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【结 构 式】 
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【分子编号】13920 【品名】(3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine 【CA登记号】5763-61-1 |
【 分 子 式 】C9H13NO2 【 分 子 量 】167.20776 【元素组成】C 64.65% H 7.84% N 8.38% O 19.14% |
合成路线1
该中间体在本合成路线中的序号：6-Hydroxy-2(1H)-quinolinone (I) is alkylated with epichlorohydrin in the presence of K2CO3 in MeOH to afford 6-(2,3-epoxypropoxy)-2(1H)-quinolinone (II). Ring opening of the epoxide (II) with 3,4-dimethoxybenzylamine gives OPC-18790. This compound is also obtained by the reductive alkylation of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone (III) with 3,4-dimethoxybenzaldehyde.
| 【1】 Sumida, T.; Fujioka, T.; Teramoto, S.; Tominaga, M.; Yabuuchi, Y.; Mori, T.; Hosokawa, T.; Novel positive inotropic agents; synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives. J Med Chem 1992, 35, 20, 3607-12. |
| 【2】 Fujioka, T.; OPC-18790. Drugs Fut 1993, 18, 12, 1114. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 | |
| 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 | |
| 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 | |
| (I) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 13914 | 6-(2-Oxiranylmethoxy)-2(1H)-quinolinone | C12H11NO3 | 详情 | 详情 | |
| (III) | 13915 | 6-(3-Amino-2-hydroxypropoxy)-2(1H)-quinolinone | C12H14N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The synthesis of the (+)-(R)-isomer of OPC-18790 has been published: The condensation of 6-hydroxyquinolin-2(1H)-one (I) with (S)-(+)-epichlorohydrin (II) by means of triethylamine in methanol gives (S)-(+)-6-(3-chloro-2-hydroxypropoxy)quinolin-2(1H)-one (III), which by reaction with KOH in isopropanol/water yields the (R)-(-)-epoxide (IV). Finally, this compound is condensed with 3,4-dimethoxybenzylamine (V) by heating its mixture at 80 C. The (+)-(R)-isomer is about 10-fold more potent than the (-)-(S)-isomer.
| 【1】 Fujioka, T.; Teramoto, S.; Tominaga, M.; Mori, T.; Sumida, T.; Yabuuchi, Y.; Tsujimi, S.; Takemoto, K.; Hosokawa, T.; Synthesis and biological activities of optically active 6-[3-(3,4-dimethox ybenzylamino)-2 hydroxypropoxy]-2(1H)-quinolinone (OPC-18790). Chem Pharm Bull 1996, 44, 8, 1596. |
| 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) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (III) | 13918 | 6-[[(2S)-3-Chloro-2-hydroxypropyl]oxy]-2(1H)-quinolinone | C12H12ClNO3 | 详情 | 详情 | |
| (IV) | 13919 | 6-[(2R)Oxiranylmethoxy]-2(1H)-quinolinone | C12H11NO3 | 详情 | 详情 | |
| (V) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A novel synthetic route to pemetrexed disodium has been reported: The reaction of 3,4-dimethoxybenzylamine with methyl chloroformate gives the corresponding carbamate (II), which is alkylated with 2-butenyl bromide (III) yielding the N-alkyl carbamate (IV). The cleavage of (IV) with hydrazine and KOH affords the secondary amine (V), which is condensed with dimethyl malonate to give the malonamic ester (VI). The radical cyclization of (VI) by means of manganese triacetate dihydrate/copper acetate hydrate affords the pyrrolidinone (VII), which is treated with P2S5 in THF to give the thione (VIII). The cyclization of (VIII) with guanidine (IX) yields the pyrrolopyrimidinone (X), which is condensed with N-(4-iodobenzoyl)-L-glutamic acid diethyl ester (XI) by means of palladium diacetate to afford the ethano-bridged pyrrolopyrimidine (XII). Elimination of the dimethoxybenzyl-protecting group of (XII) with TFA/H2SO4 gives the diethyl ester of pemetrexed (XIII), which is finally saponified with NaOH in THF/water.
| 【1】 Taylor, E.C.; Liu, B.; A novel synthetic route to 7-substituted derivatives of the antitumor agent LY231514 (MTA). Tetrahedron Lett 1999, 40, 29, 5291. |
| 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) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 35244 | methyl 3,4-dimethoxybenzylcarbamate | C11H15NO4 | 详情 | 详情 | |
| (III) | 35252 | (E)-1-bromo-2-butene | 29576-14-5 | C4H7Br | 详情 | 详情 |
| (IV) | 35245 | methyl (E)-2-butenyl(3,4-dimethoxybenzyl)carbamate | C15H21NO4 | 详情 | 详情 | |
| (V) | 35246 | N-[(E)-2-butenyl]-N-(3,4-dimethoxybenzyl)amine; (E)-N-(3,4-dimethoxybenzyl)-2-buten-1-amine | C13H19NO2 | 详情 | 详情 | |
| (VI) | 35247 | methyl 3-[(E)-2-butenyl(3,4-dimethoxybenzyl)amino]-3-oxopropanoate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 35248 | methyl 1-(3,4-dimethoxybenzyl)-2-oxo-4-vinyl-3-pyrrolidinecarboxylate | C17H21NO5 | 详情 | 详情 | |
| (VIII) | 35249 | methyl 1-(3,4-dimethoxybenzyl)-2-thioxo-4-vinyl-3-pyrrolidinecarboxylate | C17H21NO4S | 详情 | 详情 | |
| (IX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (X) | 35250 | 2-amino-7-(3,4-dimethoxybenzyl)-5-vinyl-3,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | C17H20N4O3 | 详情 | 详情 | |
| (XI) | 14283 | diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate | C16H20INO5 | 详情 | 详情 | |
| (XII) | 35251 | diethyl (2S)-2-[(4-[2-[2-amino-7-(3,4-dimethoxybenzyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl)amino]pentanedioate | C33H39N5O8 | 详情 | 详情 | |
| (XIII) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)Treatment of Wang resin with acryloyl chloride (XI) in the presence of diisopropyl ethylamine produced the acrylate bound resin (XII). Conjugate addition of 3,4-dimethoxybenzylamine (XIII) to the acrylate (XII) afforded the beta-amino ester resin (XIV). This was coupled with the intermediate carboxylic acid (X) employing O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to furnish (XV). The title compound was finally liberated from the resin (XV) by cleavage with trifluoroacetic acid.
| 【1】 Morley, A.D.; Harris, N.V.; Astles, P.C. (Rhone-Poulenc Rorer Ltd.); Substd. beta-alanines. WO 9933789 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 39720 | 2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetic acid | C19H21N3O5 | 详情 | 详情 | |
| (XI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (XIII) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (XIV) | 39721 | N-(3,4-dimethoxybenzyl)-beta-alanine | C12H17NO4 | 详情 | 详情 | |
| (XV) | 39722 | N-(3,4-dimethoxybenzyl)-N-[2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetyl]-beta-alanine | C31H36N4O8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)2-Fluoro-5-nitrobenzoic acid (I) was converted to the corresponding acid chloride (II) by chlorination of with SOCl2. Condensation of acid chloride (II) with 3,4-dimethoxybenzylamine (III) provided amide (IV). The aromatic fluorine atom of (IV) was then displaced with (R)-2-amino-1-propanol (V) in hot pyridine to furnish the title anthranilic acid derivative.
| 【1】 Oku, T.; Sawada, K.; Kuroda, A.; Kayakiri, N.; Sawada, Y.; Inoue, T.; Mizutani, T. (Fujisawa Pharmaceutical Co., Ltd.); Anthranilic acid derivs. as inhibitors of the cGMP-phosphodiesterase. EP 1080069; JP 2001508811; US 6384080; WO 9954284 . |
| 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) | 52996 | 2-Fluoro-5-nitrobenzoic acid | 320-98-9 | C7H4FNO4 | 详情 | 详情 |
| (II) | 52997 | 2-fluoro-5-nitrobenzoyl chloride | n/a | C7H3ClFNO3 | 详情 | 详情 |
| (III) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (IV) | 52998 | N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide | n/a | C16H15FN2O5 | 详情 | 详情 |
| (V) | 21414 | (2R)-2-Amino-1-propanol; D-Alaninol; D-(-)-Alaninol | 35320-23-1 | C3H9NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The acylation of 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (I) with acetic anhydride gives the N-acetyl derivative (II), which is condensed with epichlorohydrin (III) by means of K2CO3 at 90-5 C yielding 4-acetyl-7-(2,3-epoxypropoxy)-3,4-dihydro-2H-1,4-benzoxazine (IV). Finally, the addition of 3,4-dimethoxybenzylamine (V) to the epoxy group of (IV) in hot isopropanol affords the target compound.
| 【1】 Iakovou, K.; et al.; Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities. Eur J Med Chem 1999, 34, 11, 903. |
| 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) | 38404 | 3,4-dihydro-2H-1,4-benzoxazin-7-ol | C8H9NO2 | 详情 | 详情 | |
| (II) | 38405 | 1-(7-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-ethanone | C10H11NO3 | 详情 | 详情 | |
| (III) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (IV) | 38406 | 1-[7-(2-oxiranylmethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-1-ethanone | C13H15NO4 | 详情 | 详情 | |
| (V) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Condensation of 3,4-dimethoxybenzylamine (I) with 3,4-dimethoxybenzaldehyde (II) afforded imine (III), that was subsequently reduced to amine (IV) by means of NaBH4. Reaction of (V) with 2,4,6,8-tetrachloropyridopyrimidine (V) in THF at room temperature produced the 4,8-diamino derivative (VI). The remaining 2- and 6-chloro groups of (VI) were then displaced by aminoalcohol (VII) in boiling THF to furnish adduct (VIII). Finally, selective cleavage of two dimethoxybenzyl groups using trifluoroacetic acid gave rise to the title compound.
| 【1】 Barlow, H.C.; et al.; Resistance-modifying agents. Part 7: 2,6-Disubstituted-4,8-dibenzylaminopyrimido[5,4-d]pyrimidines that inhibit nucleoside transport in the presence of alpha1-acid glycoprotein (AGP). Bioorg Med Chem Lett 2000, 10, 6, 585. |
| 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) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (III) | 41393 | (3,4-dimethoxyphenyl)-N-[(E)-(3,4-dimethoxyphenyl)methylidene]methanamine; N-(3,4-dimethoxybenzyl)-N-[(E)-(3,4-dimethoxyphenyl)methylidene]amine | C18H21NO4 | 详情 | 详情 | |
| (IV) | 41394 | N-(3,4-dimethoxybenzyl)(3,4-dimethoxyphenyl)methanamine; N,N-bis(3,4-dimethoxybenzyl)amine | C18H23NO4 | 详情 | 详情 | |
| (V) | 36173 | 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine | C6Cl4N4 | 详情 | 详情 | |
| (VI) | 41395 | N-[8-[bis(3,4-dimethoxybenzyl)amino]-2,6-dichloropyrimido[5,4-d]pyrimidin-4-yl]-N,N-bis(3,4-dimethoxybenzyl)amine; 2,6-dichloro-N(4),N(4),N(8),N(8)-tetrakis(3,4-dimethoxybenzyl)pyrimido[5,4-d]pyrimidine-4,8-diamine | C42H44Cl2N6O8 | 详情 | 详情 | |
| (VII) | 41397 | 1-amino-2-propanol | 78-96-6 | C3H9NO | 详情 | 详情 |
| (VIII) | 41396 | 1-([4,8-bis[bis(3,4-dimethoxybenzyl)amino]-6-[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidin-2-yl]amino)-2-propanol | C48H60N8O10 | 详情 | 详情 |