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【结 构 式】 
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【分子编号】10362 【品名】ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate 【CA登记号】609-14-3 |
【 分 子 式 】C7H12O3 【 分 子 量 】144.17048 【元素组成】C 58.32% H 8.39% O 33.29% |
合成路线1
该中间体在本合成路线中的序号：(X)The reaction of ethyl 2-methylacetoacetate (X) with NH3 in ethanol in an autoclave at 80 C gives ethyl 3-amino-2-methylcrotonate (XI), which is cyclized with diethyl 2-methylmalonate (XII) yielding 2,4-dihydroxy-3,5,6-trimethylpyridine (XIII). The reaction of (XIII) with POCl3 at 150 C affords 2,4-dichloro-3,5,6-trimethylpyridine (XIV), which is partially dechlorinated with H2 over Pd/C in ethanol/H2SO4 giving 4-chloro-2,3,5-trimethylpyridine (XV). The reaction of (XV) with sodium methoxide in hot DMSO yields 4-methoxy-2,3,5-trimethylpyridine (XVI), which is oxidized with H2O2 in AcOH affording the corresponding N-oxide (XVIII). The reaction of (XVIII) with acetic anhydride in hot acetic acid provides the acetate ester (XIX), which is finally hydrolyzed in the usual way to the target intermediate the 4-methoxy-3,5-dimethylpyridine-2-methanol (VI). The intermediate 4-chloro-2,3,5-trimethylpyridine (XV), can be oxidized with H2O2 in AcOH as before to give the corresponding N-oxide (XVII), which is treated with sodium methoxide in DMSO/methanol affording the previously described 4-methoxy-2,3,5-trimethylpyridine N-oxide (XVIII).
| 【1】 Junek, H.; Mittelbach, M.; Schmidt, H.-W.; Uray, G. (Hassle Lakemedel AB); Chemical intermediates and method for their preparation. EP 0226558 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
| (X) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (XI) | 31576 | ethyl (Z)-3-amino-2-methyl-2-butenoate | C7H13NO2 | 详情 | 详情 | |
| (XII) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
| (XIII) | 31577 | 3,5,6-trimethyl-2,4-pyridinediol | C8H11NO2 | 详情 | 详情 | |
| (XIV) | 31578 | 2,4-dichloro-3,5,6-trimethylpyridine | C8H9Cl2N | 详情 | 详情 | |
| (XV) | 31579 | 4-chloro-2,3,5-trimethylpyridine | C8H10ClN | 详情 | 详情 | |
| (XVI) | 31580 | 4-methoxy-2,3,5-trimethylpyridine; methyl 2,3,5-trimethyl-4-pyridinyl ether | C9H13NO | 详情 | 详情 | |
| (XVII) | 31582 | 4-chloro-2,3,5-trimethyl-1-pyridiniumolate | C8H10ClNO | 详情 | 详情 | |
| (XVIII) | 31581 | 4-methoxy-2,3,5-trimethyl-1-pyridiniumolate | 86604-80-0 | C9H13NO2 | 详情 | 详情 |
| (XIX) | 31583 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl acetate | C11H15NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The total synthesis of picumast dihydrochloride has been described: The alkylation of piperazine (I) with 4-chlorobenzyl chloride (II) in ethanol gives 1-(4-chlorobenzyl)piperazine (III), which is alkylated again with 1-bromo-3-chloropropane (IV) by means of triethylamine in a suitable solvent to yield 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (V). Finally, this compound is condensed with 7-hydroxy-3,4-dimethylcoumarin (VI) by means of K2CO3 in refluxing butanone. Compound (VI) is obtained by cyclization of resorcinol (VII) with ethyl 2-methylacetoacetate (VIII) by means of refluxing acetic acid containing HCl.
| 【1】 Witte, E.-C.; Chemical synthesis of picumast dihydrochloride. Arzneim-Forsch Drug Res 1989, 39, 10a, 1309. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 10357 | 1-(4-Chlorobenzyl)piperazine; N-(4-Chlorobenzyl)piperazine | C11H15ClN2 | 详情 | 详情 | |
| (IV) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (V) | 10359 | 1-(4-Chlorobenzyl)-4-(3-chloropropyl)piperazine | C14H20Cl2N2 | 详情 | 详情 | |
| (VI) | 10360 | 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one | 2107-78-0 | C11H10O3 | 详情 | 详情 |
| (VII) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (VIII) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)As shown in Scheme 21591401a, the Pechmann reaction of 2-methoxy-hydroquinone (I) with 2-methyl-3-oxobutanoic acid ethyl ester (II) in 75% sulfuric acid gives 6-hydroxy-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (III), which is condensed with 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazin (IV) in the presence of K2CO3 and KI in ethanol yielding the target product as free base.
| 【1】 Noldner, M.; Hauer, H.; Chatterjee, S.S.; Anseculin Hydrochloride. Drugs Fut 1996, 21, 8, 779. |
| 【2】 Chatterjee, S.S.; Noldner, M.; Hauer, H. (Willmar Schwabe GmbH); Benzopyranones, a method for producing them and uses therefor. DE 4111861; JP 1994506922; US 5428038; WO 9218493 . |
| 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) | 16845 | 2-methoxy-1,4-benzenediol | 824-46-4 | C7H8O3 | 详情 | 详情 |
| (II) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (III) | 16847 | 6-hydroxy-7-methoxy-3,4-dimethyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (IV) | 16848 | 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine; 2-[4-(3-chloropropyl)piperazino]phenyl methyl ether | C14H21ClN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The intermediate epoxyamide (XVIII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensa-tion of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 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 intermediate benzyl 5,7-dimethylindole-2-carboxylate (X) was prepared by several procedures. Diazotization of 2,4-dimethylaniline (I), followed by Japp-Klingemann condensation of the diazonium salt (II) with ethyl 2-methyl-3-oxobutyrate (III) furnished hydrazone (IV). Subsequent Fischer indole synthesis in formic acid at 75 C provided ethyl 5,7-dimethylindole-2-carboxylate (V). An alternative route to indole (V) involved condensation of 3,5-dimethylbenzaldehyde (VI) with ethyl azidoacetate (VII) in ethanolic NaOEt, followed by thermal cyclization of the resulting azidocinnamate ester (VIII). Basic hydrolysis of ethyl ester (V) gave carboxylic acid (IX), which was converted to the benzyl ester (X) upon treatment with benzyl bromide and DBU.
| 【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 32911 | 2,4-dimethylaniline; 2,4-dimethylphenylamine | 95-68-1 | C8H11N | 详情 | 详情 |
| (II) | 32912 | 2,4-dimethylbenzenediazonium | C8H9N2 | 详情 | 详情 | |
| (III) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (IV) | 32913 | ethyl 2-[(Z)-2-(2,4-dimethylphenyl)hydrazono]propanoate | C13H18N2O2 | 详情 | 详情 | |
| (V) | 32914 | ethyl 5,7-dimethyl-1H-indole-2-carboxylate | C13H15NO2 | 详情 | 详情 | |
| (VI) | 32915 | 3,5-dimethylbenzaldehyde | 5779-95-3 | C9H10O | 详情 | 详情 |
| (VII) | 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 |
| (VIII) | 32917 | ethyl (Z)-2-azido-3-(3,5-dimethylphenyl)-2-propenoate | C13H15N3O2 | 详情 | 详情 | |
| (IX) | 32918 | 5,7-dimethyl-1H-indole-2-carboxylic acid | C11H11NO2 | 详情 | 详情 | |
| (X) | 32919 | benzyl 5,7-dimethyl-1H-indole-2-carboxylate | C18H17NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The intermediate epoxyamide (XVII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensation of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide (XVII).
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Pechmann condensation of resorcinol (I) with ethyl 2-methylacetylacetate (II) in concentrated sulfuric acid at room temperature provided coumarine (III). Further treatment with one equivalent of sodium hydride and an excess of sulfamoyl chloride yielded the target sulfamate.
| 【1】 Woo, L.W.C.; et al.; Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase. J Med Chem 1998, 41, 7, 1068. |
| 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) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (II) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (III) | 10360 | 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one | 2107-78-0 | C11H10O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)In an alternative procedure, 4-fluoroaniline (XI) was condensed with cyanamide under acidic conditions to afford the fluorophenyl guanidine (XII). Cyclization of guanidine (XII) with ethyl 2-methylacetoacetate (XIII) in hot DMF produced pyrimidine (XIV). After chlorination of (XIV) with POCl3, the resultant chloropyrimidine (XV) was condensed with tetrahydroisoquinoline (IV) in the presence of either KOAc or Et3N to furnish the title diaminopyrimidine.
| 【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 | |
| (XI) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XII) | 54977 | N-(4-fluorophenyl)guanidine | C7H8FN3 | 详情 | 详情 | |
| (XIII) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (XIV) | 54978 | 2-(4-fluoroanilino)-5,6-dimethyl-4-pyrimidinol | C12H12FN3O | 详情 | 详情 | |
| (XV) | 54979 | N-(4-chloro-5,6-dimethyl-2-pyrimidinyl)-N-(4-fluorophenyl)amine; 4-chloro-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine | C12H11ClFN3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(X)The synthesis of intermediate (VIII) can be achieved by following two different routes: 1) Treatment of 2-bromo-5-methylnitrobenzene (I) with vinyl magnesium bromide (II) in THF yields bromoindole derivative (III), which is then converted into carboxylic acid (IV) by means of BuLi and CO2 in THF. Treatment of (IV) with diphenylphosphoryl azide (DPPA) and Et3N converts the carboxylic group into an amine intermediate which is then treated with hot t-BuOH to afford derivative (V). Formylation of (V) by means of DMF, POCl3 and aqueous NaOH provides aldehyde (VI), which is then treated with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) and then heated with Et3N to furnish cyano derivative (VII). Finally, removal of the Boc group of (VII) by treatment with TFA in CH2Cl2 gives intermediate (VIII). 2) Alternatively, conversion of 5-methyl-2-nitroaniline (IX) into hydrazone derivative (XI) is achieved by first reaction with NaNO2 in hydrochloric acid media followed by condensation with ethyl 2-methylacetoacetate (X) in EtOH and aqueous KOH. Treatment of (XI) with refluxing H3PO4 in xylene yields indole derivative (XII), which is hydrolyzed by means of aqueous NaOH in THF to afford carboxylic acid (XIII). Decarboxylation of (XIII) with CuCO3 in 1,3-dimethyl-2-imidazolidinone furnishes 4-methyl-7-nitro-1H-indole (XIV), which is then formylated by means of DMF, POCl3 and aqueous NaOH to give aldehyde (XV). Conversion of formyl derivative (XV) into cyano derivative (XVI) is achieved by treatment with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) followed by heating with Et3N. Finally, hydrogenation of the nitro group of (XVI) over PtO2 affords the target intermediate (VIII).
| 【1】 Kamata, J.; Semba, T.; Nara, K.; Ohwa, T.; Hata, N.; Haneda, T.; Funahashi, Y.; Hamaoka, S.; Tsuruoka, A.; Ueda, N.; Wakabayashi, T.; Ozawa, Y.; Yamamoto, Y.; Okabe, T.; Takahashi, K.; Tsukahara, N. (Eisai Co., Ltd.); Sulfonamide-containing indole cpds.. EP 1074542; JP 2000247949; WO 0050395 . |
| 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) | 44784 | 1-bromo-4-methyl-2-nitrobenzene | 5326-34-1 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 44717 | 7-bromo-4-methyl-1H-indole | C9H8BrN | 详情 | 详情 | |
| (IV) | 44718 | 4-methyl-1H-indole-7-carboxylic acid | C10H9NO2 | 详情 | 详情 | |
| (V) | 44731 | tert-butyl 4-methyl-1H-indol-7-ylcarbamate | C14H18N2O2 | 详情 | 详情 | |
| (VI) | 44734 | tert-butyl 3-formyl-4-methyl-1H-indol-7-ylcarbamate | C15H18N2O3 | 详情 | 详情 | |
| (VII) | 44736 | tert-butyl 3-cyano-4-methyl-1H-indol-7-ylcarbamate | C15H17N3O2 | 详情 | 详情 | |
| (VIII) | 44742 | 7-amino-4-methyl-1H-indole-3-carbonitrile | C10H9N3 | 详情 | 详情 | |
| (IX) | 44745 | 5-methyl-2-nitrophenylamine; 5-methyl-2-nitroaniline | 578-46-1 | C7H8N2O2 | 详情 | 详情 |
| (X) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (XI) | 44754 | ethyl 2-[(E)-2-(5-methyl-2-nitrophenyl)hydrazono]propanoate | C12H15N3O4 | 详情 | 详情 | |
| (XII) | 44755 | ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate | C12H12N2O4 | 详情 | 详情 | |
| (XIII) | 44756 | 4-methyl-7-nitro-1H-indole-2-carboxylic acid | C10H8N2O4 | 详情 | 详情 | |
| (XIV) | 44757 | 4-methyl-7-nitro-1H-indole | C9H8N2O2 | 详情 | 详情 | |
| (XV) | 44760 | 4-methyl-7-nitro-1H-indole-3-carbaldehyde | C10H8N2O3 | 详情 | 详情 | |
| (XVI) | 44761 | 4-methyl-7-nitro-1H-indole-3-carbonitrile | C10H7N3O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with diethylamine, with concomitant double bond rearrangement, produced the title allylic amine.
| 【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 . |
| 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) | 52340 | 2,6-Dichloro-3-nitrobenzonitrile | 5866-98-8 | C7H2Cl2N2O2 | 详情 | 详情 |
| (II) | 52341 | 6-chloro-2-(methylamino)-3-nitrobenzonitrile | C8H6ClN3O2 | 详情 | 详情 | |
| (III) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (IV) | 52342 | ethyl 2-[2-cyano-3-(methylamino)-4-nitrophenyl]-2-methyl-3-oxobutanoate | C15H17N3O5 | 详情 | 详情 | |
| (V) | 52343 | ethyl 2-[4-amino-2-cyano-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate | C15H19N3O3 | 详情 | 详情 | |
| (VI) | 52344 | 2,6-Dichlorophenyl isothiocyanate | 6590-95-0 | C7H3Cl2NS | 详情 | 详情 |
| (VII) | 52345 | ethyl 2-[2-cyano-4-({[(2,6-dichlorophenyl)amino]carbothioyl}amino)-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate | C22H22Cl2N4O3S | 详情 | 详情 | |
| (VIII) | 52346 | ethyl 2-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}-2-methyl-3-oxobutanoate | C22H20Cl2N4O3 | 详情 | 详情 | |
| (IX) | 52347 | 2-[(2,6-dichlorophenyl)amino]-1,6,7-trimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one | C19H16Cl2N4O | 详情 | 详情 | |
| (X) | 52348 | 2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde | C19H14Cl2N4O2 | 详情 | 详情 | |
| (XI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XII) | 52349 | 2-[(2,6-dichlorophenyl)amino]-7-(1-hydroxy-2-propenyl)-1,6-dimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one | C21H18Cl2N4O2 | 详情 | 详情 | |
| (XIII) | 52350 | 1-{2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl}-2-propenyl acetate | C23H20Cl2N4O3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with dimethylamine, with concomitant double bond rearrangement, produced the title allylic amine.
| 【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 . |
| 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) | 52340 | 2,6-Dichloro-3-nitrobenzonitrile | 5866-98-8 | C7H2Cl2N2O2 | 详情 | 详情 |
| (II) | 52341 | 6-chloro-2-(methylamino)-3-nitrobenzonitrile | C8H6ClN3O2 | 详情 | 详情 | |
| (III) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (IV) | 52342 | ethyl 2-[2-cyano-3-(methylamino)-4-nitrophenyl]-2-methyl-3-oxobutanoate | C15H17N3O5 | 详情 | 详情 | |
| (V) | 52343 | ethyl 2-[4-amino-2-cyano-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate | C15H19N3O3 | 详情 | 详情 | |
| (VI) | 52344 | 2,6-Dichlorophenyl isothiocyanate | 6590-95-0 | C7H3Cl2NS | 详情 | 详情 |
| (VII) | 52345 | ethyl 2-[2-cyano-4-({[(2,6-dichlorophenyl)amino]carbothioyl}amino)-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate | C22H22Cl2N4O3S | 详情 | 详情 | |
| (VIII) | 52346 | ethyl 2-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}-2-methyl-3-oxobutanoate | C22H20Cl2N4O3 | 详情 | 详情 | |
| (IX) | 52347 | 2-[(2,6-dichlorophenyl)amino]-1,6,7-trimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one | C19H16Cl2N4O | 详情 | 详情 | |
| (X) | 52348 | 2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde | C19H14Cl2N4O2 | 详情 | 详情 | |
| (XI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XII) | 52349 | 2-[(2,6-dichlorophenyl)amino]-7-(1-hydroxy-2-propenyl)-1,6-dimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one | C21H18Cl2N4O2 | 详情 | 详情 | |
| (XIII) | 52350 | 1-{2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl}-2-propenyl acetate | C23H20Cl2N4O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)In an alternative method, 2,6-dichloro-3-nitrobenzonitrile (I) is heated with ethanolic ammonia in a sealed vessel to produce the 2-amino benzonitrile (II). Subsequent condensation of 2-amino-6-chloro-3-nitrobenzonitrile (II) with ethyl methylacetoacetate (III) in the presence of K2CO3 leads to the aryl methyl acetoacetate ester (IV). Decarboxylation and cyclization of (IV) under acidic conditions then produces isoquinolinone (V). Nitro group reduction in (V) with H2 and Pd/C leads to diamine (VI), which is further coupled with 2,6-dichlorophenyl isothiocyanate (VII), yielding thiourea (VIII). Finally, ring closure of amino thiourea (VIII) with DCC in hot DMF affords the target tricyclic compound (2).
| 【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 . |
| 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) | 52340 | 2,6-Dichloro-3-nitrobenzonitrile | 5866-98-8 | C7H2Cl2N2O2 | 详情 | 详情 |
| (II) | 65079 | 2-amino-6-chloro-3-nitrobenzonitrile | C7H4ClN3O2 | 详情 | 详情 | |
| (III) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (IV) | 65080 | ethyl 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutanoate | C14H15N3O5 | 详情 | 详情 | |
| (V) | 65082 | 8-amino-3,4-dimethyl-7-nitro-1(2H)-isoquinolinone | C11H11N3O3 | 详情 | 详情 | |
| (VI) | 65081 | 7,8-diamino-3,4-dimethyl-1(2H)-isoquinolinone | C11H13N3O | 详情 | 详情 | |
| (VII) | 52344 | 2,6-Dichlorophenyl isothiocyanate | 6590-95-0 | C7H3Cl2NS | 详情 | 详情 |
| (VIII) | 65083 | N-(8-amino-3,4-dimethyl-1-oxo-1,2-dihydro-7-isoquinolinyl)-N'-(2,6-dichlorophenyl)thiourea | C18H16Cl2N4OS | 详情 | 详情 |