4-nitrobenzoic acid; p-nitrobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】18119

【品名】4-nitrobenzoic acid; p-nitrobenzoic acid

【CA登记号】62-23-7

【分子式】C₇H₅NO₄

【分子量】167.12104

【元素组成】C 50.31% H 3.02% N 8.38% O 38.29%

与该中间体有关的原料药合成路线共 9 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5 合成路线6 合成路线7 合成路线8 合成路线9

合成路线1

该中间体在本合成路线中的序号：(VIII)

A new enantioselective synthesis of neplanocin A has been reported: The enantiocontrolled condensation of the 6-chloropurine (I) with cis-1,3-bis(benzoyloxy)-4-cyclopentene (II) catalyzed by a chiral Pd catalyst gives the alkylated purine (III), which is condensed with the nitrosulfone (IV) by means of PPh3 and TEA yielding the intermediate (V). Epoxidation of (V) with MCPBA in dichloromethane affords the epoxide (VI), which is oxidized with O3 and DBU in methanol/THF giving the cyclopentenecarboxylate (VII). The esterification of the beta-OH group of (VII) with 4-nitrobenzoic acid (VIII), PPh3 and DEAD in THF, using a Mitsunobu reaction to invert the OH group, yields the ester (IX), with the desired alpha-OH configuration. The reduction of (IX) with DIBAL in THF/dichloromethane affords the unsaturated the diol (X), which is dihydroxylated with OsO4 and NMO in acetone/water providing the tetraol (XI). The reaction of (XI) with 2,2-dimethoxypropane and TsOH gives the diacetonide (XII), which is selectively monodeprotected with FeCl3 on silica gel yielding the dihydroxylated acetonide (XIII). The regioselective hydroxylation of the primary OH of (XIII) with pivaloyl chloride (Piv-Cl) in pyridine yields the pivalate (XIV), which is dehydrated with SOCl2 in DMF/pyridine affording the fully protected 6-chloropurine derivative (XV). Compound (XV) is treated with ammonia in order to eliminate the pivaloyl group and to form the adenine derivative (XVI), which is finally treated with hot aqueous HCl to eliminate the acetonide group.

参考文献中间体

合成目标

【1】 Madsen, R.; Brown, B.; Guile, S.D.; Trost, B.M.; Palladium-catalyzed enantioselective synthesis of carbanucleosides. J Am Chem Soc 2000, 122, 25, 5947.

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)	17692	6-Chloropurine; 6-chloro-9H-purine	87-42-3	C₅H₃ClN₄	详情	详情
(II)	37776	(1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate		C₁₉H₁₆O₄	详情	详情
(III)	41036	(1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl benzoate		C₁₇H₁₃ClN₄O₂	详情	详情
(IV)	37778	(nitromethyl)(dioxo)phenyl-lambda(6)-sulfane; nitromethyl phenyl sulfone	21272-85-5	C₇H₇NO₄S	详情	详情
(V)	41037	6-chloro-9-[(1R,4S)-4-[(S)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9H-purine; (S)-[(1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl](nitro)methyl phenyl sulfone		C₁₇H₁₄ClN₅O₄S	详情	详情
(VI)	41038	(S)-[(1S,2S,4R,5R)-4-(6-chloro-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl](nitro)methyl phenyl sulfone; 6-chloro-9-[(1R,2R,4S,5S)-4-[(S)-nitro(phenylsulfonyl)methyl]-6-oxabicyclo[3.1.0]hex-2-yl]-9H-purine		C₁₇H₁₄ClN₅O₅S	详情	详情
(VII)	41039	methyl (3S,4R)-4-(6-chloro-9H-purin-9-yl)-3-hydroxy-1-cyclopentene-1-carboxylate		C₁₂H₁₁ClN₄O₃	详情	详情
(VIII)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(IX)	41040	(1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(methoxycarbonyl)-2-cyclopenten-1-yl 4-nitrobenzoate		C₁₉H₁₄ClN₅O₆	详情	详情
(X)	41041	(1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(hydroxymethyl)-2-cyclopenten-1-ol		C₁₁H₁₁ClN₄O₂	详情	详情
(XI)	41042	(1S,2S,3S,4R)-4-(6-chloro-9H-purin-9-yl)-1-(hydroxymethyl)-1,2,3-cyclopentanetriol		C₁₁H₁₃ClN₄O₄	详情	详情
(XII)	41043			C₁₇H₂₁ClN₄O₄	详情	详情
(XIII)	41044	(3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol		C₁₄H₁₇ClN₄O₄	详情	详情
(XIV)	41045	[(3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate		C₁₉H₂₅ClN₄O₅	详情	详情
(XV)	41046	[(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate		C₁₉H₂₃ClN₄O₄	详情	详情
(XVI)	41047	[(3aR,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol		C₁₄H₁₇N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

The treatment of (XI) under the Sharpless asymmetric epoxidation conditions (but using (+)-DET and titanium tetraisopropoxide) gives, after cyclization with NaOH, 1(S)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(R)-yl)-1,2-ethanediol (XVI), which is benzoylated with 4-nitrobenzoic acid (XVII), DEAD and PPh3 yielding the dibenzoate (XVIII), with inversion of the configuration at the OH group. The hydrolysis of (XVIII) with NaOMe in methanol affords, 1(R)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(R)-yl)-1,2-ethanediol (XIX), which is selectively tosylated with TsCl and pyridine giving the monotosylate (XX). The cyclization of (XX) with NaOMe furnishes the expected epoxide (XXI), which is finally condensed with the previously described intermediate amine (XV).

参考文献中间体

合成目标

【1】 Chandrasekhar, S.; Reddy, M.V.; Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. Tetrahedron 2000, 56, 34, 6339.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	40855	4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol		C₁₁H₁₃FO₂	详情	详情
(XV)	40859	(1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₄FNO₂	详情	详情
(XVI)	40856	(1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XVII)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(XVIII)	40860	(1R)-1-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-[(4-nitrobenzoyl)oxy]ethyl 4-nitrobenzoate		C₂₅H₁₉FN₂O₉	详情	详情
(XIX)	40861	(1R)-1-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XX)	40862	(2R)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XXI)	40863	(2R)-6-fluoro-2-[(2R)oxiranyl]-3,4-dihydro-2H-chromene		C₁₁H₁₁FO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Cyclization of 5(R)-hydroxy-L-lysine (VIII) by means of EDC and HOBt, followed by treatment of the resulting amino lactam (IX) with Boc2O, furnished the N-Boc aminolactam (X). The configuration of the (R)-secondary alcohol was inverted by Mitsunobu coupling with p-nitrobenzoic acid (XI) to produce the (S)-p-nitrobenzoate ester (XII). Methylation of the lactam N of (XII) yielded (XIII), and hydrolysis of the p-nitrobenzoate ester of (XIII) with LiOH afforded the (S)-hydroxy lactam (XIV). Esterification of (XIV) with myristic acid (XV) in the presence of EDC and DMAP produced the myristate ester (XVI). Treatment of (XVI) with trifluoroacetic acid removed the Boc protecting group to yield amine (XVII). This was then condensed with the intermediate lactone (VIII) in refluxing isopropanol to produce amide (XVIII). Finally, acetonide hydrolysis in (XVIII) employing trifluoroacetic acid generated the title compound.

参考文献中间体

合成目标

【1】 Kinder, F.R. Jr.; et al.; Total synthesis of bengamides B and E. J Org Chem 2001, 66, 6, 2118.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	47773	(4R,4aR,7R,7aS)-7-methoxy-2,2-dimethyl-4-[(E)-3-methyl-1-butenyl]tetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one		C₁₄H₂₂O₅	详情	详情
(VIII)	47774	(2S,5R)-2,6-diamino-5-hydroxyhexanoic acid		C₆H₁₄N₂O₃	详情	详情
(IX)	47775	(3S,6R)-3-amino-6-hydroxy-2-azepanone		C₆H₁₂N₂O₂	详情	详情
(X)	47776	tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate		C₁₁H₂₀N₂O₄	详情	详情
(XI)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(XII)	47777	(3S,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl 4-nitrobenzoate		C₁₈H₂₃N₃O₇	详情	详情
(XIII)	47778	(3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl 4-nitrobenzoate		C₁₉H₂₅N₃O₇	详情	详情
(XIV)	47779	tert-butyl (3S,6S)-6-hydroxy-1-methyl-2-oxoazepanylcarbamate		C₁₂H₂₂N₂O₄	详情	详情
(XV)	47780	myristic acid		C₁₄H₂₈O₂	详情	详情
(XVI)	47781	(3S,6S)-6-[(tert-butoxycarbonyl)amino]-1-methyl-7-oxoazepanyl myristate		C₂₆H₄₈N₂O₅	详情	详情
(XVII)	47783	(3S,6S)-6-amino-1-methyl-7-oxoazepanyl myristate		C₂₁H₄₀N₂O₃	详情	详情
(XVIII)	47782	(3S,6S)-6-[((2R)-2-[(4R,5R,6R)-5-hydroxy-2,2-dimethyl-6-[(E)-3-methyl-1-butenyl]-1,3-dioxan-4-yl]-2-methoxyethanoyl)amino]-1-methyl-7-oxoazepanyl myristate		C₃₅H₆₂N₂O₈	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIII)

The bromination of 1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (IX) with Br2 in CHCl3 gives the alpha-bromo ketone (X), which is cyclized with acetamidine hydrochloride (VIII) by means of K2CO3, yielding the expected imidazo-benzazepine (XI). This compound is detosylated with hot H2SO4 to provide 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (XII). Acylation of (XII) with 4-nitroben-zoic acid (XIII) by means of pyridine in either hot MeCN or DMF affords the 6-(4-nitro-benzoyl) derivative (XIV), which is reduced with H2 and Raney-Ni in MeOH to the corres-ponding 6-(4-aminobenzoyl) compound (XV). Finally, this compound is condensed with biphenyl-2-carbonyl chloride (XVI) [ obtained by treatment of biphenyl-2-carboxylic acid (V) with oxalyl chloride in CH2Cl2/DMF] by means of pyridine in acetonitrile and treated with 4N HCl.

参考文献中间体

合成目标

【1】 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121.
【2】 Yamazaki, A.; Tanaka, A.; Tsunoda, T. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of condensed benzazepine derivs.. JP 1996198879 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	18505	[1,1'-biphenyl]-2-carboxylic acid	947-84-2	C₁₃H₁₀O₂	详情	详情
(VIII)	15866	ethanimidamide		C₂H₆N₂	详情	详情
(IX)	14763	1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one		C₁₇H₁₇NO₃S	详情	详情
(X)	41815	4-bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one		C₁₇H₁₆BrNO₃S	详情	详情
(XI)	41816	2-methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine		C₁₉H₁₉N₃O₂S	详情	详情
(XII)	41817	2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine	318237-73-9	C₁₂H₁₃N₃	详情	详情
(XIII)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(XIV)	41818	[2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl](4-nitrophenyl)methanone		C₁₉H₁₆N₄O₃	详情	详情
(XV)	41819	(4-aminophenyl)[2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl]methanone		C₁₉H₁₈N₄O	详情	详情
(XVI)	18506	[1,1'-biphenyl]-2-carbonyl chloride		C₁₃H₉ClO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

Esterification of 3,4-(methylenedioxy)phenylacetic acid (I) with methanol in the presence of sulfuric acid provided methyl ester (II). Fiedel Crafts acylation of (II) with 4-nitrobenzoic acid (III) under the action of P2O5 in refluxing dichloroethane yielded ketone (IV). This compound was refluxed with hydrazine hydrate in ethanol to afford benzodiazepinone (V). Finally, the nitro group was reduced by hydrogenation in acetic acid with Pd/C as the catalyst or with Raney-Ni and hydrazine to give the corresponding amine.

参考文献中间体

合成目标

【1】 Wang, Y.; et al.; Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists. J Med Chem 1998, 41, 14, 2621.
【2】 Xia, H.; Field, G.; Lan, N.C.; Wang, Y. (Acea Pharmaceuticals); Substd. 2,3-benzodiazepin-4-ones and the use thereof. EP 1021418; JP 2000506890; US 5891871; WO 9734878 .

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)	18117	2-(1,3-benzodioxol-5-yl)acetic acid; 3,4-(Methylenedioxy)phenylacetic acid	2861-28-1	C₉H₈O₄	详情	详情
(II)	18118	methyl 2-(1,3-benzodioxol-5-yl)acetate		C₁₀H₁₀O₄	详情	详情
(III)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(IV)	18120	methyl 2-[6-(4-nitrobenzoyl)-1,3-benzodioxol-5-yl]acetate		C₁₇H₁₃NO₇	详情	详情
(V)	18121	5-(4-nitrophenyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one		C₁₆H₁₁N₃O₅	详情	详情

合成路线6

该中间体在本合成路线中的序号：(III)

Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.

参考文献中间体

合成目标

【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.

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)	13386	(5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone	6485-40-1	C₁₀H₁₄O	详情	详情
(II)	18758	(1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(III)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(IV)	18760	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate		C₁₇H₁₉NO₄	详情	详情
(V)	18761	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(VI)	18762	1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene	109-92-2	C₄H₈O	详情	详情
(VII)	18763	2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene		C₁₄H₂₃BrO₂	详情	详情
(VIII)	18764	(3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether		C₁₄H₂₄O₂	详情	详情
(IX)	18765	2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde		C₁₂H₂₀O₂	详情	详情
(X)	18766	(1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol		C₁₂H₂₂O₂	详情	详情
(XI)	18767	(1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol		C₃₁H₃₆O₂	详情	详情
(XII)	18768	(2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone		C₃₁H₃₄O₂	详情	详情
(XIII)	18769	methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₆O₄	详情	详情
(XIV)	18770	methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₈O₄	详情	详情
(XV)	18771	methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₄H₄₀O₄	详情	详情
(XVI)	18772	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol		C₃₃H₄₀O₃	详情	详情
(XVII)	18773	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate		C₃₄H₄₂O₅S	详情	详情

合成路线7

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.

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)	13386	(5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone	6485-40-1	C₁₀H₁₄O	详情	详情
(II)	18758	(1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(III)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(IV)	18760	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate		C₁₇H₁₉NO₄	详情	详情
(V)	18761	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(VI)	18762	1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene	109-92-2	C₄H₈O	详情	详情
(VII)	18763	2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene		C₁₄H₂₃BrO₂	详情	详情
(VIII)	18764	(3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether		C₁₄H₂₄O₂	详情	详情
(IX)	18765	2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde		C₁₂H₂₀O₂	详情	详情
(X)	18766	(1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol		C₁₂H₂₂O₂	详情	详情
(XI)	18767	(1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol		C₃₁H₃₆O₂	详情	详情
(XII)	18768	(2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone		C₃₁H₃₄O₂	详情	详情
(XIII)	18769	methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₆O₄	详情	详情
(XIV)	18770	methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₈O₄	详情	详情
(XV)	18771	methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₄H₄₀O₄	详情	详情
(XVI)	18772	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol		C₃₃H₄₀O₃	详情	详情
(XVII)	18773	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate		C₃₄H₄₂O₅S	详情	详情

合成路线8

该中间体在本合成路线中的序号：(II)

Benzophenone (III) was prepared by Friedel-Crafts acylation of methyl 3,4-methylenedioxyphenylacetate (I) with 4-nitrobenzoic acid (II). Subsequent cyclization of (III) with hydrazine gave rise to benzodiazepinone (IV). This was treated with methyl isocyanate in the presence of triethylamine to yield the corresponding urea (V). Finally, the nitro group of (V) was reduced to the title aniline by catalytic hydrogenation using Pd-C.

参考文献中间体

合成目标

【1】 De Sarro, G.; Micale, N.; Baraldi, M.; De Sarro, A.; Pula, G.; De Micheli, C.; Zappala, M.; Grasso, S.; Synthesis and anticonvulsant activity of novel and potent 2,3-benzodiazepine AMPA/kainate receptor antagonists. J Med Chem 1999, 42, 21, 4414.

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)	18118	methyl 2-(1,3-benzodioxol-5-yl)acetate		C₁₀H₁₀O₄	详情	详情
(II)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(III)	18120	methyl 2-[6-(4-nitrobenzoyl)-1,3-benzodioxol-5-yl]acetate		C₁₇H₁₃NO₇	详情	详情
(IV)	18121	5-(4-nitrophenyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one		C₁₆H₁₁N₃O₅	详情	详情
(V)	41984	N-methyl-5-(4-nitrophenyl)-8-oxo-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide		C₁₈H₁₄N₄O₆	详情	详情

合成路线9

该中间体在本合成路线中的序号：(XLVI)

A different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic Baeyer-Villiger reaction. Keto ester (XXXVIII) was protected as the ethylene ketal (XXXIX) and subsequently reduced to alcohol (XL) using LiAlH4. Acetylation of alcohol (XL) to acetate (XLI), followed by acidic ketal hydrolysis afforded cyclohexanone (XLII) (9,10). The racemic ketone (XLII) was then subjected to oxidative cleavage by monooxigenase 2 obtained from Pseudomonas putida to furnish the (R)-lactone (XLIV) along with unreacted (S)-cyclohexanone (XLIII) (9-11). The use of cyclohexanone monooxigenase from Acinetobacter NCIMB 9871 has also been reported for this reaction (12). Methanolysis of lactone (XLIV) in the presence of NaOMe gave rise to the (R)-dihydroxy ester (XLV). Inversion of the configuration of (XLV) was accomplished by Mitsunobu coupling with p-nitrobenzoic acid (XLVI) to produce the (S)-p-nitrobenzoate ester (XLVII). Smooth hydrolysis of ester (XLVII) provided methyl (S)-6,8-dihydroxyoctanoate (XLVIII), which was processed through intermediates (XLIX) and (L), as for the isopropyl (X) (Scheme 29605101a) and ethyl (XXIX) (Scheme 29605103a) homologues, to afford the title compound.

参考文献中间体

合成目标

【1】 Adger, B.; et al.; The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. Bioorg Med Chem 1997, 5, 2, 253.
【2】 Adger, B.; et al.; Application of enzymatic Baeyer-Villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (R)-(+)-lipoic acid. J Chem Soc Chem Commun 1995, 15, 1563.
【3】 McCague, R.; Roberts, S.M.; Adger, B.M. (Celltech Group plc); Process for the production of lipoic acid. WO 9638437 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXVIII)	57966	Ethyl 2-cyclohexanone acetate; Ethyl 2-oxocyclohexane acetate	24731-17-7	C₁₀H₁₆O₃	详情	详情
(XXXIX)	57967	ethyl 2-(1,4-dioxaspiro[4.5]dec-6-yl)acetate		C₁₂H₂₀O₄	详情	详情
(XL)	57968	2-(1,4-dioxaspiro[4.5]dec-6-yl)-1-ethanol		C₁₀H₁₈O₃	详情	详情
(XLI)	57969	2-(1,4-dioxaspiro[4.5]dec-6-yl)ethyl acetate		C₁₂H₂₀O₄	详情	详情
(XLII)	57970	2-(2-oxocyclohexyl)ethyl acetate		C₁₀H₁₆O₃	详情	详情
(XLIII)	57971	2-[(1S)-2-oxocyclohexyl]ethyl acetate		C₁₀H₁₆O₃	详情	详情
(XLIV)	57972	2-[(2R)-7-oxooxepanyl]ethyl acetate		C₁₀H₁₆O₄	详情	详情
(XLV)	57973	methyl (6R)-6,8-dihydroxyoctanoate		C₉H₁₈O₄	详情	详情
(XLVI)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(XLVII)	57974	(1S)-6-methoxy-1-{2-[(4-nitrobenzoyl)oxy]ethyl}-6-oxohexyl 4-nitrobenzoate		C₂₃H₂₄N₂O₁₀	详情	详情
(XLVIII)	57977	methyl (6S)-6,8-dihydroxyoctanoate		C₉H₁₈O₄	详情	详情
(XLIX)	57975	methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate		C₁₁H₂₂O₈S₂	详情	详情
(L)	57976	methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate		C₉H₁₆O₂S₂	详情	详情

Extended Information