ethyl 2-(diethoxyphosphoryl)butanoate -Drug Synthesis Database

【结构式】

【分子编号】20274

【品名】ethyl 2-(diethoxyphosphoryl)butanoate

【CA登记号】17145-91-4

【分子式】C₁₀H₂₁O₅P

【分子量】252.247502

【元素组成】C 47.62% H 8.39% O 31.71% P 12.28%

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：(IV)

A new and stereoselective synthesis of (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), a key intermediate in the synthesis of PS-5 has been developed: The oxidation of 3-benzyloxy-1-propanol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of NaH yielding a mixture of the (Z)- and (E)-isomers of 5-benzyloxy-2-ethyl-2-pentenoic acid ethyl ester (IV) and (V). The undesired (Z)-isomer (IV) is isomerized by treating the mixture with diphenyldisulfide in refluxing THF. The hydrolysis of (V) with LiOH in THF/methanol/water gives the expected free acid (VI), which is treated with SOCl2 in refluxing benzene to afford the acid chloride (VII). The condensation of (VII) with the chiral oxazolidinone (VIII) by means of butyllithium in THF gives the acylated compound (IX), which is treated with benzenethiol and butyllithium in THF to give the addition compound (X) that is purified by medium pressure column chromatography to eliminate the undesired diastereomer. The elimination of the oxazolidinone group of (X) by reaction with trimethylaluminum, benzylthiol and butyllithium in THF yields the thioester (XI), which is treated with silver trfluoroacetate and water to afford the corresponding free acid (XII). The reaction of (XII) with methoxyamine and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDPC) in water affords the methoxyamide (XIII), which is methylated by means of methyl iodide and silver perchlorate to give the sulfonium salt (XIV). The cyclization of (XIV) by means of K2CO3 yields the azetidinone (XV), which is debenzylated by means of calcium in liquid ammonia affording (3R-trans)-3-ethyl-4-(2-hydrxyethyl)azetidin-2-one (XVI). Finally, this compound is silylated with tert-butyldimethylsilyl (TBDMS) trifluoromethanesulfonate affording (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), the desired target key intermediate in the synthesis of PS-5.

参考文献中间体

合成目标

【1】 Fujiwara,Y.; Ninomiya, I.; Miyata, O.; Naito, T.; Efficient stereoselective route to beta-lactams and their application to the stereoselective synthesis of a key intermediate for carbapenem antibiotic (+)-PS-5. J Chem Soc - Perkins Trans I 1998, 14, 14, 2167.

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)	14687	3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol	4799-68-2	C₁₀H₁₄O₂	详情	详情
(II)	14688	3-(benzyloxy)propanal		C₁₀H₁₂O₂	详情	详情
(IV)	20274	ethyl 2-(diethoxyphosphoryl)butanoate	17145-91-4	C₁₀H₂₁O₅P	详情	详情
(V)	20275	ethyl (Z)-5-(benzyloxy)-2-ethyl-2-pentenoate		C₁₆H₂₂O₃	详情	详情
(VI)	20277	(E)-5-(benzyloxy)-2-ethyl-2-pentenoic acid		C₁₄H₁₈O₃	详情	详情
(VII)	20278	(E)-5-(benzyloxy)-2-ethyl-2-pentenoyl chloride		C₁₄H₁₇ClO₂	详情	详情
(VIII)	12867	(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone	17016-83-0	C₆H₁₁NO₂	详情	详情
(IX)	20280	(4S)-3-[(E)-5-(benzyloxy)-2-ethyl-2-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one		C₂₀H₂₇NO₄	详情	详情
(X)	20281	(4S)-3-[(2S,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanoyl]-4-isopropyl-1,3-oxazolidin-2-one		C₂₆H₃₃NO₄S	详情	详情
(XI)	20282	S-benzyl (2R,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanethioate		C₂₇H₃₀O₂S₂	详情	详情
(XII)	20283	(2S,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanoic acid		C₂₀H₂₄O₃S	详情	详情
(XIII)	20284	(2S,3S)-5-(benzyloxy)-2-ethyl-N-methoxy-3-(phenylsulfanyl)pentanamide		C₂₁H₂₇NO₃S	详情	详情
(XIV)	20285	[(1S,2S)-1-[2-(benzyloxy)ethyl]-2-[(methoxyamino)carbonyl]butyl](methyl)phenylsulfonium iodide		C₂₂H₃₀INO₃S	详情	详情
(XV)	20286	(3R,4R)-4-[2-(benzyloxy)ethyl]-3-ethyl-1-methoxy-2-azetidinone		C₁₅H₂₁NO₃	详情	详情
(XVI)	20287	(3R,4R)-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone		C₇H₁₃NO₂	详情	详情
(XVII)	20051	(3R,4R)-1-[tert-butyl(dimethyl)silyl]-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone		C₁₉H₄₁NO₂Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Mitsunobu coupling of geranylgeraniol (I) with N-hydroxyphthalimide (II) in the presence of diethyl azodicarboxylate and triphenylphosphine produced the N-alkoxyphthalimide (III). Subsequent hydrazinolysis of the phthaloyl group of (III) gave rise to the O-alkyl hydroxylamine (IV). (2-Diethylphosphono)butyric acid (VI), prepared by partial hydrolysis of triethyl ester (V), was then coupled with hydroxylamine (IV) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl and 1-hydroxybenzotriazole to furnish the N-alkoxyamide (VII). The phosphonate ester groups were finally cleaved by treatment with bromotrimethylsilane and 2,4,6-collidine.

参考文献中间体

合成目标

【1】 Balsamo, A.; Macchia, B.; Macchia, M.; Baldacci, M.; Danesi, R.; Del Tacca, M. (Laboratori Baldacci SpA); Novel geranylgeranyl-derivs., process for the preparation thereof and related pharmaceutical compsns.. EP 0862575; JP 2000500758; WO 9719091 .

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)	34476	(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol		C₂₀H₃₄O	详情	详情
(II)	13505	N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione	524-38-9	C₈H₅NO₃	详情	详情
(III)	34477	2-[[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]oxy]-1H-isoindole-1,3(2H)-dione		C₂₈H₃₇NO₃	详情	详情
(IV)	34478	O-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]hydroxylamine; (2E,6E,10E)-1-(aminooxy)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene		C₂₀H₃₅NO	详情	详情
(V)	20274	ethyl 2-(diethoxyphosphoryl)butanoate	17145-91-4	C₁₀H₂₁O₅P	详情	详情
(VI)	34479	2-(diethoxyphosphoryl)butyric acid		C₈H₁₇O₅P	详情	详情
(VII)	34480	diethyl 1-[([[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]oxy]amino)carbonyl]propylphosphonate		C₂₈H₅₀NO₅P	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

5-Formyl-2-methoxybenzoic acid (I) is converted to the corresponding benzyl ester (II) upon treatment with benzyl bromide and potassium bicarbonate. Subsequent Wadsworth-Emmons condensation between aldehyde (II) and triethyl 2-phosphonobutyrate (III) gives the unsaturated ester (IV). Double bond hydrogenation in (IV) with concomitant hydrogenolysis of the benzyl ester affords acid (V), which is subsequently coupled with 4-(trifluoromethyl)benzyl amine (VI), via the mixed anhydride with ethyl chloroformate, to produce amide (VII). The ethyl ester group of (VII) is finally hydrolyzed to the title carboxylic acid employing NaOH in aqueous ethanol.

参考文献中间体

合成目标

【1】 Tanase, T.; Nomura, M.; Miyachi, H.; et al.; Design, synthesis and evaluation of substituted phenylpropanoic acid derivatives as peroxisome proliferator-activated receptor (PPAR) activators: Novel human PPARalpha-selective activators. Bioorg Med Chem Lett 2002, 12, 1, 77.
【2】 Murakami, K.; Takahashi, Y.; Nomura, M.; Miyachi, H.; Ide, T.; Tsunoda, M.; Tanase, T. (Kyorin Pharmaceutical Co., Ltd.); Substd. phenylpropionic acid derivs. as agonists to human peroxisome proliferator-activated receptor (PPAR) alpha. EP 1184366; JP 2001055367; WO 0075103 .

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)	57501	5-formyl-2-methoxybenzoic acid		C₉H₈O₄	详情	详情
(II)	57502	benzyl 5-formyl-2-methoxybenzoate		C₁₆H₁₄O₄	详情	详情
(III)	20274	ethyl 2-(diethoxyphosphoryl)butanoate	17145-91-4	C₁₀H₂₁O₅P	详情	详情
(IV)	57503	benzyl 5-[(E)-2-(ethoxycarbonyl)-1-butenyl]-2-methoxybenzoate		C₂₂H₂₄O₅	详情	详情
(V)	57504	5-[2-(ethoxycarbonyl)butyl]-2-methoxybenzoic acid		C₁₅H₂₀O₅	详情	详情
(VI)	21925	[4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine	3300-51-4	C₈H₈F₃N	详情	详情
(VII)	57505	ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoate		C₂₃H₂₆F₃NO₄	详情	详情

Extended Information