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【结 构 式】

【分子编号】49918

【品名】3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one

【CA登记号】

【 分 子 式 】C14H9NO2

【 分 子 量 】223.231

【元素组成】C 75.33% H 4.06% N 6.27% O 14.33%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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2

该中间体在本合成路线中的序号:(IV)

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3

该中间体在本合成路线中的序号:(IV)

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4

该中间体在本合成路线中的序号:(IV)

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5

该中间体在本合成路线中的序号:(IV)

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6

该中间体在本合成路线中的序号:(IV)

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
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