3-Bromopropionic acid -Drug Synthesis Database

【结构式】

【分子编号】15472

【品名】3-Bromopropionic acid

【CA登记号】590-92-1

【分子式】C₃H₅BrO₂

【分子量】152.9755

【元素组成】C 23.55% H 3.29% Br 52.23% O 20.92%

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：(I)

The reaction of 3-bromopropionic acid (I) with triphenylphosphine (II) in refluxing acetonitrile gives (2-carboxyethyl)-triphenylphosphonium bromide (III), which by a Wittig reaction with 2-oxa-3-hydroxy-6-syn-(3alpha-tetrahydropyranyloxy-4,4-dimethyl-1-trans-octen-1-yl)-7-anti-tetrahydropyranyloxybicyclo- [3.3.0]cis-octane (IV) (prepared according to reference 2) by means of sodium dimethylsulfinate in DMSO yields 9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16,16-dimethyl-alpha-dinorprosta-5-cis-13-trans-dienoic acid (V). The reduction of (V) with H2 over Pd/C in methanol affords the 13-trans-prostenoic acid (VI), which is methylated with CH2N2 in ether yielding the methyl ester (VII). The reduction of (VII) with diisobutyl aluminum hydride in toluene affords the corresponding aldehyde (VIII), which by a Wittig reaction with triethyl phosphonoacetate (IX) by means of NaH in THF is converted into 9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16,16-dimethylprosta-2-trans-dienoic acid ethyl ester (X). The hydrolysis of the ester (X) with KOH in ethanol-water gives the corresponding acid (XI), which is oxidized with CrO3, MnSO4 and H2SO4 in ether - water yielding the protected ketoacid (XII). The hydrolysis of (XII) with acetic acid-water at 80 C gives 9-oxo-11alpha,15alpha-dihydroxy-16,16-dimethyl-prosta-2-trans-13-trans-dienoic acid (16,16-dimethyl-DELTA2-trans-PGE1) (XIII), which is finally methylated with CH2N2 in ether

参考文献中间体

合成目标

【1】 Oshima, K.; Effect of ONO-802 on uterine activity and plasma levels of steroid hormones in japanese monkeys (Macaca Fuscata Fuscata). Acta Obs Gyn Jpn 1977, 29, 12, 1923.
【2】 Hayashi, M.; Kori, S.; Wakatsuka, H.; Prostaglandin-analoge. BE 0850084 .
【3】 Castaner, J.; Leeson, P.; ONO-802. Drugs Fut 1979, 4, 1, 38.

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)	15472	3-Bromopropionic acid	590-92-1	C₃H₅BrO₂	详情	详情
(II)	12437	Triphenylphosphine; Triphenyl phosphine	603-35-0	C₁₈H₁₅P	详情	详情
(III)	33280	(2-carboxyethyl)(triphenyl)phosphonium bromide	51114-94-4	C₂₁H₂₀BrO₂P	详情	详情
(IV)	33281	(2S,3aR,4S,5R,6aS)-4-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₉H₅₀O₆	详情	详情
(V)	33282	(Z)-5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-3-pentenoic acid		C₃₂H₅₄O₇	详情	详情
(VI)	33283	5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanoic acid		C₃₂H₅₆O₇	详情	详情
(VII)	33284	methyl 5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanoate		C₃₃H₅₈O₇	详情	详情
(VIII)	33285	5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanal		C₃₂H₅₆O₆	详情	详情
(IX)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(X)	33286	ethyl (E)-7-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoate		C₃₆H₆₂O₇	详情	详情
(XI)	33287	(E)-7-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoic acid		C₃₄H₅₈O₇	详情	详情
(XII)	33288	(E)-7-[(1R,2S,3R)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoic acid		C₃₄H₅₆O₇	详情	详情
(XIII)	33289	(E)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-oxocyclopentyl]-2-heptenoic acid		C₂₂H₃₆O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The optical resolution of (±)-tetrahydropapaverine (I) with N-acetyl-L-leucine yields (R)-tetrahydropapaverine (II), which is condensed with 1,5-pentamethylene diacrylate (III) (obtained by esterification of 1,5-pentanediol (IV) with 3-bromopropionic acid by means of p-toluenesulfonic acid followed by dehydromination with triethylamine) in hot glacial acetic acid and treated with oxalic acid to afford the bis-tetrahydropapaverine derivative (VI). Finally, this compound is treated with aqueous Na2CO3 to eliminate the oxalic acid and then treated with methyl benezenesulfonate (VII) at room temperature. The resulting product is a 58:34:6 mixture of the (1R-cis, 1'R-cis)- (1R-cis, 1'R-trans)- and (1R-trans, 1'R-trans)-isomers, which is resolved by column chromatography over silica gel using an 80:20:5 mixture of dichloromethane methanol and methanesulfonic acid.

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Cisatracurium Besylate. Drugs Fut 1996, 21, 1, 14.
【2】 Hill, D.A.; Turner, G.L. (Glaxo Wellcome plc); Neuromuscular blocking agents. CH 683427; EP 0539470; FR 2665791; GB 2260763; JP 1993508648; JP 1998139763; US 5453510; WO 9200965 .

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)	15468	1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 1-(3,4-dimethoxybenzyl)-6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether		C₂₀H₂₅NO₄	详情	详情
(II)	15469	(1R)-1-(3,4-dimethoxybenzyl)-6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether; (1R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline		C₂₀H₂₅NO₄	详情	详情
(III)	15470	5-(acryloyloxy)pentyl acrylate; 1,6-Hexanediol Diacrylate	36840-85-4	C₁₁H₁₆O₄	详情	详情
(IV)	15471	1,5-pentanediol	111-29-5	C₅H₁₂O₂	详情	详情
(V)	15472	3-Bromopropionic acid	590-92-1	C₃H₅BrO₂	详情	详情
(VI)	15473	5-([3-[(1R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]propanoyl]oxy)pentyl 3-[(1R)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]propanoate		C₅₁H₆₆N₂O₁₂	详情	详情
(VII)	15474	methyl benzenesulfonate	80-18-2	C₇H₈O₃S	详情	详情

Extended Information