3-bromo-2,6-difluorophenol -Drug Synthesis Database

【结构式】

【分子编号】34648

【品名】3-bromo-2,6-difluorophenol

【CA登记号】221220-99-1

【分子式】C₆H₃BrF₂O

【分子量】208.9900264

【元素组成】C 34.48% H 1.45% Br 38.23% F 18.18% O 7.66%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

Aromatic hydroxylation of 1-bromo-2,4-difluorobenzene (I) using tert-butyl hydroperoxide and LDA afforded phenol (II), which was methylated with iodomethane and K2CO3 to give methyl ether (III). The required benzoic acid (IV) was then obtained from (III) by lithium-bromine exchange with n-butyllithium, followed by carboxylation with CO2 gas at -70 C. Treatment of (IV) with oxalyl chloride and DMF gave acid chloride (V). This was condensed with the lithium salt of monoethyl malonate to yield, after acid decarboxylation, ketoester (VI). Subsequent condensation of (VI) with triethyl orthoformate in refluxing Ac2O provided methoxyacrylate (VII), and further treatment with cyclopropylamine (VIII) furnished aminoacrylate (IX). Cyclization of (IX) by means of NaH in THF generated the quinolone system (X). Acid hydrolysis of the ethyl ester group of (X) gave quinolinecarboxylic acid (XI), which was converted to the boron difluoride complex (XII) by treatment with BF3-Et2O in hot THF. Displacement of the aromatic fluorine of (XII) with 3R-(1S-tert-butoxycarbonylaminoethyl)pyrrolidine (XIII) in the presence of DIEA, followed by boron complex cleavage with Et3N in EtOH provided the pyrrolidinylquinoline (XIV). Finally, the Boc protecting group of (XIV) was removed by hydrolysis with ethanolic HCl.

参考文献中间体

合成目标

【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15086	3-ethoxy-3-oxopropionic acid	1071-46-1	C₅H₈O₄	详情	详情
(I)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(II)	34648	3-bromo-2,6-difluorophenol	221220-99-1	C₆H₃BrF₂O	详情	详情
(III)	34649	3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene	221221-00-7	C₇H₅BrF₂O	详情	详情
(IV)	30621	2,4-difluoro-3-methoxybenzoic acid	178974-97-5	C₈H₆F₂O₃	详情	详情
(V)	34650	2,4-difluoro-3-methoxybenzoyl chloride		C₈H₅ClF₂O₂	详情	详情
(VI)	34651	ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate		C₁₂H₁₂F₂O₄	详情	详情
(VII)	34652	ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate		C₁₅H₁₆F₂O₅	详情	详情
(VIII)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(IX)	34653	ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate		C₁₆H₁₇F₂NO₄	详情	详情
(X)	34654	ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₆H₁₆FNO₄	详情	详情
(XI)	34655	1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid	221221-16-5	C₁₄H₁₂FNO₄	详情	详情
(XII)	34656			C₁₄H₁₁BF₃NO₄	详情	详情
(XIII)	34657	tert-butyl (1S)-1-[(3R)pyrrolidinyl]ethylcarbamate		C₁₁H₂₂N₂O₂	详情	详情
(XIV)	34658	7-((3R)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]ethyl]pyrrolidinyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid		C₂₅H₃₃N₃O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Metalation of 1-bromo-2,4-difluorobenzene (I) by means of LDA, followed by treatment with tert-butyl hydroperoxide gave rise to phenol (II), which was further converted to methyl ether (III) by alkylation with iodomethane and K2CO3. Lithium halogen exchange of (III) with n-butyllithium, and subsequent quenching with CO2 produced 3-methoxy-2,4-difluorobenzoic acid (IV). After activation of (IV) as the acid chloride (V), condensation with the lithium derivative of monoethyl malonate (A) led to the benzoyl acetate ester (VI). The benzoyl ethoxyacrylate (VII), obtained by condensation of ketoester (VI) with triethyl orthoformate, was then reacted with cyclopropylamine (VIII) to afford enamine (IX). This was cyclized to the quinolone compound (X) upon treatment with NaH in THF. Acidic hydrolysis of ester (X) gave a keto acid, which was subsequently converted to the boron chelate (XI) by treatment with boron trifluoride etherate. Fluoride displacement of quinolone (XI) with the amino piperidine (XII) produced the piperidino quinolone (XIII). The boron difluoride complex of (XIII) was finally removed by means of triethylamine in boiling EtOH.

参考文献中间体

合成目标

【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	15086	3-ethoxy-3-oxopropionic acid	1071-46-1	C₅H₈O₄	详情	详情
(I)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(II)	34648	3-bromo-2,6-difluorophenol	221220-99-1	C₆H₃BrF₂O	详情	详情
(III)	34649	3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene	221221-00-7	C₇H₅BrF₂O	详情	详情
(IV)	30621	2,4-difluoro-3-methoxybenzoic acid	178974-97-5	C₈H₆F₂O₃	详情	详情
(V)	34650	2,4-difluoro-3-methoxybenzoyl chloride		C₈H₅ClF₂O₂	详情	详情
(VI)	34651	ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate		C₁₂H₁₂F₂O₄	详情	详情
(VII)	34652	ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate		C₁₅H₁₆F₂O₅	详情	详情
(VIII)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(IX)	34653	ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate		C₁₆H₁₇F₂NO₄	详情	详情
(X)	34654	ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₆H₁₆FNO₄	详情	详情
(XI)	59792	1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-7-fluoro-8-methoxy-4(1H)-quinolinone		C₁₄H₁₁BF₃NO₄	详情	详情
(XII)	59793	(3S,4R)-4-ethyl-3-piperidinamine; (3S,4R)-4-ethylpiperidinylamine		C₇H₁₆N₂	详情	详情
(XIII)	59794	7-[(3S,4R)-3-amino-4-ethylpiperidinyl]-1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-methoxy-4(1H)-quinolinone		C₂₁H₂₆BF₂N₃O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIV)

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

合成目标

【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

Extended Information