NVP-VID-400, -Drug Synthesis Database

【结构式】

【药物名称】NVP-VID-400

【化学名称】(R)-4'-Chloro-N-[2-(1-imidazolyl)-2-phenylethyl]biphenyl-4-carboxamide

【CA登记号】174262-10-3, 174262-09-0 ((S)-isomer), 174262-13-6 (racemate)

【分子式】C₂₄H₂₀ClN₃O

【分子量】401.8995

【开发单位】Novartis (Originator)

【药理作用】Antipsoriatics, DERMATOLOGIC DRUGS, ONCOLYTIC DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.

参考文献中间体

【1】 Moenius, T.; et al.; C-14 labelling of NVPVID400 - a specific vitamin D-3-hydroxylase inhibitor. J Label Compd Radiopharm 1999, 42, 11, 1053.

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)	13365	Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene	108-86-1	C₆H₅Br	详情	详情
(II)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(III)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(IV)	38669	2-chloro-1-phenyl-1-ethanone	532-27-4	C₈H₇ClO	详情	详情
(V)	38670	(1R)-2-chloro-1-phenyl-1-ethanol	1674-30-2	C₈H₉ClO	详情	详情
(VI)	38671	(2R)-2-phenyloxirane		C₈H₈O	详情	详情
(VII)	10173	(1R)-2-Amino-1-phenyl-1-ethanol	2549-14-6	C₈H₁₁NO	详情	详情
(VIII)	38672	4'-chloro[1,1'-biphenyl]-4-carboxylic acid		C₁₃H₉ClO₂	详情	详情
(IX)	38673	4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide		C₂₁H₁₈ClNO₂	详情	详情
(X)	38674	(5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole		C₂₁H₁₆ClNO	详情	详情
(XI)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情

合成路线2

The reaction of (R)-2-phenyloxirane (I) with ammonia in ethanol gives 2-amino-1(R)-phenylethanol (II), which is condensed with 4'-chlorobiphenyl-4-carboxylic acid (III) by means of isobutyl chloroformate and TEA in DMF yielding the amide (IV). The cyclization of (IV) by means of methanesulfonic anhydride in pyridine affords the oxazoline (V), which is finally condensed with imidazole by heating at 120 C.

参考文献中间体

【1】 Schuster, I.; Egger, H. (Novartis AG; Novartis Deutschland GmbH); Acylated aminoalkanimidazoles and -triazoles. CA 2149459; EP 0683156; JP 1996053422; US 5622982 .

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)	38671	(2R)-2-phenyloxirane		C₈H₈O	详情	详情
(II)	10173	(1R)-2-Amino-1-phenyl-1-ethanol	2549-14-6	C₈H₁₁NO	详情	详情
(III)	38672	4'-chloro[1,1'-biphenyl]-4-carboxylic acid		C₁₃H₉ClO₂	详情	详情
(IV)	38673	4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide		C₂₁H₁₈ClNO₂	详情	详情
(V)	38674	(5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole		C₂₁H₁₆ClNO	详情	详情
(VI)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情

合成路线3

The esterification of 2(S)-amino-2-phenylethanol (VII) with hot sulfuric acid gives the expected O-sulfate (VIII), which by treatment with hot aqueous NaOH yields the aziridine (IX). The condensation of (IX) with imidazole (VI) by heating at 120 C affords 2(R)-(1-imidazolyl)-2-phenylethan-1-amine (X). Finally, this compound is condensed with 4'-chlorobiphenyl-4-thiocarboxylic acid 2-pyridylthioester in DMF.

参考文献中间体

【1】 Schuster, I.; Egger, H. (Novartis AG; Novartis Deutschland GmbH); Acylated aminoalkanimidazoles and -triazoles. CA 2149459; EP 0683156; JP 1996053422; US 5622982 .

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)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情
(VII)	10973	(2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol	20989-17-7	C₈H₁₁NO	详情	详情
(VIII)	38675	(2S)-2-amino-2-phenylethyl hydrogen sulfate		C₈H₁₁NO₄S	详情	详情
(IX)	38676	(2S)-2-phenylaziridine		C₈H₉N	详情	详情
(X)	38677	(2R)-2-(1H-imidazol-1-yl)-2-phenyl-1-ethanamine; (2R)-2-(1H-imidazol-1-yl)-2-phenylethylamine		C₁₁H₁₃N₃	详情	详情
(XI)	38678	S-(2-pyridinyl) 4'-chloro[1,1'-biphenyl]-4-carbothioate		C₁₈H₁₂ClNOS	详情	详情

Extended Information