Asenapine maleate, Org-5222

阿塞那平马来酸盐 阿塞那平 Chemical Name: trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate (1:1)
CAS No. 85650-56-2, 65576-45-6 (free base)
项目整合开发状态: Phase III
项目研究机构: Organon (Originator), Pfizer (Licensee)
合成路线: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.

合成路线: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.

合成路线: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.

合成路线: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.

合成路线: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.