpds. having selectivity for retinoid X receptors. EP 0983991; EP 0983992; JP 1996505359; JP 1996505852; JP 1996511027; US 5780676; US 5962731; WO 9321146; WO 9415902 . |
| 【3】 Zhang, L.; Boehm, M.F.; Badea, B.A.; White, S.K.; Mais, D.E.; Berger, E.; Suto, C.M.; Goldman, M.E..; Heyman, R.A.; Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 1994, 37, 18, 2930. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60245 | 2,5-dimethyl-2,5-hexanediol | C8H18O2 | 详情 | 详情 | |
| (II) | 35216 | 2,5-dichloro-2,5-dimethylhexane | C8H16Cl2 | 详情 | 详情 | |
| (III) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (IV) | 35217 | 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene | C15H22 | 详情 | 详情 | |
| (V) | 25029 | p-Phthalic acid monomethyl ester chloride; Terephthalic acid monomethyl ester chloride; Methyl 4-chlorocarbonylbenzoate | 7377-26-6 | C9H7ClO3 | 详情 | 详情 |
| (VI) | 35218 | methyl 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoate | C24H28O3 | 详情 | 详情 | |
| (VII) | 60246 | methyl 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoate | C25H30O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The intermediate tetrahydronaththalene (VI) has been prepared by an alternative procedure. Friedel-Crafts condensation of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (I) with toluene (II) by means of AlCl3 produces tetrahydronaphthalenone (III). This is reduced to alcohol (IV) employing NaBH4 in MeOH. Subsequent dehydration of (IV) with POCl3 in pyridine leads to the dihydronaphthalene (V). Then, catalytic hydrogenation of (V) over Pd/C provides the key pentamethyltetrahydronaphthalene (VI)
| 【1】 Zhang, L.; Badea, B.A.; Enyeart, D.; Berger, E.M.; Mais, D.E.; Boehm, M.F.; Syntheses of isotopically labeled 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid X receptor-selective ligand. J Label Compd Radiopharm 1995, 36, 7, 701. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60248 | 2,2,5,5-tetramethyldihydro-3(2H)-furanone | C8H14O2 | 详情 | 详情 | |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 60249 | 1,1,4,4,7-pentamethyl-3,4-dihydro-2(1H)-naphthalenone | C15H20O | 详情 | 详情 | |
| (IV) | 60250 | 1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydro-2-naphthalenol | C15H22O | 详情 | 详情 | |
| (V) | 60251 | 1,1,4,4,6-pentamethyl-1,4-dihydronaphthalene | C15H20 | 详情 | 详情 | |
| (VI) | 35217 | 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene | C15H22 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The Friedel Crafts condensation of 2,5-dichloro-2,2,5,5-tetramethylhexane (I) with toluene (II) by means of AlCl3 gives 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (III), which is submitted to a new condensation with the pyridine-2-carbonyl chloride (IV) by means of AlCl3 in dichloromethane to yield the diaryl ketone (V). The reaction of (V) with methyltriphenylphosphonium bromide (VI) and NaNH2 affords the 1,1-diarylethylene (VII), which is treated with Et2Zn and Cl-CH2-I in dichloromethane to provide the 1,1-diarylcyclopropane (VIII). Finally, the ester group of (VIII) is hydrolyzed with KOH in methanol/water to yield the target carboxylic acid.
| 【1】 Faul, M.M.; Ratz, A.M.; Sullivan, K.A.; Trankle, W.G.; Winneroski, L.L.; Synthesis of novel retinoid X receptor-selective retinoids. J Org Chem 2001, 66, 17, 5772. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35216 | 2,5-dichloro-2,5-dimethylhexane | C8H16Cl2 | 详情 | 详情 | |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 35217 | 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene | C15H22 | 详情 | 详情 | |
| (IV) | 64262 | methyl 6-(chlorocarbonyl)nicotinate | C8H6ClNO3 | 详情 | 详情 | |
| (V) | 64263 | methyl 6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]nicotinate | C23H27NO3 | 详情 | 详情 | |
| (VI) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (VII) | 64264 | methyl 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)vinyl]nicotinate | C24H29NO2 | 详情 | 详情 | |
| (VIII) | 64265 | methyl 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]nicotinate | C25H31NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Friedel-Crafts condensation of 2,5-dichloro-2,5-dimethylhexane (I) with toluene (II) in the presence of AlCl3 or FeCl3 afforded the tetrahydronaphthalene (III). Subsequent acylation of (III) with monomethyl terephthalic acid chloride (IV) provided keto ester (V), which was hydrolyzed to keto acid (VI) with methanolic KOH. Condensation of (VI) with hydroxylamine hydrochloride gave the corresponding oxime as a mixture of geometric isomers. The required Z isomer was then isolated by recrystallization from chloroform/hexane.
| 【1】 Faul, M.M.; Ratz, A.M.; Sullivan, K.A.; Trankle, W.G.; Winneroski, L.L.; Synthesis of novel retinoid X receptor-selective retinoids. J Org Chem 2001, 66, 17, 5772. |
| 【2】 Boehm, M.F.; Canan Koch, S.S.; Cesario, R.M.; Dardashti, L.J.; Nadzan, A.M.; Croston, G.E.; Heyman, R.A.; Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells. J Med Chem 1999, 42, 4, 742. |
| 【3】 Zhang, L.; Boehm, M.F.; Badea, B.A.; White, S.K.; Mais, D.E.; Berger, E.; Suto, C.M.; Goldman, M.E..; Heyman, R.A.; Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 1994, 37, 18, 2930. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32201 | Hydroxylamine | 7803-49-8 | H3NO | 详情 | 详情 | |
| (I) | 35216 | 2,5-dichloro-2,5-dimethylhexane | C8H16Cl2 | 详情 | 详情 | |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 35217 | 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene | C15H22 | 详情 | 详情 | |
| (IV) | 25029 | p-Phthalic acid monomethyl ester chloride; Terephthalic acid monomethyl ester chloride; Methyl 4-chlorocarbonylbenzoate | 7377-26-6 | C9H7ClO3 | 详情 | 详情 |
| (V) | 35218 | methyl 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoate | C24H28O3 | 详情 | 详情 | |
| (VI) | 35219 | 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoic acid | C23H26O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The Friedel-Crafts condensation of 2-[4-(methylsulfanyl)phenyl]acetyl chloride (I) with toluene (II) gives 1-(3-methylphenyl)-2-[4-(methylsulfanyl)phenyl]ethanone (III), which is oxidized with MCPBA to yield the corresponding sulfonyl compound (IV). The bromination of (IV) with Br2 affords the bromoethanone (V), which is finally cyclized with pyridine-2-amine (VI) to provide the target imidazopyridine compound.
| 【1】 Farrerons, C.; et al.; Diarylimidazo[1,2-a]pyridine derivatives as a new class of selective COX-2 inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P2. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 55386 | 1-(3-methylphenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C16H16OS | 详情 | 详情 | |
| (IV) | 55387 | 1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone | C16H16O3S | 详情 | 详情 | |
| (V) | 55388 | 2-bromo-1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone | C16H15BrO3S | 详情 | 详情 | |
| (VI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |