(2R)-2-isobutyl-4-pentenoic acid -Drug Synthesis Database

【结构式】

【分子编号】26985

【品名】(2R)-2-isobutyl-4-pentenoic acid

【CA登记号】

【分子式】C₉H₁₆O₂

【分子量】156.22484

【元素组成】C 69.19% H 10.32% O 20.48%

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)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound.

参考文献中间体

合成目标

【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	25391	(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one		C₁₆H₂₁NO₃	详情	详情
(II)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(III)	26985	(2R)-2-isobutyl-4-pentenoic acid		C₉H₁₆O₂	详情	详情
(IV)	27021	(3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone		C₉H₁₅IO₂	详情	详情
(V)	27022	(3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone		C₂₈H₃₀O₂S	详情	详情
(VI)	27023	(2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid		C₃₄H₄₆O₃SSi	详情	详情
(VII)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(VIII)	27024	(2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide		C₃₅H₄₆N₂O₃S	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 alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is treated with dimethylamine and cyanophosphonic acid diethyl ester yielding the dimethylamide (IV). The iodination of (IV) with I2/dimethoxyethane (DME) with simultaneous cyclization yields 5(S)-(iodomethyl)-3(R)-isobutyltetrahydrofuran-2-one (V). The condensation of (V) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and TFA affords 3(R)-isobutyl-5(S)-(triphenylmethylsulfanylmethyl)tetrahydrofuran-2-one (VI). The ring opening of (VI) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives 4(S)-(tert-butyldimethylsilyloxy)-2(R)-isobutyl-5-(tritylsulfanyl)pentanoic acid (VII), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VIII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(S)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (IX). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target campound (X).

参考文献中间体

合成目标

【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	25391	(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one		C₁₆H₂₁NO₃	详情	详情
(II)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(III)	26985	(2R)-2-isobutyl-4-pentenoic acid		C₉H₁₆O₂	详情	详情
(IV)	26986	(2R)-2-isobutyl-N,N-dimethyl-4-pentenamide		C₁₁H₂₁NO	详情	详情
(V)	26987	(3R,5S)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone		C₉H₁₅IO₂	详情	详情
(VI)	26988	(3R,5S)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone		C₂₈H₃₀O₂S	详情	详情
(VII)	26989	(2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid		C₃₄H₄₆O₃SSi	详情	详情
(VIII)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(IX)	26990	(2R,4S)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide		C₃₅H₄₆N₂O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.

参考文献中间体

合成目标

【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	25391	(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one		C₁₆H₂₁NO₃	详情	详情
(II)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(III)	26985	(2R)-2-isobutyl-4-pentenoic acid		C₉H₁₆O₂	详情	详情
(IV)	27021	(3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone		C₉H₁₅IO₂	详情	详情
(V)	27022	(3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone		C₂₈H₃₀O₂S	详情	详情
(VI)	27023	(2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid		C₃₄H₄₆O₃SSi	详情	详情
(VII)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(VIII)	27024	(2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide		C₃₅H₄₆N₂O₃S	详情	详情

Extended Information