(1S)-4-(3-phenoxyphenyl)-1-phosphono-1-butanesulfonic acid -Drug Synthesis Database

【结构式】

【分子编号】30173

【品名】(1S)-4-(3-phenoxyphenyl)-1-phosphono-1-butanesulfonic acid

【CA登记号】

【分子式】C₁₆H₁₉O₇PS

【分子量】386.362422

【元素组成】C 49.74% H 4.96% O 28.99% P 8.02% S 8.3%

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：(IX)

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

合成目标

【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

该中间体在本合成路线中的序号：(IX)

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3

该中间体在本合成路线中的序号：(IX)

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

合成路线4

该中间体在本合成路线中的序号：(IX)

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

合成目标

【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