(2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone -Drug Synthesis Database

【结构式】

【分子编号】17099

【品名】(2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone

【CA登记号】

【分子式】C₇H₁₃NO₂

【分子量】143.18576

【元素组成】C 58.72% H 9.15% N 9.78% O 22.35%

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)

A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid

参考文献中间体

合成目标

【1】 Andrews, D.R.; Gala, D.; Gosteli, J.; Guenter, F.; Leong, W.; Mergelsberg, I.; Sudhakar, A. (Schering Corp.); Process for the preparation of triazolones. WO 9633178 .

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)	16659	ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate	687-47-8	C₅H₁₀O₃	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	17099	(2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone		C₇H₁₃NO₂	详情	详情
(IV)	17100	(2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone	122151-32-0	C₁₄H₁₉NO₂	详情	详情
(V)	17101	(2S)-2-(benzyloxy)-3-pentanone		C₁₂H₁₆O₂	详情	详情
(VI)	17102	(2S)-2-(benzyloxy)-3-pentanol		C₁₂H₁₈O₂	详情	详情
(VII)	15787	4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride	98-60-2	C₆H₄Cl₂O₂S	详情	详情
(VIII)	17104	(2S)-2-(benzyloxy)-1-ethylpropyl 4-chlorobenzenesulfonate		C₁₈H₂₁ClO₄S	详情	详情
(IX)	17105	1-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]hydrazine; benzyl (1S,2S)-2-hydrazino-1-methylbutyl ether		C₁₂H₂₀N₂O	详情	详情
(X)	17106	N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide		C₁₃H₂₀N₂O₂	详情	详情
(XI)	17107	phenyl 4-(4-[4-[(trimethylsilyl)methyl]phenyl]-1-piperazinyl)phenylcarbamate		C₂₇H₃₃N₃O₂Si	详情	详情
(XII)	17108	2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₀H₃₅N₅O₃	详情	详情
(XIII)	17109	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate		C₂₀H₁₈ClF₂N₃O₄S	详情	详情
(XIV)	17110	4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine	74853-08-0	C₁₆H₁₉N₃O	详情	详情
(XV)	17111	phenyl N-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]carbamate		C₂₃H₂₃N₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXIV)

In an alternative synthesis of compound (XXXII), methyl (S)-lactate (XXXIII) was converted to amide (XXXIV) by treatment with pyrrolidine, and then protected as the benzyl ether (XXXV). Reduction of (XXXV) by means of sodium bis(methoxyethoxy)aluminum hydride produced aldehyde (XXXVI). Condensation of (XXXVI) with formic hydrazide produced the formyl hydrazone (XXXVII), to which was added ethylmagnesium bromide affording a mixture of diastereoisomeric hydrazides. Separation by column chromatography provided the required (S,S) isomer (XXXVIII). Cyclization of (XXXVIII) with the phenyl carbamate (XXIII) in the presence of DBU furnished the triazolone (XXXIX). This was deprotected by hydrogenation in the presence of Pd/C and formic acid to produce compound (XXXII)

参考文献中间体

合成目标

【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
	15486	formic hydrazide; Formylhydrazine	624-84-0	CH₄N₂O	详情	详情
(XXIII)	16349	phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate		C₃₇H₃₆F₂N₆O₄	详情	详情
(XXXII)	34850	4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₇H₄₂F₂N₈O₄	详情	详情
(XXXIII)	17075	propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate	27871-49-4	C₄H₈O₃	详情	详情
(XXXIV)	17099	(2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone		C₇H₁₃NO₂	详情	详情
(XXXV)	17100	(2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone	122151-32-0	C₁₄H₁₉NO₂	详情	详情
(XXXVI)	34851	(2R)-2-(benzyloxy)propanal		C₁₀H₁₂O₂	详情	详情
(XXXVII)	34852	N'-[(E,2R)-2-(benzyloxy)propylidene]formic hydrazide		C₁₁H₁₄N₂O₂	详情	详情
(XXXVIII)	17106	N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide		C₁₃H₂₀N₂O₂	详情	详情
(XXXIX)	34853	2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₄₄H₄₈F₂N₈O₄	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 reaction of (S)-(+)-methyl lactate (I) with pyrrolidine (II) gives the corresponding acyl pyrrolidine (III), which is silylated with Tbdms-Cl and imidazole to yield the silyl ether (IV). The condensation of (IV) with 3,4-difluorobromobenzene (V) by means of BuLi in THF affords the chiral propiophenone derivative (VI), which is treated with hydroxylamine and NaOAc in methanol to provide the corresponding oxime (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether gives the expected amine (VIII), which is treated with (Boc)2O in chloroform, yielding the carbamate (IX). The cyclization of (IX) by means of NaH in THF gives a mixture of cis- and trans-oxazolidinones, from which the desired trans-(4S,5S)-isomer (X) is separated by flash chromatography. The reaction of (X) with 4-nitrophenyl chloroformate (XI) by means of NaH yields the oxazolidinone-carboxylate (XII), which is finally condensed with 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine (XIII) in THF to afford the target amide.

参考文献中间体

合成目标

【1】 Lagu, B.; Wetzel, J.M.; Forray, C.; Patane, M.A.; Bock, M.G.; Determination of the relative and absolute stereochemistry of a potent and alpha1A-selective adrenoceptor antagonist. Bioorg Med Chem Lett 2000, 10, 24, 2705.

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)	17075	propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate	27871-49-4	C₄H₈O₃	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	17099	(2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone		C₇H₁₃NO₂	详情	详情
(IV)	51565	(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(1-pyrrolidinyl)-1-propanone		C₁₃H₂₇NO₂Si	详情	详情
(V)	51566	1-Bromo-3,4-difluorobenzene; 3,4-Difluorobromobenzene; 4-Bromo-1,2-difluorobenzene	348-61-8	C₆H₃BrF₂	详情	详情
(VI)	51567	(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone		C₁₅H₂₂F₂O₂Si	详情	详情
(VII)	51568	(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-difluorophenyl)-1-propanone oxime		C₁₅H₂₃F₂NO₂Si	详情	详情
(VIII)	51569	(2S)-1-amino-1-(3,4-difluorophenyl)-2-propanol		C₉H₁₁F₂NO	详情	详情
(IX)	51570	tert-butyl (2S)-1-(3,4-difluorophenyl)-2-hydroxypropylcarbamate		C₁₄H₁₉F₂NO₃	详情	详情
(X)	43324	(4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one		C₁₀H₉F₂NO₂	详情	详情
(XI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(XII)	43325	3,4-difluorobenzylamine; (3,4-difluorophenyl)methanamine	72235-53-1	C₇H₇F₂N	详情	详情
(XIII)	39302	3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine		C₁₄H₂₁FN₂	详情	详情

Extended Information