Nemonoxacin, TG-873870, -Drug Synthesis Database

【结构式】

【药物名称】Nemonoxacin, TG-873870

【化学名称】7-[(3S,5S)-3-amino-5-methylpiperidin-1-yl]-1-cyclopropyl-8-methoxy-4- oxo-1,4-dihydroquinoline-3-carboxylic acid

【CA登记号】378746-64-6

【分子式】C₂₀H₂₅N₃O₄

【分子量】371.4302

【开发单位】Procter & Gamble Pharmaceuticals (US); licensed to TaiGen Biotechnology for development and commercialization in China, Taiwan, Hong Kong, Singapore, Korea and other ASEAN countries.

【药理作用】Quinolone Antibiotic

合成路线1 合成路线2 合成路线3

合成路线1

Esterification of L-pyroglutamic acid (I) using SOCl2 in MeOH, followed by protection of the resulting methyl ester (II) with Boc2O and DMAP in acetonitrile affords N-Boc-L-pyroglutamic acid methyl ester (III). Subsequent treatment of pyroglutamate (III) with Bredereck’s reagent in hot DME yields the [(dimethylamino)methylene]pyrrolidinone (IV), which is diastereoselectively reduced to the 4(S)-methyl derivative (V) by catalytic hydrogenation over Pd/C. Further reduction of the amide and ester groups of compound (V) using in situ-generated Ca(BH4)2 in EtOH/MTBE furnishes diol (VI), which is converted to the bis-mesylate (VII) under the usual conditions. The bis-mesylate (VII) is then cyclized with benzylamine in refluxing dimethoxyethane followed by catalytic hydrogenolysis of the resulting N-benzylpiperidine (VIII) to provide 3(S)-Boc-amino-5(S)-methylpiperidine (IX). Coupling of the protected aminopiperidine (IX) with the fluoroquinolone boron chelate (X) in the presence of Et3N in hot acetonitrile affords, after alkaline decomplexation, the piperidinyl quinolone (XI), which is finally deprotected by treatment with HCl in CH2Cl2 (1, 2). Scheme 1.

参考文献中间体

【1】 Reilly, M. (The Procter & Gamble Co.). A coupling process for preparing quinolone intermediates. CA 2647454, EP 1999125, US 2007232804, US 7456279, WO 2007110835.
【2】 Hayes, M.P., Schunk, T.T. (The Procter & Gamble Co.). A hydride reduction process for preparing quinolone intermediates. CA 2647457, EP 1999106, US 2007232806, WO 2007110836.

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)	65879	L-Pyroglutamic acid; 5-Oxoproline; 5-Oxopyrrolidine-2-carboxylic acid; L-5-Pyrrolidone-2-carboxylic acid; (S)-(-)-2-Pyrrolidone-5-carboxylic acid	98-79-3	C₅H₇NO₃	详情	详情
(II)	65880	Methyl L-pyroglutamate; Methyl (S)-(+)-2-pyrrolidone-5-carboxylate	4931-66-2	C₆H₉NO₃	详情	详情
(III)	65881	Boc-L-Pyroglutamic acid methyl ester; Boc-Pyr-Ome	108963-96-8	C₁₁H₁₇NO₅	详情	详情
(IV)	65882			C₁₄H₂₂N₂O₅	详情	详情
(V)	65883			C₁₂H₁₉NO₅	详情	详情
(VI)	65884			C₁₁H₂₃NO₄	详情	详情
(VII)	65885			C₁₃H₂₇NO₄	详情	详情
(VIII)	65886	1-Benzyl-3(S)-boc-amino-5(S)-methylpiperidine		C₁₈H₂₈N₂O₂	详情	详情
(IX)	65887	3(S)-Boc-amino-5(S)-methylpiperidine		C₁₁H₂₂N₂O₂	详情	详情
(X)	65888			C₁₈H₁₇BFNO₆	详情	详情
(XI)	65889			C₂₅H₃₃N₃O₆	详情	详情

合成路线2

In an alternative route to the quinolone precursor (XX), deprotonation of 2,4-difluorobromobenzene (XXIII) with LDA in THF followed by addition of tert-butyl hydroperoxide gives 3-bromo-2,6-difluorophenol (XXIV), which is converted to the corresponding methyl ether (XXV) by treatment with iodomethane and K2CO3. Metalation of the aryl bromide (XXV) with butyl lithium in cold diethyl ether and subsequent addition of CO2 gas leads to 3-methoxy-2,4-difluorobenzoic acid (XXVI). After chlorination of acid (XXVI) with oxalyl chloride and catalytic DMF, the obtained acid chloride (XXVII) is condensed with monoethyl malonate (XXVIII) in the presence of butyl lithium in THF at –50 °C to yield the 2-(benzoyl)acetate (XVII). Subsequent reaction of keto ester (XVII) with triethyl orthoformate in boiling Ac2O provides the enol ether (XXIX), which is then condensed with cyclopropylamine (XIX) in EtOH to give the key enamine (XX) (3). Scheme 3.

参考文献中间体

【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	34651	ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate		C₁₂H₁₂F₂O₄	详情	详情
(XIX)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(XX)	34653	ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate		C₁₆H₁₇F₂NO₄	详情	详情
(XXIII)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(XXIV)	34648	3-bromo-2,6-difluorophenol	221220-99-1	C₆H₃BrF₂O	详情	详情
(XXV)	34649	3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene	221221-00-7	C₇H₅BrF₂O	详情	详情
(XXVI)	30621	2,4-difluoro-3-methoxybenzoic acid	178974-97-5	C₈H₆F₂O₃	详情	详情
(XXVII)	34650	2,4-difluoro-3-methoxybenzoyl chloride		C₈H₅ClF₂O₂	详情	详情
(XXVIII)	15086	3-ethoxy-3-oxopropionic acid	1071-46-1	C₅H₈O₄	详情	详情
(XXIX)	34652	ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate		C₁₅H₁₆F₂O₅	详情	详情

合成路线3

The intermediate quinolone boron chelate (X) is prepared as follows. Ketalization of 2’,4’-difluoroacetophenone (XII) with ethylene glycol and p-TsOH provides compound (XIII), which is hydroxylated to phenol (XIV) by ortho-metalation with BuLi in THF at –65 °C, followed by treatment with trimethyl borate in AcOH and then with aqueous H2O2. Acidic hydrolysis of the ethylene ketal moiety of compound (XIV) provides the hydroxyketone (XV), which is alkylated with dimethyl sulfate and K2CO3 in toluene to give 2’,4’-difluoro-3’-methoxyacetophenone (XVI). Carboxylation of acetophenone (XVI) with diethyl carbonate and NaH gives the 2-(benzoyl)acetate (XVII), which is further condensed with dimethylformamide dimethyl acetal (DMFDMA) to produce adduct (XVIII). Subsequent displacement of the dimethylamino group of (XVIII) with cyclopropylamine (XIX) in hot toluene furnishes the N-cyclopropyl analogue (XX) (1, 2). Then, cyclization of (XX) by means of either NaH in THF or N,O-bis(trimethylsilyl)acetamide (BSA) in boiling toluene yields the quinolone carboxylate (XXI), which is hydrolyzed to the corresponding carboxylic acid (XXII) under acidic conditions. Finally, the boron chelate (X) is obtained by complexation of the keto acid (XXII) with the reagent generated from boron oxide and acetic anhydride in AcOH (1-3). Scheme 2.

参考文献中间体

【1】 Reilly, M. (The Procter & Gamble Co.). A coupling process for preparing quinolone intermediates. CA 2647454, EP 1999125, US 2007232804, US 7456279, WO 2007110835.
【2】 Hayes, M.P., Schunk, T.T. (The Procter & Gamble Co.). A hydride reduction process for preparing quinolone intermediates. CA 2647457, EP 1999106, US 2007232806, WO 2007110836.
【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	65888			C₁₈H₁₇BFNO₆	详情	详情
(XII)	65890	2',4'-Difluoroacetophenone; 1-(2,4-Difluorophenyl)ethanone	364-83-0	C₈H₆F₂O	详情	详情
(XIII)	65891	2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolane		C₁₀H₁₀F₂O₂	详情	详情
(XIV)	65892	2-(2,4-difluoro-3-hydroxyphenyl)-2-methyl-1,3-dioxolane		C₁₀H₁₀F₂O₃	详情	详情
(XV)	65893	2',4'-Difluoro-3'-hydroxyacetophenone; 1-(2,4-Difluoro-3-hydroxyphenyl)ethanone	951163-65-8	C₈H₆F₂O₂	详情	详情
(XVI)	65894	2',4'-Difluoro-3'-methoxyacetophenone; 1-(2,4-Difluoro-3-methoxyphenyl)ethanone	373603-19-1	C₉H₈F₂O₂	详情	详情
(XVII)	34651	ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate		C₁₂H₁₂F₂O₄	详情	详情
(XVIII)	65895			C₁₅H₁₇F₂NO₄	详情	详情
(XIX)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(XX)	34653	ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate		C₁₆H₁₇F₂NO₄	详情	详情
(XXI)	34654	ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₆H₁₆FNO₄	详情	详情
(XXII)	34655	1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	221221-16-5	C₁₄H₁₂FNO₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)