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【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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 10418 (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
(V) 63013 (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
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