DW-286, -Drug Synthesis Database

【结构式】

【药物名称】DW-286

【化学名称】7-[3(R)-(Aminomethyl)-4(Z)-(methoxyimino)-3-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid hydrochloride

【CA登记号】309762-48-9 ((-)-enantiomer)

【分子式】C₁₉H₂₃ClFN₅O₄

【分子量】439.87766

【开发单位】Dong-Wha (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Antimycobacterial Agents, Treatment of Tuberculosis, Naphthyridines

合成路线1 合成路线2 合成路线3

合成路线1

Alkylation of ethyl 1-benzyloxycarbonyl-3-oxopyrrolidine-4-carboxylate (I) with iodomethane and K2CO3 produced the 4-methylpyrrolidine (II). The keto group of (III) was then protected as the corresponding ketal (IV) with 2,2-dimethyl-1,3-propanodiol (III). Replacement of the benzyloxycarbonyl protecting group of (IV) with a benzyl group (V) was accomplished by catalytic hydrogenolysis, followed by alkylation of the resulting pyrrolidine with benzyl chloride. The ester group of (V) was then reduced to the primary alcohol (VI) using LiAlH4. After conversion of alcohol (VI) to the corresponding mesylate, displacement with NaN3 provided the alkyl azide (VII). This was reduced to the primary amine (VIII) by catalytic hydrogenation over Raney-Ni. Resolution of the racemic amine (VIII) was carried out via acylation with N-tosyl-L-proline (IX), followed by chromatographic separation of the diastereomeric amides. Base-promoted hydrolysis of the chiral auxiliary from the desired diastereoisomer (X) provided the (R)-amine, which was further protected as the N-Boc derivative (XI). The N-benzyl group of (XI) was then removed by catalytic hydrogenolysis over Pd/C to yield the target pyrrrolidine (XII).

参考文献中间体

【1】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 .

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)	53053	1-benzyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate	n/a	C₁₅H₁₇NO₅	详情	详情
(II)	53054	1-benzyl 3-ethyl 3-methyl-4-oxo-1,3-pyrrolidinedicarboxylate	n/a	C₁₆H₁₉NO₅	详情	详情
(III)	12641	Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol	126-30-7	C₅H₁₂O₂	详情	详情
(IV)	53055	2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate	n/a	C₂₁H₂₉NO₆	详情	详情
(V)	53056	ethyl 2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-4-carboxylate	n/a	C₂₀H₂₉NO₄	详情	详情
(VI)	53057	(2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanol	n/a	C₁₈H₂₇NO₃	详情	详情
(VII)	50358	(5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one		C₁₄H₂₈O₃Si	详情	详情
(VIII)	53059	(2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanamine; (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methylamine	n/a	C₁₈H₂₈N₂O₂	详情	详情
(IX)	53060	(2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid	n/a	C₁₂H₁₅NO₄S	详情	详情
(X)	53061	(2S)-N-{[(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methyl}-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxamide	n/a	C₃₀H₄₁N₃O₅S	详情	详情
(XI)	53062	tert-butyl [(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate	n/a	C₂₃H₃₆N₂O₄	详情	详情
(XII)	53063	tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate	n/a	C₁₆H₃₀N₂O₄	详情	详情

合成路线2

In a similar procedure, ester (IV) was reduced to the corresponding alcohol (XIII) using LiAlH4. After conversion of (XIII) to the corresponding mesylate (XIV), displacement by NaN3 provided azide (XV). Reduction of (XV) to the primary amine (XVI) was effected by treatment with PPh3 in moist acetonitrile. Resolution of the racemic amine (XVI) was achieved by acylation with N-tosyl-L-proline (IX) followed by chromatographic separation. The desired isomer (XVII) was hydrolyzed with KOH in isopropanol, and the resultant amine was further protected as the N-Boc derivative (XVIII). Catalytic hydrogenolysis of (XVIII) then provided the target pyrrolidine (XII).

参考文献中间体

【1】 Lee, C.-W.; et al.; Synthesis antibacterial activities of DW286, a new fluoronaphthyridone antibiotic as an enantiomer. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-553.

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)	53055	2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate	n/a	C₂₁H₂₉NO₆	详情	详情
(IX)	50360	2-amino-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-4-pyrimidinol		C₂₁H₂₃F₂N₇O	详情	详情
(XII)	53063	tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate	n/a	C₁₆H₃₀N₂O₄	详情	详情
(XIII)	53064	benzyl 4-(hydroxymethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₁₉H₂₇NO₅	详情	详情
(XIV)	53065	benzyl 4,8,8-trimethyl-4-{[(methylsulfonyl)oxy]methyl}-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₂₀H₂₉NO₇S	详情	详情
(XV)	53066	benzyl 4-(azidomethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₁₉H₂₆N₄O₄	详情	详情
(XVI)	53067	benzyl 4-(aminomethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₁₉H₂₈N₂O₄	详情	详情
(XVII)	53068	benzyl (4R)-4,8,8-trimethyl-4-{[({(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]methyl}-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₃₁H₄₁N₃O₇S	详情	详情
(XVIII)	53069	benzyl (4R)-4-{[(tert-butoxycarbonyl)amino]methyl}-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate	n/a	C₂₄H₃₆N₂O₆	详情	详情

合成路线3

Condensation of the intermediate pyrrolidine (XII) with the fluoronaphthyridine (XIX) provided adduct (XX). Simultaneous cleavage of the ketal and N-Boc groups under acidic conditions gave (XXI). The keto group of (XXI) was finally converted to the title O-methyloxime by treatment with O-methylhydroxylamine in pyridine.

参考文献中间体

【1】 Lee, C.-W.; et al.; Synthesis antibacterial activities of DW286, a new fluoronaphthyridone antibiotic as an enantiomer. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-553.
【2】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	53063	tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate	n/a	C₁₆H₃₀N₂O₄	详情	详情
(XIX)	17034	7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid	100361-18-0	C₁₂H₈ClFN₂O₃	详情	详情
(XX)	53070	7-((4R)-4-{[(tert-butoxycarbonyl)amino]methyl}-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid	n/a	C₂₈H₃₇FN₄O₇	详情	详情
(XXI)	53071	7-[(3R)-3-(aminomethyl)-3-methyl-4-oxopyrrolidinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid	n/a	C₁₈H₁₉FN₄O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)