【结 构 式】 |
【分子编号】22231 【品名】4-Bromobenzaldehyde 【CA登记号】1122-91-4 |
【 分 子 式 】C7H5BrO 【 分 子 量 】185.0201 【元素组成】C 45.44% H 2.72% Br 43.19% O 8.65% |
合成路线1
该中间体在本合成路线中的序号:(I)After protection of 4-bromobenzaldehyde (I) with triethyl orthoformate in MeOH, the resultant bromo ketal (II) was converted to the corresponding Grignard reagent (III) with magnesium in THF. Conjugate addition of (III) to the steroid epoxide (IV) in the presence of CuCl gave rise to the 11-beta-aryl steroid (V). Introduction of a 17-spiro oxirane moiety into ketone (V) to yield (VI) was accomplished by reaction with the sulfur ylide generated from trimethylsulfonium iodide and potassium tert-butoxide. Subsequent epoxide opening in (VI) with NaOMe gave rise to the methoxy alcohol (VII), which was further alkylated with iodomethane under Williamson's ether synthesis conditions to provide the dimethoxy derivative (VIII). Acid hydrolysis of both ketal groups of (VIII) with concomitant alcohol dehydration led to the dienone (IX). The aldehyde function of (IX) was finally converted to the target oxime by treatment with hydroxylamine hydrochloride in pyridine.
【1】 Schubert, G.; Kaufmann, G.; Sobeck, L.; Oettel, M.; Elger, W.; Kurischko, A. (Jenapharm GmbH); 11-Benzaldoximeestradiene-derivates, a process for their preparation and pharmaceutical compsns. containing them. CA 2130516; DE 4322283; EP 0648778 . |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 23438 | (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene | C9H11BrO2 | 详情 | 详情 | |
(III) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
(IV) | 56197 | C20H28O4 | 详情 | 详情 | ||
(V) | 56198 | (5R,8S,11R,13S,14S)-11-[4-(dimethoxymethyl)phenyl]-5-hydroxy-3,3-dimethoxy-13-methyl-1,2,3,4,5,6,7,8,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C29H40O6 | 详情 | 详情 | |
(VI) | 56199 | C30H42O6 | 详情 | 详情 | ||
(VII) | 56200 | (8S,11R,13S,14S,17S)-11-[4-(dimethoxymethyl)phenyl]-3,3-dimethoxy-17-(methoxymethyl)-13-methyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-5H-cyclopenta[a]phenanthrene-5,17-diol | C31H46O7 | 详情 | 详情 | |
(VIII) | 56201 | (8S,11R,13S,14S,17S)-11-[4-(dimethoxymethyl)phenyl]-3,3,17-trimethoxy-17-(methoxymethyl)-13-methyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-5H-cyclopenta[a]phenanthren-5-ol | C32H48O7 | 详情 | 详情 | |
(IX) | 56202 | 4-[(8S,11R,13S,14S,17S)-17-methoxy-17-(methoxymethyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl]benzaldehyde | C28H34O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)1) The reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate (II) and p-toluenesulfonic acid in methanol gives ketal (III), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIII) in hot isopropanol gives the expected addition product (IX), which by treatment with HCl or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF.
【1】 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387. |
【2】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 . |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 23438 | (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene | C9H11BrO2 | 详情 | 详情 | |
(III) | 23439 | bromo(2-pyridinylmethyl)magnesium | C6H6BrMgN | 详情 | 详情 | |
(IV) | 23440 | 4-(2-pyridinyl)benzaldehyde | C12H9NO | 详情 | 详情 | |
(V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
(VI) | 23442 | tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate | C17H19N3O2 | 详情 | 详情 | |
(VII) | 23443 | tert-butyl 2-[4-(2-pyridinyl)benzyl]-1-hydrazinecarboxylate | C17H21N3O2 | 详情 | 详情 | |
(VIII) | 23444 | tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate | C15H21NO3 | 详情 | 详情 | |
(IX) | 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 | |
(X) | 23446 | (2S,3S)-3-amino-4-phenyl-1-[1-[4-(2-pyridinyl)benzyl]hydrazino]-2-butanol | C22H26N4O | 详情 | 详情 | |
(XI) | 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:(I)Condensation of 4-bromobenzaldehyde (I) with 4-fluorophenol (II) in the presence of K2CO3 in refluxing dimethylacetamide gave ether (III). Subsequent reductive amination of (III) with cycloheptylamine (IV) using ethanolic NaBH4 afforded secondary amine (V). Phenyl carbamate (VIII) was obtained by treatment of aminopyridine (VI) with phenyl chloroformate (VII) and dimethylaniline. Condensation of this carbamate with amine (V) in the presence of Et3N in refluxing toluene furnished urea (IX) (1). Both sulfide groups of (IX) were finally oxidized to sulfone using meta-chloroperbenzoic acid in CH2Cl2.
【1】 Tanaka, A.; Terasawa, T.; Hagihara, H.; Ishibe, N.; Sawada, M.; Sakuma, Y.; Hashimoto, M.; Takasugi, H.; Tanaka, H.; Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas with weak toxicological effects on adrenal glands. J Med Chem 1998, 41, 22, 4408. |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
(III) | 22233 | 4-(4-fluorophenoxy)benzaldehyde | C13H9FO2 | 详情 | 详情 | |
(IV) | 22234 | cycloheptanamine; cycloheptylamine | 5452-35-7 | C7H15N | 详情 | 详情 |
(VI) | 22235 | N-cycloheptyl-N-[4-(4-fluorophenoxy)benzyl]amine; N-[4-(4-fluorophenoxy)benzyl]cycloheptanamine | C20H24FNO | 详情 | 详情 | |
(VI) | 22239 | 6-methyl-2,4-bis(methylsulfanyl)-3-pyridinylamine; 6-methyl-2,4-bis(methylsulfanyl)-3-pyridinamine | C8H12N2S2 | 详情 | 详情 | |
(VII) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
(VIII) | 18000 | phenyl 6-methyl-2,4-bis(methylsulfanyl)-3-pyridinylcarbamate | C15H16N2O2S2 | 详情 | 详情 | |
(IX) | 22241 | N-cycloheptyl-N-[4-(4-fluorophenoxy)benzyl]-N'-[6-methyl-2,4-bis(methylsulfanyl)-3-pyridinyl]urea | C29H34FN3O2S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)Condensation of 4-bromobenzaldehyde (I) with 4-fluorophenol (II) in the presence of K2CO3 in refluxing dimethylacetamide gave ether (III). Subsequent reductive amination of (III) with cycloheptylamine (IV) using ethanolic NaBH4 afforded secondary amine (V). Phenyl carbamate (VIII) was obtained by treatment of aminopyridine (VI) with phenyl chloroformate (VII) and dimethylaniline. Finally, condensation of this carbamate with amine (V) in the presence of Et3N in DMF at 100 C furnished the target urea.
【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . |
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
(III) | 22233 | 4-(4-fluorophenoxy)benzaldehyde | C13H9FO2 | 详情 | 详情 | |
(IV) | 22234 | cycloheptanamine; cycloheptylamine | 5452-35-7 | C7H15N | 详情 | 详情 |
(V) | 22235 | N-cycloheptyl-N-[4-(4-fluorophenoxy)benzyl]amine; N-[4-(4-fluorophenoxy)benzyl]cycloheptanamine | C20H24FNO | 详情 | 详情 | |
(VI) | 22236 | 2,4,6-trimethyl-3-pyridinylamine; 2,4,6-trimethyl-3-pyridinamine | C8H12N2 | 详情 | 详情 | |
(VII) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
(VIII) | 22238 | phenyl 2,4,6-trimethyl-3-pyridinylcarbamate | C15H16N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(I)Palladium-catalyzed coupling of 4-bromobenzaldehyde (I) with methyl acrylate (II) furnished methyl 4-formylcinnamate (III). After aldehyde protection as the ethylene acetal (IV), ester group reduction using DIBAL in cold CH2Cl2 gave rise to the cinnamyl alcohol (V). O-Alkylation of (V) with ethyl iodide in the presence of NaH produced the corresponding ethyl ether (VI). The acetal protecting group of (VI) was then hydrolyzed with HCl to yield aldehyde (VII).
【2】 Zhang, C.; Mjalli, A.M.M. (Ontogen Corp.); Imidazole derivs. as MDR modulators. EP 0999835; US 5840721; WO 9902155 . |
【1】 Dixon, R.; Zhang, C.; Sarshar, S.; Mjalli, A.M.M.; Rodarte, J.C.; Moran, E.J.; Benbatoul, K.D.; Krane, S.; 2,4,5-Trisubstituted imidazoles: Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2. Bioorg Med Chem Lett 2000, 10, 23, 2603. |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
(III) | 46515 | methyl (E)-3-(4-formylphenyl)-2-propenoate | 7560-50-1 | C11H10O3 | 详情 | 详情 |
(IV) | 46516 | methyl (E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenoate | C13H14O4 | 详情 | 详情 | |
(V) | 46517 | (E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propen-1-ol | C12H14O3 | 详情 | 详情 | |
(VI) | 46518 | (E)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-propenyl ethyl ether; 2-[4-[(E)-3-ethoxy-1-propenyl]phenyl]-1,3-dioxolane | C14H18O3 | 详情 | 详情 | |
(VII) | 46519 | 4-[(E)-3-ethoxy-1-propenyl]benzaldehyde | C12H14O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(XII)Suzuki coupling between 4-bromobenzaldehyde (XII) and 4-trifluoromethylbenzeneboronic acid (XIII) produced the biphenyl compound (XIV). The reductive amination of aldehyde (XIV) with N,N-diethyl ethylenediamine (XV) gave diamine (XVI) (1). This was finally coupled with the intermediate carboxylic acid (XI) to afford the title amide.
【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst . |
【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 . |
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) | 53050 | 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid | n/a | C18H17FN4O3S | 详情 | 详情 |
(XII) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(XIII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
(XIV) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
(XV) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
(XVI) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号:(I)The cyclization of 4-bromobenzaldehyde (I) with butanedione monooxime (II) by means of HCl in acetic acid gives 2-(4-bromophenyl)-4,5-dimethyloxazole N-oxide (III), which is chlorinated with POCl3 in refluxing chloroform to yield the chloromethyl derivative (IV). The reaction of (IV) with KCN and KI in hot DMF affords the cyanomethyl compound (V), which is hydrolyzed with KOH in water/2-methoxyethanol to provide the acetic acid derivative (VI). The reduction of (VI) with BH3/THF in THF gives the ethanol intermediate (VII), which is condensed with phenylboronic acid (VIII) by means of PPh3 and Pd(OAc)2 in propanol to yield the biphenyl derivative (IX). The reaction of the OH group of (IX) with tosyl anhydride in dichloromethane affords the tosylate (X), which is condensed with 2-(4-hydroxyphenoxy)-2-methylpropionic aid ethyl ester (XI) by means of Cs2CO3 in hot DMF to provide the ethyl ester precursor (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to obtain the target propionic acid.
【1】 Brooks, D.A.; et al.; Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]phenoxy}propionic acids: A new class of dual PPARalpha/gamma agonists. J Med Chem 2001, 44, 13, 2061. |
【2】 Matthews, D.P.; Hay, D.A.; Ardecky, R.J.; Warshawsky, A.M.; Gossett, L.S.; Dominianni, S.J.; Rito, C.J.; Shuker, A.J.; Brooks, D.A.; Michellys, P.-Y.; Tyhonas, J.S. (Eli Lilly and Company; Ligand Pharmaceuticals, Inc.); Biaryl-oxa(thia)zole derivs. and their use as PPARs modulators. EP 1206457; US 6417212; WO 0116120 . |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 55397 | 2,3-Butanedione 2-oxime; 2,3-Butanedione monoxime; 2,3-Butanedione oxime; 2,3-Butanedione-2-monoxime; Diacetyl monoxime | 57-71-6 | C4H7NO2 | 详情 | 详情 |
(III) | 55398 | 2-(4-bromophenyl)-4,5-dimethyl-1,3-oxazol-3-ium-3-olate | C11H10BrNO2 | 详情 | 详情 | |
(IV) | 55399 | 2-(4-bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole | C11H9BrClNO | 详情 | 详情 | |
(V) | 55400 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetonitrile | C12H9BrN2O | 详情 | 详情 | |
(VI) | 55401 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetic acid | C12H10BrNO3 | 详情 | 详情 | |
(VII) | 55402 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]-1-ethanol | C12H12BrNO2 | 详情 | 详情 | |
(VIII) | 16593 | Phenylboronic acid;Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
(IX) | 55403 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)-1-ethanol | C18H17NO2 | 详情 | 详情 | |
(X) | 55404 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethyl 4-methylbenzenesulfonate | C25H23NO4S | 详情 | 详情 | |
(XI) | 55405 | ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate | C12H16O4 | 详情 | 详情 | |
(XII) | 55406 | ethyl 2-{4-[2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethoxy]phenoxy}-2-methylpropanoate | C30H31NO5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号:(XI)Suzuki coupling between 4-bromobenzaldehyde (XI) and 4-trifluoromethylbenzeneboronic acid (XII) affords the biphenylyl aldehyde (XIII). This is then reductively aminated with N,N-diethylethylenediamine (XIV) and NaBH4 to produce diamine (XV) (1,3). Finally, coupling between amine (XV) and carboxylic acid (VIII) leads to the title carboxamide
【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067. |
【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 . |
【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIII) | 63494 | 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid | C16H15FN2O3S | 详情 | 详情 | |
(XI) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(XII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
(XIII) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
(XIV) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
(XV) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号:(III)The esterification of 4-formylcinnamic acid (I) with methanol and HCl gives the methyl ester (II), which can be obtained by Heck coupling of 4-bromobenzaldehyde (III) with methyl acrylate (IV). The reductocondensation of (II) with tryptamine (V) by means of NaBH(OAc)3 in dichloroethane yields the secondary amine (VI), which is alkylated with 2-(tert-butyldimethylsilyloxy)ethyl bromide (VII) by means of DIEA in DMSO to afford the tertiary amine (VIII). The reaction of the methyl ester group of (VIII) with KOH and hydroxylamine in methanol provides the silylated hydroxamic acid (IX), which is finally deprotected with TFA in water.
【1】 Perez, L.B.; Remiszewski, S.; Sambucetti, L.; et al.; Discovery and SAR of NVP-LAQ824, a novel histone deacetylase inhibitor with in vitro and in vivo antitumor activity. Proc Am Assoc Cancer Res 2002, 43, Abst 3671. |
【2】 Bair, K.W.; Versace, R.W.; Green, M.A.; Remiszewski, S.W.; Perez, L.B.; Sambucetti, L.; Sharma, S.K. (Novartis AG; Novartis-Erfindungen VmbH); Deacetylase inhibitors. WO 0222577 . |
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) | 55571 | 4-Formylcinnamic acid | 23359-08-2 | C10H8O3 | 详情 | 详情 |
(II) | 46515 | methyl (E)-3-(4-formylphenyl)-2-propenoate | 7560-50-1 | C11H10O3 | 详情 | 详情 |
(III) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
(V) | 40537 | Tryptamine; 2-(1H-Indol-3-yl)-1-ethanamine; 2-(1H-Indol-3-yl)ethylamine | 61-54-1 | C10H12N2 | 详情 | 详情 |
(VI) | 55572 | methyl 3-[4-({[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-2-propenoate | C21H22N2O2 | 详情 | 详情 | |
(VII) | 55573 | 2-Bromoethoxy-t-butyldimethylsilane | 86864-60-0 | C8H19BrOSi | 详情 | 详情 |
(VIII) | 55574 | C29H40N2O3Si | 详情 | 详情 | ||
(IX) | 55575 | 3-[4-({(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[2-(1H-indol-3-yl)ethyl]amino}methyl)phenyl]-N-hydroxy-2-propenamide | C28H39N3O3Si | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号:(I)
【1】 Fassler A, Bold G, Capraro H, et aL 1996. Aza-peptide analogs as potent human immunodeficiency virus type-l protease inhibitors with oral bioavailability.JMed Cha;n, 39, 3203一3216 |
【2】 Fassler A, Bold G, Capraro H, et aL 1997. lruermediates Ior the prepantion of peptide analogues, W0 9746514 |
【3】 Giordano C, Pozzoli C, Benedetti F.2001. Ptocess for the pr帕嘣tion可8ryl-pyritlinyl compounds, W0 012083 |
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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
(II) | 23438 | (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene | C9H11BrO2 | 详情 | 详情 | |
(III) | 29052 | 2-Bromopyridine;α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
(IV) | 23440 | 4-(2-pyridinyl)benzaldehyde | C12H9NO | 详情 | 详情 | |
(V) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
(VI) | 23442 | tert-butyl 2-[(Z)-[4-(2-pyridinyl)phenyl]methylidene]-1-hydrazinecarboxylate | C17H19N3O2 | 详情 | 详情 | |
(VII) | 23452 | tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate | C14H19NO3 | 详情 | 详情 | |
(VIII) | 23444 | tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate | C15H21NO3 | 详情 | 详情 | |
(XXI) | 66122 | (2R,3R)-3-amino-4-phenyl-1-(1-(4-(pyridin-2-yl)benzyl)hydrazinyl)butan-2-ol trihydrochloride | C22H29Cl3N4O | 详情 | 详情 | |
(XXII) | 66123 | 1,1,3,3-tetramethyl-2-(2-oxopiperidin-1-yl)isouronium tetrafluoroborate | C10H20F4N3O2 | 详情 | 详情 |