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【结 构 式】 
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【分子编号】20599 【品名】(E)-2-butenoic acid; crotonic acid 【CA登记号】3724-65-0 |
【 分 子 式 】C4H6O2 【 分 子 量 】86.09044 【元素组成】C 55.81% H 7.02% O 37.17% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The cyclization of 4-fluorophenol (I) with chronic acid (II) by means of polyphosphonic acid (PPA) at 120 C gives 6-fluoro-2-methyl-chroman-4-one (III), which is then condensed with KCN and ammonium carbonate in hot acetamide.
| 【1】 Ueda, K.; Nomura, K.; Tanaka, S.; Nakai, N. (Eisai Co., Ltd.); Hydantoin derivatives, processes for preparing them and pharmaceutical compositions containing them. EP 0193855; JP 61197581 . |
| 【2】 Ueda, K.; et al. (Eisai Co., Ltd.); Treating complications of diabetes mellitus with hydantoin derivatives. BE 889698; DE 3128606; FR 2487353; GB 2080304; JP 57045185; US 4780472; US 4874869 . |
| 【3】 Prous, J.; Castaner, J.; METHOSORBINIL. Drugs Fut 1989, 14, 4, 325. |
合成路线2
该中间体在本合成路线中的序号：(I)Conjugate addition of crotonic acid (I) to aniline (II) gave amino acid (III), which was cyclized to the quinolinone (IV) with polyphosphoric acid at 110 C. Protection of the amino group of (IV) with Boc2O gave carbamate (V), which was subsequenty alkylated with iodoethane in the presence of NaH to yield (VI) as a diastereomeric mixture. Acid deprotection of the Boc group of (VI) gave amine (VII). The ketone group was then reduced with triethylsilane and boron trifluoride to the tetrahydroquinoline (VIII). Nitration of (VIII), followed by hydrogenation of the resulting nitro derivative (IX) furnished the aminoquinoline (X). Further Knorr cyclization of (X) with ethyl 4,4,4-trifluoroacetoacetate (XI) by means of ZnCl2 in refluxing EtOH yielded the corresponding pyridoquinoline. The required trans isomer was finally isolated by preparative HPLC.
| 【1】 Zhi, L.; Marschke, K.B.; Jones, T.K.; Tegley, C.M.; Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg Med Chem Lett 1999, 9, 7, 1009. |
| 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) | 20599 | (E)-2-butenoic acid; crotonic acid | 3724-65-0 | C4H6O2 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 31314 | 3-anilinobutyric acid | 14676-01-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 31315 | 2-methyl-2,3-dihydro-4(1H)-quinolinone | C10H11NO | 详情 | 详情 | |
| (V) | 31316 | tert-butyl 2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 31317 | tert-butyl 3-ethyl-2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C17H23NO3 | 详情 | 详情 | |
| (VII) | 31318 | 3-ethyl-2-methyl-2,3-dihydro-4(1H)-quinolinone | C12H15NO | 详情 | 详情 | |
| (VIII) | 31319 | 3-ethyl-2-methyl-1,2,3,4-tetrahydroquinoline | C12H17N | 详情 | 详情 | |
| (IX) | 31320 | 3-ethyl-2-methyl-7-nitro-1,2,3,4-tetrahydroquinoline | C12H16N2O2 | 详情 | 详情 | |
| (X) | 31321 | 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinylamine; 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinamine | C12H18N2 | 详情 | 详情 | |
| (XI) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)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 |