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【结 构 式】 
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【分子编号】43563 【品名】ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate 【CA登记号】94-05-3 |
【 分 子 式 】C8H11NO3 【 分 子 量 】169.18028 【元素组成】C 56.8% H 6.55% N 8.28% O 28.37% |
合成路线1
该中间体在本合成路线中的序号：(III)2-Cyano-3-neopentyloxyaniline (I) was diazotized with NaNO2/HCl and then reduced with SnCl2 to give hydrazine (II). The required pyrazole system (IV) was then obtained by condensation of hydrazine (II) with ethyl 2-cyano-3-ethoxyacrylate (III). Deamination of (IV) was achieved by diazotization of the amino group by means of isoamyl nitrite, with concomitant decomposition of the diazonium salt in refluxing THF to yield (V). Finally, saponification of the ethyl ester group of (V) provided the title carboxylic acid.
| 【1】 Ishibuchi, S.; et al.; Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors. Bioorg Med Chem Lett 2001, 11, 7, 879. |
| 【2】 Ishibuchi, S.; Morimoto, H.; Inoue, H.; Naka, Y.; Fukunari, A. (Welfide Corporation); 1-Phenylpyrazole cpds. and medicinal application thereof. EP 0936217; US 6015829; WO 9818765 . |
| 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) | 43752 | 5-amino-2-(neopentyloxy)benzonitrile | C12H16N2O | 详情 | 详情 | |
| (II) | 43753 | 5-hydrazino-2-(neopentyloxy)benzonitrile | C12H17N3O | 详情 | 详情 | |
| (III) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (IV) | 43754 | ethyl 5-amino-1-[3-cyano-4-(neopentyloxy)phenyl]-1H-pyrazole-4-carboxylate | C18H22N4O3 | 详情 | 详情 | |
| (V) | 43755 | ethyl 1-[3-cyano-4-(neopentyloxy)phenyl]-1H-pyrazole-4-carboxylate | C18H21N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IIb)Condensation of S-methylisothiourea (I) and cyano acetate derivative (II) by means of NaOMe in MeOH affords pyrimidine derivative (III), whose hydroxy group is converted into chloro by means of refluxing POCl3, yielding derivative (IV). Alkylation of (IV) with cyclopentylamine (V) and Et3N in CH2Cl2 provides derivative (VI), whose nitrile group is then reduced by means of LiAlH4 in THF to afford aminomethyl compound (VII). Treatment of (VII) with 1,1-carbonyldiimidazole (CDI) in refluxing THF gives pyrimidopyrimidinone (VIII), whose methylsulfanyl group is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (IX) in CHCl3 to afford methyl sulfoxide derivative (X). Displacement of the methyl sulfoxide group of (X) with substituted aniline (XI) in TFA/acetonitrile yields 3,4-dihydropyrimidopyrimidinone (XII), which is finally oxidized by means of KOtBu in THF or DMSO.
| 【1】 Kramer, J.B.; et al.; Synthesis and biological activity of a novel series of pyrimidopyrimidinones as inhibitors of cyclin-dependent kinases. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 40. |
| 【2】 Dobrusin, E.M.; Showalter, H.D.H.; Schroeder, M.C.; Toogood, P.; Kramer, J.B.; Trumpp-Kallmeyer, S.A.; Hamby, J.M. (Pfizer Inc.); Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation. WO 9961444 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 43041 | ethyl (Z)-2-cyano-3-ethoxy-2-propenoate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (IIb) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (I) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (III) | 43555 | 4-hydroxy-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C6H5N3OS | 详情 | 详情 | |
| (IV) | 43556 | 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C6H4ClN3S | 详情 | 详情 | |
| (V) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (VI) | 43557 | 4-(cyclopentylamino)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C11H14N4S | 详情 | 详情 | |
| (VII) | 43558 | N-[5-(aminomethyl)-2-(methylsulfanyl)-4-pyrimidinyl]-N-cyclopentylamine; 5-(aminomethyl)-N-cyclopentyl-2-(methylsulfanyl)-4-pyrimidinamine | C11H18N4S | 详情 | 详情 | |
| (VIII) | 43559 | 1-cyclopentyl-7-(methylsulfanyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C12H16N4OS | 详情 | 详情 | |
| (IX) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (X) | 43560 | 1-cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C12H16N4O2S | 详情 | 详情 | |
| (XI) | 43561 | 1-(4-aminophenyl)-4-piperidinol | C11H16N2O | 详情 | 详情 | |
| (XII) | 43562 | 1-cyclopentyl-7-[4-(4-hydroxy-1-piperidinyl)anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C22H28N6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 1-(2-fluorobenzyl)pyrazolo[3,4-b]pyridine-3-carboxamidine (I) (see scheme no. 28591301a, intermediate (IX)) with ethyl 2-(ethoxymethylene)cyanacetate (II) in refluxing toluene gives the pyrimidine-5-carboxylate derivative (III), which is cyclized to the target 1-hydroxycyclopropyl derivation by reaction with CH2I2 and SmI2 in hot THF.
| 【1】 Straub, A.; Benet-Buckholz, J.; Fröde, R.; Kern, A.; Kohlsdorfer, C.; Schmitt, P.; Schwarz, T.; Siefert, H.-M.; Stasch, J.-P.; Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase. Bioorg Med Chem 2002, 10, 6, 1711. |
| 【2】 Perzborn, E.; Kern, A.; Stasch, J.-P.; Straub, A.; Feurer, A.; Dembowsky, K.; Alonso-Alija, C.; Stahl, E. (Bayer AG); Substd. pyrazole deriv.. DE 19920352; WO 0066582 . |
| 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) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (II) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (III) | 63161 | ethyl 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinecarboxylate | C20H17FN6O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Benzaldehyde (I) is converted into the corresponding hydrazone (II) upon treatment with methylhydrazine in toluene. Condensation of hydrazone (II) with ethyl (ethoxymethylene)cyanoacetate (III) produces the hydrazinomethylene cyanoacetate (IV), which is further cyclized to the pyrazole (V) under acidic conditions (1). Heating of amino ester (V) with formamide gives rise to the pyrazolopyrimidinone (VI). This is finally alkylated with 2,6-difluorobenzyl chloride (VII) to furnish the title compound
| 【1】 Unverferth, K.; Lankau, H-J.; Arnold, T.; Synthesis and anticonvulsant activity of AWD 34-176. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Lankau, H.-J.; Unverferth, K.; Tober, C.; Rundfeldt, C.; Arnold, T.; Dost, R.; Gasparic, A.; Bernöster, K. (AWD.pharma GmbH & Co. KG); 2,5-Dihydro-pyrazolo[3,4-d]pyrimidin-4-ones with an anticonvulsive action and methods for producing the same. WO 0218387 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 62055 | benzaldehyde N-methylhydrazone | C8H10N2 | 详情 | 详情 | |
| (III) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (IV) | 62056 | ethyl (E)-2-cyano-3-{1-methyl-2-[(E)-phenylmethylidene]hydrazino}-2-propenoate | C14H15N3O2 | 详情 | 详情 | |
| (V) | 62057 | ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate | C7H11N3O2 | 详情 | 详情 | |
| (VI) | 62058 | 2-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one | C6H6N4O | 详情 | 详情 | |
| (VII) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIV)N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .
| 【1】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955. |
| 【2】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443. |
| 【3】 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797. |
| 【4】 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VII) | 69196 | 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline | 848133-76-6 | C14H12ClN3O2 | 详情 | 详情 |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (XXI) | 69203 | N-(2-hydroxy-4-nitrophenyl)acetamide | C8H8N2O4 | 详情 | 详情 | |
| (XXII) | 69204 | N-(2-ethoxy-4-nitrophenyl)acetamide | C10H12N2O4 | 详情 | 详情 | |
| (XXIII) | 69205 | N-(4-amino-2-ethoxyphenyl)acetamide | C10H14N2O2 | 详情 | 详情 | |
| (XXIV) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (XXV) | 69206 | (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate | C16H19N3O4 | 详情 | 详情 | |
| (XXVI) | 69207 | N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide | C14H13N3O3 | 详情 | 详情 | |
| (XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVIII) | 69208 | 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile | 15029-32-0 | C7H10N2O2 | 详情 | 详情 |
| (XXIX) | 69209 | (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide | C18H22N4O4 | 详情 | 详情 |