(1S,5R)bicyclo[3.2.0]hept-2-en-6-one -Drug Synthesis Database

【结构式】

【分子编号】24421

【品名】(1S,5R)bicyclo[3.2.0]hept-2-en-6-one

【CA登记号】

【分子式】C₇H₈O

【分子量】108.13992

【元素组成】C 77.75% H 7.46% O 14.8%

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：(I)

The reaction of bicyclo[3.2.0]hept-2-en-6-one (I) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in acetic acid gives 3-endo-acetoxy-2-exo-bromo-bicyclo[3.2.0]heptan-6-one (II), which is treated with morpholine in dichloromethane to yield 5-endo-acetoxy-7-anti morpholinobicyclo[2.2.l]heptan-2-one (III). Hydrolysis of (III) with NaOH gives the norbornanone (IV), which is alkylated with biphenyl methylbromide under phase transfer catalysis to give 5-endo[(1,1'-biphenyl)-4 yl]methoxy-7-anti-morpholinobicyclo[2.2.1]heptan 2-one (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VI), which is then homologated to the aldehyde (VII) using methoxymethylenetriphenyl phosphorane and subsequent treatment with 2N HCl. Condensation of (VII) with 3 carboxypropyl triphenylphosphorane in tetrahydrofuran affords the acid (VIII). Finally, this compound is oxidized with Jones' reagent.

参考文献中间体

合成目标

【1】 Lumley, P.; AH-23848. Drugs Fut 1986, 11, 2, 85.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(A)	24427	6-(2-[1,1'-biphenyl]-4-ylethoxy)-8-(4-morpholinyl)-2-oxabicyclo[3.2.1]octan-3-one		C₂₅H₂₉NO₄	详情	详情
(I)	24421	(1S,5R)bicyclo[3.2.0]hept-2-en-6-one		C₇H₈O	详情	详情
(II)	24422	3-Acetoxy-2-bromobicyclo[3,2,0]hept-2-en-6-one		C₈H₉BrO	详情	详情
(III)	24424	5(endo)-Acetoxy-7(R)-(4-morpholinyl)bicyclo[2,2,1]heptan-2-one		C₁₂H₁₉NO₂	详情	详情
(IV)	24425	5-hydroxy-7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one		C₁₁H₁₇NO₃	详情	详情
(V)	24426	5-(2-[1,1'-biphenyl]-4-ylethoxy)-7-(4-morpholinyl)bicyclo[2.2.1]heptan-2-one		C₂₅H₂₉NO₃	详情	详情
(VI)	24428	2-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]acetaldehyde		C₂₅H₃₁NO₄	详情	详情
(VII)	24429	3-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]propanal		C₂₆H₃₃NO₄	详情	详情
(VIII)	24431	(E)-6-[(1R,2R,3R,5S)-5-(2-[1,1'-biphenyl]-4-ylethoxy)-3-hydroxy-2-(4-morpholinyl)cyclopentyl]-3-hexenoic acid		C₂₉H₃₇NO₅	详情	详情
(C)	24430	3-Carboxypropyltriphenylphosphonium bromide		C₂₂H₂₃BrO₂P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I), (II)

Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II), which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV), which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII), which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl. Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX). The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol. Finally, the ester is hydrolyzed with hydrochloric acid to give the required acid.

参考文献中间体

合成目标

【1】 Coleman, M.J.; et al.; Baeyer-villiger oxidation of 5-endo-(biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1] process development and scale-Up. Org Process Res Dev 1997, 1, 1, 20.
【2】 Lumley, P.; Finch, H.; Collington, E.W.C.; Humphrey, P.P.A.; VAPIPROST HYDROCHLORIDE < Rec INNM; BAN >. Drugs Fut 1990, 15, 11, 1087.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	37404	(3-carboxypropyl)(triphenyl)phosphonium bromide	17857-14-6	C₂₂H₂₂BrO₂P	详情	详情
(A)	15148	1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine	618-36-0	C₈H₁₁N	详情	详情
(I), (II)	24421	(1S,5R)bicyclo[3.2.0]hept-2-en-6-one		C₇H₈O	详情	详情
(B)	31210	4-(bromomethyl)-1,1'-biphenyl	2567-29-5	C₁₃H₁₁Br	详情	详情
(III)	31208	(1R,2S,3S,5R)-2-bromo-6-oxobicyclo[3.2.0]hept-3-yl acetate		C₉H₁₁BrO₃	详情	详情
(IV)	31209	5-hydroxy-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one		C₁₂H₁₉NO₂	详情	详情
(V)	31211	5-([1,1'-biphenyl]-4-ylmethoxy)-7-(1-piperidinyl)bicyclo[2.2.1]heptan-2-one		C₂₅H₂₉NO₂	详情	详情
(VI)	31212	6-([1,1'-biphenyl]-4-ylmethoxy)-8-(1-piperidinyl)-2-oxabicyclo[3.2.1]octan-3-one		C₂₅H₂₉NO₃	详情	详情
(VII)	31213	2-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]acetaldehyde		C₂₅H₃₁NO₃	详情	详情
(VIII)	31214	3-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]propanal		C₂₆H₃₃NO₃	详情	详情
(IX)	31215	trityl (Z)-7-[(1R,2R,3R,5S)-5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoate		C₄₉H₅₃NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(-)-(I)

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

Extended Information