2-bromo-1-(2,4-difluorophenyl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】47646

【品名】2-bromo-1-(2,4-difluorophenyl)-1-ethanone

【CA登记号】

【分子式】C₈H₅BrF₂O

【分子量】235.0279064

【元素组成】C 40.88% H 2.14% Br 34% F 16.17% O 6.81%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.

参考文献中间体

合成目标

【1】 Bartroli, J.; et al.; Aldol condensation of Evans chiral enolates with acetophenones. Its application to the stereoselective synthesis of homochiral antifungal agents. J Org Chem 1995, 60, 10, 3000.
【2】 Bartroli, J.; et al.; New azole antigungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J Med Chem 1998, 41, 11, 1869.
【3】 Bartrolí, J.; Turmo, E.; Anguita, M. (J. Uriach & Cía., SA); New pyrimidone derivs. with antifungal activity. EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130 .

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)	25713	(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one		C₁₃H₁₅NO₃	详情	详情
(II)	47646	2-bromo-1-(2,4-difluorophenyl)-1-ethanone		C₈H₅BrF₂O	详情	详情
(III)	56711	(4S)-4-benzyl-3-{(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoyl}-1,3-oxazolidin-2-one		C₂₁H₁₉F₂NO₄	详情	详情
(IV)	56712	(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoic acid		C₁₁H₁₀F₂O₃	详情	详情
(V)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(VI)	56713	(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid		C₁₃H₁₃F₂N₃O₃	详情	详情
(VII)	56714	(4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-oxazolidin-2-one		C₁₃H₁₂F₂N₄O₂	详情	详情
(VIII)	56715	(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₂H₁₄F₂N₄O	详情	详情
(IX)	52504	4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid	89-77-0	C₇H₆ClNO₂	详情	详情
(X)	56716	2-amino-4-chloro-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]benzamide		C₁₉H₁₈ClF₂N₅O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).

参考文献中间体

合成目标

【1】 Kaneko, Y.; Takeda, S.; Eto, H.; et al.; New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety. Chem Pharm Bull 2001, 49, 2, 173.
【2】 Sato, S.; Kaneko, Y.; Takeda, S.; Eto, H.; Tokizawa, M.; SS750, a new triazole agent: Structure-activity relationship of novel triazole-containing gem-difluoromethylsulfonyl moiety. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1080.
【3】 Matsumoto, M.; Kaneko, Y.; Maebashi, K.; Takeda, S.; Sato, S.; Tokizawa, M.; Ishida, K.; Eto, H.; Asaoka, T. (SSP Co., Ltd.); Triazole deriv. or salt thereof, preparation process thereof as well as pharmaceutical containing said cpd.. CA 2256060; EP 0927719; JP 1999240871; US 6083968 .

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)	13095	m-Difluorobenzene; 1,3-Difluorobenzene	372-18-9	C₆H₄F₂	详情	详情
(II)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(III)	47646	2-bromo-1-(2,4-difluorophenyl)-1-ethanone		C₈H₅BrF₂O	详情	详情
(IV)	23712	1-ethanethiol; ethylhydrosulfide	75-08-1	C₂H₆S	详情	详情
(V)	47647	1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-1-ethanone		C₁₀H₁₀F₂OS	详情	详情
(VI)	47648	1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-2,2-difluoro-1-ethanone		C₁₀H₈F₄OS	详情	详情
(VII)	47649	2-(2,4-difluorophenyl)-2-[(ethylsulfanyl)(difluoro)methyl]oxirane; [2-(2,4-difluorophenyl)-2-oxiranyl](difluoro)methyl ethyl sulfide		C₁₁H₁₀F₄OS	详情	详情
(VIII)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(IX)	47650	2-(2,4-difluorophenyl)-1-(ethylsulfanyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol		C₁₃H₁₃F₄N₃OS	详情	详情
(X)	47651	2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol		C₁₃H₁₃F₄N₃O₃S	详情	详情
(XI)	47652	Chlorodifluoroacetic acid ethyl ester; Difluorochloroacetic acid ethyl ester; Ethyl chlorodifluoroacetate; ethyl 2-chloro-2,2-difluoroacetate	383-62-0	C₄H₅ClF₂O₂	详情	详情
(XII)	47653	ethyl 2-(ethylsulfanyl)-2,2-difluoroacetate		C₆H₁₀F₂O₂S	详情	详情
(XIII)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情

Extended Information