bicyclo[3.2.0]hept-2-en-6-one -Drug Synthesis Database

【结构式】

【分子编号】53261

【品名】bicyclo[3.2.0]hept-2-en-6-one

【CA登记号】13173-09-6

【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 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：(rac)-(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

合成路线2

该中间体在本合成路线中的序号：(IX)

The first method required the chiral building block (S)-(4-fluorophenyl)glycine (VI), which was prepared from 4-fluorophenyl acetic acid (I) by two routes. Condensation of (I) with (S)-4-benzyl-2-oxazolidinone (II), via activation as the corresponding mixed anhydride with pivaloyl chloride, furnished the N-acyl oxazolidinone (III). The potassium enolate of (III) was then reacted with 2,4,6-triisopropylphenylsulfonyl azide, producing stereoselectively azide (IV). Hydrolytic removal of the chiral auxiliary of (IV) gave (S)-azido-(4-fluorophenyl)acetic acid (V), which was then reduced to the desired amino acid (VI) by catalytic hydrogenation over Pd/C. Alternatively, 4-fluorophenyl acetic acid (I) was converted to the corresponding acid chloride (VII) with SOCl2. Bromination of (VII) under Hell-Volhard-Zelinskii conditions, followed by quenching with MeOH, afforded the racemic alpha-bromo ester (VIII). Displacement of the bromide of (VIII) with NaN3 using a phase-transfer catalyst produced the azido ester (IX). Catalytic hydrogenation of the azido group of (IX) gave the racemic amino ester, which was resolved via formation of the diastereomeric salts with (+)-dibenzoyltartaric acid. The desired (S)-amino ester (X) was then hydrolyzed to (VI) under acidic conditions.

参考文献中间体

合成目标

【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .

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)	18999	4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid	405-50-5	C₈H₇FO₂	详情	详情
(II)	14694	(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone	90719-32-7	C₁₀H₁₁NO₂	详情	详情
(III)	44186	(4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one		C₁₈H₁₆FNO₃	详情	详情
(IV)	44188	(4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one		C₁₈H₁₅FN₄O₃	详情	详情
(V)	44189	(2S)-2-azido-2-(4-fluorophenyl)ethanoic acid		C₈H₆FN₃O₂	详情	详情
(VI)	37104	(8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one		C₂₂H₃₂O₃	详情	详情
(VII)	44191	methyl 2-bromo-2-(4-fluorophenyl)acetate		C₉H₈BrFO₂	详情	详情
(VIII)	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
(IX)	53261	bicyclo[3.2.0]hept-2-en-6-one	13173-09-6	C₇H₈O	详情	详情
(X)	43098	(2R)-2-amino-2-(4-fluorophenyl)ethanoic acid	7292-73-1	C₈H₈FNO₂	详情	详情

Extended Information