CP-93318, -Drug Synthesis Database

【结构式】

【药物名称】CP-93318

【化学名称】4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole

【CA登记号】129486-32-4, 130096-16-1 (tritiated analog)

【分子式】C₁₅H₁₅N₃OS

【分子量】285.3703

【开发单位】Pfizer Central Research (Originator)

【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists

合成路线1 合成路线2

合成路线1

The synthesis of CP-93,318 is summarized: Treatment of 4-methyl-5-imidazolemethanol (I) with thionyl chloride affords chloromethylimidazole (II). Exposure of (II) to potassium cyanide provides nitrile (III), and subsequent reaction of (III) with diethyldithiophosphate in the presence of hydrochloric acid gives thioamide (IV), as its hydrochloride salt. Condensation of this hygroscopic salt with 2-bromo-2'-methoxyacetophenone (V) provides thiazole CP-93,318. Analogues of CP-93,318, modified at the methoxyphenyl moiety, were prepared similarly by condensation of convergent intermediate (IV) and the appropriate alpha-haloketone.

参考文献中间体

【1】 Rizzi, J.P.; Guarino, K.; Vincent, L.A.; Ganong, A.H.; Siok, C.J.; Ives, J.L.; Nowakowski, J.T.; Seeger, T.F.; Rosen, T.; Heym, J.; Nagel, A.A.; Daffeh, J.B.; McLean, S.; Schmidt, A.W.; Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists. J Med Chem 1990, 33, 2715-20.
【2】 Rosen, T.; Nagel, A.A.; CP-93,318. Drugs Fut 1991, 16, 11, 992.

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)	14216	(5-Methyl-1H-imidazol-4-yl)methanol	29636-87-1	C₅H₈N₂O	详情	详情
(II)	14217	4-(Chloromethyl)-5-methyl-1H-imidazole		C₅H₇ClN₂	详情	详情
(III)	14218	2-(5-Methyl-1H-imidazol-4-yl)acetonitrile		C₆H₇N₃	详情	详情
(IV)	14219	2-(5-Methyl-1H-imidazol-4-yl)ethanethioamide hydrochloride		C₆H₉N₃S	详情	详情
(V)	14220	2-Bromo-1-(2-methoxyphenyl)-1-ethanone	31949-21-0	C₉H₉BrO₂	详情	详情

合成路线2

The synthesis of a tritiated analogue of CP-93,318 is as follows: Treatment of the phenacyl bromide (V) with N-bromosuccinimide in methanol affords selectively bromo derivative (VI). Subsequent condensation of (VI) and thioamide (IV) (Scheme 1) provides tritiation precursor (VII). Exposure of (VII) to tritium in the presence of palladium on carbon (triethylamine/tetrahydrofuran) followed by purification using high-performance liquid chromatography provides [3H]-CP-93,318 (specific activity: 16.2 Ci/mmol, radiochemical purity greater than or equal to 98%).

参考文献中间体

【1】 Guarino, K.J.; Furman, J.; Rosen, T.; Chalabi, P.M.; Ives, J.L.; Windels, J.H.; McLean, S.; Nagel, A.A.; Bryce, D.; Seeger, T.F.; Roth, R.W.; Synthesis, in vitro binding profile, and central nervous system penetrability of the highly potent 5-HT3 receptor antagonist [3H]-4-(2-methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole. J Med Chem 1990, 33, 11, 3020-3.
【2】 Rosen, T.; Nagel, A.A.; CP-93,318. Drugs Fut 1991, 16, 11, 992.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	14219	2-(5-Methyl-1H-imidazol-4-yl)ethanethioamide hydrochloride		C₆H₉N₃S	详情	详情
(V)	14220	2-Bromo-1-(2-methoxyphenyl)-1-ethanone	31949-21-0	C₉H₉BrO₂	详情	详情
(VI)	14221	2-Bromo-1-(5-bromo-2-methoxyphenyl)-1-ethanone		C₉H₈Br₂O₂	详情	详情
(VII)	14222	4-Bromo-2-[2-[(5-methyl-1H-imidazol-4-yl)methyl]-1,3-thiazol-4-yl]phenyl methyl ether; 4-(5-Bromo-2-methoxyphenyl)-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1,3-thiazole		C₁₅H₁₄BrN₃OS	详情	详情

Extended Information