2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide -Drug Synthesis Database

【结构式】

【分子编号】19267

【品名】2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide

【CA登记号】497-23-4

【分子式】C₄H₄O₂

【分子量】84.07456

【元素组成】C 57.14% H 4.8% O 38.06%

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：(III)

Reaction of 3-furancarboxaldehyde (I) with potassium cyanide in the presence of tert-butyldimethylsilyl chloride and ZnI2 gave the O-silylated cyanohydrin (II). Addition of 2(5H)-furanone (III) to the lithium anion of (II), followed by addition of 3,4-dimethoxybenzaldehyde (V) to the intermediate (IV), yielded adduct (VI). Subsequent acid cyclization of (VI) by means of trifluoroacetic acid or methanesulfonic acid provided the tricyclic derivative (VII) as a diastereomeric mixture. Desilylation of (VII) with concomitant cyanide elimination using either tetrabutylammonium fluoride at low temperature or aqueous ammonium fluoride gave rise to ketone (VIII). This was then epimerized to the title compound by treatment with triethylamine in boiling toluene. Alternatively, desilylation of (VII) with tetrabutylammonium fluoride at room temperature provided directly the title diastereoisomer.

参考文献中间体

合成目标

【1】 Iwasaki, T.; Sugiura, M.; Matsuoka, Y.; Matsumoto, M.; Kitamura, K. (Tanabe Seiyaku Co., Ltd.); Biphenyl derivs.. EP 0386778; JP 1990235884; US 5066669 .

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)	47247	3-Furaldehyde	498-60-2	C₅H₄O₂	详情	详情
(II)	47248	2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-furyl)acetonitrile		C₁₂H₁₉NO₂Si	详情	详情
(III)	19267	2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide	497-23-4	C₄H₄O₂	详情	详情
(IV)	47249			C₁₆H₂₂LiNO₄Si	详情	详情
(V)	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(VI)	47250	2-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(3,4-dimethoxyphenyl)(hydroxy)methyl]-5-oxotetrahydro-3-furanyl]-2-(3-furyl)acetonitrile		C₂₅H₃₃NO₇Si	详情	详情
(VII)	47251	(4S,4aR,7aR,8R)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-(3,4-dimethoxyphenyl)-7-oxo-4,4a,5,7,7a,8-hexahydrofuro[2,3-f][2]benzofuran-4-carbonitrile		C₂₅H₃₁NO₆Si	详情	详情
(VIII)	47252	(4R,4aR,7aR,8R)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-(3,4-dimethoxyphenyl)-7-oxo-4,4a,5,7,7a,8-hexahydrofuro[2,3-f][2]benzofuran-4-carbonitrile		C₂₅H₃₁NO₆Si	详情	详情
(IX)	47253	(4aR,7aR,8R)-8-(3,4-dimethoxyphenyl)-4a,5,7a,8-tetrahydrofuro[2,3-f][2]benzofuran-4,7-dione		C₁₈H₁₆O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

6) The reaction of 4-bromothioanisole (XIV) with furan-2(5H)-one (XV) by means of tert-BuLi/CuI in ethyl ether, followed by silylation with trimethylsilyl chloride gives 4-[4-(methylsulfanyl)phenyl]-2-(trimethylsilyloxy)-3,4-dihydrofuran (XVI), which is desilylated with palladium acetate in acetonitrile to afford the furanone (XVII). The iodination of (XVII) with I2 in pyridine yields 3-iodo-4-[4-(methylsulfanyl)phenyl]furan-2(5H)-one (XVIII), which is condensed with phenylboronic acid (XIX) by means of triphenylarsine and a Pd catalyst in refluxing benzene, giving 4-[4-(methylsulfanyl)phenyl]-3-phenylfuran-2(5H)-one (VIII), already described in Scheme 1. Finally, this compound is oxidized with monoperoxyphthalic acid magnesium salt in dichloromethane/methanol.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287.
【2】 Atkinson, J.G.; Wang, Z. (Merck Frosst Canada Inc.); Stilbene derivs. useful as cyclooxygenase-2 inhibitors. EP 0788476; JP 1998507765; WO 9613483 .
【3】 Hancock, B.; Winters, C.; Gertz, B.; Ehrich, E. (Merck & Co., Inc.; Merck Frosst Canada Inc.); Compsns. for a once a day treatment of cyclooxygenase-2 mediated diseases. JP 1999512754; WO 9744028 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	19260	4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone		C₁₇H₁₄O₂S	详情	详情
(XIV)	19266	4-bromophenyl methyl sulfide; 1-bromo-4-(methylsulfanyl)benzene	104-95-0	C₇H₇BrS	详情	详情
(XV)	19267	2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide	497-23-4	C₄H₄O₂	详情	详情
(XVI)	19268	trimethyl([4-[4-(methylsulfanyl)phenyl]-4,5-dihydro-2-furanyl]oxy)silane; 4-[4-(methylsulfanyl)phenyl]-4,5-dihydro-2-furanyl trimethylsilyl ether		C₁₄H₂₀O₂SSi	详情	详情
(XVII)	19269	4-[4-(methylsulfanyl)phenyl]-2(5H)-furanone		C₁₁H₁₀O₂S	详情	详情
(XVIII)	19270	3-iodo-4-[4-(methylsulfanyl)phenyl]-2(5H)-furanone		C₁₁H₉IO₂S	详情	详情
(XIX)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIII)

5-Hydroxy-4-propyl-2-furanone (V) is obtained by aldol condensation of glyoxylic acid (XXI) with valeraldehyde (XXII) in the presence of morpholine in heptane, followed by cyclization of the intermediate aldehyde acid under acidic conditions .
Preparation of iodoacyl chloride (VIII) starts with the conjugate addition of propylmagnesium bromide (XXIV) to 2-furanone (XXIII) in the presence of CuI and TMSCl in ethyl ether to produce 4-propylbutyrolactone (XXV), which undergoes lactone ring opening by means of iodotrimethylsilane in CH2Cl2, affording 3-(iodomethyl)hexanoic acid (XXVI), and finally, chlorination of acid (XXVI) with SOCl2 in benzene .

参考文献中间体

合成目标

【1】 Surtees, J., Lurquin, F., Diouf, O. (UCB SA). Process for preparing 2-oxo-1-pyrrolidine derivatives. CA 2538938, EP 1667967, JP 2007515387, US 2007100150, US 7629474, WO 2005028435.
【2】 Kenda, B.M., Matagne, A.C., Talaga, P.E. et al. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem 2004, 47(3): 530-49.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	58391	5-hydroxy-4-propyl-2(5H)-furanone；5-hydroxy-4-propyl-2-furanone	78920-10-2	C₇H₁₀O₃	详情	详情
(VIII)	69031	3-(iodomethyl)hexanoyl chloride		C₇H₁₂ClIO	详情	详情
(XXI)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(XXII)	13409	n-Valeraldehyde; Pentanal	110-62-3	C₅H₁₀O	详情	详情
(XXIII)	19267	2(5H)-furanone；furan-2(5H)-one；2-Buten-1,4-olide	497-23-4	C₄H₄O₂	详情	详情
(XXIV)	10790	Bromo(propyl)magnesium；bromopropylMagnesium；4-propylbutyrolactone；propylmagnesiumbromide；n-propylmagnesium bromide；Bromopropylmagnesium;	927-77-5	C₃H₇BrMg	详情	详情
(XXV)	69043	4-propyldihydrofuran-2(3H)-one		C₇H₁₂O₂	详情	详情
(XXVI)	69044	3-(iodomethyl)hexanoic acid		C₇H₁₃IO₂	详情	详情

Extended Information