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【结 构 式】

【分子编号】30319

【品名】4,4-diphenylcyclohexanol

【CA登记号】

【 分 子 式 】C18H20O

【 分 子 量 】252.3562

【元素组成】C 85.67% H 7.99% O 6.34%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IX)

The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)

1 Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 .
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) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(III) 30315 (2S)-2-amino-N-(2-aminoethyl)-3-hydroxypropanamide C5H13N3O2 详情 详情
(IV) 30316 (2R)-2-amino-3-[(2-aminoethyl)amino]-1-propanol C5H15N3O 详情 详情
(V) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VI) 30317 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester C35H65N3O11 详情 详情
(VII) 22791 2-Cyanoethyl N,N-diisopropylphosphoramidochloridite 89992-70-1 C9H18ClN2OP 详情 详情
(VIII) 30318 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(diisopropylamino)phosphinyloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C44H82N5O12P 详情 详情
(IX) 30319 4,4-diphenylcyclohexanol C18H20O 详情 详情
(X) 30320 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(4,4-diphenylcyclohexyloxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C56H87N4O14P 详情 详情
(XI) 30321 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester ammonium salt C53H87N4O14P 详情 详情
(XII) 30322 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid C33H44N3O14P 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 reduction of benzoin (XIII) with NaBH4 in ethanol/water gives the diol (XIV), which by a pinacol rearrangement by means of H2SO4 in hot acetic acid yields the diphenylacetaldehyde (XXV). The cyclization of (XV) with methyl vinyl ketone (XVI) by means of KOH in ethanol affords the cyclohexenone (XVII), which is reduced first with H2 over Pd/C in THF and then with NaBH4 in ethanol/water giving the 4,4-diphenylcyclohexanol (IX). The reaction of (IX) with PCl3 in THF yields the dichlorophosphite (XVIII), which is treated with imidazole (XIX) in THF affording the bis imidophosphite (XX). The condensation of (XX) with the previously obtained penta tert-butyl acetate compound (VI) in THF/heptane gives the imidophosphite (XXI), which is oxidized with sodium periodate yielding the phosphoric acid diester (XXII). Finally, the hydrolysis of (XXII) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII).

1 Amedio, J.C. Jr.; et al.; A practical preparation of 4,4-diphenylcyclohexanol: A key intermediate in the synthesis of MS-325. Synth Commun 1998, 28, 20, 3895.
2 Dunham, S.O.; Lauffer, R.B. (Epix Medical, Inc.); Contrast-enhanced diagnostic imaging method for monitoring interventional therapies. WO 9917809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 30317 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester C35H65N3O11 详情 详情
(IX) 30319 4,4-diphenylcyclohexanol C18H20O 详情 详情
(XII) 30322 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid C33H44N3O14P 详情 详情
(XIII) 24135 2-hydroxy-1,2-diphenyl-1-ethanone; benzoin 579-44-2 C14H12O2 详情 详情
(XIV) 30331 Hydrobenzoin; 1,2-diphenyl-1,2-ethanediol 655-48-1 C14H14O2 详情 详情
(XV) 30323 2,2-diphenylacetaldehyde 947-91-1 C14H12O 详情 详情
(XVI) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(XVII) 30325 4,4-diphenyl-2-cyclohexen-1-one C18H16O 详情 详情
(XVIII) 30326 Dichlorophosphorous acid 4,4-diphenylcyclohexyl ester C18H19Cl2OP 详情 详情
(XIX) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(XX) 30327 4,4-diphenylcyclohexyl di(1H-imidazol-1-yl)phosphinite C24H25N4OP 详情 详情
(XXI) 30328 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(1-imidazolyl)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C56H86N5O12P 详情 详情
(XXII) 30329 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester C53H84N3O14P 详情 详情
Extended Information