|
【结 构 式】 
|
【分子编号】24551 【品名】Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester 【CA登记号】762-42-5 |
【 分 子 式 】C6H6O4 【 分 子 量 】142.11124 【元素组成】C 50.71% H 4.26% O 45.03% |
合成路线1
该中间体在本合成路线中的序号：(V)The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.
| 【1】 Berkowitz, D.B.; et al.; Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin. J Org Chem 2000, 65, 3, 847. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 | |
| 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 | |
| (I) | 32361 | 6-Bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal; 5-Bromo-6-(dimethoxymethyl)-1,3-benzodioxole; (6-Bromo-1,3-benzodioxol-5-yl)(methoxy)methyl methyl ether | C10H11BrO4 | 详情 | 详情 | |
| (II) | 32362 | 6-(dimethoxymethyl)-1,3-benzodioxole-5-carbaldehyde | C11H12O5 | 详情 | 详情 | |
| (III) | 32363 | [6-(dimethoxymethyl)-1,3-benzodioxol-5-yl]methanol | C11H14O5 | 详情 | 详情 | |
| (IV) | 32364 | furo[3,4-f][1,3]benzodioxole | C9H6O3 | 详情 | 详情 | |
| (V) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (VI) | 32365 | dimethyl (1R,11S)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8,12-tetraene-12,13-dicarboxylate | C15H12O7 | 详情 | 详情 | |
| (VII) | 32366 | dimethyl (1R,11S,12S,13R)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12,13-dicarboxylate | C15H14O7 | 详情 | 详情 | |
| (VIII) | 32367 | [(1S,11R,12S,13R)-13-(hydroxymethyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methanol | C13H14O5 | 详情 | 详情 | |
| (IX) | 32368 | [(1R,11S,12S,13R)-13-[(acetoxy)methyl]-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C17H18O7 | 详情 | 详情 | |
| (X) | 32369 | [(1S,11R,12S,13R)-13-(hydroxymethyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C15H16O6 | 详情 | 详情 | |
| (XI) | 32370 | [(1S,11R,12S,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methyl acetate | C21H30O6Si | 详情 | 详情 | |
| (XII) | 32371 | [(1S,11R,12S,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-trien-12-yl]methanol | C19H28O5Si | 详情 | 详情 | |
| (XIII) | 32372 | (1S,11R,12R,13R)-13-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12-carbaldehyde | C19H26O5Si | 详情 | 详情 | |
| (XIV) | 32373 | (1S,11R,12R,13R)-13-[[(triisopropylsilyl)oxy]methyl]-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12-carbaldehyde | C22H32O5Si | 详情 | 详情 | |
| (XV) | 32374 | (7R,8R)-8-hydroxy-7-[[(triisopropylsilyl)oxy]methyl]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carbaldehyde | C22H32O5Si | 详情 | 详情 | |
| (XVI) | 32375 | (7R,8R)-7-[[(triisopropylsilyl)oxy]methyl]-8-[[2-(trimethylsilyl)ethoxy]methoxy]-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6-carbaldehyde | C28H46O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LVIII)The cyclization of 6-[1-hydroxy-1-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-carbaldehyde dimethylacetal (LVI) by means of AcOH gives 5-(3,4,5-trimethoxyphenyl)-1,3-dioxolo[4,5-f]isobenzofuran (LVII), which is submitted to a Diels-Alder cyclization with acetylenedicarboxylic acid dimethyl ester (LVIII) yielding the epoxy derivative (LIX). The selective reduction of (LIX) with LiBEt3H and H2 affords the carbinol (LX), which is treated with H2 over RaNi in order to open the epoxide ring to give the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to (LXII) with the suitable configuration. Finally, this compound is cyclized with DCC to the desired target compound.
| 【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LVI) | 35007 | [6-(dimethoxymethyl)-1,3-benzodioxol-5-yl](3,4,5-trimethoxyphenyl)methanol | C20H24O8 | 详情 | 详情 | |
| (LVII) | 35008 | 4-furo[3,4-f][1,3]benzodioxol-5-yl-2,6-dimethoxyphenyl methyl ether; 5-(3,4,5-trimethoxyphenyl)furo[3,4-f][1,3]benzodioxole | C18H16O6 | 详情 | 详情 | |
| (LVIII) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (LIX) | 35009 | dimethyl (1R,11S)-1-(3,4,5-trimethoxyphenyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8,12-tetraene-12,13-dicarboxylate | C24H22O10 | 详情 | 详情 | |
| (LX) | 35010 | methyl (1R,11R,12S,13R)-13-(hydroxymethyl)-11-(3,4,5-trimethoxyphenyl)-5,7,14-trioxatetracyclo[9.2.1.0(2,10).0(4,8)]tetradeca-2(10),3,8-triene-12-carboxylate | C23H24O9 | 详情 | 详情 | |
| (LXI) | 35011 | methyl (5R,6R,7R,8S)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H26O9 | 详情 | 详情 | |
| (LXII) | 35012 | (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylic acid | C22H24O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)The metal-ammonia reduction of 4,6-dimethoxy-m-xylene (I) gives 1,5-dimethyl-2,4-dimethoxy-1,4-cyclohexadiene (II), which by treatment with potassium tert-butoxide in DMSO is converted into the conjugated diene (III). The Dies-Alder reaction of (III) with dimethyl acetylenedicarboxylate (A), and subsequent elimination of the bridge affords dimethyl 3-methyl-4,6-dimethoxyphthalate (IV), which is selectively monodemethylated with BCl3 yielding the o-hydroxyphthalic ester (V). The hydrolysis and anhydrization of (V) gives 3-hydroxy-5-methoxy-6-methylphthalic anhydride (VI), which is reduced with Zn and HCl in acetic acid affording 4-methyl-5-methoxy-7-hydroxyphthalide (VII). The reaction of (VII) with allyl bromide (B) by means of K2CO3 in ether gives the allylic ether (VIII), which undergoes thermal rearrangement into 4-methyl-5-methoxy-7-hydroxy-6-allyl-phthalide (IX). The ozonolysis of (IX) affords the aldehyde (X), which by a Wittig condensation with 1-formylethylydenetriphenylphosphorane (XI) is converted into the new aldehyde (XII). A new Wittig reaction of (XII) with the phosphorane (XIII) gives the ethyl ester (XIV), which is finally hydrolyzed and partially reduced with diimide.
| 【1】 Castaner, J.; Hillier, K.; Mycophenolic acid. Drugs Fut 1978, 3, 8, 594. |
| 【2】 Wright, J.J.; Birch, A.J.; A total synthesis of mycophenolic acid. J Chem Soc 1969, 14, 788-789. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (A) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (I) | 39930 | 1,5-dimethoxy-2,4-dimethylbenzene; 5-methoxy-2,4-dimethylphenyl methyl ether | C10H14O2 | 详情 | 详情 | |
| (II) | 39931 | 1,5-dimethoxy-2,4-dimethyl-1,4-cyclohexadiene; 5-methoxy-2,4-dimethyl-1,4-cyclohexadien-1-yl methyl ether | C10H16O2 | 详情 | 详情 | |
| (III) | 39932 | 3-methoxy-4,6-dimethyl-1,3-cyclohexadien-1-yl methyl ether; 2,4-dimethoxy-1,5-dimethyl-1,3-cyclohexadiene | C10H16O2 | 详情 | 详情 | |
| (IV) | 39933 | dimethyl 4,6-dimethoxy-3-methylphthalate | C13H16O6 | 详情 | 详情 | |
| (V) | 39934 | dimethyl 6-hydroxy-4-methoxy-3-methylphthalate | C12H14O6 | 详情 | 详情 | |
| (VI) | 39935 | 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1,3-dione | C10H8O5 | 详情 | 详情 | |
| (VII) | 39936 | 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C10H10O4 | 详情 | 详情 | |
| (VIII) | 39937 | 7-(allyloxy)-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C13H14O4 | 详情 | 详情 | |
| (IX) | 39938 | 6-allyl-7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one | C13H14O4 | 详情 | 详情 | |
| (X) | 39939 | 2-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde | C12H12O5 | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 39941 | (E)-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-methyl-2-butenal | C15H16O5 | 详情 | 详情 | |
| (XIII) | 39942 | ethyl 2-(triethylphosphoranylidene)acetate | C10H21O2P | 详情 | 详情 | |
| (XIV) | 39943 | ethyl (2E,4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-2,4-hexadienoate | C19H22O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The alkylation of 4-(N-acetyl-N-ethylamino)-2-hydroxyacetophenone (I) with allyl bromide (II) by means of K2CO3 in DMF gives the allyl ether (III), which is isomerized by refluxing in diethylaniline to 4-(N-acetyl-N-ethylamino)-3-allyl-2-hydroxyacetophenone (IV) The reduction of (IV) with H2 over Pd/C in ethanol affords the corresponding propyl derivative (V), which is deacetylated with HBr in refluxing acetic acid water to 4-(ethylamino)-3-propyl-2-hydroxyacetophenone (VI). The addition of (VI) dimethyl acetylenedicarboxylate (VII) in refluxing ethanol affords the aminomaleate (VIII), which by cyclization witn polyphosphoric acid at 100 C gives methyl 1-ethyl-6-acetyl-7-hydroxy-4 oxo-8-propyl-4H-quinoline-2-carboxylate (IX). The condensation of (IX) with diethyl oxalate in DMF by means of NaH results in the ester of the final product (X), which is then hydrolyzed with NaHCO3 iin refluxing ethanol.
| 【1】 Wilkinson, D.J.; Lockley, W.J.S.; Synthesis of nedocromil sodium labelled with tritium, deuterium and carbon-14. J Label Compd Radiopharm 1985, 22, 9, 883. |
| 【2】 Caims, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); Nouvelles pyranoquinoleinones et leurs compositions pharmaceutiques. DE 2819215; ES 469391; JP 1199909; JP 53137969 . |
| 【3】 Cairns, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); 4,6-Dioxo-4H,6H-pyrano[3,2-g]quinoline-2,8-dicarbocyclic acids. GB 2022078 . |
| 【4】 Prous, J.; Castaner, J.; Nedocromil sodium. Drugs Fut 1986, 11, 9, 756. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (I) | 24545 | N-(4-acetyl-3-hydroxyphenyl)-N-ethylacetamide | C12H15NO3 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 24547 | 3-[4-acetyl-3-(allyloxy)phenyl]-2-pentanone | C16H20O3 | 详情 | 详情 | |
| (IV) | 24548 | N-(4-acetyl-2-allyl-3-hydroxyphenyl)-N-ethylacetamide | 69049-64-5 | C15H19NO3 | 详情 | 详情 |
| (V) | 24549 | N-(4-acetyl-3-hydroxy-2-propylphenyl)-N-ethylacetamide | C15H21NO3 | 详情 | 详情 | |
| (VI) | 24550 | 1-[4-(ethylamino)-2-hydroxy-3-propylphenyl]-1-ethanone | 69049-68-9 | C13H19NO2 | 详情 | 详情 |
| (VII) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (VIII) | 24552 | dimethyl (Z)-2-[4-acetyl(ethyl)-3-hydroxy-2-propylanilino]-2-butenedioate | 77941-04-9 | C19H25NO6 | 详情 | 详情 |
| (IX) | 24553 | methyl 6-acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-1,4-dihydro-2-quinolinecarboxylate | 69049-70-3 | C18H21NO5 | 详情 | 详情 |
| (X) | 24554 | diethyl 9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate | 69049-72-5 | C23H25NO7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The silylation of butane-2,3-dione(I) with TMSCl and TEA in hot DMF gives the silylated enol (II), which is cyclized with dimethyl acetylenedicarboxylate (III) in refluxing toluene to yield 4,5-bis(trimethylsilyloxy)-3,6-dihydrophthalic acid dimethyl ester (IV). The condensation of (IV) with aniline (V), with simultaneous aromatization in refluxing acetic acid affords 4,5-bis(phenylamino)phthalic acid dimethyl ester (VI), which is hydrolyzed with LiOH in methanol and anhydrized with acetic anhydride in toluene giving the corresponding phthalic anhydride (VII). Finally this compound is treated with ammonium formate at 140-50 C to furnish the target phthalimide.
| 【1】 Traxler, P.; Lydon, N.; Recent advances in protein tyrosine kinase inhibitors. Drugs Fut 1995, 20, 12, 1261. |
| 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) | 37053 | biacetyl | 431-03-8 | C4H6O2 | 详情 | 详情 |
| (II) | 41193 | 2,2,7,7-tetramethyl-4,5-dimethylene-3,6-dioxa-2,7-disilaoctane; 1-methylene-2-[(trimethylsilyl)oxy]-2-propenyl trimethylsilyl ether | C10H22O2Si2 | 详情 | 详情 | |
| (III) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (IV) | 41194 | dimethyl 4,5-bis[(trimethylsilyl)oxy]-1,4-cyclohexadiene-1,2-dicarboxylate | C16H28O6Si2 | 详情 | 详情 | |
| (V) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VI) | 41195 | dimethyl 4,5-dianilinophthalate | C22H20N2O4 | 详情 | 详情 | |
| (VII) | 41196 | 5,6-dianilino-2-benzofuran-1,3-dione | C20H14N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The silylation of butane-2,3-dione(I) with TMSCl and TEA in hot DMF gives the silylated enol (II), which is cyclized with dimethyl acetylenedicarboxylate (III) in refluxing toluene to yield 4,5-bis(trimethylsilyloxy)-3,6-dihydrophthalic acid dimethyl ester (IV). The condensation of (IV) with 4-fluoroaniline (V), with simultaneous aromatization in refluxing acetic acid affords 4,5-bis(4-fluorophenylamino)phthalic acid dimethyl ester (VI), which is hydrolyzed with LiOH in methanol and anhydrized with acetic anhydride in toluene giving the corresponding phthalic anhydride (VII). Finally this compound is treated with ammonium formate at 140-50 C to furnish the target phthalimide.
| 【1】 Traxler, P.; Lydon, N.; Recent advances in protein tyrosine kinase inhibitors. Drugs Fut 1995, 20, 12, 1261. |
| 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) | 37053 | biacetyl | 431-03-8 | C4H6O2 | 详情 | 详情 |
| (II) | 41193 | 2,2,7,7-tetramethyl-4,5-dimethylene-3,6-dioxa-2,7-disilaoctane; 1-methylene-2-[(trimethylsilyl)oxy]-2-propenyl trimethylsilyl ether | C10H22O2Si2 | 详情 | 详情 | |
| (III) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (IV) | 41194 | dimethyl 4,5-bis[(trimethylsilyl)oxy]-1,4-cyclohexadiene-1,2-dicarboxylate | C16H28O6Si2 | 详情 | 详情 | |
| (V) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (VI) | 41197 | dimethyl 4,5-bis(4-fluoroanilino)phthalate | C22H18F2N2O4 | 详情 | 详情 | |
| (VII) | 41198 | 5,6-bis(4-fluoroanilino)-2-benzofuran-1,3-dione | C20H12F2N2O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of uniformly 14C-labeled phenol (I) with acetylenedicarboxylic acid dimethyl ester (II) gives the adduct (III), which is reduced with ammonium formate and Pd/C to yield the 2-phenoxysuccinic acid dimethyl ester (IV). The hydrolysis of (IV) in acidic medium (HCl) affords the succinic acid derivative (V), which is cyclized by means of P2O5 to provide 4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VI). The reduction of (VI) by means of Ph3SiH and TFA gives 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VII), which is condensed with 1(R)-phenylethylamine (VIII) by means of CDI to yield the corresponding amide (IX) as a diastereomeric mixture. The reduction of (IX) by means of NaAlH2(OC2H4OMe)2 affords the secondary amine (X), also as a diastereomeric mixture, which is resolved by chromatography. The desired isomer (XI) is condensed with the butyl bromide derivative (XII) by means of NaHCO3 and KI to provide the tertiary amine (XIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to furnish the target labeled Repinotan.
| 【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 62010 | dimethyl (E)-2-phenoxy-2-butenedioate | C12H12O5 | 详情 | 详情 | |
| (IV) | 62011 | dimethyl 2-phenoxysuccinate | C12H14O5 | 详情 | 详情 | |
| (V) | 62012 | 2-phenoxysuccinic acid | C10H10O5 | 详情 | 详情 | |
| (VI) | 62013 | 4-oxo-2-chromanecarboxylic acid | C10H8O4 | 详情 | 详情 | |
| (VII) | 17037 | 2-chromanecarboxylic acid | C10H10O3 | 详情 | 详情 | |
| (VIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IX) | 17040 | (2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide | C18H19NO2 | 详情 | 详情 | |
| (X) | 17041 | (1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine | C18H21NO | 详情 | 详情 | |
| (XI) | 62014 | (1R)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1R)-1-phenylethyl]amine | C18H21NO | 详情 | 详情 | |
| (XII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 | |
| (XIII) | 62015 | 2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl][(1R)-1-phenylethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C29H32N2O4S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The title compound has been prepared by two related procedures. Alkylation of 2-propylpyridine (I) with 4-methoxyphenacyl bromide (II) in refluxing acetone gave the pyridinum salt (III), which was further cyclized to the indolizine (IV) using aqueous NaHCO3. Condensation of (IV) with dimethyl acetylenedicarboxylate (V), followed by oxidation with 2,3-dichloro-5,6-dicyanoquinone furnished the tricyclic system (VI). Hydrolysis of the diester of (VI) and subsequent decarboxylation of the resulting diacid (VII) produced the methoxy derivative (VIII). Finally, demethylation of (VIII) using AlCl3 and ethanethiol gave rise to the title phenol compound.
| 【1】 Christiansen, L.B.; Kanstrup, A.; Jacobsen, P.; Jorgensen, A.S.; Bury, P.S. (Novo Nordisk A/S); Pyrrolo[2,1,5-cd]indolizine derivs. useful in the prevention or treatment of estrogen related diseases or syndromes. EP 0986560; US 6075036; WO 9855482 . |
| 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) | 39281 | 2-propylpyridine | 622-39-9 | C8H11N | 详情 | 详情 |
| (II) | 21991 | 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone | 2632-13-5 | C9H9BrO2 | 详情 | 详情 |
| (III) | 39282 | 1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-propylpyridinium bromide | C17H20BrNO2 | 详情 | 详情 | |
| (IV) | 39283 | 4-(1-ethyl-2-indolizinyl)phenyl methyl ether; 1-ethyl-2-(4-methoxyphenyl)indolizine | C17H17NO | 详情 | 详情 | |
| (V) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (VI) | 39284 | dimethyl 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate | C23H21NO5 | 详情 | 详情 | |
| (VII) | 39285 | 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid | C21H17NO5 | 详情 | 详情 | |
| (VIII) | 39286 | 1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine; 4-(1-ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenyl methyl ether | C19H17NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)In a very close procedure, alkylation of 2-propylpyridine (I) was effected with 4-benzyloxyphenacyl bromide (IX). The resulting pyridinium salt (X) was cyclized with NaHCO3 to give (XI), which was then condensed with dimethyl acetylenedicarboxylate (V) as before to give the tricyclic system (XII). Hydrolysis of diester (XII) to diacid (XIII), followed by decarboxylation with copper in hot quinoline yielded (XIV). The benzyl protecting group of (XIV) was then removed by catalytic hydrogenolysis in the presence of Pd/C.
| 【1】 Wassermann, K.; Kanstrup, A.; Jorgensen, A.S.; Bain, S.; Naerum, L.; Jacobsen, P.; Christiansen, L.B.; Bury, P.S.; Thorpe, S.M.; Synthesis and pharmacology of a novel pyrrolo[2,1,5-cd] indolizine (NNC 45-0095), a high affinity non-steroidal agonist for the estrogen receptor. Bioorg Med Chem Lett 2000, 10, 4, 399. |
| 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) | 39281 | 2-propylpyridine | 622-39-9 | C8H11N | 详情 | 详情 |
| (V) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (IX) | 36424 | 1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanone | C15H13BrO2 | 详情 | 详情 | |
| (X) | 39287 | 1-[2-[4-(benzyloxy)phenyl]-2-oxoethyl]-2-propylpyridinium bromide | C23H24BrNO2 | 详情 | 详情 | |
| (XI) | 39288 | benzyl 4-(1-ethyl-2-indolizinyl)phenyl ether; 2-[4-(benzyloxy)phenyl]-1-ethylindolizine | C23H21NO | 详情 | 详情 | |
| (XII) | 39289 | dimethyl 3-[4-(benzyloxy)phenyl]-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate | C29H25NO5 | 详情 | 详情 | |
| (XIII) | 39290 | 3-[4-(benzyloxy)phenyl]-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid | C27H21NO5 | 详情 | 详情 | |
| (XIV) | 39291 | 2-[4-(benzyloxy)phenyl]-1-ethylpyrrolo[2,1,5-cd]indolizine; benzyl 4-(1-ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenyl ether | C25H21NO | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The 1,3-dipolar cycloaddition of N-aminopyridinium iodide (I) to dimethyl acetylenedicarboxylate (II) afforded the pyrazolopyridine system (III). Ester groups hydrolysis and regioselective decarboxylation of (III) with hot 50% sulfuric acid gave the mono-carboxylic acid (IV), which was further esterified with ethanol and sulfuric acid. Finally, reductive amination of the ethyl ester (V) with (p-chlorophenyl)piperazine (VI) in the presence of LiAlH4 provided the target compound.
| 【1】 Lober, S.; et al.; Rationally based efficacy tuning of selective dopamine D4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl) piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). J Med Chem 2001, 44, 17, 2691. |
| 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) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (II) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 51036 | dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate | C11H10N2O4 | 详情 | 详情 | |
| (IV) | 51037 | pyrazolo[1,5-a]pyridine-2-carboxylic acid | C8H6N2O2 | 详情 | 详情 | |
| (V) | 51038 | ethyl pyrazolo[1,5-a]pyridine-2-carboxylate | C10H10N2O2 | 详情 | 详情 | |
| (VI) | 33593 | 1-(4-chlorophenyl)piperazine | 38869-46-4 | C10H13ClN2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of methyl 4-chloroanthranilate (I) with dimethyl butynedioate (II), followed by cyclization in the presence of potassium tert-butoxide leads to the quinolone dicarboxylate (III). Partial hydrolysis of diester (III) under basic conditions affords mono-acid (IV), which is converted to acid chloride (V) by treatment with SOCl2. Condensation of acid chloride (V) with pyrrolidine provides the corresponding amide (VI). The methyl ester group of (VI) is subsequently hydrolyzed with NaOH to afford the intermediate acid (VII).
| 【1】 Horchler, C.L.; et al.; Synthesis of 7-chloro-4-hydroxy-2-(3-(aryl/heteroaryl)prop-2-ynyl)1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-diones (PQD I); potent oral glycine antagonists. 28th Natl Med Chem Symp (June 8 2002, San Diego) 2002, Abst 19. |
| 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) | 49161 | 4-Chloroanthranilic acid methyl ester; Methyl 4-chloroanthranilate; Methyl 2-amino-4-chlorobenzoate; 2-Amino-4-chlorobenzoic acid methyl ester | 5900-58-3 | C8H8ClNO2 | 详情 | 详情 |
| (II) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 58494 | dimethyl 7-chloro-4-oxo-1,4-dihydro-2,3-quinolinedicarboxylate | C13H10ClNO5 | 详情 | 详情 | |
| (IV) | 58495 | 7-chloro-3-(methoxycarbonyl)-4-oxo-1,4-dihydro-2-quinolinecarboxylic acid | C12H8ClNO5 | 详情 | 详情 | |
| (V) | 58496 | methyl 7-chloro-2-(chlorocarbonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C12H7Cl2NO4 | 详情 | 详情 | |
| (VI) | 58497 | methyl 7-chloro-4-oxo-2-(1-pyrrolidinylcarbonyl)-1,4-dihydro-3-quinolinecarboxylate | C16H15ClN2O4 | 详情 | 详情 | |
| (VII) | 58498 | 7-chloro-4-oxo-2-(1-pyrrolidinylcarbonyl)-1,4-dihydro-3-quinolinecarboxylic acid | C15H13ClN2O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XXX)Sandmeyer reaction of 2-amino-3-nitrophenol (XXVI) using NaNO2 and HBr in the presence of CuBr in H2O/dioxane gives 2-bromo-3-nitrophenol (XXVII), which by O-alkylation with MeI in the presence of Cs2CO3 in DMF affords the methyl ether (XXVIII). Subsequent reduction of the nitro derivative (XXVIII) with Fe powder in refluxing AcOH/EtOH provides 2-bromo-3-methoxyaniline (XXIX) . Addition of aniline (XXIX) to dimethyl acetylene dicarboxylate (XXX) in refluxing MeOH produces the amino diester (XXXI), which by cyclization at 240 °C in diphenyl ether affords the quinoline (X) .
| 【1】 Llinas-Brunet, M., Bailey, M.D., Goudreau, N. et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 2010, 53(17): 6466-76. |
| 【2】 Llinas-Brunet, M., Bailey, M., Bhardwaj, P. et al. (Boehringer Ingelheim International GmbH & Co. KG). Hepatitis C inhibitor compounds. US 7585845. |
| 【3】 Bhardwaj, P., Forgione, P., Goudreau, N. et al. (Boehringer Ingelheim International GmbH). Hepatitis C inhibitor compounds. EP 1654261, JP 2006528937, JP 2010043129, US 2005020503, US 2011177030, US 8067438, WO 2004103996. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 68434 | methyl 8-bromo-4-hydroxy-7-methoxyquinoline-2-carboxylate | C12H10BrNO4 | 详情 | 详情 | |
| (XXVI) | 41985 | 2-amino-3-nitrophenol | 603-85-0 | C6H6N2O3 | 详情 | 详情 |
| (XXVII) | 68448 | 2-bromo-3-nitrophenol | 101935-40-4 | C6H4BrNO3 | 详情 | 详情 |
| (XXVIII) | 68449 | 2-bromo-1-methoxy-3-nitrobenzene;2-Bromo-3-nitroanisole | 67853-37-6 | C7H6BrNO3 | 详情 | 详情 |
| (XXIX) | 68451 | 2-bromo-3-methoxyaniline | C7H8BrNO | 详情 | 详情 | |
| (XXX) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (XXXI) | 68450 | dimethyl 2-((2-bromo-3-methoxyphenyl)amino)maleate | C13H14BrNO5 | 详情 | 详情 |