|
【结 构 式】 
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【分子编号】16720 【品名】2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone 【CA登记号】536-38-9 |
【 分 子 式 】C8H6BrClO 【 分 子 量 】233.49174 【元素组成】C 41.15% H 2.59% Br 34.22% Cl 15.18% O 6.85% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of N-methyl-3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propylamine (desipramine) (I) with 4-chlorophenacyl chloride (II) by means of NaHCO3 in benzene-water.
| 【1】 Eriksoo, E.; Rohte, O.; Chemistry and pharmacology of a new potential antidepressant. Arzneim-Forsch Drug Res 1970, 20, 10, 1561. |
| 【2】 Castaner, J.; Arrigoni-Martelli, E.; Lofepramine. Drugs Fut 1976, 1, 3, 129. |
| 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) | 34005 | N-[3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl]-N-methylamine; 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methyl-1-propanamine | C18H22N2 | 详情 | 详情 | |
| (II) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)1) 4-Chloro-2'-bromoacetophenone (I) is condensed with 2-amino 5-chloropyridine (II) to give 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (III). 2) The above compound is reacted with formaldehyde and dimethylamine under Mannich conditions affording the 3-dimethylaminomethyl derivative (IV), which is subsequently quaternized with methyl iodide to afford the quaternary iodide (V). 3) Displacement of trimethylamine from salt (V) with cyanide ion leads to formation of the nitrile (VI), which on hydrolysis with hydrochloric acid in acetic acid gives the corresponding acid (VII). 4) In situ conversion of the acid to its acid chloride with phosphorus oxychloride followed by treatment with di-n-propylamine then leads to alpidem.
| 【1】 George, P.; Kaplan, J.-P. (Sanofi-Synthelabo ); Imidazo[1,2-a] pyridine derivs. and their applicat. EP 0050563; US 4382938 . |
| 【2】 Friedmann, J.C.; Morselli, P.L.; Dimsdale, M.; Zivkovic, B.; Alpidem. Drugs Fut 1988, 13, 2, 106. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (2) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (I) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 21851 | 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine | C13H8Cl2N2 | 详情 | 详情 | |
| (IV) | 21852 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dimethylmethanamine; N-[[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-N,N-dimethylamine | C16H15Cl2N3 | 详情 | 详情 | |
| (V) | 21853 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N,N-trimethylmethanaminium iodide | C17H18Cl2IN3 | 详情 | 详情 | |
| (VI) | 21854 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile | C15H9Cl2N3 | 详情 | 详情 | |
| (VII) | 21855 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid | C15H10Cl2N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole (I) with 4-chlorophenacyl bromide (II) ethyl ether/ethanol gives 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (III), which is condensed with ethyl diazoacetate (IV) by means of copper powder in refluxing toluene to afford 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid ethyl ester (V). Finally, this ester is hydrolyzed with NaOH in ethanol/water.
| 【1】 Rabasseda, X.; Mealy, N.; Castañer, J.; ML-3000. Drugs Fut 1995, 20, 10, 1007. |
| 【2】 Augustin, J.; Kiefer, W.; Dannhardt, G.; Laufer, S.A.; (6,7-Diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase. J Med Chem 1994, 37, 12, 1894-7. |
| 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) | 16719 | 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole | 116673-95-1 | C13H17N | 详情 | 详情 |
| (II) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (III) | 16721 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine | C21H20ClN | 详情 | 详情 | |
| (IV) | 15911 | Ethyldiazoacetate; ethyl 2-diazoacetate | 623-73-4 | C4H6N2O2 | 详情 | 详情 |
| (V) | 16723 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate | C25H26ClNO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The cyclization of 4-chloro-3,3-dimethylbutyronitrile (I) with benzylmagnesium chloride (II) in ethyl ether containing some iodine gives 2-benzyl-4,4-dimethyl-1-pyrroline (III), which is cyclized with 4'-chlorophenacyl bromide (IV) by means of NaHCO3 in methanol, yielding 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro.1H-pyrrolizine (V). The condensation of (V) with oxalyl chloride (VI) in THF affords 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride (VII), which is finally reduced and hydrolyzed with hydrazine in hot diethyleneglycol to provide the target licofelone.
| 【1】 Laufer, S.; Striegel, H.-G.; Kammermeier, T.; Merckle, P. (Merckle GmbH); Method for producing 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl acetic acid. US 6417371; WO 0155149 . |
| 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) | 60052 | 4-chloro-3,3-dimethylbutanenitrile | C6H10ClN | 详情 | 详情 | |
| (II) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (III) | 16719 | 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole | 116673-95-1 | C13H17N | 详情 | 详情 |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 16721 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine | C21H20ClN | 详情 | 详情 | |
| (VI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (VII) | 60053 | 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride | C23H19Cl2NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The overall synthetic approach to eliprodil hydrochloride is shown in Scheme 21238101a: 1-Acetylpiperidine-4-carboxylic acid (I) is converted into its acid chloride and reacted with fluorobenzene in the presence of aluminum chloride to give the ketone (II). Wolff-Kishner reduction of the ketone (II) affords 4-[(4-fluorophenyl)methyl]piperidine (III), which is purified by distillation and isolated as its hydrochloride salt. Condensation of the piperidine derivate (III) (as the free base) with 2-bromo-1-(4-chlorophenyl)ethanone (IV) in the presence of potassium carbonate yields the aminoketone which is isolated as its hydrochloride salt (V). Reduction of (V) with potassium borohydride and salification of the resulting base with anhydrous hydrogen chloride in ether provides eliprodil hydrochloride (VI), which is purified by recrystallization.
| 【1】 Wick, A.; Frost, J.; Gaudilliere, B.; Bertin, J.; Dupont, R.; Rousseau, J. (Sanofi-Synthelabo ); 1-Phenyl-2-piperidino propanol derivs., their preparation and medicines containing them. EP 0109317 . |
| 【2】 Benavides, J.; Scatton, B.; Carter, C.; George, P.; Frost, J.; Thenot, J.P.; Giroux, C.; Eliprodil Hydrochloride. Drugs Fut 1994, 19, 10, 905. |
| 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) | 16788 | 1-acetyl-4-piperidinecarboxylic acid | 25503-90-6 | C8H13NO3 | 详情 | 详情 |
| (II) | 16789 | 1-[4-(4-fluorobenzoyl)piperidino]-1-ethanone | C14H16FNO2 | 详情 | 详情 | |
| (III) | 16790 | 4-(4-fluorobenzyl)piperidine hydrochloride | 92822-02-1 | C12H17ClFN | 详情 | 详情 |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 16792 | 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)-1-piperidinyl]-1-ethanone hydrochloride | C20H22Cl2FNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)A new synthesis of eliprodil and the asymmetric synthesis of its two enantiomers have been reported: 1) Racemic eliprodil is obtained by condensation of 4-chlorophenacyl bromide (I) with 4-(4-fluorobenzyl)piperidine (II) by means of K2CO3 in refluxing ethanol to give 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanone (III), which is then reduced with KBH4 in methanol.
| 【1】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551. |
合成路线7
该中间体在本合成路线中的序号：(II)Alkylation of ethyl 1-piperazinecarboxylate (I) with 2-bromo-4'-chloroacetophenone (II) afforded disubstituted piperazine (III). Further cleavage of the carbamate group of (III) in refluxing HCl produced piperazine (IV). Bromide (VII) was prepared by reduction of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (V) with NaBH4, followed by treatment of the resulting alcohol (VI) with PBr3. Piperazine (IV) was then condensed with bromide (VII) to give adduct (VIII). Finally, ketone reduction using LiAlH4 furnished the title alcohol.
| 【1】 Collis, M.P.; Robertson, A.D.; Kenche, V.B.; Jackson, W.R.; Jarrott, B.; Beart, P.M. (Monash University); Arylalkylpiperazine cpds. as antioxidants. JP 2000510126; WO 9743259 . |
| 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) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (II) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (III) | 37704 | ethyl 4-[2-(4-chlorophenyl)-2-oxoethyl]-1-piperazinecarboxylate | C15H19ClN2O3 | 详情 | 详情 | |
| (IV) | 37705 | 1-(4-chlorophenyl)-2-(1-piperazinyl)-1-ethanone | C12H15ClN2O | 详情 | 详情 | |
| (V) | 14875 | 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde | 1620-98-0 | C15H22O2 | 详情 | 详情 |
| (VI) | 37706 | 2,6-di(tert-butyl)-4-(hydroxymethyl)phenol | 88-26-6 | C15H24O2 | 详情 | 详情 |
| (VII) | 37707 | 4-(bromomethyl)-2,6-di(tert-butyl)phenol | C15H23BrO | 详情 | 详情 | |
| (VIII) | 37708 | 1-(4-chlorophenyl)-2-[4-[3,5-di(tert-butyl)-4-hydroxybenzyl]-1-piperazinyl]-1-ethanone | C27H37ClN2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The cyclization of 3-methoxythiophenol (I) with 4-methoxyphenacyl bromide (II) by means of KOH in ethanol gives 2-(4-methoxyphenyl)-6-methoxybenzothiophene (III), which is treated with pyridinium hydrochloride at 220 C to yield 2-(4-hydroxyphenyl)-6-hydroxybenzothiophene (IV). The protection of the hydroxy groups of (IV) by reaction with 4-chlorophenacyl bromide (V) and K2CO3 - 18-crown 6 in refluxing ether affords the bis p-chlorophenacyloxy derivative (VI), which by a Friedel-Kraft's reaction with 4-(2-pyrrolidinoethoxy)benzoyl chloride (VII) by means of AlCl3 in refluxing dichloroethane is converted into 2-[4-(4-chlorophenacyloxy)phenyl]-3-[4-(2-pyrrolidinoethoxy)benzoyl]-6-(4-chlorophenacyloxy)benzothiophene (VIII). Finally, this compound is deprotected by treatment with Zn and acetic acid.
| 【1】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 . |
| 【2】 Jones, C.D.; Suarez, T.; 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents. DE 2647907; ES 452694; ES 452695; FR 2329271; GB 1570610; JP 52053851; US 4133814 . |
| 【3】 Blancafort, P.; Castañer, J.; Serradell, M.N.; LY-117018. Drugs Fut 1982, 7, 2, 112. |
| 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) | 25756 | 3-methoxybenzenethiol | 15570-12-4 | C7H8OS | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 10121 | 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene | 63675-74-1 | C16H14O2S | 详情 | 详情 |
| (IV) | 36414 | 2-(4-hydroxyphenyl)-1-benzothiophen-6-ol | C14H10O2S | 详情 | 详情 | |
| (V) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (VI) | 36415 | 1-(4-chlorophenyl)-2-(4-[6-[2-(4-chlorophenyl)-2-oxoethoxy]-1-benzothiophen-2-yl]phenoxy)-1-ethanone | C30H20Cl2O4S | 详情 | 详情 | |
| (VII) | 36416 | 4-[2-(1-pyrrolidinyl)ethoxy]benzoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (VIII) | 36417 | 1-(4-chlorophenyl)-2-[(2-[4-[2-(4-chlorophenyl)-2-oxoethoxy]phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzoyl]-1-benzothiophen-6-yl)oxy]-1-ethanone | C43H35Cl2NO6S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)The alkylation of 4-(dimethoxymethyl)pyridine (I) with 4-bromobenzyl bromide (II) in the presence of n-butyllithium, followed by ketal hydrolysis with formic acid provided the diaryl ethanone (III). Further alkylation of (III) with 4-chlorophenacyl bromide (IV) employing sodium hexamethyldisilazide yielded diketone (V), which was cyclized in the presence of ammonium acetate in boiling AcOH to produce pyrrole (VI). Finally, Suzuki coupling of (VI) with 3-methoxybenzeneboronic acid (VII) by means of Pd(PPh3)4 furnished the title compound.
| 【1】 McMillan, M.; Cudaback, E.; Misra-Press, A.; et al.; Synthesis and biological studies of a novel inhibitor of NF-kappaB. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 213. |
| 【2】 de Laszlo, S.E.; Kim, D.; Chang, L.L.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. US 5776954 . |
| 【3】 De Laszlo, S.E.; Chang, L.L.; Kim, D.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. EP 0859771; JP 1999514651; WO 9716442 . |
| 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) | 29418 | 4-(dimethoxymethyl)pyridinemethoxy(4-pyridinyl)methyl methyl ether | C8H11NO2 | 详情 | 详情 | |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 29423 | 2-(4-bromophenyl)-1-(4-pyridinyl)-1-ethanone | C13H10BrNO | 详情 | 详情 | |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 29424 | 2-(4-bromophenyl)-4-(4-chlorophenyl)-1-(4-pyridinyl)-1,4-butanedione | C21H15BrClNO2 | 详情 | 详情 | |
| (VI) | 29425 | 4-[3-(4-bromophenyl)-5-(4-chlorophenyl)-1H-pyrrol-2-yl]pyridine | C21H14BrClN2 | 详情 | 详情 | |
| (VII) | 29426 | 3-methoxyphenylboronic acid | 10365-98-7 | C7H9BO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)The alkylation of 4-(dimethoxymethyl)pyridine (I) with 4-bromo-2-fluorobenzyl bromide (II) in the presence of n-butyllithium, followed by ketal hydrolysis with formic acid provided the diaryl ethanone (III). Further alkylation of (III) with 4-chlorophenacyl bromide (IV) employing sodium hexamethyldisilazide yielded diketone (V), which was cyclized in the presence of ammonium acetate in boiling AcOH to produce pyrrole (VI). Finally, Suzuki coupling of (VI) with 5-butyl-2-thiopheneboronic acid (VII) by means of Pd(PPh3)4 furnished the title compound.
| 【1】 McMillan, M.; Cudaback, E.; Misra-Press, A.; et al.; Synthesis and biological studies of a novel inhibitor of NF-kappaB. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 213. |
| 【2】 De Laszlo, S.E.; Chang, L.L.; Kim, D.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. EP 0859771; JP 1999514651; WO 9716442 . |
| 【3】 de Laszlo, S.E.; Kim, D.; Chang, L.L.; Mantlo, N.B. (Merck & Co., Inc.); Substd. pyridyl pyrroles, compsns. containing such cpds. and methods of use. US 5776954 . |
| 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) | 29418 | 4-(dimethoxymethyl)pyridinemethoxy(4-pyridinyl)methyl methyl ether | C8H11NO2 | 详情 | 详情 | |
| (II) | 22904 | 2-fluoro-4-bromobenzyl bromide; 4-bromo-1-(bromomethyl)-2-fluorobenzene | 76283-09-5 | C7H5Br2F | 详情 | 详情 |
| (III) | 29419 | 2-(4-bromo-2-fluorophenyl)-1-(4-pyridinyl)-1-ethanone | C13H9BrFNO | 详情 | 详情 | |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 29420 | 2-(4-bromo-2-fluorophenyl)-4-(4-chlorophenyl)-1-(4-pyridinyl)-1,4-butanedione | C21H14BrClFNO2 | 详情 | 详情 | |
| (VI) | 29421 | 4-[3-(4-bromo-2-fluorophenyl)-5-(4-chlorophenyl)-1H-pyrrol-2-yl]pyridine | C21H13BrClFN2 | 详情 | 详情 | |
| (VII) | 29422 | 5-butyl-2-thienylboronic acid | C8H13BO2S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Bromoacetophenone (I) was converted into a cis/trans mixture of ketals (III) by treatment with glycerin (II) and p-toluenesulfonic acid. Subsequent reaction of (III) with 2-naphthalenesulfonyl chloride gave the corresponding mixture of sulfonate esters. After separation of the desired cis-isomer (IV), its condensation with the phenol derivative (V) produced ether (VI). Finally, displacement of the bromine atom of (VI) with 3-mercapto-4-methyl-1,2,4-triazole (VII) using Na2CO3 in DMF gave rise to the title thioether.
| 【1】 Backx, L.; Meerpoel, L.; Heeres, J.; et al.; Structure-activity relationship of a novel chemical family of MTP inhibitors with lipid-lowering properties. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-142. |
| 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) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (II) | 13289 | Glycerine; Glycerin; Glycerol | 56-81-5 | C3H8O3 | 详情 | 详情 |
| (III) | 44994 | [2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methanol | C11H12BrClO3 | 详情 | 详情 | |
| (IV) | 44990 | [(2S,4S)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methyl 2-naphthalenesulfonate | C21H18BrClO5S | 详情 | 详情 | |
| (V) | 44991 | 4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[(1R)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C22H27N5O2 | 详情 | 详情 | |
| (VI) | 44992 | 4-[4-[4-(4-[[(2S,4R)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1R)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C33H37BrClN5O4 | 详情 | 详情 | |
| (VII) | 44993 | 4-methyl-4H-1,2,4-triazole-3-thiol; 4-methyl-4H-1,2,4-triazol-3-ylhydrosulfide | C3H5N3S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Reaction of p-chlorophenacyl bromide (I) with imidazole (II) affords 4'-chloro-2-(1-imidazolyl)acetophenone (III). Sodium borohydride reduction gives the corresponding alcohol (IV) which is then alkylated with 2,6-dichlorobenzyl chloride (V) to give orconazole (VI). Treatment of (VI) with nitric acid yield the title compound
| 【1】 Godefroi, E.F.; et al.; The preparation and properties of derivatives of 1-phenethyl imidazole. J Med Chem 1969, 12, 5, 784. |
| 【2】 Godefroi, E.F.; Heeres, J. (Janssen Pharmaceutica NV); BE 737575; DE 1940388; FR 2015913; GB 1244530; JP 76115; US 3717655; US 3839574; ZA 6905965 . |
| 【3】 Arya, V.P.; Orconazole nitrate. Drugs Fut 1979, 4, 6, 432. |
| 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) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (II) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (III) | 60948 | 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanone | C11H9ClN2O | 详情 | 详情 | |
| (IV) | 60949 | 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanol | C11H11ClN2O | 详情 | 详情 | |
| (V) | 60951 | 1,3-dichloro-2-(chloromethyl)benzene | C7H5Cl3 | 详情 | 详情 | |
| (VI) | 60950 | 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl 2,6-dichlorobenzyl ether; 1-{2-(4-chlorophenyl)-2-[(2,6-dichlorobenzyl)oxy]ethyl}-1H-imidazole | C18H15Cl3N2O | 详情 | 详情 |