Capravirine, AG-1549, S-1153, -Drug Synthesis Database

【结构式】

【药物名称】Capravirine, AG-1549, S-1153

【化学名称】Carbamic acid 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1-(4-pyridylmethyl)imidazol-2-ylmethyl ester

【CA登记号】178979-85-6, 253199-04-1 (deleted CAS)

【分子式】C₂₀H₂₀Cl₂N₄O₂S

【分子量】451.378

【开发单位】Shionogi (Originator), Pfizer (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase 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5

合成路线1

Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Sugita, K.; Makino, I.; Sugimoto, H.; et al.; Synthesis and biological activity of imidazole derivatives as a novel class of HIV-1 nonnucleoside reverse transcriptase inhibitors. Symp Med Chem 1999, Abst 2P-05.
【3】 Aono, K.; Ichihashi, T.; Sugawara, T.; Hirano, K. (Shionogi & Co. Ltd.); Lymph-absorbable imidazole derivs.. EP 0893442; US 6054591; WO 9735843 .
【4】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40725	2,2,2-trichloroacetyl isocyanate	3019-71-4	C₃Cl₃NO₂	详情	详情
(I)	35840	2,2-dichloro-3-methylbutanal		C₅H₈Cl₂O	详情	详情
(II)	26052	3-methylbutanal	590-86-3	C₅H₁₀O	详情	详情
(III)	17346	Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde	60656-87-3	C₉H₁₀O₂	详情	详情
(IV)	36995	4-[2-(1-piperidinyl)ethoxy]benzoyl chloride		C₁₄H₁₈ClNO₂	详情	详情
(V)	63296	1-({[(Z)-4-(benzyloxy)-2-butenyl]oxy}methyl)benzene; benzyl (Z)-4-(benzyloxy)-2-butenyl ether		C₁₈H₂₀O₂	详情	详情
(VI)	35841	benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole		C₁₄H₁₈N₂O	详情	详情
(VII)	35842	2-[(benzyloxy)methyl]-5-iodo-4-isopropyl-1H-imidazole; benzyl (5-iodo-4-isopropyl-1H-imidazol-2-yl)methyl ether		C₁₄H₁₇IN₂O	详情	详情
(VIII)	35843	bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene	137897-99-5	C₁₂H₆Cl₄S₂	详情	详情
(IX)	35844	benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole		C₂₀H₂₀Cl₂N₂OS	详情	详情
(X)	10844	4-(Chloromethyl)pyridine	10445-91-7	C₆H₆ClN	详情	详情
(XI)	35845	4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether		C₂₆H₂₅Cl₂N₃OS	详情	详情
(XII)	35846	[5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol		C₁₉H₁₉Cl₂N₃OS	详情	详情

合成路线2

The debenzylation of 2-(benzyloxymethyl)-5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole (IX) with hot aqueous HCl gives 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazole-2-methanol (XIII), which is condensed with chlorosulfonyl isocyanate in acetonitrile to yield carbamic acid 5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1H-imidazol-2-ylmethyl ester (XIV). Finally, this compound is alkylated with 4-(chloromethyl)pyridine (X) - obtained by reaction of 4-(hydroxymethyl)pyridine (XV) and SOCl2 in acetonitrile - by means of NaHCO3 in ethyl acetate/water.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 .

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)	35844	benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole		C₂₀H₂₀Cl₂N₂OS	详情	详情
(X)	10844	4-(Chloromethyl)pyridine	10445-91-7	C₆H₆ClN	详情	详情
(XIII)	63297	{5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methanol		C₁₃H₁₄Cl₂N₂OS	详情	详情
(XIV)	63298	{5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl}methyl carbamate		C₁₄H₁₅Cl₂N₃O₂S	详情	详情
(XV)	32835	4-pyridinylmethanol	586-95-8	C₆H₇NO	详情	详情

合成路线3

Alkylation of 2-(benzyloxymethyl)-4-isopropyl-1H-imidazole (VI) with 4-(chloromethyl)pyridine (X) by means of NaOH in toluene gives 2-(benzyloxymethyl)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazole (XVI), which is then condensed with 3,5-dichlorophenylsulfanyl chloride (XVII) - obtained by reaction of bis(3,5-dichlorophenyl)-disulfide (VIII) first with chlorine gas in CCl4 or toluene and then dried nitrogen gas - by means of triethylamine in toluene/water to afford 2-(benzyloxymethyl)-5-(3,5-dichlorophenylsulfanyl)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazole (XI). Debenzylation of compound (XI) by means of hot aqueous HCl provides the hydroxymethyl derivative (XII), which is finally esterified with chlorosulfonyl isocyanate in ethyl acetate.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Kabaki, M.; Hajima, M.; Hozumi, Y. (Shionogi & Co. Ltd.); Process for producing imidazole derivs.. EP 0949249; US 6057448; WO 9829395 .

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)	35841	benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole		C₁₄H₁₈N₂O	详情	详情
(X)	10844	4-(Chloromethyl)pyridine	10445-91-7	C₆H₆ClN	详情	详情
(XI)	35845	4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether		C₂₆H₂₅Cl₂N₃OS	详情	详情
(XII)	35846	[5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol		C₁₉H₁₉Cl₂N₃OS	详情	详情
(XV)	35843	bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene	137897-99-5	C₁₂H₆Cl₄S₂	详情	详情
(XVI)	63299	benzyl [4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether; 4-({2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazol-1-yl}methyl)pyridine		C₂₀H₂₃N₃O	详情	详情
(XVII)	63000	methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate; methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate		C₂₉H₂₈Br₂O₃	详情	详情

合成路线4

Debenzylation of 2-(benzyloxymethyl)-4-isopropyl-1-(4-pyridylmethyl)-1H-imidazole (XVI) with hot aqueous HCl gives the hydroxymethyl derivative (XVIII), which is condensed with chlorosulfonyl isocyanate in ethyl acetate to yield carbamic acid 1-(4-pyridylmethyl)-4-isopropyl-1H-imidazol-2-ylmethyl ester (XIX). Finally, this compound is condensed with 3,5-dichlorophenylsulfanyl chloride (XVII) by means of triethylamine in DMF/toluene.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Kabaki, M.; Hajima, M.; Hozumi, Y. (Shionogi & Co. Ltd.); Process for producing imidazole derivs.. EP 0949249; US 6057448; WO 9829395 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVI)	63299	benzyl [4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether; 4-({2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazol-1-yl}methyl)pyridine	C₂₀H₂₃N₃O	详情	详情
(XVII)	63000	methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate; methyl 6-[3-(1-adamantyl)-5-bromo-4-methoxyphenyl]-5-bromo-2-naphthoate	C₂₉H₂₈Br₂O₃	详情	详情
(XVIII)	63301	[4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol	C₁₃H₁₇N₃O	详情	详情
(XIX)	63302	[4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl carbamate	C₁₄H₁₈N₄O₂	详情	详情

合成路线5

Esterification of 4-isopropyl-1-(4-pyridylmethyl)-1H-imidazol-2-ylmethanol (XVIII) by means of acetyl chloride and triethylamine in dichloromethane gives the acetate ester (XX), which is condensed with 3,5-dichlorophenylsulfanyl chloride (XVII) by means of triethylamine in toluene/acetonitrile to yield the thioether (XXI). Hydrolysis of the acetate group of compound (XXI) by means of NaOH in ethanol affords the hydroxymethyl compound (XII), which is finally condensed with chlorosulfonyl isocyanate in acetonitrile.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149.
【2】 Kabaki, M.; Hajima, M.; Hozumi, Y. (Shionogi & Co. Ltd.); Process for producing imidazole derivs.. EP 0949249; US 6057448; WO 9829395 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	35846	[5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol	C₁₉H₁₉Cl₂N₃OS	详情	详情
(XVII)	63300	3,5-dichlorobenzenesulfenyl chloride	C₆H₃Cl₃S	详情	详情
(XVIII)	63301	[4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol	C₁₃H₁₇N₃O	详情	详情
(XX)	63303	[4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl acetate	C₁₅H₁₉N₃O₂	详情	详情
(XXI)	63304	[5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl acetate	C₂₁H₂₁Cl₂N₃O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)