【结 构 式】 |
【分子编号】25127 【品名】bromo(4-chlorophenyl)magnesium 【CA登记号】873-77-8 |
【 分 子 式 】C6H4BrClMg 【 分 子 量 】215.75946 【元素组成】C 33.4% H 1.87% Br 37.03% Cl 16.43% Mg 11.26% |
合成路线1
该中间体在本合成路线中的序号:(II)The Grignard reaction of 2,2,8-trimethyl-5-formylpyrido[4,3-e]-1,3-dioxane (I) with 4-chlorophenyl magnesium bromide (II) in refluxing ether gives 2,2,8-trimethyl-5-(4-chloro-alpha-hydroxybenzyl)pyrido[4,3-e]-1,3-dioxane (III), which is then hydrolyzed and cyclized by a treatment with aqueous concentrated HCl
【1】 Esanu, A (SCRAS (Societe de Conseils de Recherches et d'Applications Scientifiques)); Furo[3,4-c]pyridine derivatives and their pharmaceutical use. BE 0891797; DE 3204596; FR 2499406; FR 2499574; GB 2092586; JP 82150688; US 4383998 . |
【2】 Castaner, J.; Serradell, M.N.; Thorpe, P.; Cycletanide. Drugs Fut 1985, 10, 5, 378. |
合成路线2
该中间体在本合成路线中的序号:(A)The synthesis of (rac)-BN-1267 is presented. The Grignard reaction of 2,2,8-trimethyl-5-formylpyrido[4,3-e]-1,3-dioxane (I) with 4-chloro phenyl magnesium bromide in refluxing ether gives 2,2,8-trimethyl-5-(4-chloro-alpha-hydroxybenzyl)pyrido[4,3-e]-1,3-dioxane (II), which by oxidation with MnO2 affords the corresponding ketone (III). The Grignard reaction of (III) with methyl maynesium iodide gives 2,2,8-trimethyl-5-(4-chloro-alpha-methyl-alpha-hydraxybenzyl)pyrido[4,3-e]-1,3-dioxane (IV), which is then hydrolyzed and cyclized by treatment with aqueous concentrated HCl.
【1】 De Salvia, R.; et al.; J Meet Franco-Ital Pharmacol Soc (June, Paris) 1984, 135, 1-2, 1. |
【2】 Esanu, A. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Furo[3,4-c]pyridine derivatives and therapeutic compositions containing the same. BE 0899222; CH 660191; GB 2137618; JP 1984193888; US 4581363; US 4735950 . |
【3】 Esanu, A.; Etienne, A.; Laurent, J.-P.; Braquet, P.; Mencia Huerta, J.M. Clostre, F.; Touvay, C.; Clofurenadine hydrochloride. Drugs Fut 1987, 12, 7, 627. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(I) | 28771 | 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde | C11H13NO3 | 详情 | 详情 | |
(II) | 28772 | (3-chlorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol | C17H18ClNO3 | 详情 | 详情 | |
(III) | 28773 | (3-chlorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone | C17H16ClNO3 | 详情 | 详情 | |
(IV) | 28774 | 1-(3-chlorophenyl)-1-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-1-ethanol | C18H20ClNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IX)Compound can be prepared in several different ways: 1) The reduction of 2-bromomethyl-4'-chlorobenzophenone (I) with NaBH4 in methanol gives 2-bromomethyl-4'-chlorobenzhydrol (II), which is then treated with methylamine in methanol. 2) The reduction of 2-cyano-4'-chlorobenzophenone (III) with LiAlH4 in THF gives 2-aminomethyl-4'-chlorobenzhydrol (IV), which is acylated with p-toluenesulfonyl chloride in pyridine and methylated with methyl iodide and NaOH in ethanol to give 2-(N-methyl-N-tosylaminomethyl)-4'-chlorobenzhydrol (V). Finally, this compound is hydrolyzed with H2SO4 water at 180 C. 3) The reaction of 3-(4-chlorophenyl)phthalide (VI) with methylamine in benzene gives 2-methylaminocarbonyl-4'-chlorobenzhydrol (VII), which is then reduced with LiAlH4 in THF. 4) The Grignard reaction of N-methylphthalimide (VIII) with 4-chlorophenylmagnesium bromide (IX) gives 1-(4'-chlorophenyl)-1-hydroxy-2-methyl-3-oxoisoindoline (X), which is reduced with LiAlH4 affording 1-(4'-chlorophenyl)-2-methylisoindoline (XI). The treatment of (XI) with refluxing acetic anhydride yields 2-[(N-methyl-N-acetylamino)methyl]-4'-chloro-O-acetylbenzhydrol (XII), which is finally hydrolyzed with KOH in refluxing ethylene glycol.
【1】 Goetz, M.; Freter, K.; 2-(Aminomethyl)benzhydrols. Can J Chem 1970, 48, 11, 1670-76. |
【2】 Freter, K.; et al.; ZA 6902707 . |
【3】 Freter, K.; et al.; US 3728460 . |
【4】 Boehringer, C.H.; Sohn; US 3635974 . |
【5】 Freter, K.; et al.; CA 982608 . |
【6】 Freter, K.; et al.; New group of anorexigenic compounds. J Med Chem 1970, 13, 6, 1228-30. |
【7】 Hillier, K.; Setazindol. Drugs Fut 1979, 4, 5, 365. |
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) | 39480 | [2-(bromomethyl)phenyl](4-chlorophenyl)methanone | C14H10BrClO | 详情 | 详情 | |
(II) | 39481 | [2-(bromomethyl)phenyl](4-chlorophenyl)methanol | C14H12BrClO | 详情 | 详情 | |
(III) | 39482 | 2-(4-chlorobenzoyl)benzonitrile | C14H8ClNO | 详情 | 详情 | |
(IV) | 39483 | [2-(aminomethyl)phenyl](4-chlorophenyl)methanol | C14H14ClNO | 详情 | 详情 | |
(V) | 39484 | N-[2-[(4-chlorophenyl)(hydroxy)methyl]benzyl]-N,4-dimethylbenzenesulfonamide | C22H22ClNO3S | 详情 | 详情 | |
(VI) | 39485 | 6-chloro-3-(4-chlorophenyl)-2-benzofuran-1(3H)-one | C14H8Cl2O2 | 详情 | 详情 | |
(VII) | 39486 | 2-[(4-chlorophenyl)(hydroxy)methyl]-N-methylbenzamide | C15H14ClNO2 | 详情 | 详情 | |
(VIII) | 39487 | 2-methyl-1H-isoindole-1,3(2H)-dione | 550-44-7 | C9H7NO2 | 详情 | 详情 |
(IX) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(X) | 39488 | 3-(4-chlorophenyl)-3-hydroxy-2-methyl-1-isoindolinone | C15H12ClNO2 | 详情 | 详情 | |
(XI) | 39489 | 1-(4-chlorophenyl)-2-methylisoindoline | C15H14ClN | 详情 | 详情 | |
(XII) | 39490 | (2-[[acetyl(methyl)amino]methyl]phenyl)(4-chlorophenyl)methyl acetate | C19H20ClNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(VII)Fischer esterification of 1-aminocyclohexanecarboxylic acid (I) provided the ethyl ester (II), which was alkylated with ethyl 4-bromobutyrate (III) in the presence of K2CO3 at 100 C to give aminodiester (IV). Dieckmann cyclization of (IV) using NaOEt afforded the azaspiro ketoester (V), which was decarboxylated under acidic conditions to yield ketone (VI). Addition of 4-chlorophenylmagnesium bromide (VII) to (VI) produced the tertiary acohol (VIII). This was dehydrated with concentrated H2SO4 to give the corresponding olefin as the sulfate salt, which was further treated with NaOH and then with HCl to furnish the corresponding hydrochloride.
【1】 Harris, P.J.; Kerrigan, F. (The Boots Company plc); Aza spiro alkanes derivs. as therapeutic agents. EP 0667860; JP 1996502985; US 5610161; WO 9411346 . |
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) | 31282 | 1-aminocyclohexanecarboxylic acid | 2756-85-6 | C7H13NO2 | 详情 | 详情 |
(II) | 31283 | ethyl 1-aminocyclohexanecarboxylate | C9H17NO2 | 详情 | 详情 | |
(III) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
(IV) | 31284 | ethyl 1-[(4-ethoxy-4-oxobutyl)amino]cyclohexanecarboxylate | C15H27NO4 | 详情 | 详情 | |
(V) | 31285 | ethyl 5-oxo-1-azaspiro[5.5]undecane-4-carboxylate | C13H21NO3 | 详情 | 详情 | |
(VI) | 31286 | 1-azaspiro[5.5]undecan-5-one | C10H17NO | 详情 | 详情 | |
(VII) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(VIII) | 31287 | 5-(4-chlorophenyl)-1-azaspiro[5.5]undecan-5-ol | C16H22ClNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)Grignard reagent (II), prepared from 4-chlorobromobenzene (I) and Mg in refluxing THF, was coupled with 1,10-dibromodecane (III) in the presence of Li2CuCl4 as the catalyst to afford the bromodecyl compound (IV). Then, the dianion of dichloroacetic acid (V), generated in the presence of two equivalents of LDA in cold THF, was alkylated with bromide (IV) to provide the title compound.
【1】 Meyer, K.; et al.; omega-Substituted alkyl carboxylic acids as antidiabetic and lipid-lowering agents. Eur J Med Chem 1998, 33, 10, 775. |
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) | 14733 | 4-Bromochlorobenzene; 1-bromo-4-chlorobenzene | 106-39-8 | C6H4BrCl | 详情 | 详情 |
(II) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(III) | 18615 | 1,10-dibromodecane | 4101-68-2 | C10H20Br2 | 详情 | 详情 |
(IV) | 25128 | 1-(10-bromodecyl)-4-chlorobenzene | C16H24BrCl | 详情 | 详情 | |
(V) | 25129 | 2,2-dichloroacetic acid | 79-43-6 | C2H2Cl2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(I)Addition of 4-chlorophenylmagnesium bromide (II) to arecoline (I) in Et2O at -10 C afforded the corresponding 4-arylpiperidine-3-carboxylate as a mixture of trans (III) and cis (IV) isomers. After chromatographic isolation of the racemic cis isomer (IV), resolution employing dibenzoyl-D-tartaric acid furnished the dextro enantiomer (cis)(+)-(IV). Its epimerization in the presence of NaOMe produced a 1:5.6 mixture of cis/trans isomers, from which the major compound (-)-(trans)(III) was isolated by flash chromatography. Acid hydrolysis of its methyl ester group provided carboxylic acid (V), that was further converted to acid chloride (VI) using oxalyl chloride (1,2). Finally, coupling of (VI) with 1,8-octanediamine (VII) gave the title diamide.
【1】 Tamiz, A.P.; Johnson, K.M.; Wang, C.Z.; Kozikowski, A.P.; Zhang, J.; Zhang, M.; Application of the bivalent ligand approach to the design of novel dimeric serotonin reuptake inhibitors. J Am Chem Soc 2000, 122, 22, 5393. |
【2】 Tamiz, A.P.; Araldi, G.L.; Kozikowski, A.P. (Georgetown University); Monomeric and dimeric heterocycles, and therapeutic uses thereof. WO 0020390 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(rac)-(III) | 41630 | (rac)-methyl (3S*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | n/a | C14H18ClNO2 | 详情 | 详情 |
(rac)-(IV) | 41631 | (rac)-methyl (3R*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
(+)-(IV) | 41632 | (+)-methyl (3R,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
(-)-(III) | 41633 | (-)-methyl (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
(I) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
(V) | 41634 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylic acid | C13H16ClNO2 | 详情 | 详情 | |
(VI) | 41635 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarbonyl chloride | C13H15Cl2NO | 详情 | 详情 | |
(VII) | 20965 | 1,8-octanediamine; 8-aminooctylamine | 373-44-4 | C8H20N2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号:(XXX)In a further method, Mannich reaction of 4,4-dimethylcyclohexanone (XVII) with tert-butyl 4-piperazinobenzoate (XXVIII) and paraformaldehyde by means of HCl in tert-butanol affords the piperazinylmethyl-cyclohexanone (XXIX), which is further condensed with 4-chlorophenylmagnesium bromide (XXX), yielding carbinol (XXXI). Simultaneous dehydration of alcohol (XXXI) and cleavage of the tert-butyl ester in refluxing 6 M HCl gives carboxylic acid (IX) (3). Scheme 4.
【3】 Zhang, H., Zhou, J., Ha, C., Pei, D., Ding, K. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis 2008, (15): 2398-404. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IX) | 65759 | C26H31ClN2O2 | 详情 | 详情 | ||
(XVII) | 65767 | 4,4-Dimethylcyclohexanone; 4,4-Dimethyl-1-cyclohexanone | 4255-62-3 | C8H14O | 详情 | 详情 |
(XXVIII) | 65777 | 2-Methyl-2-Propanyl 4-(1-Piperazinyl)Benzoate; tert-butyl 4-(1-Piperazinyl)Benzoate | 187669-28-9 | C15H22N2O2 | 详情 | 详情 |
(XXIX) | 65778 | C24H35N2O3 | 详情 | 详情 | ||
(XXX) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
(XXXI) | 65779 | C30H40ClN2O3 | 详情 | 详情 |