|
【结 构 式】 
|
【分子编号】19369 【品名】2-iodopropane 【CA登记号】75-30-9 |
【 分 子 式 】C3H7I 【 分 子 量 】169.99305 【元素组成】C 21.2% H 4.15% I 74.65% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 4-fluorophenol (I) with 1,2-dibromoethane (II) in basic medium gives 2-(4-fluorophenyl)ethyl bromide (III), which by reaction with N-benzoyl-2-hydroxyglycine (IV) in methanesulfonic acid yields N-benzoyl-2-[2-(2-bromoethoxy)-5-fluorophenyl]glycine (V). The cyclization of (V) with acetic anhydride and triethylamine at 50 C affords 6-fluoro-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4,4'-oxazolidine]-5'-one (VI), which is hydrolyzed with refluxing formic acid-HCl giving the amino acid (VII). The esterification of (VII) with SOCl2 and methanol in the usual way yields the methyl ester (VIII), which is submitted to optical resolution by selective hydrolysis with alpha-chymotrypsine affording methyl 4(S)-amino-6-fluoro-2,3-dihydro-4H-1-benzopyrano-4-carboxylate (IX). Finally, this compound is converted into sorbinil by cyclization with sodium cyanate in acetic acid at room temperature.
| 【1】 Dirlam, N.L.; Moore, B.S.; Urban, F.J.; Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin resolution. J Org Chem 1987, 52, 16, 3587-91. |
| 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) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 20830 | 1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether | 332-48-9 | C8H8BrFO | 详情 | 详情 |
| (IV) | 20606 | 2-(benzoylamino)-2-hydroxyacetic acid | 16555-77-4 | C9H9NO4 | 详情 | 详情 |
| (V) | 20832 | 2-(benzoylamino)-2-[2-(2-bromoethoxy)-5-fluorophenyl]acetic acid | C17H15BrFNO4 | 详情 | 详情 | |
| (VI) | 20833 | 6-Fluoro-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one | C17H12FNO3 | 详情 | 详情 | |
| (VII) | 20834 | 4-amino-6-fluoro-4-chromanecarboxylic acid | C10H10FNO3 | 详情 | 详情 | |
| (VIII) | 20835 | methyl 4-amino-6-fluoro-4-chromanecarboxylate | C11H12FNO3 | 详情 | 详情 | |
| (IX) | 20836 | [(4S)-4-amino-6-fluoro-3,4-dihydro-2H-chromen-4-yl]methyl formate | C11H12FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine) (I) is alkylated with 2-iodopropane in refluxing pentan-2-one. The free base, obtained following treatment of the hydroiodide with methanolic sodium hydroxide, is converted to the title compound with methanolic hydrogen chloride.
| 【1】 Miller, A.A.; Allan, G.; Sawyer, D.A. (Glaxo Wellcome plc); 1,2,4-Triazines. EP 0142306; ES 8606304; JP 1985109577; US 4649139 . |
| 【2】 Donoghue, S.; Sawyer, D.; Allan, G.; BW-A256C. Drugs Fut 1987, 12, 7, 621. |
合成路线3
该中间体在本合成路线中的序号：(XI)The oxidation of mannitol diacetonide (I) with Pb(OAc)4 in benzene gives the glyceraldehyde acetonide (II), which is reductocondensed with benzylamine (III) by means of H2 over Pd/C in methanol to yield, after acidification with HCl, (S)-3-(benzylamino)propane-1,2-diol (IV). The cyclization of (IV) with benzaldehyde (V) in refluxing toluene affords the chiral oxazolidine (VI), which is treated with tosyl chloride and pyridine to provide the corresponding tosylate (VII). The condensation of (VII) with 4-[2-(cyclopropylmethoxy)ethyl]phenol (VIII) by means of NaH in DMF gives the phenolic ether (IX), which is treated with conc. HCl to open the oxazolidine ring and yield the chiral propanolamine (X). The alkylation of the secondary amino group of (X) with isopropyl iodide (XI) in refluxing ethanol affords the tertiary amine (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target betaxolol.
| 【1】 Kitteringham, J.; Mitchell, M.B. (GlaxoSmithKline plc); Stereoselective process and chiral intermediates for aryloxydropanolamines. WO 8606368 . |
| 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) | 55678 | (4S)-4-{(1S,2S)-2-[(4S)-1,3-dioxolan-4-yl]-1-methylpropyl}-2,2-dimethyl-1,3-dioxolane | C12H22O4 | 详情 | 详情 | |
| (II) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 55679 | (2S)-3-(benzylamino)-1,2-propanediol | C10H15NO2 | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 55680 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methanol | C17H19NO2 | 详情 | 详情 | |
| (VII) | 55681 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate | C24H25NO4S | 详情 | 详情 | |
| (VIII) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (IX) | 55682 | (5S)-3-benzyl-5-({4-[2-(cyclopropylmethoxy)ethyl]phenoxy}methyl)-2-phenyl-1,3-oxazolidine; 4-{[(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methoxy}phenethyl cyclopropylmethyl ether | C29H33NO3 | 详情 | 详情 | |
| (X) | 55683 | (2S)-1-(benzylamino)-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C22H29NO3 | 详情 | 详情 | |
| (XI) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XII) | 55684 | (2S)-1-[benzyl(isopropyl)amino]-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C25H35NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IXa)The oxidation of protected hydroxymethyl lactone (I) with DCC/DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the pentenone (IV). The reduction of (IV) with NaBH4 in methanol affords the pentenol (Va-b), which is further reduced with DIBAL to provide the lactol (VIa-d). The condensation of (VIa-d) with phosphorane (VII) by means of KOtBu gives the trihydroxyheptenoic acid (VIIIa-b), which is esterified with isopropyl iodide (A) and DBU, yielding the isopropyl ester (IXa-b). Finally, this compound is selectively oxidized with DDQ to afford the target compound.
| 【1】 Stjernschantz, J.; Resul, B.; Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Fut 1992, 17, 8, 691. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (Va) | 43181 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (Vb) | 43182 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H30O5 | 详情 | 详情 | |
| (VIa) | 43183 | (2R,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIb) | 43184 | (2S,3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIc) | 43185 | (2R,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VId) | 43186 | (2S,3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-2,5-diol | C18H24O4 | 详情 | 详情 | |
| (VIIIa) | 43187 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | C23H32O5 | 详情 | 详情 | |
| (VIIIb) | 43188 | (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoic acid | 38344-08-0 | C23H32O5 | 详情 | 详情 |
| (IXb) | 43189 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 | |
| (I) | 43178 | (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | 31752-99-5 | C21H20O5 | 详情 | 详情 |
| (II) | 32042 | (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (III) | 43179 | 4-phenyl-1-(triphenylphosphoranylidene)-2-butanone | C28H25OP | 详情 | 详情 | |
| (IV) | 43180 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-5-phenyl-1-pentenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H28O5 | 详情 | 详情 | |
| (VII) | 37805 | methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (X) | 43190 | isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-heptenoate | C26H38O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：Reaction of the labeled chiral bromoacetylbornanesultam (I) with benzophenone imine (II) and DIEA in hot acetonitrile gives the imine (III), which is enantioselectively alkylated with isopropyl iodide and n-BuLi yielding the L-valine derivative (IV). Treatment of (IV) with HCl in THF in order to eliminate the diphenylmethylene group affords compound (V) with a free amino group that by protection with Boc2O in THF provides the L-valine derivative (VI). The hydrolysis of (VI) with LiOH in THF/water affords labeled N-(tert-butoxycarbonyl)-L-valine (VII), which is condensed with the decapeptide (VIII) by means of BOP and NMM in dichloromethane providing the linear undecapeptide (IX).
| 【1】 Metz, Y.; Kohler, B.; Burtscher, P.; Voges, R.; Wenger, R.; Synthesis of [S-[1-C-14]Val(7)]VALSPODAR application of (+)/(-)-[C-13,14(N)]BABS and (+)/(-)-[C-13,14(N)]DPMGBS, part 4. J Label Compd Radiopharm 2000, 43, 3, 205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 | |
| (I) | 41048 | (1R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19BrO3S | 详情 | 详情 | |
| (I) | 45254 | (1R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19BrO3S | 详情 | 详情 | |
| (II) | 32024 | diphenylmethanimine | 1013-88-3 | C13H11N | 详情 | 详情 |
| (III) | 41049 | (1R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C26H29NO3S | 详情 | 详情 | |
| (III) | 45255 | (1R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C26H29NO3S | 详情 | 详情 | |
| (IV) | 41050 | (1R)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C29H35NO3S | 详情 | 详情 | |
| (IV) | 45256 | (1R)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C29H35NO3S | 详情 | 详情 | |
| (V) | 41051 | (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C16H27NO3S | 详情 | 详情 | |
| (V) | 45257 | (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C16H27NO3S | 详情 | 详情 | |
| (VI) | 41052 | tert-butyl (1S)-1-[[(1R)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate | C21H35NO5S | 详情 | 详情 | |
| (VI) | 45258 | tert-butyl (1S)-1-[[(1R)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate | C21H35NO5S | 详情 | 详情 | |
| (VII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VII) | 45259 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 41053 | C59H108N10O12 | 详情 | 详情 | ||
| (IX) | 41054 | C69H125N11O15 | 详情 | 详情 | ||
| (IX) | 45260 | methyl (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-36-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexenyl]-12,18,27,30-tetraisobutyl-6,15,33-triisopropyl-2,2,8,11,17,21,24,26,29,32,35-undecamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23, | C69H125N11O15 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The reaction of 14C labeled chiral bromoacetyl sultam (I) with benzophenoneimine (II) in hot acetonitrile gives the substituted benzophenoneimine (III), which is estereoselectively alkylated with isopropyl iodide (IV) and n-BuLi in THF yielding the labeled L-valine derivative (V). The hydrolysis of (V) with HCl in THF affords the valine derivative (VI) with a free amino group that is protected with Boc2O in THF providing the carbamate (VII). The basic hydrolysis of (VII) with LiOH in THF gives the labeled N-(tert-butoxycarbonyl)-L-valine (VIII), which is esterified with Bn-OH, EDC and DMAP in dichloromethane yielding the protected benzyl ester (IX). Treatment of (IX) with TFA in dichloromethane affords L-valine benzyl ester (X), which is condensed with the bromomethylbiphenyl (XI) by means of DIEA in hot DMF to give the N-alkylated valine ester (XII). The acylation of (XII) with pentanoyl chloride (XIII) by means of DIEA in toluene yields the N-disubstituted valine ester (XIV), which is finally deprotected by hydrogenation with H2 over Pd/C in EtOH.
| 【1】 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245. |
| 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) | 41945 | (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (I) | 45269 | (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (II) | 32024 | diphenylmethanimine | 1013-88-3 | C13H11N | 详情 | 详情 |
| (III) | 41946 | (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C25H28N2O3S | 详情 | 详情 | |
| (III) | 45270 | (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C25H28N2O3S | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 41940 | (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C28H34N2O3S | 详情 | 详情 | |
| (V) | 45271 | (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C28H34N2O3S | 详情 | 详情 | |
| (VI) | 41941 | tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate | C20H34N2O5S | 详情 | 详情 | |
| (VI) | 45272 | (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C16H27NO3S | 详情 | 详情 | |
| (VII) | 41947 | tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate | C20H34N2O5S | 详情 | 详情 | |
| (VII) | 45273 | tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate | C20H34N2O5S | 详情 | 详情 | |
| (VIII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 45274 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 41942 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate | C17H25NO4 | 详情 | 详情 | |
| (IX) | 45275 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate | C17H25NO4 | 详情 | 详情 | |
| (X) | 41936 | benzyl (2S)-2-amino-3-methylbutanoate | C12H17NO2 | 详情 | 详情 | |
| (X) | 45276 | benzyl (2S)-2-amino-3-methylbutanoate | C12H17NO2 | 详情 | 详情 | |
| (XI) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (XII) | 41943 | benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C45H41N5O2 | 详情 | 详情 | |
| (XII) | 45277 | benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C45H41N5O2 | 详情 | 详情 | |
| (XIII) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (XIV) | 41944 | benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C50H49N5O3 | 详情 | 详情 | |
| (XIV) | 45278 | benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C50H49N5O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Benzoxazinone (III) was obtained by the two-step condensation of methyl 3-amino-4-hydroxybenzoate (I) and 2-bromoisobutyryl bromide (II), first with NaHCO3 in H2O-EtOAc to afford the corresponding amide, and then cyclization with K2CO3 in DMF. Subsequent N-alkylation of (III) with 2-iodopropane (IV) in the presence of NaH in DMF at 60 C provided the isopropylated compound (V). Refluxing of (V) with an excess of guanidine (VI) in MeOH yielded the desired acylguanidine, which was finally converted to the mesylate salt upon treatment with methanesulfonic acid in isopropanol.
| 【1】 Yamamoto, T.; Hori, M.; Watanabe, I.; Tsutsui, H.; Harada, K.; Ikeda, S.; Maruo, J.; Morita, T.; Ohtaka, H.; Synthesis and quantitative structure-activity relationships of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines as Na/H exchange inhibitors. Chem Pharm Bull 1998, 46, 11, 1716. |
| 【2】 Yamamoto, T.; et al.; An acid-catalyzed O,N-acyl migration and application to the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a novel Na/H exchange inhibitor. Chem Pharm Bull 1999, 47, 1, 22. |
| 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) | 19366 | methyl 3-amino-4-hydroxybenzoate | 536-25-4 | C8H9NO3 | 详情 | 详情 |
| (II) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (III) | 19368 | methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate | C12H13NO4 | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 19370 | methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of ethyl piperazine-2-carboxylate (I) with two equivalents of isopropyl iodide (II) afforded disubstituted piperazine (III). The title imidazoline was then obtained by reaction of the ester function of (III) with ethylenediamine (IV) in the presence of trimethylaluminum.
| 【1】 Le Bihan, G.; et al.; Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines an. J Med Chem 1999, 42, 9, 1587. |
| 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) | 18343 | ethyl 2-piperazinecarboxylate | 89941-07-1 | C7H14N2O2 | 详情 | 详情 |
| (II) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (III) | 24419 | ethyl 1,4-diisopropyl-2-piperazinecarboxylate | C13H26N2O2 | 详情 | 详情 | |
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)The condensation of 2,6-dichloropurine (I) with 4-methoxybenzylamine (II) in butanol at 120 C gives 2-chloro-6-(4-methoxybenzylamino)purine (II), which is treated with isopropyl iodide (IV) and NaH in DMF yielding 2-chloro-9-isopropyl-6-(4-methoxybenzylamino)purine (V). Finally, this compound is condensed with diethanolamine (VI) in DMSO at 160 C.
| 【1】 Schow, S.R.; et al.; Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg Med Chem Lett 1997, 7, 21, 2697. |
| 【2】 Lum, R.T.; Blum, C.L.; Mackman, R.; Wick, M.M.; Schow, S.R. (CV Therapeutics, Inc.); Purine inhibitors of cyclin dependent kinase 2 and IkappaB-alpha. EP 1021186; US 5866702; WO 9805335 . |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (II) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (III) | 38022 | N-(2-chloro-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine | C13H12ClN5O | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 38023 | 2-chloro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine; N-(2-chloro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine | C16H18ClN5O | 详情 | 详情 | |
| (VI) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XLI)Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).
| 【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 【2】 Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fassler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
| (XXX) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
| (XXXVI) | 50580 | (E)-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid | C14H18O5 | 详情 | 详情 | |
| (XXXVII) | 50581 | 3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid | C14H20O5 | 详情 | 详情 | |
| (XXXVIII) | 50582 | 3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propanoyl chloride | C14H19ClO4 | 详情 | 详情 | |
| (XXXIX) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (XL) | 50583 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-N-methylpropanamide | C24H33NO5 | 详情 | 详情 | |
| (XLI) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XLII) | 50584 | (2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-N,3-dimethylbutanamide | C27H39NO5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XII)The condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (I) with methylphosphonic acid dimethyl ester (II) by means of BuLi in THF gives 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester (III), which is condensed with the known bicyclic aldehyde (IV) by means of BuLi in dimethoxyethane, yielding the unsaturated ketone (V). The reduction of (V) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (VI), which is treated with K2CO3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (VII). The protection of (VII) with dihydropyran and TsOH in dichloromethane provides the bis(tetrahydropyranyl) ether (VIII), which by reduction of the lactone ring with diisobutylaluminum hydride in THF gives the lactol (IX). The condensation of (IX) with the phosphonium bromide (X) by means of NaH in DMSO yields the prostenoic acid (XI), which is esterified with isopropyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to afford the corresponding isopropyl ester (XII). Finally, this compound is deprotected with acetic acid in hot THF/water.
| 【1】 Klimko, P.G.; Bishop, J.A.; DeSantis, L. Jr.; Sallee, V.L. (Alcon Laboratories, Inc.); Use of cloprostenol, fluprostenol and their analogues for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension. EP 0639563; JP 1995165703; JP 1998182465; US 5665773 . |
| 【2】 Castañer, J.; Sorbera, L.A.; Travoprost. Drugs Fut 2000, 25, 1, 41. |
| 【3】 Bowler, J.; Crossley, N.S. (AstraZeneca plc); Method of inducing luteolysis using 16-aryloxy-17,18,19,20-tetranor-prostanoic acid derivs. US 4321275 . |
| 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) | 32120 | 2-[3-(trifluoromethyl)phenoxy]acetyl chloride | C9H6ClF3O2 | 详情 | 详情 | |
| (II) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (III) | 32121 | dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate | C12H14F3O5P | 详情 | 详情 | |
| (IV) | 32042 | (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (V) | 32122 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H25F3O6 | 详情 | 详情 | |
| (VI) | 32123 | (3aR,4R,5R,6aS)-4-[(E)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C31H27F3O6 | 详情 | 详情 | |
| (VII) | 32124 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C18H19F3O5 | 详情 | 详情 | |
| (VIII) | 32125 | (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C28H35F3O7 | 详情 | 详情 | |
| (IX) | 32126 | (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C28H37F3O7 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 32128 | (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoic acid | C33H45F3O8 | 详情 | 详情 | |
| (XII) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XIII) | 32129 | isopropyl (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3R)-3-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl)-5-heptenoate | C36H51F3O8 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The condensation of 2-amino-4-methylbenzophenone (I) with isopropyl iodide (II) by means of sodium carbonate gives 4-methyl-2-isopropylaminobenzophenone (III), which is the cyclized with urethane (A) under the catalytic action of ZnCl2 at 190 C.
| 【1】 Castañer, J.; Thorpe, P.; Proquazone. Drugs Fut 1976, 1, 11, 540. |
| 【2】 Ott, H.; Denzer, M.; o-Isopropylaminobenzophenones. DE 180550,1; FR 2002598; GB 1248428 . |