|
【结 构 式】 
|
【分子编号】17575 【品名】4-chlorophenylboronic acid 【CA登记号】1679-18-1 |
【 分 子 式 】C6H6BClO2 【 分 子 量 】156.37614 【元素组成】C 46.09% H 3.87% B 6.91% Cl 22.67% O 20.46% |
合成路线1
该中间体在本合成路线中的序号：(XI)A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.
| 【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900. |
| 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) | 17565 | 1-(3-chloro-1-propynyl)benzene | C9H7Cl | 详情 | 详情 | |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 17567 | 2,2-dimethyl-5-phenyl-4-pentynal | C13H14O | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 17569 | methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate | C16H21NO2 | 详情 | 详情 | |
| (VI) | 17570 | 2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one | C15H17NO | 详情 | 详情 | |
| (VII) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VIII) | 17572 | ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C19H21NO4 | 详情 | 详情 | |
| (IX) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
| (X) | 17574 | ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C20H20F3NO6S | 详情 | 详情 | |
| (XI) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (XII) | 17576 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate | C25H24ClNO3 | 详情 | 详情 | |
| (XIII) | 17577 | p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide | 1576-35-8 | C7H10N2O2S | 详情 | 详情 |
| (XIV) | 16723 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate | C25H26ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)5-Bromo-2-furoic acid (I) was converted to the mixed anhydride with isobutyl chloroformate and then reduced to alcohol (II) using NaBH4. After formation of the sodium alkoxide of (II) with NaH, condensation with chloride (III) in the presence of 15-crown-5 provided ether (IV). Hydrolysis of the methyl ester of (IV), followed by coupling of the resulting carboxylic acid (V) with L-methionine methyl ester (VI) gave amide (VII). Further Suzuki coupling of (VII) with 4-chlorophenyl boronic acid (VIII) produced the aryl-substituted furan (IX). Finally, hydrolysis of the methionine methyl ester of (IX) with LiOH, followed by lyophilization furnished the corresponding lithium carboxylate salt.
| 【1】 Augeri, D.J.; Kalvin, D.; Anowick, D.; et al.; Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase. Bioorg Med Chem Lett 1999, 9, 8, 1069. |
| 【2】 Donner, B.G.; Janowick, D.A.; Larsen, J.J.; Rosenberg, S.H.; Hamilton, A.D.; Barr, K.J.; Sorensen, B.K.; Augeri, D.J.; Kalvin, D.M.; O'Connor, S.J.; Fakhoury, S.A.; Swenson, R.E.; Liu, G.; Sebti, S.M.; Shen, W. (University of Pittsburgh); Inhibitors of protein isoprenyl transferases. EP 0986384; WO 9850029; WO 9850030; WO 9850031 . |
| 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) | 31326 | 5-bromo-2-furoic acid | 585-70-6 | C5H3BrO3 | 详情 | 详情 |
| (II) | 31327 | (5-bromo-2-furyl)methanol | C5H5BrO2 | 详情 | 详情 | |
| (III) | 31328 | methyl 5-(chloromethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C16H15ClO2 | 详情 | 详情 | |
| (IV) | 31329 | methyl 5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate | C21H19BrO4 | 详情 | 详情 | |
| (V) | 31330 | 5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C20H17BrO4 | 详情 | 详情 | |
| (VI) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VII) | 31331 | methyl (2S)-2-[[(5-[[(5-bromo-2-furyl)methoxy]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C26H28BrNO5S | 详情 | 详情 | |
| (VIII) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (IX) | 31332 | methyl (2S)-2-([[5-([[5-(4-chlorophenyl)-2-furyl]methoxy]methyl)-2'-methyl[1,1'-biphenyl]-2-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C32H32ClNO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Nitration of 5-bromoisoquinoline (I) employing KNO3 in H2SO4 provides 5-bromo-8-nitroisoquinoline (II). Quaternization of isoquinoline (II) with dimethyl sulfate, followed by reduction of the resultant N-methyl isoquinolinium salt (III) with NaBH4 in cold HOAc furnishes the tetrahydroisoquinoline (IV). Subsequent Suzuki coupling between the bromotetrahydroisoquinoline (IV) and 4-chlorophenylboronic acid (V) yields the 5-aryl isoquinoline derivative (VI). The nitro group of (VI) is further reduced to amine (VII) by catalytic hydrogenation over Raney nickel. The key isatin compound (IX) is then obtained by condensation of amine (VII) with chloral (VIII) in the presence of hydroxylamine hydrochloride and sodium sulfate. Finally, isatin (IX) is converted to the desired oxime by treatment with hydroxylamine hydrochloride in EtOH.
| 【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); AMPA antagonists and a method of treatment therewith. EP 0698025; JP 1996510221; US 5780493; US 5843945; WO 9426747 . |
| 【2】 Moeller, A.; Peters, D.; Groenborg, M. (NeuroSearch A/S); Isatine derivs. with neurotrophic activity. EP 1255734; US 2003040518; WO 0155110 . |
| 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) | 22811 | 5-bromoisoquinoline | C9H6BrN | 详情 | 详情 | |
| (II) | 22812 | 5-bromo-8-nitroisoquinoline | C9H5BrN2O2 | 详情 | 详情 | |
| (III) | 58406 | 5-bromo-2-methyl-8-nitroisoquinolinium methanesulfonate | C11H11BrN2O5S | 详情 | 详情 | |
| (IV) | 22814 | 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C10H11BrN2O2 | 详情 | 详情 | |
| (V) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (VI) | 58407 | 5-(4-chlorophenyl)-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C16H15ClN2O2 | 详情 | 详情 | |
| (VII) | 58408 | 5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinamine; 5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinylamine | C16H17ClN2 | 详情 | 详情 | |
| (VIII) | 58409 | 2,2,2-trichloroacetaldehyde | 75-87-6 | C2HCl3O | 详情 | 详情 |
| (IX) | 58410 | 5-(4-chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione | C18H15ClN2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)1-Amino-5,6,7,8-tetrahydronaphthalene (I) is protected as the corresponding acetamide (II) by treatment with Ac2O in the presence of NaOAc. Bromination of (II) with bromine in trifluoroacetic acid leads to (III). Then, Suzuki coupling between aryl bromide (III) and 4-chlorophenylboronic acid (IV) furnishes the aryl tetrahydronaphthalene (V). Acetamide hydrolysis in (V) under alkaline conditions provides amine (VI). Condensation of (VI) with chloral and hydroxylamine, followed by cyclization in hot methanesulfonic acid generates the isatin derivative (VII). This is finally converted to the title oxime upon treatment with hydroxylamine hydrochloride in ethanol.
| 【1】 Moeller, A.; Peters, D.; Groenborg, M. (NeuroSearch A/S); Isatine derivs. with neurotrophic activity. EP 1255734; US 2003040518; WO 0155110 . |
| 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) | 61282 | 1-Amino-5,6,7,8-tetrahydronaphthalene 5,6,7,8-Tetrahydro-1-naphthylamine 5-Aminotetralin 1-Amino-5,6,7,8-tetrahydronaphthalene, tech. 1-Amino-5,6,7,8-tetrahydronaphthalin 5-Aminotetraline (1-AMINO-5,6,7,8-TETRAHYDRONAPHTHALENE) | 2217-41-6 | C10H13N | 详情 | 详情 |
| (II) | 61283 | N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide | C12H15NO | 详情 | 详情 | |
| (III) | 61284 | N-(4-bromo-5,6,7,8-tetrahydro-1-naphthalenyl)acetamide | C12H14BrNO | 详情 | 详情 | |
| (IV) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (V) | 61285 | N-[4-(4-chlorophenyl)-5,6,7,8-tetrahydro-1-naphthalenyl]acetamide | C18H18ClNO | 详情 | 详情 | |
| (VI) | 61286 | 4-(4-chlorophenyl)-5,6,7,8-tetrahydro-1-naphthalenamine; 4-(4-chlorophenyl)-5,6,7,8-tetrahydro-1-naphthalenylamine | C16H16ClN | 详情 | 详情 | |
| (VII) | 61287 | 5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-benzo[g]indole-2,3-dione | C18H14ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXI)The building block (IX) can be obtained by several related methods:
Reaction of 4,4-dimethylcyclohexanone (XVII) with DMF and PBr3 under Vilsmeier formylation conditions provides the carbaldehyde (XVIII), which is subjected to reductive amination with 4-piperazinobenzoic acid ethyl ester (XIX) and NaBH3CN resulting in the cyclohexenylmethyl piperazine (XX). Subsequent Suzuki coupling of compound (XX) with 4-chlorophenylboronic acid (XXI) followed by ethyl ester hydrolysis of the resultant adduct (XXII) leads to the target intermediate (IX) (1). Scheme 3.
In a related procedure, 2-hydroxy-5,5-dimethyl-1-cyclohexenecarboxylic acid methyl ester (XXIII) is converted to the corresponding triflate (XXIV), which undergoes Suzuki coupling with boronic acid (XXI) to yield the 2-arylcyclohexenecarboxylate derivative (XXV). After reduction of ester (XXV) with LiBH4, the resulting primary alcohol (XXVI) is converted to the corresponding mesylate (XXVII) with methanesulfonyl chloride, and then condensed with the piperazine derivative (XIX) followed by ethyl ester hydrolysis to yield the key precursor (IX) (4). Scheme 3.
| 【1】 Bruncko, M., Ding, H., Elmore, S.W. et al. (Abbott Laboratories Inc.). Apoptosis promoters. EP 1888550, US 2007027135, US 7390799, WO 2007040650. |
| 【4】 Song, X., Bruncko, M., Ding, H. et al. P2 site SAR development toward ABT-263, an orally bioavailable inhibitor of Bcl-2 family proteins. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 78. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 65759 | C26H31ClN2O2 | 详情 | 详情 | ||
| (XVII) | 65767 | 4,4-Dimethylcyclohexanone; 4,4-Dimethyl-1-cyclohexanone | 4255-62-3 | C8H14O | 详情 | 详情 |
| (XVIII) | 65768 | C9H13BrO | 详情 | 详情 | ||
| (XIX) | 65769 | Ethyl 4-(1-piperazinyl)benzoate | 80518-57-6 | C13H18N2O2 | 详情 | 详情 |
| (XX) | 65770 | C22H31BrN2O2 | 详情 | 详情 | ||
| (XXI) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (XXII) | 65771 | C28H35ClN2O2 | 详情 | 详情 | ||
| (XXIII) | 65772 | C10H16O3 | 详情 | 详情 | ||
| (XXIV) | 65773 | C11H16F3O5S | 详情 | 详情 | ||
| (XXV) | 65774 | C16H20ClO2 | 详情 | 详情 | ||
| (XXVI) | 65775 | C15H19ClO | 详情 | 详情 | ||
| (XXVII) | 65776 | C16H21ClO3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)In one strategy, 2,4-difluoroaniline (I) is lithiated with BuLi in the presence of 1,2-bis(chlorodimethylsilyl)ethane in THF at –78 °C, and subsequently acylated with benzyl chloroformate, yielding benzyl 3-amino-2,6-difluorobenzoate (II). N-Sulfonylation of aniline (II) with propane-1-sulfonyl chloride (III) using pyridine in CH2Cl2 gives the corresponding sulfonamide (IV), which is then debenzylated with H2 over Pd(OH)2/C in MeOH to provide the benzoic acid derivative (V). After chlorination of acid (V) with SOCl2 in refluxing toluene, the resulting acid chloride (VI) is subjected to Friedel–Crafts reaction with 5-bromopyrrolo[2,3-b]pyridine (VII) in the presence of AlCl3 in CH2Cl2 to afford ketone (VIII). Finally, the aryl bromide (VIII) is submitted to a Suzuki coupling with 4-chlorophenylboronic acid (IX) in the presence of Pd(PPh3)4 and K2CO3 in acetonitrile .
In an alternative strategy, 2,4-difluoroaniline (I) is coupled with propane-1-sulfonyl chloride (III) by means of Et3N in THF to give N-(2,4-difluorophenyl)propane-1-sulfonamide (X), which, after lithiation with LDA in THF, is formylated by reaction with DMF, yielding 2,6-difluoro-3-(propylsulfonamido)benzaldehyde (XI). Condensation of aldehyde (XI) with 5-(4-chlorophenyl)pyrrolo[2,3-b]pyridine (XII) (obtained by Suzuki coupling of 5-bromopyrrolo[2,3-b]pyridine (VII) with boronic acid (IX) in the presence of Pd(PPh3)4 and K2CO3 in acetonitrile/H2O) using KOH in MeOH provides a mixture of the diarylcarbinol (XIII) and its corresponding methyl ether, which is further enriched in the desired alcohol (XIII) by demethylation with HBr in AcOH. Alcohol (XIII) is finally oxidized using DDQ in dioxane .
| 【1】 Ibrahim, P.N., Artis, D.R., Bremer, R. et al. (Plexxicon, Inc.). Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors. JP 20008546797, WO 2007002325. |
| 【2】 Ibrahim, P.N., Artis, D.R., Bremer, R. et al. (Plexxicon, Inc.). Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors. EP 1893612, WO 200700233. |
| 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) | 19462 | 2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene | 367-25-9 | C6H5F2N | 详情 | 详情 |
| (II) | 68766 | 1-(3-amino-2,6-difluorophenyl)-2-phenylethanone | C14H11F2NO | 详情 | 详情 | |
| (III) | 45871 | 1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; | 10147-36-1 | C3H7ClO2S | 详情 | 详情 |
| (IV) | 68767 | N-(2,4-difluoro-3-(2-phenylacetyl)phenyl)propane-1-sulfonamide | C17H17F2NO3S | 详情 | 详情 | |
| (V) | 68768 | 2,6-difluoro-3-(propylsulfonamido)benzoic acid | C10H11F2NO4S | 详情 | 详情 | |
| (VI) | 68769 | 2,6-difluoro-3-(propylsulfonamido)benzoyl chloride | C10H10ClF2NO3S | 详情 | 详情 | |
| (VII) | 68771 | 5-bromopyrrolo[2,3-b]pyridine;5-Bromo-1H-pyrrolo[2,3-b]pyridine | 183208-35-7 | C7H5BrN2 | 详情 | 详情 |
| (VIII) | 68770 | N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide | C17H14BrF2N3O3S | 详情 | 详情 | |
| (IX) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (X) | 68772 | N-(2,4-difluorophenyl)propane-1-sulfonamide | C9H11F2NO2S | 详情 | 详情 | |
| (XI) | 68773 | 2,6-difluoro-3-(propylsulfonamido)benzaldehyde;N-(2,4-difluoro-3-formylphenyl)propane-1-sulfonamide | 918523-58-7 | C10H11F2NO3S | 详情 | 详情 |
| (XII) | 68774 | 5-(4-chlorophenyl)pyrrolo[2,3-b]pyridine | C13H9ClN2 | 详情 | 详情 | |
| (XIII) | 68775 | N-(3-((5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(hydroxy)methyl)-2,4-difluorophenyl)propane-1-sulfonamide | C23H20ClF2N3O3S | 详情 | 详情 |