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【结 构 式】 
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【分子编号】24611 【品名】1-(bromomethyl)-4-fluorobenzene 【CA登记号】459-46-1 |
【 分 子 式 】C7H6BrF 【 分 子 量 】189.0270432 【元素组成】C 44.48% H 3.2% Br 42.27% F 10.05% |
合成路线1
该中间体在本合成路线中的序号：(IX)Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).
| 【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 32096 | 4-Methyl-1-penten-3-ol bromomagnesium salt | C6H11BrMgO | 详情 | 详情 | |
| (IV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (V) | 32097 | 1-ethyl 3-(1-isopropyl-2-propenyl) malonate | C11H18O4 | 详情 | 详情 | |
| (VI) | 32098 | methyl (E)-6-methyl-4-heptenoate | C9H16O2 | 详情 | 详情 | |
| (VII) | 32104 | (1R,2R)-2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VIII) | 32099 | (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C17H25NO2 | 详情 | 详情 | |
| (IX) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (X) | 32100 | (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C24H30FNO2 | 详情 | 详情 | |
| (XI) | 32101 | (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18BrFO2 | 详情 | 详情 | |
| (XII) | 32102 | (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18FN3O2 | 详情 | 详情 | |
| (XIII) | 32103 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.
| 【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 24605 | 4-methyl-1-penten-3-ol | C6H12O | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 24607 | diethyl 2-[(E)-4-methyl-2-pentenyl]malonate | C13H22O4 | 详情 | 详情 | |
| (VI) | 24608 | (E)-6-methyl-4-heptenoic acid | C8H14O2 | 详情 | 详情 | |
| (VII) | 24609 | (1R,2R)-2-(methylamino)-1-phenyl-1-propanol | C10H15NO | 详情 | 详情 | |
| (VIII) | 24610 | (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide | C18H27NO2 | 详情 | 详情 | |
| (IX) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (X) | 24612 | (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide | C25H32FNO2 | 详情 | 详情 | |
| (XI) | 24613 | (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18BrFO2 | 详情 | 详情 | |
| (XII) | 24614 | (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18FN3O2 | 详情 | 详情 | |
| (XIII) | 24615 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 | |
| (XIV) | 24616 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid | C20H30FNO5 | 详情 | 详情 | |
| (XV) | 24617 | (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid | C20H28FNO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The alkylation of 2-acetylpyrrole (I) with 4-fluorobenzyl bromide (II) in the presence of NaH provided the N-benzyl indole (III). Subsequent Claisen condensation of (III) with dimethyl oxalate furnished diketo ester (IV), which was finally hydrolyzed with NaOH to the title carboxylic acid.
| 【1】 Selnick, H.G.; Hazuda, D.J.; Egbertson, M.; Guare, J.P. Jr.; Clark, D.L.; Wai, J.S.; Young, S.D.; Medina, J.C. (Merck & Co., Inc.; Tularik Inc.); HIV integrase inhibitors. WO 9962513 . |
| 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) | 37917 | 1-(1H-pyrrol-2-yl)-1-ethanone | 1072-83-9 | C6H7NO | 详情 | 详情 |
| (II) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (III) | 37918 | 1-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-1-ethanone | C13H12FNO | 详情 | 详情 | |
| (IV) | 37919 | methyl 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutanoate | C16H14FNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Alkylation of (R)-2-methylpiperazine (I) with 4-fluorobenzyl bromide (II) provides 1-(4-fluorobenzyl)-3-methylpiperazine (III). Subsequent acylation of piperazine (III) with (4-chlorophenoxy)acetyl chloride (IV) furnishes the title amide.
| 【1】 Monahan, S.D.; Xu, W.; Morissey, M.M.; Bauman, J.G.; Ng, H.P.; Hesselgesser, J.E.; Liang, M.; Zheng, W.; Islam, I.; May, K.B.; Ghannam, A.F.; Buckman, B.O.; Horuk, R.; Wei, G.P. (Schering AG); Piperazine derivs. and their use as anti-inflammatory agents. US 6207665; WO 9856771 . |
合成路线5
该中间体在本合成路线中的序号：(Xa)Cycloaddition of norbornene (I) with chlorosulfonyl isocyanate (II) in EtOAc or Et2O followed by treatment with aqueous Na2SO3 affords (±)-exo-3-azatricyclo[4.2.1.O2,5]nonan-4-one (III), which by hydrolysis with HCl gives 3-aminonorbornane-2-carboxylic acid hydrochloride (IV). Treatment of amino acid (IV) with EtOH or MeOH by means of SOCl2 at reflux provides the hydrochloride salts of the corresponding ethyl (Va) or methyl (Vb) esters, respectively, which are neutralized with NaHCO3 to yield the free amines (VIa) and (VIb). Resolution of the racemic amino esters (VIa) or (VIb) with (S)-(+)-CSA in EtOAc/EtOH followed by neutralization of the obtained CSA salts (VIIa) or (VIIb) with Na2CO3 or K2CO3 in EtOAc leads to ethyl (VIIIa) or methyl (VIIIb) (1S,2R,3S,4R)-3-aminonorbornane-2-carboxylate, respectively. Alternatively, amino ester (VIIa) can be obtained by ring opening of racemic lactam (III) with EtOH in the presence of (S)-(+)-CSA in EtOAc at 50-75 °C. Reductive alkylation of amines (VIIIa) and (VIIIb) with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and AcOH or NaOAc in EtOH gives the secondary amines (XIa) or (XIb) , which can also be prepared by alkylation of amines (VIII) with 4-fluorobenzyl bromide (Xa) or iodide (XIb) in the presence of Et3N in DMF at 70 °C . N-Acylation of amino esters (XIa) or (XIb) with the carboxylic acid (XII) using as coupling reagents EDC in the presence of DMAP , or NMM in DMF, or DCC in CH2Cl2/DMF, or HATU and NMM in DMF , yields amides (XIIIa) and (XIIIb) . Finally, amide esters (XIII) are submitted to intramolecular Claisen condensation by means of NaOEt in EtOH at 60 °C or Et3N at 60 °C . Alternatively, methyl ester (XIb) can be condensed with the carboxylic acid (XII) in the presence of DCC, NMM and Et3N in DMF at 50 °C , or in acetonitrile .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazine 1,1-dioxide compounds. CN 10236871, US 2009306057, US 80976131, WO 2009152166. |
| 【3】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 【4】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12. |
| 【5】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazin-3-yl acetic acid compound[[s]] and methods of making the acetic acid compound. US 2012116077, US 8222404. |
| 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) | 68649 | bicyclo[2.2.1]hept-2-ene | C7H10 | 详情 | 详情 | |
| (Va) | 68657 | (±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C10H17NO2.HCl | 详情 | 详情 | |
| (Vb) | 68658 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride | C9H15NO2.HCl | 详情 | 详情 | |
| (VIa) | 68655 | (±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (VIb) | 68656 | (±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C9H15NO2 | 详情 | 详情 | |
| (VIIa) | 68652 | (1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate | C10H17NO2.C10H16O4S | 详情 | 详情 | |
| (VIIb) | 68651 | (1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate | C9H15NO2S.C10H16O4S | 详情 | 详情 | |
| (VIIIa) | 68654 | (1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (VIIIb) | 68653 | (1S,2R,3S,4R)ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate | C9H15NO2 | 详情 | 详情 | |
| (Xa) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (Xb) | 23601 | 1-fluoro-4-(iodomethyl)benzene | C7H6FI | 详情 | 详情 | |
| (XIa) | 68660 | (1S,2R,3S,4R)-ethyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C17H22FNO2 | 详情 | 详情 | |
| (XIb) | 68661 | (1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate | C16H20FNO2 | 详情 | 详情 | |
| (XIIIa) | 68663 | (1S,2R,3S,4R)-ethyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate | C27H31FN4O7S2 | 详情 | 详情 | |
| (XIIIb) | 68664 | (1S,2R,3S,4R)-methyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate | C26H29FN4O7S2 | 详情 | 详情 | |
| (II) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (III) | 68650 | (±)-exo-3-azatricyclo[4.2.1.O2.5 nonan-4-one;(1S,2R,5S,6R)-3-azatricyclo[4.2.1.02.5]nonan-4-one | C8H11NO | 详情 | 详情 | |
| (IV) | 68659 | (±)-(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride | C8H13NO2.HCl | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (XII) | 68662 | 2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid | C10H11N3O6S2 | 详情 | 详情 |