2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one -Drug Synthesis Database

【结构式】

【分子编号】41299

【品名】2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one

【CA登记号】59-49-4

【分子式】C₇H₅NO₂

【分子量】135.12224

【元素组成】C 62.22% H 3.73% N 10.37% O 23.68%

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：(I)

The acylation of benzoxazolin-2-one (I) with propionic anhydride (II) by means of P2O5 and MsOH gives 6-propionylbenzoxazolin-2-one (III), which is treated with chloroacetyl chloride to yield 7-propionyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (IV). The Mannich condensation of (IV) with CH2O and NH3 followed by methylation with methyl iodide affords the trimethylammonium compound (V), which by reaction with KCN, followed by hydrolysis with HCl gives 3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbonyl)butyric acid (VI). Finally this compound is cyclized with hydrazine to furnish the target pyridazinone.

参考文献中间体

合成目标

【1】 Bonte, J.P.; Lesier, D.; Lespagnol, C.; et al.; 6-Acyl benzoxazolinones. I. Eur J Med Chem - Chim Ther 1974, 9, 491.
【2】 Kryvenko, M.; Techer, H.; Lavergne, M.; et al.; Electrophilic substitutions of 2H-1,4-benzoxazine-3-one: Acylation and chlorosulfonation. CR Acad Sci Paris Ser C 1970, 270, 19, 1601.
【3】 Lesier, D.; Lespagnol, C.; Bonte, J.P.; et al.; 6-Acyl benzoxazolinones. II. Preparation of some transformation products. Eur J Med Chem - Chim Ther 1974, 9, 497-500.
【4】 Thyes, M.; Lehmann, H.D.; Gries, J.; et al.; 6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities. J Med Chem 1983, 26, 6, 800.
【5】 Moussavi, Z.; Lesieur, D.; Depreux, P.; An aternative synthesis of cardiotonic 6-(3,4-dihydro-3-oxo-1,4[2H]benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-ones. Synth Commun 1991, 21, 2, 271.
【6】 Combs, D.W.; Bemoradan and related pyridazinone cardiotonics. Drugs Fut 1993, 18, 2, 139.

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)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(I)	41299	2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one	59-49-4	C₇H₅NO₂	详情	详情
(II)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(III)	41300	6-propionyl-1,3-benzoxazol-2(3H)-one		C₁₀H₉NO₃	详情	详情
(IV)	41301	7-propionyl-2H-1,4-benzoxazin-3(4H)-one		C₁₁H₁₁NO₃	详情	详情
(V)	41302	N,N,N,2-tetramethyl-3-oxo-3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-propanaminium		C₁₅H₂₁N₂O₃	详情	详情
(VI)	41303	3-methyl-4-oxo-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)butyric acid		C₁₃H₁₃NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXVIII)

The synthetic precursor (XXIV) can be prepared by a number of alternative methods.
Condensation of 2,3-O-isopropylidene-D-glyceraldehyde (XVI) with ethyl 2-fluoropropionate (XXXI) by means of LDA in cold THF gives a mixture of diastereomeric fluoro-hydroxy esters (XXXIIa) and (XXXI-Ib) along with minor amounts of isomer (XXXIIc). After removal of the undesired (2S,3R)-isomer (XXXIIb) by selective enzymatic hydrolysis with Candida antarctica lipase form B (CALB), the remaining mixture of fluoro-hydroxy esters (XXXIIa) and (XXXIIc) undergoes cyclization to the respective lactones (XXIII) and (XXXIII) upon heating with aqueous H2SO4 (8). Esterification of the mixture of diols (XXIII) and (XXXIII) with benzoyl chloride and DMAP in Et3N/CH3CN followed by recrystallization of the resulting dibenzoates from isopropanol provides compound (XXIV) (8, 9). Scheme 4.
In a related method, chlorination of 2-fluoropropionic acid (XXXIV) with oxalyl chloride and catalytic DMF in toluene followed by reaction with pyrrolidine leads to amide (XXXV). Subsequent condensation of fluoro-amide (XXXV) with glyceraldehyde acetonide (XVI) by means of LDA in THF produces fluoro-hydroxyamide (XXXVIa), which upon heating with aqueous AcOH generates lactone (XXIII) along with minor amounts of its diastereoisomer (XXXIII). Similarly, condensation of S-phenyl 2-fluoropropanethioate (XXXVII) with aldehyde (XVI) yields hydroxy thioester (XXXVIb), which undergoes cyclization to lactones (XXIII) and (XXXIII) under acidic conditions (9). Scheme 4.
In a further related method, acyl benzoxazolone (XXXIX) —prepared by coupling 2-fluoropropionic acid (XXXIV) with benzoxazolone (XXXVIII) in the presence of DCC and DMAP— is condensed with glyceraldehyde acetonide (XVI) by means of TiCl4 and Et3N in CH2Cl2 to furnish adduct (XL). Subsequent hydrolysis and cyclization of (XL) in AcOH/H2O at 90 °C produces the mixture of lactones (XXIII) and (XXXIII) (9). Scheme 4.

参考文献中间体

合成目标

【8】 Cedilote, M., Cleary, T.P., Iding, H., Zhang, P. (F. Hoffmann-La Roche AG). Process for preparing 3,5-di-Omicron-acyl-2-fluoro-2-C-methyl-D-ribono-gamma-lactone. WO 2008074693.
【9】 Cedilote, M., Cleary, T.P., Zhang, P. (F. Hoffmann-La Roche AG). Alternate process for preparing 3,5-di-Omicron-acyl-2-fluoro-2-C-methyl-D-ribono-gamma-lactone. WO 2008090046.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXIIA)	65935			C₁₁H₁₉FO₅	详情	详情
(XXXIIB)	65936			C₁₁H₁₉FO₅	详情	详情
(XXXIIC)	65937			C₁₁H₁₉FO₅	详情	详情
(XXXVIA)	65941			C₁₃H₂₂FNO₄	详情	详情
(XXXVIB)	65942			C₁₅H₁₉FO₄S	详情	详情
(XVI)	36759	(4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde	15186-48-8	C₆H₁₀O₃	详情	详情
(XXIII)	65926	(3R,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one; (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid gamma-lactone	879551-04-9	C₆H₉FO₄	详情	详情
(XXIV)	65927	(2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic acid gamma-lactone 3,5-dibenzoate	874638-80-9	C₂₀H₁₇FO₆	详情	详情
(XXXI)	65934	Ethyl 2-fluoropropionate; Ethyl 2-fluoropropanoate; 2-Fluoropropanoic acid ethyl ester	349-43-9	C₅H₉FO₂	详情	详情
(XXXIII)	65938	(3S,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one		C₆H₉FO₄	详情	详情
(XXXIV)	65939	2-Fluoropropionic acid	6087-13-4	C₃H₅FO₂	详情	详情
(XXXV)	65940			C₇H₁₂FNO	详情	详情
(XXXVII)	65943			C₉H₉FOS	详情	详情
(XXXVIII)	41299	2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one	59-49-4	C₇H₅NO₂	详情	详情
(XXXIX)	65944			C₁₀H₈FNO₃	详情	详情
(XL)	65945			C₁₆H₈FNO₆	详情	详情

Extended Information