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【结 构 式】

【分子编号】30175

【品名】3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene

【CA登记号】

【 分 子 式 】C15H15IO

【 分 子 量 】338.18797

【元素组成】C 53.27% H 4.47% I 37.52% O 4.73%
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：(XI)

The cyclization of (R,R)-N,N'-dimethylcyclohexane-1,2-diamine (I) with methylphosphonic acid dichloride by means of triethylamine in benzene gives the 1,2,3-trimethyloctahydro-1,3,2-benzodiazaphosphole (X), which is condensed with 3-(3-phenoxyphenyl)propyl iodide (XI) by means of BuLi in THF yielding the 2-[4-(3-phenoxyphenyl)butyl] derivative (XII). The condensation of (XII) with tetramethylthiuram disulfide (XIII) by means of BuLi in THF affords, after chromatographic resolution of the resulting diastereomeric mixture, the previously reported dithiocarbamic ester (VII), which is hydrolyzed to the phosphonic acid (VIII), which is oxidized with HCO2H and H2O2 in acetic acid affording the target sulfonic acid (IX).

参考文献 中间体
合成目标
【1】 Magnin, D.R.; Biller, S.A.; Dickson, J.K. Jr.; Lawrence, M.R.; Sulsky, R.B. (Bristol-Myers Squibb Co.); Alpha-phosphorous substd. sulfonate derivs. as squalene synthetase inhibitors. EP 0595635; JP 1994199879; US 5712396 .
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) 30165 trans-(1R,2R)-N,N'-Bismethyl-1,2-cyclohexanediamine; (1R,2R)-N(1),N(2)-dimethyl-1,2-cyclohexanediamine; N-methyl-N-[(1R,2R)-2-(methylamino)cyclohexyl]amine 67579-81-1 C8H18N2 详情 详情
(VII) 30171 (1S)-1-[(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]-4-(3-phenoxyphenyl)butyl dimethylcarbamodithioate C27H38N3O2PS2 详情 详情
(VIII) 30172 (1S)-1-[[(dimethylamino)carbothioyl]sulfanyl]-4-(3-phenoxyphenyl)butylphosphonic acid C19H24NO4PS2 详情 详情
(X) 30174 (3aR,7aR)-1,2,3-trimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C9H19N2OP 详情 详情
(XI) 30175 3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene C15H15IO 详情 详情
(XII) 30176 (3aR,7aR)-1,3-dimethyl-2-[4-(3-phenoxyphenyl)butyl]octahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C24H33N2O2P 详情 详情
(XIII) 30177 [([[(dimethylamino)carbothioyl]disulfanyl]carbothioyl)(methyl)amino]methane 137-26-8 C6H12N2S4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The cyclization of (R,R)-N,N'-dimethylcyclohexane-1,2-diamine (I) with POCl3 by means of triethylamine in THF gives the 2-chlorooctahydro-1,3,2-benzodiazaphophole (XIV), which is condensed with ethyl methanesulfonate by means of BuLi in THF yielding the substituted methanesulfonate (XV). The hydrolysis of (XV) with tetrabutylammonium iodide in THF affords the corresponding tetrabutylammonium sulfonate (XVI), which is then condensed with 3-(3-phenoxyphenyl) propyl iodide (XI) by means of BuLi in THF giving the precursor sulfonic acid (XVII). Finally, this compound is hydrolyzed to the target compound with HCl.

参考文献 中间体
合成目标
【1】 Magnin, D.R.; Biller, S.A.; Dickson, J.K. Jr.; Lawrence, M.R.; Sulsky, R.B. (Bristol-Myers Squibb Co.); Alpha-phosphorous substd. sulfonate derivs. as squalene synthetase inhibitors. EP 0595635; JP 1994199879; US 5712396 .
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) 30165 trans-(1R,2R)-N,N'-Bismethyl-1,2-cyclohexanediamine; (1R,2R)-N(1),N(2)-dimethyl-1,2-cyclohexanediamine; N-methyl-N-[(1R,2R)-2-(methylamino)cyclohexyl]amine 67579-81-1 C8H18N2 详情 详情
(XI) 30175 3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene C15H15IO 详情 详情
(XIV) 30178 (3aR,7aR)-2-chloro-1,3-dimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C8H16ClN2OP 详情 详情
(XV) 30179 ethyl [(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]methanesulfonate C11H23N2O4PS 详情 详情
(XVI) 30180 N,N,N-tributyl-1-butanaminium [(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]methanesulfonate C25H54N3O4PS 详情 详情
(XVII) 30181 (1S)-1-[(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]-4-(3-phenoxyphenyl)-1-butanesulfonic acid C24H33N2O5PS 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XI)

The cyclization of (R,R)-N,N'-dimethylcyclohexane-1,2-diamine (I) with methylphosphonic acid dichloride by means of triethylamine in benzene gives the 1,2,3-trimethyloctahydro-1,3,2-benzodiazaphosphole (X), which is condensed with 3-(3-phenoxyphenyl)propyl iodide (XI) by means of BuLi in THF yielding the 2-[4-(3-phenoxyphenyl)butyl] derivative (XII). The condensation of (XII) with tetramethylthiuram disulfide (XIII) by means of BuLi in THF affords, after chromatographic resolution of the resulting diastereomeric mixture, the previously reported dithiocarbamic ester (VII), which is hydrolyzed to the phosphonic acid (VIII), which is oxidized with HCOOH and H2O2 in acetic acid affording the intermediate sulfonic acid (IX).

参考文献 中间体
合成目标
【1】 Magnin, D.R.; Biller, S.A.; Dickson, J.K. Jr.; Lawrence, M.R.; Sulsky, R.B. (Bristol-Myers Squibb Co.); Alpha-phosphorous substd. sulfonate derivs. as squalene synthetase inhibitors. EP 0595635; JP 1994199879; US 5712396 .
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) 30165 trans-(1R,2R)-N,N'-Bismethyl-1,2-cyclohexanediamine; (1R,2R)-N(1),N(2)-dimethyl-1,2-cyclohexanediamine; N-methyl-N-[(1R,2R)-2-(methylamino)cyclohexyl]amine 67579-81-1 C8H18N2 详情 详情
(VII) 30171 (1S)-1-[(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]-4-(3-phenoxyphenyl)butyl dimethylcarbamodithioate C27H38N3O2PS2 详情 详情
(VIII) 30172 (1S)-1-[[(dimethylamino)carbothioyl]sulfanyl]-4-(3-phenoxyphenyl)butylphosphonic acid C19H24NO4PS2 详情 详情
(IX) 30173 (1S)-4-(3-phenoxyphenyl)-1-phosphono-1-butanesulfonic acid C16H19O7PS 详情 详情
(X) 30174 (3aR,7aR)-1,2,3-trimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C9H19N2OP 详情 详情
(XI) 30175 3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene C15H15IO 详情 详情
(XII) 30176 (3aR,7aR)-1,3-dimethyl-2-[4-(3-phenoxyphenyl)butyl]octahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C24H33N2O2P 详情 详情
(XIII) 30177 [([[(dimethylamino)carbothioyl]disulfanyl]carbothioyl)(methyl)amino]methane 137-26-8 C6H12N2S4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XI)

The cyclization of (R,R)-N,N'-dimethylcyclohexane-1,2-diamine (I) with POCl3 by means of triethylamine in THF gives the 2-chlorooctahydro-1,3,2-benzodiazaphophole (XIV), which is condensed with ethyl methanesulfonate by means of BuLi in THF yielding the substituted methanesulfonate (XV). The hydrolysis of (XV) with tetrabutylammonium iodide in THF affords the correponding tetrabutylammonium sulfonate (XVI), which is then condensed with 3-(3-phenoxyphenyl)propyl iodide (XI) by means of BuLi in THF giving the precursor sulfonic acid (XVII). Finally, this compound is hydrolyzed to the intermediate sulfonic acid compound (IX) with HCl.

参考文献 中间体
合成目标
【1】 Magnin, D.R.; Biller, S.A.; Dickson, J.K. Jr.; Lawrence, M.R.; Sulsky, R.B. (Bristol-Myers Squibb Co.); Alpha-phosphorous substd. sulfonate derivs. as squalene synthetase inhibitors. EP 0595635; JP 1994199879; US 5712396 .
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) 30165 trans-(1R,2R)-N,N'-Bismethyl-1,2-cyclohexanediamine; (1R,2R)-N(1),N(2)-dimethyl-1,2-cyclohexanediamine; N-methyl-N-[(1R,2R)-2-(methylamino)cyclohexyl]amine 67579-81-1 C8H18N2 详情 详情
(IX) 30173 (1S)-4-(3-phenoxyphenyl)-1-phosphono-1-butanesulfonic acid C16H19O7PS 详情 详情
(XI) 30175 3-(3-iodopropyl)phenyl phenyl ether; 1-(3-iodopropyl)-3-phenoxybenzene C15H15IO 详情 详情
(XIV) 30178 (3aR,7aR)-2-chloro-1,3-dimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C8H16ClN2OP 详情 详情
(XV) 30179 ethyl [(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]methanesulfonate C11H23N2O4PS 详情 详情
(XVI) 30180 N,N,N-tributyl-1-butanaminium [(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]methanesulfonate C25H54N3O4PS 详情 详情
(XVII) 30181 (1S)-1-[(3aR,7aR)-1,3-dimethyl-2-oxooctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-yl]-4-(3-phenoxyphenyl)-1-butanesulfonic acid C24H33N2O5PS 详情 详情
Extended Information