TAK-637, -Drug Synthesis Database

【结构式】

【药物名称】TAK-637

【化学名称】(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-9-methyl-5-(4-methylphenyl)-7,8,9,10,11,13-hexahydro-6H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione

【CA登记号】183549-93-1, 183549-95-3 ((S)-isomer), 244106-86-3 (Deuterium labeled), 217185-75-6 (stereoisomer), 217186-02-2 (stereoisomer),

【分子式】C₃₀H₂₅F₆N₃O₂

【分子量】573.54305

【开发单位】Takeda (Originator)

【药理作用】Antidepressants, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Tachykinin NK1 Antagonists

合成路线1 合成路线2

合成路线1

Addition of 4-tolylmagnesium bromide (II) to 2,3-pyridinedicarboxylic acid anhydride (I) afforded ketoacid (III). Subsequent condensation of (III) with diethyl bromomalonate (VII) in the presence of Et3N, followed by DBU-promoted cyclization produced the pyridine lactone (VI). In an alternative procedure, acid (III) was converted to acid chloride (IV) using SOCl2, and then condensed with diethyl hydroxymalonate (V) in the presence of NaH to give (VI). The tertiary alcohol group of (VI) was then dehydrated with HCl in AcOH to give (VIII). Acid chloride (IX), prepared by treatment of (VIII) with SOCl2, was coupled with 3,5-bis(trifluoromethyl)benzylamine (X) to furnish amide (XI). The tetrahydropyranyl-protected aminoalcohol (XIII) was obtained by reduction of nitrile (XII) with LiAlH4. Reaction of (XIII) with lactone (XI), followed by treatment with DBU, produced the 1,7-naphthyridine system (XIV). Acid-catalyzed deprotection of the tetrahydropyranyl group yielded alcohol (XV).

参考文献中间体

【1】 Tanaka, T.; Kawada, M.; Ishichi, Y.; Kamo, I.; Ishimaru, T.; Fujishima, A.; Ikeura, Y.; Natsugari, H.; Doi, T.; Kasahara, F.; Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions. J Med Chem 1999, 42, 19, 3982.
【2】 Natsugari, H.; Ishimaru, T.; Doi, T.; Ikeura, Y.; Kimura, C. (Takeda Chemical Industries, Ltd.); Cyclic cpds., their production and use as tachykinin receptor antagonists. CA 2172421; EP 0733632; JP 1997263585; JP 1997263587; US 5786352 .

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)	17247	furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride	699-98-9	C₇H₃NO₃	详情	详情
(II)	35657	bromo(4-methylphenyl)magnesium	4294-57-9	C₇H₇BrMg	详情	详情
(III)	35643	3-(4-methylbenzoyl)-2-pyridinecarboxylic acid		C₁₄H₁₁NO₃	详情	详情
(IV)	35644	3-(4-methylbenzoyl)-2-pyridinecarbonyl chloride		C₁₄H₁₀ClNO₂	详情	详情
(V)	35645	diethyl tartronate		C₇H₁₂O₅	详情	详情
(VI)	35646	diethyl 5-hydroxy-5-(4-methylphenyl)-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine-6,6-dicarboxylate		C₂₁H₂₁NO₇	详情	详情
(VII)	35647	diethyl 2-bromomalonate	685-87-0	C₇H₁₁BrO₄	详情	详情
(VIII)	35648	5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid		C₁₆H₁₁NO₄	详情	详情
(IX)	35649	5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carbonyl chloride		C₁₆H₁₀ClNO₃	详情	详情
(X)	35650	[3,5-bis(trifluoromethyl)phenyl]methanamine; 3,5-bis(trifluoromethyl)benzylamine	85068-29-7	C₉H₇F₆N	详情	详情
(XI)	35651	N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide		C₂₅H₁₆F₆N₂O₃	详情	详情
(XII)	35652	(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile		C₁₀H₁₇NO₂	详情	详情
(XIII)	35653	(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butylamine; (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine		C₁₀H₂₁NO₂	详情	详情
(XIV)	35654	N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-7-[(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide		C₃₅H₃₅F₆N₃O₄	详情	详情
(XV)	35655	N-[3,5-bis(trifluoromethyl)benzyl]-7-[(3R)-4-hydroxy-3-methylbutyl]-5-(4-methylphenyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide		C₃₀H₂₇F₆N₃O₃	详情	详情

合成路线2

Intermediate (XV) was converted to mesylate (XVI) with methanesulfonyl chloride and Et3N. Finally, cyclization of (XVI) in the presence of NaH in refluxing THF produced the target diazocinonaphthyridine.

参考文献中间体

【1】 Tanaka, T.; Kawada, M.; Ishichi, Y.; Kamo, I.; Ishimaru, T.; Fujishima, A.; Ikeura, Y.; Natsugari, H.; Doi, T.; Kasahara, F.; Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions. J Med Chem 1999, 42, 19, 3982.
【2】 Natsugari, H.; Ishimaru, T.; Doi, T.; Ikeura, Y.; Kimura, C. (Takeda Chemical Industries, Ltd.); Cyclic cpds., their production and use as tachykinin receptor antagonists. CA 2172421; EP 0733632; JP 1997263585; JP 1997263587; US 5786352 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	35655	N-[3,5-bis(trifluoromethyl)benzyl]-7-[(3R)-4-hydroxy-3-methylbutyl]-5-(4-methylphenyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide		C₃₀H₂₇F₆N₃O₃	详情	详情
(XVI)	35656	(2R)-4-[6-([[3,5-bis(trifluoromethyl)benzyl]amino]carbonyl)-5-(4-methylphenyl)-8-oxo[1,7]naphthyridin-7(8H)-yl]-2-methylbutyl methanesulfonate		C₃₁H₂₉F₆N₃O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)