L-374943, -Drug Synthesis Database

【结构式】

【药物名称】L-374943

【化学名称】1-[1-[2-[4-(1-Acetylpiperidin-4-yloxy)-2-(2,2,2-trifluoroethoxy)phenyl]acetyl]piperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one

【CA登记号】221284-06-6

【分子式】C₃₀H₃₄F₃N₃O₆

【分子量】589.61718

【开发单位】Merck & Co. (Originator)

【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Tocolytics, Uterine Stimulants and Tocolytics, Oxytocin Antagonists

合成路线1 合成路线2

合成路线1

4-Piperidinone hydrochloride (I) was protected as the tert-butyl carbamate (II) using Boc2O and diisopropyl ethylamine. Condensation of (II) with 2-aminobenzyl alcohol (III) in boiling toluene, followed by reduction with sodium cyanoborohydride gave secondary amine (IV). Subsequent cyclization of (IV) in the presence of triphosgene and diisopropyl ethylamine produced the benzoxazinone (V), from which the Boc group was removed with HCl in EtOAc to yield intermediate (VI).

参考文献中间体

【1】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 .

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)	27115	4-piperidinone	40064-34-4	C₅H₉NO	详情	详情
(II)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(III)	18619	(2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol	5344-90-1	C₇H₉NO	详情	详情
(IV)	18621	tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate		C₁₇H₂₆N₂O₃	详情	详情
(V)	18622	tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate		C₁₈H₂₄N₂O₄	详情	详情
(VI)	19420	1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one		C₁₃H₁₆N₂O₂	详情	详情

合成路线2

Regioselective Mitsunobu condensation of 2',4'-dihydroxyacetophenone (VII) with N-Boc-4-piperidinol (VIII) afforded ether (IX). The 2'-hydroxyl group of (IX) was then alkylated with 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of Cs2CO3 to give (X). Oxidative rearrangement of the acetophenone (X) employing thallium trinitrate and trimethyl orthoformate generated the phenylacetic ester (XI), which was hydrolyzed to acid (XII) with NaOH in aqueous MeOH. Subsequent EDC-mediated coupling of (XII) with piperidine intermediate (VI) yielded amide (XIII). The N-Boc group of (XIII) was cleaved using HCl in EtOAc, and the secondary amine (XIV) was acylated with acetic anhydride in the presence of diisopropyl ethylamine to afford the target acetamide.

参考文献中间体

【1】 Bock, M.G.; Evans, B.E.; Williams, P.D.; et al.; Nonpeptide oxytocin antagonists: Analogs of L-371,257 with improved potency. Bioorg Med Chem Lett 1999, 9, 9, 1311.
【2】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40675	2,2,2-trifluoroethyl trifluoromethanesulfonate	6226-25-1	C₃H₂F₆O₃S	详情	详情
(VI)	19420	1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one		C₁₃H₁₆N₂O₂	详情	详情
(VII)	13961	Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone	89-84-9	C₈H₈O₃	详情	详情
(VIII)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(X)	27110	tert-butyl 4-[4-acetyl-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₂₀H₂₆F₃NO₅	详情	详情
(XI)	27111	tert-butyl 4-[4-(2-methoxy-2-oxoethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₂₁H₂₈F₃NO₆	详情	详情
(XII)	27112	2-[4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-(2,2,2-trifluoroethoxy)phenyl]acetic acid		C₂₀H₂₆F₃NO₆	详情	详情
(XIII)	27113	tert-butyl 4-[4-(2-oxo-2-[4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]ethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₃₃H₄₀F₃N₃O₇	详情	详情
(XIV)	27114	phenyl(1-[2-[4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl]acetyl]-4-piperidinyl)formamide		C₂₇H₃₂F₃N₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)