-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4(S)-[3-[2-[3(S)-[1(S)-Phenylethylaminomethyl]-1-pyrrolidinyl]ethyl]-1H-indol-5-ylmethyl]oxazolidin-2-one dioxalate

【CA登记号】179636-85-2, 179636-84-1 (free base)

【分子式】C₃₁H₃₈N₄O₁₀

【分子量】626.66931

【开发单位】Merck Sharp & Dohme (Originator)

【药理作用】Pharmacological Tools, 5-HT1D Agonists

合成路线1 合成路线2 合成路线3

合成路线1

Hydrogenation of the enantiomerically pure 1-(alpha-methylbenzyl)-3-(hydroxymethyl)pyrrolidine (I) in the presence of Pearlman's catalyst and di-tert-butyl dicarbonate produced the N-Boc pyrrolidine (II). Reaction of (II) with methanesulfonyl chloride, followed by condensation of the resulting mesylate (III) with (S)-alpha-methylbenzylamine (IV) in toluene at 150 C in a sealed tube afforded the aminomethyl pyrrolidine derivative (V). Then, acidic cleavage of the Boc protecting group yielded pyrrolidine (VI).

参考文献中间体

【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677.
【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 .

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)	34461	[(3R)-1-[(1R)-1-phenylethyl]pyrrolidinyl]methanol		C₁₃H₁₉NO	详情	详情
(II)	34462	tert-butyl (3R)-3-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(III)	34463	1-Boc-3-methanesulfonyloxymethylpyrrolidine; 1-Boc-3-methanesulfonyloxymethylpyrrolidine	141699-56-1	C₁₁H₂₁NO₅S	详情	详情
(IV)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(V)	34464	tert-butyl (3S)-3-([[(1S)-1-phenylethyl]amino]methyl)-1-pyrrolidinecarboxylate		C₁₈H₂₈N₂O₂	详情	详情
(VI)	34465	N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine		C₁₃H₂₀N₂	详情	详情

合成路线2

Halogenation of the substituted aniline (VII) by means of iodine monochloride gave ortho-iodoaniline (VIII). 3-Butyn-1-ol (IX) was protected as the 1,4-bis(triethylsilyl)derivative (X) by deprotonation with butyllithium, followed by treatment with triethylsilyl chloride. Palladium-catalyzed condensation of disilylated butynol (X) with iodoaniline (VIII) furnished a mixture of the bis(silylated) tryptophol (XI) and the O-desilylated analogue (XII). Treatment of the crude mixture with methanolic HCl produced the completely desilylated indole (XIII), which was converted to mesylate (XIV) by reaction with methanesulfonyl chloride and triethylamine. Alkylation of pyrrolidine (VI) with mesylate (XIV) then yielded the target (indolylethyl)pyrrolidine, which was finally converted to the title dioxalate salt.

参考文献中间体

【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677.
【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 .

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)	34465	N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine		C₁₃H₂₀N₂	详情	详情
(VI)	34470	2-(5-[[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl]-1H-indol-3-yl)ethyl methanesulfonate		C₁₅H₁₈N₂O₅S	详情	详情
(VII)	15345	(4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one		C₁₀H₁₂N₂O₂	详情	详情
(VIII)	34466	(4S)-4-(4-amino-3-iodobenzyl)-1,3-oxazolidin-2-one		C₁₀H₁₁IN₂O₂	详情	详情
(IX)	32507	3-butyn-1-ol	927-74-2	C₄H₆O	详情	详情
(X)	16862	triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane	160194-28-5	C₁₆H₃₄OSi₂	详情	详情
(XI)	34467	(4S)-4-[(2-(triethylsilyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indol-5-yl)methyl]-1,3-oxazolidin-2-one		C₂₆H₄₄N₂O₃Si₂	详情	详情
(XII)	34468	(4S)-4-[[3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one		C₂₀H₃₀N₂O₃Si	详情	详情
(XIII)	34469	(4S)-4-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one		C₁₄H₁₆N₂O₃	详情	详情

合成路线3

An alternative process consisted in the palladium-catalyzed condensation of iodoaniline (VIII) with the acyl silane (XV), to produce the 2-silyl indole (XVI). Then, acid desilylation of (XVI), followed by treatment with oxalic acid yielded the title compound.

参考文献中间体

【1】 Chen, C.-Y.; Larsen, R.D. (Merck & Co., Inc.); Palladium catalyzed indolization. US 5808064; WO 9806725 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	34466	(4S)-4-(4-amino-3-iodobenzyl)-1,3-oxazolidin-2-one	C₁₀H₁₁IN₂O₂	详情	详情
(XV)	34471	3-[(3S)-3-([[(1S)-1-phenylethyl]amino]methyl)pyrrolidinyl]-1-(trimethylsilyl)-1-propanone	C₁₉H₃₂N₂OSi	详情	详情
(XVI)	34472	(4S)-4-[[3-[2-[(3S)-3-([[(1S)-1-phenylethyl]amino]methyl)pyrrolidinyl]ethyl]-2-(trimethylsilyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one	C₃₀H₄₂N₄O₂Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)