L-372662, -Drug Synthesis Database

【结构式】

【药物名称】L-372662

【化学名称】1-[1-[2-Methoxy-4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]benzoyl]piperidin-4-yl]-2,4-dihydro-1H-3,1-benzoxazin-2-one

【CA登记号】162045-26-3

【分子式】C₃₃H₃₈N₄O₆

【分子量】586.69401

【开发单位】Merck & Co. (Originator)

【药理作用】Oxytocin Antagonists

合成路线1 合成路线2

合成路线1

1) 2-Aminobenzyl alcohol (I) was condensed with N-tert-butoxycarbonyl-4-piperidone (II) in toluene with azeotropical removal of water, and the resulting imine (III) was reduced with sodium cyanoborohydride to yield the secondary amine (IV). Further treatment of (IV) with triphosgene in the presence of N,N-diisopropyl ethylamine (DIEA) produced the benzoxazinone (V), which was then deprotected with HCl in EtOAc to give piperidine (VI).

参考文献中间体

【1】 Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl]piperidin-4-yl)-1, 4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines. J Med Chem 1998, 41, 12, 2146.
【2】 Bock, M.G.; Evans, B.E.; Hobbs, D.W.; Williams, P.D.; Anderson, P.S.; Freidinger, R.M.; Pettibone, D.J. (Merck & Co., Inc.); Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. EP 0714299; JP 1997500134; US 5665719; WO 9502405 .

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)	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
(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)	19417	tert-butyl 4-[[2-(hydroxymethyl)phenyl]imino]-1-piperidinecarboxylate		C₁₇H₂₄N₂O₃	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
(VII)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(VIII)	16623	methyl 2,4-dihydroxybenzoate	2150-47-2	C₈H₈O₄	详情	详情
(IX)	19423	tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate		C₁₈H₂₅NO₆	详情	详情
(X)	18627	tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate		C₁₉H₂₇NO₆	详情	详情
(XI)	18628	4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid		C₁₈H₂₅NO₆	详情	详情

合成路线2

2) Acidic removal of the tert-butyl carbamate from (XII) gave piperidine (XIII). 3) Ethyl 2-methyl nicotinate (XIV) was reduced with diisobutylaluminum hydride (DIBAL-H) to the alcohol (XV). Treatment of (XV) with SOCl2 in CH2Cl2 gave chloride (XVI), which was isolated as the stable HCl salt. Liberation of the base, followed by reaction with 3-chloroperbenzoic acid in CHCl3, provided the N-oxide (XVII). 4) Finally, piperidine (XIII) was alkylated with chloride (XVII) in the presence of DIEA in DMF at 50 C to yield the target compound.

参考文献中间体

【1】 Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl]piperidin-4-yl)-1, 4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines. J Med Chem 1998, 41, 12, 2146.
【2】 Bock, M.G.; Evans, B.E.; Hobbs, D.W.; Williams, P.D.; Anderson, P.S.; Freidinger, R.M.; Pettibone, D.J. (Merck & Co., Inc.); Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. EP 0714299; JP 1997500134; US 5665719; WO 9502405 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	19427	1-[1-[2-methoxy-4-(4-piperidinyloxy)benzoyl]-4-piperidinyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one		C₂₆H₃₁N₃O₅	详情	详情
(XIV)	19428	ethyl 2-methylnicotinate	1721-26-2	C₉H₁₁NO₂	详情	详情
(XV)	19429	(2-methyl-3-pyridinyl)methanol	56826-61-0	C₇H₉NO	详情	详情
(XVI)	19430	3-(chloromethyl)-2-methylpyridine hydrochloride		C₇H₉Cl₂N	详情	详情
(XVII)	19431	3-(chloromethyl)-2-methyl-1-pyridiniumolate		C₇H₈ClNO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)