2-oxaspiro[4.4]nonane-1,3-dione -Drug Synthesis Database

【结构式】

【分子编号】27158

【品名】2-oxaspiro[4.4]nonane-1,3-dione

【CA登记号】

【分子式】C₈H₁₀O₃

【分子量】154.1656

【元素组成】C 62.33% H 6.54% O 31.13%

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：(VI)

This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.

参考文献中间体

合成目标

【1】 Scott, K.R.; Nicholson, J.M.; Edafiogho, I.O.; Farrar, V.A.; Hinko, C.N.; Moore, J.A.; Imidooxy anticonvulsants: Structural analogs with special emphasis on N-(benzyloxy)-2-azaspiro[4,4]nonane-1,3-dione. Drugs Fut 1992, 17, 5, 395.

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)	15113	cyclopentanone	120-92-3	C₅H₈O	详情	详情
(II)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(III)	43191	ethyl 2-cyano-2-cyclopentylideneacetate	5407-83-0	C₁₀H₁₃NO₂	详情	详情
(IV)	43192	1-(cyanomethyl)cyclopentanecarbonitrile		C₈H₁₀N₂	详情	详情
(V)	43193	1-(carboxymethyl)cyclopentanecarboxylic acid		C₈H₁₂O₄	详情	详情
(VI)	27158	2-oxaspiro[4.4]nonane-1,3-dione		C₈H₁₀O₃	详情	详情
(VII)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(VIII)	43194	2-hydroxy-2-azaspiro[4.4]nonane-1,3-dione		C₈H₁₁NO₃	详情	详情
(IX)	43195	sodium 1,3-dioxo-2-azaspiro[4.4]nonan-2-olate		C₈H₁₀NNaO₃	详情	详情
(X)	19171	1-(Chloromethyl)benzene; Benzyl chloride	100-44-7	C₇H₇Cl	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVI)

The intermediate cyclopentanecarboxylic ester (XII) has been obtained as follows: The reaction of 2-oxaspiro[4.4]nonane-1,3-dione (XXVI) with the chiral auxiliary 4(S)-isopropyloxazolidin-2-one (XXVII) by means of BuLi in THF gives the addition product (XXVIII), which is protected as the benzyl ester (XXIX) with benzylbromide and DBU. The regioselective azidation of (XXIX) with 2,4,6-triisopropylbenzenesulfonyl azide and potassium bis(trimethylsilyl)amide affords the (S)-azide (XXX), which is treated with H2O2 in THF/water to eliminate chiral auxiliary and providing 2(S)-azido-2-[1-(benzyloxycarbonyl)cyclopentyl]acetic acid (XXXI). Condensation of (XXXI) with 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) by means of HBTU in dichloromethane gives the corresponding amide (XXXIII), which is finally reduced at the azido group with SnCl2 in methanol to afford the target intermediate (XII). The intermediate 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) has been obtained as follows: The reaction of 2,2-dimethyl-3-pentanone (XXXIV) with the chiral auxiliary 1(R)-phenylethylamine (XXXV) by means of TiCl4 in benzene gives N-(1(R)-ethyl-2,2-dimethylpropyl)-N-(1(R)-phenylethyl)amine (XXXVI), which is then hydrogenated with H2 over Pd/C in methanol to eliminate the chiral auxiliary and obtain the target amine (XXXII).

参考文献中间体

合成目标

【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	27151	benzyl 1-((1S)-1-amino-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate		C₂₂H₃₄N₂O₃	详情	详情
(XXVI)	27158	2-oxaspiro[4.4]nonane-1,3-dione		C₈H₁₀O₃	详情	详情
(XXVII)	12867	(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone	17016-83-0	C₆H₁₁NO₂	详情	详情
(XXVIII)	27159	1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylic acid		C₁₄H₂₁NO₅	详情	详情
(XXIX)	27160	benzyl 1-[2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate		C₂₁H₂₇NO₅	详情	详情
(XXX)	27161	benzyl 1-[(1S)-1-azido-2-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]cyclopentanecarboxylate		C₂₁H₂₆N₄O₅	详情	详情
(XXXI)	27162	(2S)-2-azido-2-[1-[(benzyloxy)carbonyl]cyclopentyl]ethanoic acid		C₁₅H₁₇N₃O₄	详情	详情
(XXXII)	27163	(1R)-1-ethyl-2,2-dimethylpropylamine		C₇H₁₇N	详情	详情
(XXXIII)	27164	benzyl 1-((1S)-1-azido-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate		C₂₂H₃₂N₄O₃	详情	详情
(XXXIV)	27165	2,2-dimethyl-3-pentanone	564-04-5	C₇H₁₄O	详情	详情
(XXXV)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(XXXVI)	27166	(3R)-2,2-dimethyl-N-[(1R)-1-phenylethyl]-3-pentanamine		C₁₅H₂₅N	详情	详情

Extended Information