3-(iodomethyl)hexanoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】69031

【品名】3-(iodomethyl)hexanoyl chloride

【CA登记号】　

【分子式】C₇H₁₂ClIO

【分子量】274.529

【元素组成】C 30.63% H 4.41% Cl 14.91% I 46.23% O 5.83%

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：(VIII)

Condensation of 2(S)-aminobutyramide (I) with Meldrum’s acid derivative (II) in refluxing acetonitrile affords a mixture of two pyrrolidonecarboxylic acid regioisomers, (III) and (IV), which, without isolation, are subjected to decarboxylation in methyl isobutyl ketone at 120 °C, and then separated by column chromatography .
Alternatively, 2(S)-aminobutyramide (I) –obtained by basification of either its tartrate salt with NH4OH/i-PrOH or its hydrochloride salt with NH3/i-PrOH (2)– is reductively condensed with 5-hydroxy-4-propyl-2-furanone (V) by means of NaBH4 and NaOH in H2O/toluene, yielding the dihydropyrrol-2-one (VI) . Transfer hydrogenation of compound (VI) with ammonium formate and Pd/C in H2O at 50 °C provides the diastereomeric mixture of pyrrolidinones (VII) , which are finally separated by column chromatography or recrystallization .
The intermediate dihydropyrrolone (VII) is alternatively obtained by direct condensation of furanone (V) with 2(S)-aminobutyramide (I) in the presence of H2 and Pd/C in AcOH/i-PrOH or by cyclization of aminoamide (I) with 3-(iodomethyl)hexanoyl chloride (VIII) by means of KOH and tetrabutylammonium bromide in CH2Cl2 .
Amide (VII) is also prepared from 2-(2-oxo-4-propylpyrrolidino)-butyric acid (IX) via activation as the corresponding mixed anhydride with ethyl chloroformate and Et3N in THF, followed by quenching with liquid ammonia .
Similarly, alkylation of optically pure 4(R)-propyl-2-pyrrolidinone (X) with racemic methyl 2-bromobutyrate (XI) in the presence of NaH in THF affords pyrrolidinone butyrate methyl ester (XII) as a diastereomeric mixture. Subsequent ammonolysis of ester (XII) with aqueous ammonia gives the corresponding mixture of amides (XIII) separated using column chromatography .

参考文献中间体

合成目标

【1】 Ates, C., Schule, A. (UCB SA). 3-Carboxy-2-oxo-1-pyrrolidine derivatives and their uses. EP 1993998, JP 2009518335, US 2009012313, WO 2007065634.
【2】 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.
【3】 Kenda, B., Matagne, A., Michel, P., Pasau, P., Differding, E., Lallemand, B., Talaga, P. (UCB SA). 2-Oxo-1-pyrrolidine derivatives, processes for preparing them and their uses. EP 1447399, EP 1452524, EP 1604979, JP 2003523996, JP 2003528828, JP 2006022107, JP 2007182459, US 200312000, US 2004116507, US 2005171187, US 2005171188, US 2005159475, US 2008097109, US 6784197, US 6806287, US 6911461, US 7358276, WO 2001062726, WO 2001064637.
【4】 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.
【5】 Surtees, J., Bouvy, D., Thomas, A., Combret, Y., Frank, M., Schmidt, G. (UCB SA). Process for the preparation of 2-oxo-1-pyrrolidine derivatives. EP 1806339.
【6】 Ates, C., Lurquin, F., Quesnel, Y., Schule, A. (UCB SA). 4-Substituted pyrrolidin-2-ones and their use. EP 1926710, JP 2009507870, US 2009318708, WO 2007031263.

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)	11262	(2S)-2-Aminobutanamide		C₄H₁₀N₂O	详情	详情
(II)	69027	(R)-6,6-dimethyl-1-propyl-5,7-dioxaspiro[2.5]octane-4,8-dione		C₁₁H₁₆O₄	详情	详情
(III)	69028	(4R)-1-((R)-1-amino-1-oxobutan-2-yl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid		C₁₂H₂₀N₂O₄	详情	详情
(IV)	69029	1-((R)-1-amino-1-oxobutan-2-yl)-2-oxo-5-propylpyrrolidine-3-carboxylic acid		C₁₂H₂₀N₂O₄	详情	详情
(V)	58391	5-hydroxy-4-propyl-2(5H)-furanone；5-hydroxy-4-propyl-2-furanone	78920-10-2	C₇H₁₀O₃	详情	详情
(VI)	58392	(2R)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide		C₁₁H₁₈N₂O₂	详情	详情
(VII)	69030	(2R)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide		C₁₁H₂₀N₂O₂	详情	详情
(VIII)	69031	3-(iodomethyl)hexanoyl chloride		C₇H₁₂ClIO	详情	详情
(IX)	69032	(2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanoic acid		C₁₁H₁₉NO₃	详情	详情
(X)	69034	4(R)-propyl-2-pyrrolidinone		C₇H₁₃NO	详情	详情
(XI)	69033	methyl 2-bromobutyrate;2-Bromobutyric acid methyl ester	3196-15-4	C₅H₉BrO₂	详情	详情
(XII)	69035	methyl 2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoate		C₁₂H₂₁NO₃	详情	详情
(XIII)	69036	2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide		C₁₁H₂₀N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

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