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【结 构 式】

【药物名称】BMS-188494

【化学名称】1(S)-[Bis(pivaloyloxymethoxy)phosphoryl]-4-(3-phenoxyphenyl)butanesulfonic acid

【CA登记号】191866-32-7 (undefined isomer)

【 分 子 式 】C28H39O11PS

【 分 子 量 】614.65423

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Squalene Synthase Inhibitors

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

The cyclization of (R,R)-N,N'-dimethylcyclohexane-1,2-diamine (I) with PCl3 by means of triethylamine in THF gives the octahydro-1,3,2-benzodiazaphosphole (II), which is condensed with 4-(3-phenoxyphenyl)butanal (III) by means of bis(trimethylsilyl)acetamide (BSA) in dichloromethane yielding the silylated butanol (IV) as a mixture of diastereomers that is separated by flash chromatography. The deprotection of the desired isomer (IV) with TBAF in THF affords the free butanol (V), which is esterified with zinc N,N-dimethyldithiocarbamate (VI) by means of Ph3P and diisopropyl azodicarboxylate (DIAD) in THF giving the dithiocarbamic ester (VII). The hydrolysis of (VII) with HCl in acetonitrile yields the free 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
【1】 Pendri, Y.; Chen, C.-P.; Kucera, D.J.; Martinez, E.J.; Pansegrau, P.; Thottathil, J.K.; Timmins, P. (Bristol-Myers Squibb Co.); Phosphonosulfonate squalene synthetase inhibitor salts and method. CA 2159850; EP 0710665; JP 1996208672 .
【2】 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
(II) 30166 (3aR,7aR)-1,3-dimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C8H17N2OP 详情 详情
(III) 30167 4-(3-phenoxyphenyl)butanal C16H16O2 详情 详情
(IV) 30168 (3aR,7aR)-1,3-dimethyl-2-[(1R)-4-(3-phenoxyphenyl)-1-[(trimethylsilyl)methyl]butyl]octahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C28H43N2O2PSi 详情 详情
(V) 30169 (3aR,7aR)-2-[(1R)-1-hydroxy-4-(3-phenoxyphenyl)butyl]-1,3-dimethyloctahydro-1H-1,3,2lambda(5)-benzodiazaphosphol-2-one C24H33N2O3P 详情 详情
(VI) 30170 N,N-Dimethyldithiocarbamic acid zinc salt C6H12N2S4Zn 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

合成路线2

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
【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3

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
【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

合成路线4

Finally, the target compound has been obtained as follows: The selective esterification of the phosphono group of intermediate (IX) with iodomethyl pivalate (XVIII) by means of triethylamine in DMF gives the sulfonic acid (XIX), which was purified through its calcium salt. Finally, this compound is treated with tert-butylamine in methanol to afford the target salt.

参考文献 中间体
【1】 Pendri, Y.; Chen, C.-P.; Kucera, D.J.; Martinez, E.J.; Pansegrau, P.; Thottathil, J.K.; Timmins, P. (Bristol-Myers Squibb Co.); Phosphonosulfonate squalene synthetase inhibitor salts and method. CA 2159850; EP 0710665; JP 1996208672 .
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) 30173 (1S)-4-(3-phenoxyphenyl)-1-phosphono-1-butanesulfonic acid C16H19O7PS 详情 详情
(XVIII) 11159 iodomethyl pivalate C6H11IO2 详情 详情
(XIX) 30182 (1S)-1-(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)-4-(3-phenoxyphenyl)-1-butanesulfonic acid C28H39O11PS 详情 详情
(XX) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)