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【结 构 式】 
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【分子编号】12576 【品名】2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one 【CA登记号】87-41-2 |
【 分 子 式 】C8H6O2 【 分 子 量 】134.13444 【元素组成】C 71.64% H 4.51% O 23.86% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of pipethiadene (VII) is carried out by four steps from phthalide (I) and 2-thio-phenethiol (II). A solution of the sodium salt of (II) in ethanol, prepared by dissolving (II) in ethanolic sodium ethoxide, is refluxed with (I) to give 2-(2-thienylthiomethyl)benzoic acid (III). A modified procedure for preparing (III) consists of using the crude products of reactions of 2-thienylmagnesium bromide or 2-thienylmagnesium iodide sulfur instead of the Na salt of (II).The acid (III) is then cyclized either with polyphosphoric acid in the presence of boiling toluene, with phosphorus pentoxide in boiling toluene or with phosphoric ethyl ester in toluene at 100 C. The ketone (IV) is then treated with 1-methyl-4-piperidylmagnesium chloride (A) in tetrahydrofuran and the resulting amino alcohol (V) is dehydrated with boiling dilute sulfuric acid to give the desired (VII). More recently it has been established that the expected formation of (V) is accompanied by a 1,6-addition with the subsequent air-oxidation producing the byproduct (VI). This compound melts precisely at the same temperature as compound (V), and it is necessary to separate it on the basis of its good solubility in ethanol, in which (V) is almost insoluble in the cold. Neutralization of the base (VII) with (+)-tartaric acid in ethanol affords pipethiadene (+)-tartrate.
| 【1】 Protiva, M.; Rajsner, M.; US 3519649 . |
| 【2】 Rajsner, M.; Vejdelek, Z.J.; Protiva, M.; Seidlova,V.; Adlerova, E.; Some new types of 6,11-dihydrodibenzo[b,e]thiepin derivatives and their analogues. Coll Czech Chem Commun 1964, 29, 2161. |
| 【3】 Metys, J.; Rajsner, M.; Svatek, E.; Protiva, M.; Geometric isomerism of 4-(3-dimethylaminopropylidene)-9H-thieno[2,3-b]benzo[e]thiepin. Coll Czech Chem Commun 1974, 39, 1366. |
| 【4】 Metys, J.; Protiva, M.; Svatek, E.; Rajsner, M.; 4,9-Dihyfrothieno[2,3-b]benzo[3]thiepin derivatives. Coll Czech Chem Commun 1967, 32, 2854. |
| 【5】 Rajsner, M.; Protiva, M.; Metys, J.; Holubek, J.; Ryska, M.; Polívka, Z.; Svátek, E.; Antiaminic agents derived from thieno[2,3-c][2]benzothiepin: 4-(1-methyl-4-piperidylidene)-4,9-dihydroyhieno[2,3-c][2]benzothiepin and some related compounds. Coll Czech Chem Commun 1983, 48, 623. |
| 【6】 Protiva, M.; Pipethiadene tartrate. Drugs Fut 1983, 8, 4, 334. |
| 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) | 36058 | chloro[(1-methyl-4-piperidinyl)methyl]magnesium | C7H14ClMgN | 详情 | 详情 | |
| (I) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
| (III) | 36056 | 2-[(2-thienylsulfanyl)methyl]benzoic acid | C12H10O2S2 | 详情 | 详情 | |
| (IV) | 36057 | thieno[2,3-c][2]benzothiepin-4(9H)-one | C12H8OS2 | 详情 | 详情 | |
| (V) | 36059 | 4-(1-methyl-4-piperidinyl)-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-ol | C18H21NOS2 | 详情 | 详情 | |
| (VI) | 36060 | 7-(1-methyl-4-piperidinyl)thieno[2,3-c][2]benzothiepin-4(9H)-one | C18H19NOS2 | 详情 | 详情 | |
| (VII) | 36061 | 1-methyl-4-thieno[2,3-c][2]benzothiepin-4(9H)-ylidenepiperidine | C18H19NS2 | 详情 | 详情 | |
| (VIII) | 28379 | (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid | 87-69-4 | C4H6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Reaction of the sodium salt of p-hydroxyphenylacetic acid methyl ester (I) with phthalide (II) gives 2-(4-carboxymethylphenoxymethyl)benzoic acid methyl ester (III), which is cyclized with trifluoroacetic anhydride followed by borontrifluoride etherate to yield 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (IV). Wittig reaction of compound (IV) with 3-(dimethylaminopropyl)triphenylphosphonium bromide hydrobromide (V) yields (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (VIII), which is hydrolyzed with NaOH and treated with p-toluenesulfonic acid in isopropanol to afford the p-toluenesulfonate salt (IX), from which the free base is finally liberated. Compound (V) is obtained from (3-bromopropyl)triphenylphosphonium bromide hydrobromide (VI), previously prepared from 1,3-dibromopropane (VII) and triphenylphosphine in toluene.
| 【1】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 . |
| 【2】 Oshiam, E.; Kumazawa, T.; Otaki, S.; Obase, H.; Ohmori, K.; Ishii, H.; Manabe, H.; Tamura, T.; Shuto, K. (Kyowa Hakko Kogyo Co., Ltd.); Dibenz[b,e]oxepin deriv. and antiallergic and antiinflammatory agent. EP 0235796; JP 1988010784; US 5116863 . |
| 【3】 Sano, T.; et al.; Process improvement in the production of a pharmaceutical intermediate using a reaction calorimeter for studies on the reaction kinetics of amination of a bromopropyl compound. Org Process Res Dev 1998, 2, 3, 169. |
| 【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905. |
| 【5】 Otaki, S.; Sato, H.; Ohshima, E.; et al.; Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives. J Med Chem 1992, 35, 11, 2074. |
| 【6】 Prous, J.; Castaner, J.; Graul, A.; KW-4679. Drugs Fut 1993, 18, 9, 794. |
| 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) | 12575 | sodium 4-(2-methoxy-2-oxoethyl)benzenolate | C9H9NaO3 | 详情 | 详情 | |
| (II) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (III) | 12577 | 2-[[4-(2-Methoxy-2-oxoethyl)phenoxy]methyl]benzoic acid | C17H16O5 | 详情 | 详情 | |
| (IV) | 12578 | methyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate | C17H14O4 | 详情 | 详情 | |
| (V) | 12579 | [3-(Dimethylamino)propyl](triphenyl)phosphonium bromide | C23H27BrNP | 详情 | 详情 | |
| (VI) | 12580 | (3-Bromopropyl)(triphenyl)phosphonium bromide; (3-Bromopropyl)triphenylphosphonium bromide | 3607-17-8 | C21H21Br2P | 详情 | 详情 |
| (VII) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (VIII) | 12582 | 1-[11-[(Z)-3-(Dimethylamino)propylidene]dibenzo[b,e]oxepin-2(6H)-yl]acetone | C22H25NO2 | 详情 | 详情 | |
| (IX) | 12583 | 2-[11-[(Z)-3-(Dimethylamino)propylidene]dibenzo[b,e]oxepin-2(6H)-yl]acetic acid | C21H23NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine affords the phthalazinone (V), which is finally condensed with 4-chloroaniline (VI) by means of P2O5 and TEA at 170 C to provide the target phthalazine.
| 【1】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【2】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【3】 Andersen, L.; Pedersen, E.B.; Synthesis of 4-arylamino-1H-pyrazolo[3,4-d]pyrimidines. Acta Chem Scand Ser b 1988, B42, 492-3. |
| 【4】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【5】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 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 reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3,4-bis(trifluoromethyl)aniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【3】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 51495 | 3,4-bis(trifluoromethyl)phenylamine; 3,4-bis(trifluoromethyl)aniline | C8H5F6N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-bromo-4-methylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【3】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Altmann, K.-H.; Mett, H.; Wood, J.; Stover, D.R.; Frei, J.; Bold, G.; Traxler, P. (Novartis AG); Phthalazines with angiogenesis inhibiting activity. EP 0970070; WO 9835958 . |
| 【6】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 49517 | 3-Bromo-p-toluidine; 4-Amino-2-bromotoluene; 3-Bromo-4-methylaniline | 7745-91-7 | C7H8BrN | 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 reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-bromo-5-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【2】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【3】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 51493 | 3-Amino-5-bromobenzotrifluoride | 54962-75-3 | C7H5BrF3N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 3-chloro-5-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【2】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【3】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 51492 | 3-chloro-5-(trifluoromethyl)phenylamine; 3-chloro-5-(trifluoromethyl)aniline | C7H5ClF3N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine hydrate affords the phthalazinone (V), which was activated as the imidoyl chloride (VI) by means of POCl3 and then reacted with 4-chloro-3-trifluoromethylaniline (VII) in ethanol to afford the 1-anilino-phthalazine.
| 【1】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73. |
| 【2】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80. |
| 【3】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43. |
| 【4】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310. |
| 【5】 Wietfeld, B.; Wood, J.M.; Manley, P.W.; Heng, R.; Frei, J.; Bold, G.; Dawson King, J. (Novartis AG); Phthalazine derivs. for treating inflammatory diseases. WO 0059509 . |
| 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) | 12576 | 2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one | 87-41-2 | C8H6O2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 49917 | 3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one | C14H9NO2 | 详情 | 详情 | |
| (IV) | 49918 | 3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one | C14H9NO2 | 详情 | 详情 | |
| (V) | 49919 | 4-(4-pyridinylmethyl)-1(2H)-phthalazinone | C14H11N3O | 详情 | 详情 | |
| (VI) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (VII) | 51494 | 4-Chloro-3-trifluoromethylaniline; 4-Chloro-alpha,alpha,alpha-trifluoro-m-toluidine; 5-Amino-2-chlorobenzotrifluoride; 2-Chloro-5-aminobenzotrifluoride; 2-Amino-5-chlorotrifluoromethylbenzene | 320-51-4 | C7H5ClF3N | 详情 | 详情 |