Synthesis of Benzyl 2-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)acetate

As part of our research programme, we have synthesized the title compound as an intermediate for the preparation of a zwitterionic analogue of the atypical antipsychotic, clozapine. The starting material, desmethylclozaine, 1 was synthesized in accordance with a previously reported literature procedure [1]. Subsequent treatment of 1 with benzyl 2-bromoacetate (2) afforded the title compound 3 in very good yield.

To a solution of desmethylclozapine (1, 503 mg, 1.61 mmol) and anhydrous triethylamine (0.451 mL, 3.23 mmol) in anhydrous 1,2-dimethoxyethane (25 mL) was added benzyl 2-bromoacetate (2, 0.287 mL, 1.81 mmol) via syringe. The reaction mixture was stirred at room temperature for 3 hours, filtered and then evaporated to dryness. The residue was treated with distilled water (10 mL) and extracted with dichloromethane (4 ´ 50 mL). The combined organic fractions were dried with anhydrous sodium sulfate, filtered, then evaporated to dryness. The resulting residue was purified using flash chromatography (silica gel 230-400 mesh, ethyl acetate:hexane, 1:1). The fractions containing product were combined and evaporated to dryness affording a yellow oil that solidified on standing. Recrystallisation from dichloromethane-hexane gave the title compound 3 as bright yellow prisms (536 mg, 72%).

Melting Point: 182-183°C

TLC: R_f (silica; ethyl acetate:hexane, 1:1) 0.35.

Elemental Analysis: Calculated for C₂₆H₂₅ClN₄O₂: C, 67.75%; H, 5.47%; N, 12.15%. Found: C, 67.62%; H, 5.51%; N, 12.17%.

IR (KBr, cm^-1): 3320, 1728, 1600, 1558.

UV ((EtOH; λ_max nm; log₁₀e): 209 (4.55), 228 (4.43), 260 (4.28), 297 (4.09).

¹H-NMR (300 MHz, CD2Cl2): d= 7.39-7.25 (m, 7 H, H1″, H3″, H2″″, H3″″, H4″″, H5″″, H6″″); 7.05-7.00 (m, 2 H, H2″, H4″); 6.87-6.81 (m, 2 H, H7″, H9″); 6.65 (d, J = 8.5 Hz, 1 H, H6″); 5.17 (s, 2 H, H1‴); 5.05 (s, 1 H, H5″); 3.46 (m, 4 H, H3′, H5′); 3.33 (s, 2 H, H2); 2.67 (m, 4 H, H2′, H6′).

¹³C-NMR (75 MHz, CD₂Cl₂): d= 170.6 (C=O); 163.4 (C_q); 153.4 (C_q); 142.6 (Cq); 141.2 (C_q); 136.6 (C_q); 132.5 (CH); 130.8 (CH); 129.3 (C_q); 129.1 (CH); 128.8 (CH); 127.0 (CH); 124.0 (C_q); 123.6 (CH); 123.4 (CH); 120.7 (CH); 120.7 (CH); 120.6 (CH); 66.8 (CH₂); 59.8 (CH₂); 53.2 (CH₂); 47.8 (CH₂).

MS ESI (m/z, %): 463.2 (M[³⁷Cl]H⁺, 32%); 461.2 (M[³⁵Cl]H⁺, 100%).