4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid -Drug Synthesis Database

【结构式】

【分子编号】61564

【品名】4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid

【CA登记号】87199-17-5

【分子式】C₇H₇BO₃

【分子量】149.94178

【元素组成】C 56.07% H 4.71% B 7.21% O 32.01%

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：(IV)

Reductive cyclization of 6-fluoro-3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester (I) by means of Zn and HCl in methanol/water gives 8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (II), which is brominated by means of Pyr/HBr/Br2 in THF/dichloromethane to afford the 2-bromo derivative (III). Condensation of the brominated compound (III) with 4-formylphenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing H2O/ethanol/toluene provides 8-fluoro-2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (V), which is finally reductocondensed with methylamine (VI) by means of NaBH4 (1). Scheme 1.

参考文献中间体

合成目标

【1】 Webber, S.E., Thoresen, L.H., Tikhe, H., Canan-Koch, S.S. (Agouron Pharmaceuticals, Inc.; Cancer Research UK). Tricyclic inhibitors of poly(ADP-ribose) polymerases. CA 2360003, EP 1140936, JP 2002534523, US 6495541, WO 2000042040.

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)	65864	6-fluoro-3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester		C₁₂H₁₁FN₂O₄	详情	详情
(II)	65865	8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₁H₉FN₂O	详情	详情
(III)	65866	2-bromo-8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₁H₈BrFN₂O	详情	详情
(IV)	61564	4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid	87199-17-5	C₇H₇BO₃	详情	详情
(V)	65867	8-fluoro-2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₈H₁₃FN₂O₂	详情	详情
(VI)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The intermediate carbazate (VI) has been obtained as follows. The condensation of phenylboronic acid (I) with 2-bromopyridine (II) by means of Pd(PPh3)4 gives 4-(2-pyridyl)benzaldehyde (III), which is condensed with tert-butyl carbazate (IV) in hot toluene/isopropyl alcohol to yield the benzylidenehydrazone (V). Finally, this compound is reduced with sodium formate over Pd/C in ethanol to afford the target intermediate; the carbazate (VI). The selective monosilylation of the primary OH group of diol (VII) with Tbdms-Cl, TEA and DMAP followed by reaction of the secondary OH group with MsCl gives the protected mesylate (VIII), which is desilylated with NH4F and AcOH yielding the primary alcohol (IX). The epoxidation of (IX) with t-BuOK in isopropyl alcohol affords the chiral epoxide (X), which is condensed with the intermediate carbazate (VI) in refluxing isopropanol to provide the adduct (XI). Elimination of the two Boc protecting groups of (XI) with HCl in hot THF gives the diamino compound (XII), which is finally condensed with two moles of N-(methoxycarbonyl)-L-tert-leucine (XIII) by means of WSC, HOBt and DIEA in dichloromethane to provide the target Atazanavir.

参考文献中间体

合成目标

【1】 Xu, Z.; Singh, J.; Schwinden, M.D.; Zheng, B.; Kissick, T.P.; Patel, B.; Humora, M.J.; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes, J.E.; Pudipeddi, M.; Lindrud, M.D.; Srivastava, S.K.; Kronenthal, D.R.; Mueller, R.H.; Process research and development for an efficient synthesis of the HIV protease inhibitor BMS-232632. Org. Proc. Res. & Develop. 2002, 6, 3, 323.

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)	61564	4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid	87199-17-5	C₇H₇BO₃	详情	详情
(II)	29052	2-Bromopyridine；α-bromopyridine;α-bromoazine	109-04-6	C₅H₄BrN	详情	详情
(III)	23440	4-(2-pyridinyl)benzaldehyde		C₁₂H₉NO	详情	详情
(IV)	10893	tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate	870-46-2	C₅H₁₂N₂O₂	详情	详情
(V)	23442	tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate		C₁₇H₁₉N₃O₂	详情	详情
(VI)	23443	tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate		C₁₇H₂₁N₃O₂	详情	详情
(VII)	61565	tert-butyl (1S,2S)-1-benzyl-2,3-dihydroxypropylcarbamate		C₁₅H₂₃NO₄	详情	详情
(VIII)	61566	(1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenylpropyl methanesulfonate		C₂₂H₃₉NO₆SSi	详情	详情
(IX)	61567	(1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)-3-phenylpropyl methanesulfonate		C₁₆H₂₅NO₆S	详情	详情
(X)	23444	tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate		C₁₅H₂₁NO₃	详情	详情
(XI)	23445	tert-butyl 2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate		C₃₂H₄₂N₄O₅	详情	详情
(XII)	23446	(2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol		C₂₂H₂₆N₄O	详情	详情
(XIII)	23447	(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid		C₈H₁₅NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

In an alternative method, 4-(t-butyldimethylsilyloxy)-3-(1-adamantyl)bromobenzene (I) undergoes Suzuki coupling with 4-formylbenzeneboronic acid (II) to provide the biphenyl aldehyde (III). Subsequent Wittig condensation of (III) with methyl triphenylphosphoranylideneacetate (IV) yields the unsaturated ester (V). This is finally hydrolyzed with LiOH to furnish the title compound.

参考文献中间体

合成目标

【1】 Penco, S.; Merlini, L.; Giannini, G.; Vesci, L.; Pisano, C.; Dallavalle, S. (Sigma-Tau Industrie Farmaceutiche Riunite SpA); Retinoid derivs. with antiangiogenic, antitumoral and proapoptotic activities. WO 0311808 .

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)	63332	4-bromo-2-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl (1,1-dimethylethyl)(dimethyl)silyl ether; [(4-bromo-2-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl)oxy](1,1-dimethylethyl)dimethylsilane		C₂₂H₃₃BrOSi	详情	详情
(II)	61564	4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid	87199-17-5	C₇H₇BO₃	详情	详情
(III)	63333	4'-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-carbaldehyde		C₂₉H₃₈O₂Si	详情	详情
(IV)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(V)	63334	methyl 3-(4'-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-yl)-2-propenoate		C₃₂H₄₂O₃Si	详情	详情

Extended Information