E-geometrical isomers of the common major metabolite of the well-known tricyclic antidepressants amitriptyline (AT) and nortriptyline (NT): (S/R)-5-[3-Methylamino-prop-(E)-ylidene]-10,l l-dihydro-5H- dibenzo[a,d]cyclohepten-10-ol (referred to herein as "E-IO-OH-NT"), illustrated below:
Owing to the chirality at the carbon at the 10-position (indicated with an asterisk), the E-geometrical isomer comprises two enantiomers: (+)-E-10-OH-NT and (-)-E-lO-OH-NT. The absolute configurations about the chiral 10-carbon of the (-) isomer, established by x-ray crystallographic analysis, is depicted in FIG. 6. Therefore the chirality of the (-) and (+) isomers is as depicted below:
(-)-E-lO-OH-NT (+)-E-10-OH-NT
The following working examples, which are intended to be illustrative and not limiting, highlight various features and advantages of the various E-IO-OH-NT compositions and methods described herein.
Example 1 : Chiral-Specifϊc Synthesis Of (+)-E-10-OH-NT
[0127] With reference to FIG. IA, enantiomerically pure (+)-E-10-OH-NT was synthesized as follows.
[0128] Synthesis of Compound 2. A solution of bromine (35.0 mL, 679 mmol, 1.40 eq) in carbon tetrachloride (200 mL) was added drop wise into a stirred mixture of
5-0x0-10,1 l-dihydro-dibenzo[a,b]cycloheptane (compound 1; 100.0 g, 485 mmol, 1.00 eq) and carbon tetrachloride (400 mL) at room temperature. An additional 200 mL carbon tetrachloride was added to facilitate stirring, and the mixture was stirred for 90 min at room temperature. [0129] The mixture was filtered, rinsed with carbon tetrachloride (200 mL) and dried to give 170 g of a tan solid (90% yield). This solid (170 g, 464 mmol, 1.00 eq) was combined with sodium hydroxide (55.7 g, 1.39 mol, 3.00 eq) and the mixture refluxed in methanol (2 L) for 2 hours. The hot solution was filtered and the solid dissolved in dichloromethane (400 mL) and washed with water (300 mL) and brine (200 mL). The organics were concentrated and dried to give 96.24 g of a pale orange solid. The filtrate was left to cool to room temperature overnight and more product precipitated out. The solid was filtered to give 22.2 g of light orange crystals. Combined yield: 88%. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, IH), 7.93 (m, 2H), 7.79 (s, IH), 7.68-7.51 (m, 4H), 7.44 (d, IH).
[0130] Synthesis of Compound 3. Potassium t-butoxide (62.7 g, 559 mmol, 1.40 eq) was added to a mixture of compound 2 (114 g, 400 mmol, 1.00 eq) and piperidine (79.1 mL, 800 mmol, 2.00 eq) in t-butanol (900 mL). The mixture was refluxed for 60 minutes, cooled to room temperature and concentrated in vacuo to near dryness. The crude product was dissolved in ethyl acetate (400 mL) and the resulting organic mixture was washed with water (300 mL) and brine (200 mL). The organics were concentrated and the resultant crude oil stirred in methanol (500 mL) to precipitate a yellow solid, which was filtered and dried to give 63.6 g of the desired product (55% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, IH), 7.87 (dd, IH), 7.82 (dd, IH), 7.58 (dt, IH), 7.52-7.45 (m, 2H), 7.41 (m, IH), 7.33 (dt, IH), 6.38 (s, IH), 2.89 (brs, 4H), 1.74 (m, 4H), 1.61 (brm, 2H); Mass Spectral Analysis m/z =* 290.1 (M+H)+.
[0131] Synthesis of Compound 4. A solution of cyclopropylmagnesium bromide in tetrahydrofuran (0.50 M in THF, 531 mL, 266 mmol, 1.21 eq) was added drop wise, under nitrogen, to a cooled (ice/water bath) solution of compound 3 (63.6 g, 220 mmol, 1.00 eq) dissolved in tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature for 1 hour. An additional portion of cyclopropylmagnesium bromide (0.50 M in THF, 100 mL, 50 mmol, 0.23 eq) was added and the reaction stirred for an additional hour. The reaction mixture was concentrated to near dryness, diluted with dichloromethane (600 mL) and washed with water (800 mL) and brine (300 mL). The organics were concentrated and dried to give 70.1 g of a yellow-orange sticky oil (96% yield). The crude product was used for the next step without further purification. Mass Spectral Analysis m/z = 332.2 (M+H)+.
[0132] Synthesis of a Mixture of Compounds 5 and 6. The Z- and E- geometrical isomers of 5-[3-Bromo-propylidene]-5,l l-dihydro-dibenzo[a,d]cyclohepten-10-one , compounds 5 and 6, respectively, were produced by refluxing a solution of compound 4 (70.0 g, 211 mmol, 1.00 eq) in 48% aqueous hydrobromic acid (250 mL) and acetic acid (250 mL) for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted 3 times with diethyl ether (500 mL total). The organics were combined and stirred in a large beaker, adding saturated sodium bicarbonate (300 mL) carefully until bubbling stopped. The layers were separated and the organics washed with saturated sodium bicarbonate (200 mL) and brine (150 mL) and concentrated to yield a crude semi-solid.
Before the crude product was run over silica, H g of insoluble tan solid was filtered to give a mixture of the geometrical E- (compound 6) and Z- (compound 5) isomers (ratio of compound 6/compound 5 = 87/13 by 1H NMR). The filtrate was purified by a silica gel plug using 5-10% ethyl acetate/hexanes gradient and the purified product was triturated in 10% ethyl acetate/hexanes to give 19 g of a tan solid corresponding to a mixture of geometrical isomers 5 and 6 (6/5 = 55/45 by 1H NMR). This mixture of isomers was recrystallized with 1 : 1 benzene :hexane to give 8.6 g 76% of pure compound 6. This material was then combined with the previously isolated mixture (11 g) of geometrical isomers 5 and 6 (6/5 = 87/13 by 1H NMR) and crystallized in 1:1 benzene :hexanes to give 12.7 g of a light orange solid corresponding to a mixture of geometrical isomers 5 and 6 (6/5 = 91/9 by 1H NMR). 1H
NMR (400 MHz, CDCl3) δ 8.11 (dd, IH), 7.50 (m, 2H), 7.36 (m, 2H), 7.24 (m, 3H), 6.17 (m, IH), 4.48 (d, IH), 3.78 (d, IH), 3.47 (m, 2H), 2.86-2.66 (m, 2H).
