2,5-dichloro-2,5-dimethylhexane -Drug Synthesis Database

【结构式】

【分子编号】35216

【品名】2,5-dichloro-2,5-dimethylhexane

【CA登记号】

【分子式】C₈H₁₆Cl₂

【分子量】183.12044

【元素组成】C 52.47% H 8.81% Cl 38.72%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(II)

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

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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4

该中间体在本合成路线中的序号：(I)

The tetrahydronaphthalene derivative (III) was prepared by condensation of 1-bromo-2-ethoxybenzene (II) with 2,5-dichloro-2,5-dimethylhexane (I) in the presence of AlCl3. Lithium-bromine exchange in (III), followed by treatment with trimethyl borate and acid quenching, provided boronic acid (IV). This was subjected to palladium-catalyzed coupling with 3-bromo-3-buten-1-ol (V) to afford the homoallylic alcohol (VI). A Simmons-Smith reaction of (VI) with chloroiodomethane and diethylzinc furnished the cyclopropyl alcohol (VII), which was further oxidized to aldehyde (VIII) employing PCC. Horner-Emmons condensation of aldehyde (VIII) with phosphonate (IX) gave rise to the dienoate ester (X). Finally, basic hydrolysis of the ester function of (X) yielded the corresponding carboxylic acid.

参考文献中间体

合成目标

【1】 Zhi, L.; Farmer, L.J. (Ligand Pharmaceuticals, Inc.); Retinoids, methods for their production and use. US 6005007 .

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)	44697	2-bromophenyl ethyl ether; 1-bromo-2-ethoxybenzene	583-19-7	C₈H₉BrO	详情	详情
(III)	44698	6-bromo-7-ethoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene; 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl ethyl ether		C₁₆H₂₃BrO	详情	详情
(IV)	44699	3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenylboronic acid		C₁₆H₂₅BO₃	详情	详情
(V)	44700	3-bromo-3-buten-1-ol		C₄H₇BrO	详情	详情
(VI)	44701	3-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-3-buten-1-ol		C₂₀H₃₀O₂	详情	详情
(VII)	44702	2-[1-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]-1-ethanol		C₂₁H₃₂O₂	详情	详情
(VIII)	44703	2-[1-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]acetaldehyde		C₂₁H₃₀O₂	详情	详情
(IX)	44704	ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate	41891-54-7	C₁₁H₂₁O₅P	详情	详情
(X)	44705	ethyl (2E,4E)-6-[1-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]-3-methyl-2,4-hexadienoate		C₂₈H₄₀O₃	详情	详情

Extended Information