【结 构 式】 |
【药物名称】Asenapine maleate, Org-5222 【化学名称】trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate (1:1) 【CA登记号】85650-56-2, 65576-45-6 (free base) 【 分 子 式 】C21H20ClNO5 【 分 子 量 】401.85025 |
【开发单位】Organon (Originator), Pfizer (Licensee) 【药理作用】Antipsychotic Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2 Antagonists, Dopamine D1 Antagonists, Dopamine D2 Antagonists |
合成路线1
Several radiolabeled forms of Org-5222 and its metabolite Org-30526 have been synthesized: 1) [5-36Cl]-Org-5222: The nitration of trans-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (I) with HNO3/H2SO4 gives the 5-nitro derivative (II), which is reduced with H3PO3 - Pd/C in methanol to the corresponding amino derivative (III). Finally, this compound is deaminated with NaNO2 and [36Cl]-HCl in the presence of powdered Cu.
【1】 Wagenaars, G.; Vader, J.; Sperling, E.; Terpstra, A.; Kaspersen, F.; Hilberink, P.; Schlachter, I.; The syntheses of radiolabelled Org 5222 and its main metabolite Org 30526. J Label Compd Radiopharm 1994, 34, 9, 845. |
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) | 10415 | (3aS,12bS)-2-Methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H17NO | 详情 | 详情 | |
(II) | 10416 | (3aS,12bS)-2-Methyl-5-nitro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H16N2O3 | 详情 | 详情 | |
(III) | 10417 | (3aS,12bS)-2-Methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-5-ylamine; (3aS,12bS)-2-Methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-5-amine | C17H18N2O | 详情 | 详情 |
合成路线2
2) [3a-3H]-Org-5222: The equilibration of cis-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[ 4,5-c]pyrrol-1-one (IV) with [3H]-H2O by means of NaOCH3 in hot HMPT gives the tritiated trans-amide (V) (along with the cis-isomer, which is separated by HPLC). The trans-amide (V) is then reduced with LiAlH4/AlCl3 in ethyl ether.
【1】 Wagenaars, G.; Vader, J.; Sperling, E.; Terpstra, A.; Kaspersen, F.; Hilberink, P.; Schlachter, I.; The syntheses of radiolabelled Org 5222 and its main metabolite Org 30526. J Label Compd Radiopharm 1994, 34, 9, 845. |
合成路线3
3) [11-3H]-Org-5222: The iodination of Org-5222 (VI) with N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid in CH2Cl2 gives the 11-iodo derivative (VII), which is then reduced with 3H2 and Pd/C in ethanol. 4) [7,11-3H2]-Org-5222: The nitration of Org-5222 (VI) with HNO3/H2SO4 gives the 7,11-dinitro derivative (VIII), which is reduced with Fe/acetic acid to the 7,11-diamino compound (IX). The reaction of (IX) with NaNO2/HCl in the presence of KI yields the 7,11-diiodo derivative (X), which is then reduced with 3H2 and Pd/C in ethanol as before. 5) [7,11-3H2]-Org-30526: The reaction of [7,11-3H2]- Org-5222 with ethyl chloroformate in refluxing toluene gives the carbamate (XI), which is then hydrolyzed under strongly basic conditions.
【1】 Wagenaars, G.; Vader, J.; Sperling, E.; Terpstra, A.; Kaspersen, F.; Hilberink, P.; Schlachter, I.; The syntheses of radiolabelled Org 5222 and its main metabolite Org 30526. J Label Compd Radiopharm 1994, 34, 9, 845. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 10420 | (3aS,12bS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H16ClNO | 详情 | 详情 | |
(VII) | 10421 | (3aS,12bS)-5-Chloro-11-iodo-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H15ClINO | 详情 | 详情 | |
(VIII) | 10422 | (3aS,12bS)-5-Chloro-2-methyl-7,11-dinitro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H14ClN3O5 | 详情 | 详情 | |
(IX) | 10423 | (3aS,12bS)-11-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-5,9-diamine; (3aS,12bS)-11-Amino-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-7-ylamine | C17H18ClN3O | 详情 | 详情 | |
(X) | 10424 | (3aS,12bS)-5-Chloro-7,11-diiodo-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H14ClI2NO | 详情 | 详情 | |
(XI) | 10426 | ethyl (3aS,12bS)-5-chloro-1,3,3a,12b-tetrahydro-2H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-2-carboxylate | C19H18ClNO3 | 详情 | 详情 |
合成路线4
6) [11-3H]-Org-30526: The reaction of Org-5222 (VI) with ethyl chloroformate in refluxing toluene gives the carbamate ester (XII), which is hydrolyzed with HBr to afford Org-30526 (XIII). The iodination of (XIII) with NIS and trifluoromethanesulfonic acid yields the 11-iodo derivative (XIV), which is finally reduced with 3H2 and Pd/C in ethanol.
【1】 Wagenaars, G.; Vader, J.; Sperling, E.; Terpstra, A.; Kaspersen, F.; Hilberink, P.; Schlachter, I.; The syntheses of radiolabelled Org 5222 and its main metabolite Org 30526. J Label Compd Radiopharm 1994, 34, 9, 845. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 10420 | (3aS,12bS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H16ClNO | 详情 | 详情 | |
(XII) | 10426 | ethyl (3aS,12bS)-5-chloro-1,3,3a,12b-tetrahydro-2H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-2-carboxylate | C19H18ClNO3 | 详情 | 详情 | |
(XIII) | 10427 | (3aS,12bS)-5-Chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C16H14ClNO | 详情 | 详情 | |
(XIV) | 10428 | (3aS,12bS)-5-Chloro-11-iodo-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C16H13ClINO | 详情 | 详情 |
合成路线5
7) [12b-14C]-Org-5222: The condensation of labeled sarcosine methyl ester (XVI) (prepared from sarcosine (XV) with SOCl2 and methanol) with 2-(5-chloro-2-phenoxyphenyl)acetyl chloride (XVIII) (prepared from the corresponding acid (XVII) and SOCl2) yields the acylated sarcosine (XIX), which is cyclized by means of potassium tert-butoxide in toluene to the pyrrolidinedione (XX). A further cyclization of (XX) with polyphosphoric acid affords [3a-14C]-11-chloro-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (XXI), which is reduced with Mg in methanol to the trans-isomeric amide (XXII) (along with the cis-isomer, which is separated by HPLC). Finally, the amide (XXII) is reduced with LiAlH4/AlCl3 in ethyl ether.
【1】 Wagenaars, G.; Vader, J.; Sperling, E.; Terpstra, A.; Kaspersen, F.; Hilberink, P.; Schlachter, I.; The syntheses of radiolabelled Org 5222 and its main metabolite Org 30526. J Label Compd Radiopharm 1994, 34, 9, 845. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIIa) | 10436 | (3aS,12bS)-11-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(XXIIb) | 44653 | (3aS,12bR)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(XXIIa) | 44659 | (3aS,12bS)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(XXIIb) | 44660 | (3aS,12bR)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(XV) | 10429 | N-Methylglycine; Sarcosine; 2-(Methylamino)acetic acid | 107-97-1 | C3H7NO2 | 详情 | 详情 |
(XV) | 44654 | 2-(methylamino)acetic acid | C3H7NO2 | 详情 | 详情 | |
(XVI) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
(XVI) | 44655 | methyl 2-(methylamino)acetate | C4H9NO2 | 详情 | 详情 | |
(XVII) | 10431 | 2-(5-Chloro-2-phenoxyphenyl)acetic acid | C14H11ClO3 | 详情 | 详情 | |
(XVIII) | 10432 | 2-(5-Chloro-2-phenoxyphenyl)acetyl chloride | C14H10Cl2O2 | 详情 | 详情 | |
(XIX) | 10433 | methyl 2-[[2-(5-chloro-2-phenoxyphenyl)acetyl](methyl)amino]acetate | C18H18ClNO4 | 详情 | 详情 | |
(XIX) | 44656 | methyl 2-[[2-(5-chloro-2-phenoxyphenyl)acetyl](methyl)amino]acetate | C18H18ClNO4 | 详情 | 详情 | |
(XX) | 10434 | 3-(5-Chloro-2-phenoxyphenyl)-1-methyl-2,4-pyrrolidinedione | C17H14ClNO3 | 详情 | 详情 | |
(XX) | 44657 | 3-(5-chloro-2-phenoxyphenyl)-1-methyl-2,4-pyrrolidinedione | C17H14ClNO3 | 详情 | 详情 | |
(XXI) | 10435 | 11-Chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H12ClNO2 | 详情 | 详情 | |
(XXI) | 44658 | 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H12ClNO2 | 详情 | 详情 |
合成路线6
【1】 Van der Linden M, Roeters T, Harting R, et al. 2008. Debottlenecking the synthesis route of asenapine. Organic Process Reasearch & Development, 12: 196. |
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) | 10431 | 2-(5-Chloro-2-phenoxyphenyl)acetic acid | C14H11ClO3 | 详情 | 详情 | |
(II) | 10432 | 2-(5-Chloro-2-phenoxyphenyl)acetyl chloride | C14H10Cl2O2 | 详情 | 详情 | |
(III) | 10430 | methyl 2-(methylamino)acetate; methyl N-methylglycinate | 5473-12-1 | C4H9NO2 | 详情 | 详情 |
(IV) | 44656 | methyl 2-[[2-(5-chloro-2-phenoxyphenyl)acetyl](methyl)amino]acetate | C18H18ClNO4 | 详情 | 详情 | |
(V) | 10434 | 3-(5-Chloro-2-phenoxyphenyl)-1-methyl-2,4-pyrrolidinedione | C17H14ClNO3 | 详情 | 详情 | |
(VI) | 44658 | 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H12ClNO2 | 详情 | 详情 | |
(VII) | 10436 | (3aS,12bS)-11-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(VIII) | 44653 | (3aS,12bR)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 |
合成路线7
【1】 Van der Linden M, Roeters T, Harting R, et al. 2008. Debottlenecking the synthesis route of asenapine. Organic Process Reasearch & Development, 12: 196. |
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) | 10435 | 11-Chloro-2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H12ClNO2 | 详情 | 详情 | |
(II) | 10436 | (3aS,12bS)-11-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(III) | 44653 | (3aS,12bR)-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrol-1-one | C17H14ClNO2 | 详情 | 详情 | |
(IV) | 67046 | (10R,11R)-8-chloro-11-((methylamino)methyl)-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid hydrochloride | C17H16ClNO3.HCl | 详情 | 详情 |