|
【结 构 式】 
|
【分子编号】13359 【品名】2-Hydroxy-1-ethanesulfonic acid 【CA登记号】107-36-8 |
【 分 子 式 】C2H6O4S 【 分 子 量 】126.13324 【元素组成】C 19.04% H 4.79% O 50.74% S 25.42% |
合成路线1
该中间体在本合成路线中的序号：2-Iodoisophthalic acid (II) is reacted with o-toluidine (I) to give 2-N-(2-methylphenyl)aminoisophthalic acid (III). Cyclization with concentrated H2SO4 provides the 5-methyl-9-oxoacridan-4-carboxylic acid (IV). Conversion of this compound to 5-methyl-9-chloroacridine-4-carbonyl chloride (V) and subsequent selective reaction first with methylamine to provide the methylcarboxamide (VI) and secondly with 4-amino-3-methoxymethanesulfonanilide (VII) gives the hydrochloride salt (VIII) of the desired compound. Conversion via the free base to the isethionate salt provides CI-921.
| 【1】 Baguley, B.C.; Denny, W.A.; Finlay, G.J.; Wilson, W.R.; Twigden, S.J.; Atwell, G.J.; Rewcastle, G.W.; Synthesis and antitumour activity and DNA binding properties of a new derivative of amsacrine N,5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridine carboxamide. Cancer Res 1984. |
| 【2】 Denny, W.A.; Baguley, B.C.; Atwell, G.J.; Potential antitumor agents. 40. Orally active 4,5-disubstituted derivatives of amsacrine. J Med Chem 1984, 27, 3, 363-366. |
| 【3】 Denny, W.A.; Atwell, G.J.; Baguley, B.C.; CI-921. Drugs Fut 1984, 9, 8, 575. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 | |
| (I) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (II) | 30491 | 2-Iodoisophthalic acid | C8H5IO4 | 详情 | 详情 | |
| (III) | 30492 | 2-(2-toluidino)isophthalic acid | C15H13NO4 | 详情 | 详情 | |
| (IV) | 30493 | 5-methyl-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | C15H11NO3 | 详情 | 详情 | |
| (V) | 30494 | 9-chloro-5-methyl-4-acridinecarbonyl chloride | C15H9Cl2NO | 详情 | 详情 | |
| (VI) | 30495 | 9-chloro-N,5-dimethyl-4-acridinecarboxamide | C16H13ClN2O | 详情 | 详情 | |
| (VII) | 30496 | N-(4-amino-3-methoxyphenyl)methanesulfonamide | C8H12N2O3S | 详情 | 详情 | |
| (VIII) | 30497 | 9-[2-methoxy-4-[(methylsulfonyl)amino]anilino]-4-methyl-5-[(methylamino)carbonyl]acridinium chloride | C24H25ClN4O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Synthesis of CI-980: The condensation of N-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (I) with (1R,2S)-2-amino-1-phenyl-1-propanol (II) by means of triethylamine in refluxing ethanol gives (1S,2R)-N-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (III), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (IV). The reductocyclization of (IV) with H2 over RaNi in glacial acetic acid affords the free base of title compound (V), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
| 【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980. |
| 【2】 Carroll, T.G. Jr. (Southern Research Institute); (2S)-(5-Amino-1,2-dihydro-2-methyl-3-phenyl-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid, ethyl ester. EP 0336345; JP 1989305087; US 4866059 . |
| 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) | 13354 | ethyl 6-amino-4-chloro-5-nitro-2-pyridinylcarbamate | C8H9ClN4O4 | 详情 | 详情 | |
| (II) | 13355 | 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine | 37577-28-9 | C9H13NO | 详情 | 详情 |
| (III) | 13356 | ethyl 6-amino-4-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H21N5O5 | 详情 | 详情 | |
| (IV) | 13357 | ethyl 6-amino-4-[[(1S)-1-methyl-2-oxo-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H19N5O5 | 详情 | 详情 | |
| (V) | 13358 | ethyl (2S)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate | C17H19N5O2 | 详情 | 详情 | |
| (VI) | 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Synthesis of [14C]-labeled CI-980: The reaction of N-(ethoxycarbonyl)-L-alanine (VII) with N-methoxy-N-methylamine (VIII) by means of carbonyldiimidazole (CDI) in THF/dichloromethane gives the corresponding amide (IX), which is treated with phenylmagnesium bromide (1 mol) yielding the bromomagnesium salt (X). The bromination of [14C]-labeled benzene (XI) with Br2/HBr/H2O2 gives the labeled bromobenzene (XII), which is converted into the corresponding Grignard reagent (XIII) by reaction with Mg and dibromoethane in ether. The reaction of the previously obtained magnesium salt of alaninamide (X) with the labeled Grignard reagent (XIII) affords the labeled carbamate (XIV), which is reduced with NaBH4 in methanol and treated with KOH giving a mixture of the oxazolidinone (XV) and the aminoalcohol (XVI), separated by acidic extraction. The hydrolysis of the oxazolidinone (XV) with KOH yielded the desired aminoalcohol (XVI). The aminoalcohol (XVI) by means of triethylamine in refluxing ethanol gives (1S,2R)-N-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (XVII), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (XVIII). The reductocyclization of (XVIII) with H2 over RaNi in glacial acetic acid affords the free base of title compound (XIX), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
| 【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980. |
| 【2】 Woo, P.W.K.; Lee, H.T.; Synthesis of [14C]CI-980, ethyl [5-amino-1,2-dihydro-2(S)-methyl-3-[14C]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. J Label Compd Radiopharm 1994, 34, 1, 1-10. |
| 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) | 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 |
| (VII) | 13360 | (2S)-2-[(Ethoxycarbonyl)amino]propionic acid | C6H11NO4 | 详情 | 详情 | |
| (VIII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (IX) | 13358 | ethyl (2S)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate | C17H19N5O2 | 详情 | 详情 | |
| (IX) | 13362 | ethyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate | C8H16N2O4 | 详情 | 详情 | |
| (X) | 13363 | N-(Ethoxycarbonyl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)ethyl]amide anion | C8H15N2O4 | 详情 | 详情 | |
| (XI) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (XI) | 44622 | C6H6 | 详情 | 详情 | ||
| (XII) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (XII) | 45166 | C6H5Br | 详情 | 详情 | ||
| (XIII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (XIII) | 45167 | C6H5BrMg | 详情 | 详情 | ||
| (XIV) | 13367 | ethyl (1S)-1-methyl-2-oxo-2-phenylethylcarbamate | C12H15NO3 | 详情 | 详情 | |
| (XIV) | 45168 | C12H15NO3 | 详情 | 详情 | ||
| (XV) | 13368 | (4S)-4-Methyl-5-phenyl-1,3-oxazolidin-2-one; (4S,5R)-(-)-4-Methyl-5-phenyl-2-oxazolidinone | 16251-45-9 | C10H11NO2 | 详情 | 详情 |
| (XV) | 45169 | C9H13NO | 详情 | 详情 | ||
| (XVI) | 13355 | 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine | 37577-28-9 | C9H13NO | 详情 | 详情 |
| (XVI) | 45170 | C10H11NO2 | 详情 | 详情 | ||
| (XVII) | 13356 | ethyl 6-amino-4-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H21N5O5 | 详情 | 详情 | |
| (XVII) | 63746 | C17H21N5O5 | 详情 | 详情 | ||
| (XVIII) | 13357 | ethyl 6-amino-4-[[(1S)-1-methyl-2-oxo-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H19N5O5 | 详情 | 详情 | |
| (XVIII) | 63747 | C17H19N5O5 | 详情 | 详情 | ||
| (XIX) | 63748 | C17H19N5O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)3) Synthesis of [3H]-labeled CI-980: The reaction of butyllithium with m-dibromobenene (XVII) in ether gives the monolithium derivative (XVIII), which is condensed with N-(ethoxycarbonyl)-L-alanine (VII) yielding the carbamate (XIX). The reduction of (XIX) with NaBH4 in methanol affords the hydroxylated carbamate (XX), which is treated with NaOH in methanol to give the aminoalcohol (XXI). The condensation of N-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (I) with 2(S)-amino-1-(3-bromophenyl)-1-propanol (XXI) by means of triethylamine in refluxing ethanol gives N-[2-amino-4-[2-(3-bromophenyl)-2-hydroxy-1(S)-methylethylamino]-3-nitropyridin-6-yl]carbamic acid ethyl ester (XXII), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (XXIII). The reductocyclization of (XXIII) with Fe and acetic acid affords the 3-bromo analogue of CI-980 (XXIV), which is finally hydrogenated with 3H2 over Pd/C in THF, and treated with 2-hydroxyethanesulfonic acid in methanol.
| 【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980. |
| 【2】 Lee, H.T.; Woo, P.W.K.; Synthesis of [3H]CI-980, ethyl[5-amino-1,2-dihydro-2(S)-methyl-3(3-[3H]phenyl)pyrido[3,4-b] pyrazin-7-yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. J Label Compd Radiopharm 1994, 34, 1, 11-16. |
| 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) | 13354 | ethyl 6-amino-4-chloro-5-nitro-2-pyridinylcarbamate | C8H9ClN4O4 | 详情 | 详情 | |
| (VI) | 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 |
| (VII) | 13360 | (2S)-2-[(Ethoxycarbonyl)amino]propionic acid | C6H11NO4 | 详情 | 详情 | |
| (XVII) | 13370 | 1,3-Dibromobenzene | 108-36-1 | C6H4Br2 | 详情 | 详情 |
| (XVIII) | 13371 | (3-Bromophenyl)lithium | C6H4BrLi | 详情 | 详情 | |
| (XIX) | 13372 | ethyl (1S)-2-(3-bromophenyl)-1-methyl-2-oxoethylcarbamate | C12H14BrNO3 | 详情 | 详情 | |
| (XX) | 13373 | ethyl (1S)-2-(3-bromophenyl)-2-hydroxy-1-methylethylcarbamate | C12H16BrNO3 | 详情 | 详情 | |
| (XXI) | 13374 | (2S)-2-Amino-1-(3-bromophenyl)-1-propanol | C9H12BrNO | 详情 | 详情 | |
| (XXII) | 13375 | ethyl 6-amino-4-[[(1S)-2-(3-bromophenyl)-2-hydroxy-1-methylethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H20BrN5O5 | 详情 | 详情 | |
| (XXIII) | 13376 | ethyl 6-amino-4-[[(1S)-2-(3-bromophenyl)-1-methyl-2-oxoethyl]amino]-5-nitro-2-pyridinylcarbamate | C17H18BrN5O5 | 详情 | 详情 | |
| (XXIV) | 13377 | ethyl (2S)-5-amino-3-(3-bromophenyl)-2-methyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate | C17H18BrN5O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)Amination of 5-bromo-2,4-dichloropyrimidine (VIII) with cyclopentylamine (IX) in EtOH gives 5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine (X), which is then cyclized with crotonic acid (XI) by means of DIEA, TOTP, PdCl2(PhCN)2 in THF at 70 °C followed by treatment with Ac2O to yield the 8H-pyrido[2,3-d]pyrimidinone derivative (XII). Bromination of compound (XII) with Br2 in the presence of NaOAc in AcOH provides the 6-bromopyrido[2,3-d]pyrimidinone derivative (XIII), which is then coupled with the aminopyridine derivative (IV) in the presence of LiHMDS in toluene to afford intermediate (V). Condensation of the bromo derivative (V) with butylvinylether (XIV) in the presence of DIEA, PdCl2(dppf)2.CH2Cl2 complex in n-BuOH at 95 °C affords the 6-(1-butoxyvinyl)dihydropyrido[2,3-d]pyrimidine derivative (XV) . Finally, intermediate (XV) is treated with isethionic acid (XVI) —previously prepared by acidification of sodium isethionate (XVII) with HCl in i-PrOH in MeOH/H2O at 55 °C followed by TEA in MeOH .
The aminopyridine intermediate (IV) can be prepared by condensation of Boc-piperazine (XVIII) with 5-bromo-2-nitropyridine (XIX) in the presence of TEA in DMSO at 65-70 °C to give the nitropyridine derivative (XX), which is then reduced in the presence of H2 over Pd(OH)2/C in i-PrOH .
The key intermediate diarylamine adduct (V) can also be obtained directly by coupling aminopyridine derivative (IV) with the 2-methanesulfonylpyrido[2,3-d]pyrimidinone derivative (XXI) .
| 【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406. |
| 【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236. |
| 【4】 Beylin, V.G., Blackburn, A.C., Erdman, D.T., Toogood, P.L. (Pfizer, Inc.).Isethionate salt of a selective CDK4 inhibitor. EP 1648889, JP 2007530425, US 2005059670, WO 2005005426. |
| 【3】 Erdman, D.T., Flamme, C.M., Nelson, J.D. (Pfizer Products, Inc.). Synthesis of 2-(pyridine-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 2069344, JP 2008094834, US 2008125588, US 7781583, WO 2008032157. |
| 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) | 68144 | tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate | C14H22N4O2 | 详情 | 详情 | |
| (V) | 68145 | tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C27H34BrN7O3 | 详情 | 详情 | |
| (VIII) | 68146 | 5-bromo-2,4-dichloropyrimidine | 36082-50-5 | C4HBrCl2N2 | 详情 | 详情 |
| (IX) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (X) | 68147 | 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine;5-bromo-2-chloro-4-(cyclopentylamino)pyrimidine | C9H11BrClN3 | 详情 | 详情 | |
| (XI) | 20599 | (E)-2-butenoic acid; crotonic acid | 3724-65-0 | C4H6O2 | 详情 | 详情 |
| (XII) | 68148 | 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one | C13H14ClN3O | 详情 | 详情 | |
| (XIII) | 68149 | 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one | C13H13BrClN3O | 详情 | 详情 | |
| (XIV) | 59983 | 1-butoxyethylene; butyl vinyl ether | 111-34-2 | C6H12O | 详情 | 详情 |
| (XV) | 68150 | tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C33H45N7O4 | 详情 | 详情 | |
| (XVI) | 13359 | 2-Hydroxy-1-ethanesulfonic acid | 107-36-8 | C2H6O4S | 详情 | 详情 |
| (XVII) | 68151 | sodium isethionate；sodium 2-sulfoethanolate | C2H5NaO4S | 详情 | 详情 | |
| (XVIII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XIX) | 68152 | 5-bromo-2-nitropyridine；2-Nitro-5-bromopyridine;3-Bromo-6-nitropyridine | 39856-50-3 | C5H3BrN2O2 | 详情 | 详情 |
| (XX) | 68153 | tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate | C14H20N4O4 | 详情 | 详情 | |
| (XXI) | 68154 | 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C14H16BrN3O3S | 详情 | 详情 |