Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid -Drug Synthesis Database

【结构式】

【分子编号】53267

【品名】Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid

【CA登记号】107-92-6

【分子式】C₄H₈O₂

【分子量】88.10632

【元素组成】C 54.53% H 9.15% O 36.32%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The title butyric acid prodrug was prepared by condensation of butyric acid (I) with chloromethyl pivalate (II) in the presence of Et3N in acetone.

参考文献中间体

合成目标

【1】 Nudelman, A.; Shaklai, M.; Rephaeli, A. (Bar-Ilan University); Biologically active carboxylic acid esters. EP 0302349; JP 1998152436; JP 1998152454 .
【2】 Nudelman, A.; et al.; Novel anticancer prodrugs of butyric acid. 2. J Med Chem 1992, 35, 4, 687.

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)	53267	Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid	107-92-6	C₄H₈O₂	详情	详情
(II)	16166	chloromethyl pivalate	18997-19-8	C₆H₁₁ClO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Synthesis of the tricyclic ketone intermediate (VI): Optical resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (I) by reaction with SO2 and (+)-a-methylbenzylamine (II) yields a mixture of diastereomeric salts of the a-hydroxysulfonic acid with the chiral amine (II), which are separated by crystallization. Treatment of the purified salt (III) with aqueous Na2CO3 results in the pure enantiomer ()-(I). Reaction of ()-(I) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in acetone/water affords the bromohydrin (IV), which is treated with TBDMS-Cl and imidazole to provide the silyl ether (V). Finally, reaction of the protected bromohydrin (V) with potassium tert-butoxide in toluene gives the target tricyclic ketone intermediate (VI).

参考文献中间体

合成目标

【1】 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138.

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)	24421	(1S,5R)bicyclo[3.2.0]hept-2-en-6-one		C₇H₈O	详情	详情
(rac)-(I)	53261	bicyclo[3.2.0]hept-2-en-6-one	13173-09-6	C₇H₈O	详情	详情
(II)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(III)	53267	Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid	107-92-6	C₄H₈O₂	详情	详情
(IV)	53258	(1R,2S,3S,5R)-2-bromo-3-hydroxybicyclo[3.2.0]heptan-6-one	n/a	C₇H₉BrO₂	详情	详情
(V)	53259	(1R,2S,3S,5R)-2-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}bicyclo[3.2.0]heptan-6-one	n/a	C₁₃H₂₃BrO₂Si	详情	详情
(VI)	53260	(1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one	n/a	C₁₃H₂₂O₂Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

Synthesis of the alkenyl cuprate (XVII): Enzymatic acylation of the racemic acetylenic alcohol (VII) with vinyl butyrate (VIII) by means of Chirazyme L9 gives a mixture of the ester (R)-(IX) and the alcohol (S)-(X). Reaction of this mixture with Ms-Cl and TEA yields a mixture of ester (R)-(IX) and the mesylate (S)-(XI). Treatment of this mixture with butyric acid and TEA results in the acylation of mesylate (S)-(XI) with optical inversion, providing pure ester (R)-(IX). Enzymatic hydrolysis of (R)-(IX) with Chirazyme L2 affords the enantiomerically pure alcohol (R)-(XIII). Silylation of alcohol (XIII) with TBDMS-Cl and imidazole gives the silyl ether (XIV), which is iodinated with Cp2ZrCl2 and I2 to yield the iodovinyl derivative (XV). Finally, the reaction of compound (XV) with the lithium cuprate (XVI) prepared by lithiation of thiophene with BuLi followed by treatment with copper (I) cyanide affords the alkenyl cuprate (XVII). Condensation of the alkenyl cuprate (XVII) with the tricyclic ketone (VI) in toluene provides the bicyclic ketone (XVIII), which is submitted to a Baeyer-Villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (XIX) and (XX). The minor and unwanted regioisomer (XIX) is selectively hydrolyzed by treatment with aqueous Na2CO3 and separated by crystallization. Reduction of lactone (XX) with DIBAL in toluene gives lactol (XXI), which is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-BuOK in THF, followed by esterification with isopropyl iodide and DBU, yielding a mixture of the monosilylated compounds (XXIII) and (XXIV) due to migration of the silyl group on the cyclopentane ring. Finally, this mixture is deprotected with HCl in isopropanol.

参考文献中间体

合成目标

【1】 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	53260	(1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one	n/a	C₁₃H₂₂O₂Si	详情	详情
(VII)	53262	1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol	88462-65-1	C₁₁H₉F₃O₂	详情	详情
(VIII)	53263	n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate	123-20-6	C₆H₁₀O₂	详情	详情
(IX)	53264	(1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl butyrate	n/a	C₁₅H₁₅F₃O₃	详情	详情
(X)	53265	(2S)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol	n/a	C₁₁H₉F₃O₂	详情	详情
(XI)	53266	(1S)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl methanesulfonate	n/a	C₁₂H₁₁F₃O₄S	详情	详情
(XII)	53267	Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid	107-92-6	C₄H₈O₂	详情	详情
(XIII)	53278	(2R)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol	n/a	C₁₁H₉F₃O₂	详情	详情
(XIV)	53268	tert-butyl(dimethyl)[((1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl)oxy]silane; tert-butyl(dimethyl)silyl (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl ether	n/a	C₁₇H₂₃F₃O₂Si	详情	详情
(XV)	53269	tert-butyl(dimethyl)silyl (1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl ether; tert-butyl[((1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl)oxy]dimethylsilane	n/a	C₁₇H₂₄F₃IO₂Si	详情	详情
(XVI)	53270	lithium cyano(2-thienyl)cuprate(1-)	n/a	C₅H₃CuLiNS	详情	详情
(XVII)	53271		n/a	C₂₂H₂₇CuF₃Li₂NO₂SSi	详情	详情
(XVIII)	53272	(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}bicyclo[2.2.1]heptan-2-one	n/a	C₃₀H₄₇F₃O₄Si₂	详情	详情
(XIX)	53273	(6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-oxabicyclo[3.2.1]octan-2-one	n/a	C₃₀H₄₇F₃O₅Si₂	详情	详情
(XX)	53274	(6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-one	n/a	C₃₀H₄₇F₃O₅Si₂	详情	详情
(XXI)	53275	(6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-ol	n/a	C₃₀H₄₉F₃O₅Si₂	详情	详情
(XXII)	13616	(4-Carboxybutyl)triphenylphosphonium bromide	17814-85-6	C₂₃H₂₄BrO₂P	详情	详情
(XXIII)	53276	isopropyl (Z)-7-((1R,2R,3R,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-hydroxycyclopentyl)-5-heptenoate	n/a	C₃₈H₆₃F₃O₆Si₂	详情	详情
(XXIV)	53277	isopropyl (Z)-7-((1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-5-hydroxycyclopentyl)-5-heptenoate	n/a	C₃₈H₆₃F₃O₆Si₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(X)

Intermediates (III), (IVa) and (IVb) can be synthesized as follows. Esterification of butyric acid (X) with 1,4-butanediol (V) in the presence of TsOH·H2O in refluxing n-octane gives 1,4-butanediol monobutyrate (XI), which is then nitrated with HNO3/H2SO4 in CH2Cl2, yielding nitrate ester (XII). Selective saponification of the carboxylate of ester of (XII) with NaOH in MeOH/H2O, followed by acidification with H2SO4, furnishes 4-hydroxybutyl nitrate (III) .

参考文献中间体

合成目标

【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	69253	4-hydroxybutyl nitrate		C₄H₉NO₄	详情	详情
(V)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(X)	53267	Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid	107-92-6	C₄H₈O₂	详情	详情
(XI)	69260	1,4-butanediol monobutyrate;4-hydroxybutyl butyrate		C₈H₁₆O₃	详情	详情
(XII)	69261	4-(nitrooxy)butyl butyrate		C₈H₁₅NO₅	详情	详情

Extended Information