4,4-diphenylcyclohexanol -Drug Synthesis Database

【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 合成路线2

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)

参考文献中间体

合成目标

【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).

参考文献中间体

合成目标

【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