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27th June 2011 @ 02:32
Preliminary step in procuring enantiopure PZQ; acid hydrolysis of rac-PZQ into rac-PZQamine.

See also:
Hydrolysis of PZQ - Standard Conditions (KB-PZQ-1001)
Hydrolysis of rac-PZQ (MW2-13)
Hydrolysis of rac-PZQ (MW2-14)
Optimizing the acid cleavage conditions II

image

Procedure:
rac-PZQ (4.0 g, 12.8 mmol, M.W. 312.5) was dissolved in a mixture of EtOH (30 mL) and 1N HCl (120 mL; 10.62 ml stock HCl 36%, 109.4 ml H20) before being heated to reflux for 24 hrs. The resulting solution was then allowed to cool to room temperature before subjected to EtOH removal under reduced pressure (Note 1). Solution was then extracted with EtOAc (4 x 10 mL) allowing cyclohexane-1-carboxylic acid removal (Note 2) before being treated with NaOH (5N) until pH 12. Product was then extracted with proposed solvent, EtOAc (4 x 30 mL) (Note 3). The remaining aqueous solution was extracted with DCM (4 x 30 mL). Organic layers resulting from seperate extractions were dried over NaSO4 before being evaporated under pressure; both yielding a gold oily liquid (EtOAc; crude yield: 1.3 g)(DCM; crude yield: 0.9 g(Note 4.). Products from seperate extractions were then combined and recrystallised a final time to give an orange crystalline solid (1.3 g, 50%, m.p. 116oC, lit. 117-118oC).


Notes:
(1) The EtOH removal concept facilitated the removal of cyclohexane-1-carboxylic acid and other impurities; both of which are solvated by EtOH, which is miscible in water undermining the quality of washing steps.

(2) Aqueous layer contains the salted product; PZQ-amine.H+.

(3) The industrial problems posed by DCM as an extraction solvent gave way for further examination of alternative solvents. EtOAc was hence used.

(4) Relatively even distribution between the separate extractions suggests mediocre solvent extraction efficiency.
27th June 2011 @ 02:30
See also:
Hydrolysis of PZQ - Standard Conditions (KB-PZQ-1001)
Hydrolysis of rac-PZQ (MW2-13)
Hydrolysis of rac-PZQ (MW2-14)
Optimizing the acid cleavage conditions II

MW2-13.png


Procedure:

[1] A mixture of rac-PZQ (4.0 g, 12.8 mmol), EtOH (30 mL) and 1N HCl (120 mL, 11.0 mL of HCl solution (36%) in 109.0 mL water) was heated under reflux for 22 h. The solution was cooled to room temperature and then evaporated under reduced pressure for 30 min (Note 1).

[2] The resulting pale yellow solution was washed with ethyl acetate (3 x 10 mL). The combined bottom aqueous layer was basified with 5N NaOH to pH 13 and extracted with diethyl ether (3 x 30 mL) (Note 2).

[3] The combined top organic layer was dried over Na2SO4 and evaporated under reduced pressure to give a pinch of yellow oil.

[4] The remaining bottom aqueous layer was extracted with dichloromethane (3 x 30 mL) (Note 3). The combined bottom organic layer was dried over Na2SO4 and evaporated under reduced pressure to give a pinch of dark brown oil.

[5] Both samples were solidified on standing at 3 oC overnight. No crystals were formed from [3] (Note 4), dark yellow crystals (2.0 g) could be observed from [4].

[6] The crystals from [5] was recrystallized from hot toluene to give PZQ amine as a yellow solid (1.4 g, 54%, m.p. 116 oC, lit. 118-119 oC).

Notes:

(1) The idea here was to remove most of EtOH as the formed cyclohexane-1-carboxylic acid (along with other organic impurities) can be dissolved in it while it is miscible with water so that the washing step with EA won't be as effective as it should be.

(2) In addition to using DCM as the solvent to extract PZQamine, it is experimented with the non-chlorinated solvent diethyl ether.

(3) In case that diethyl ether can't do the job very well to extract PZQamine (i.e. PZQamine still remains in the solution), extraction with DCM is performed.

(4) It showed that diethyl ether failed to be the solvent to extract PZQamine as there was absolutely no crystals being observed.
27th June 2011 @ 02:30
Preliminary step in procuring enantiopure PZQ; acid hydrolysis of rac-PZQ into rac-PZQamine.

See also:
Hydrolysis of PZQ - Standard Conditions (KB-PZQ-1001)
Hydrolysis of rac-PZQ (MW2-13)
Hydrolysis of rac-PZQ (MW2-14)
Optimizing the acid cleavage conditions II

image

Procedure:
rac-PZQ (4.0 g, 12.8 mmol, M.W. 312.5) was dissolved in a mixture of EtOH (30 mL) and 1N HCl (120 mL) before being heated to reflux for 24 hr.
9th June 2011 @ 05:56
Preliminary attempt to make the work-up for the hydrolysis step more industry friendly.

See also:
Hydrolysis of PZQ - Standard Conditions (KB-PZQ-1001)
Hydrolysis of rac-PZQ (MW2-13)
Hydrolysis of rac-PZQ (MW2-14)
Optimizing the acid cleavage conditions II

MW2-13.png


Procedure:
rac-PZQ (20.0 g, 64.0 mmol) was dissolved in a mixture of EtOH (100 mL) and 1N HCl (400 mL) and heated to reflux for 24 h. The solution was cooled to room temperature and the EtOH removed under reduced pressure. The resulting solution was cooled at 3 oC overnight, and the resulting mixture filtered to remove the cyclohexane-1-carboxylic acid (Note 1). The filtrate was basified to pH 12 with 5N NaOH and cooled overnight at 3 oC (Note 2). As no precipitate had formed, the aqueous phase was extracted with DCM (4 x 50 mL) (Note 3), dried over MgSO4, filtered and evaporated under reduced pressure, to give PZQ amine as a pale yellow solid (10.9 g, 84%, m.p 117-118 oC, lit. 117-118 oC). Further extraction of the aqueous phase (2 x 50 mL DCM) gave an additional crop of PZQ amine as a white solid (432 mg, 3%, m.p 118 oC).

Purification:
The product obtained using this procedure did not require further purification (as evidenced by NMR).

Notes:
(1) The idea here was to remove the cyclohexane-1-carboxylic acid by filteration. Initially, this oiled out (it's a low melting solid) and using a sufficiently narrow sep. funnel, could probably be separated as is. Cooling overnight allowed the acid to solidify, which could then be removed by filtration.
(2) It was hoped that the PZQ amine would crash out of solution, however, it was found to be quite soluble in the basic solution. Reducing the volume of solution (under a stream of nitrogen), seeding and cooling were all attempted to induce precipitation but were not successful.
(3) The next step would be to try replacing the DCM with a non-chlorinated solvent.

Data:
m.p 117-118 oC, lit. 117-118 oC); 1H NMR (500 MHz, MeOD): 7.24-7.18 (4H, m, Ar-H), 4.88-4.85 (1H, m, one of 6-CH2), 4.74-4.72 (1H, m, 11b-CH), 3.76 (1H, ddd, i]J[/i] = 13.2, 4.7, 0.1 Hz one of 1-CH2), 3.54 (1H, d, J = 17.65 Hz one of 3-CH2), 3.43 (1H, d, J = 17.55 Hz, one of 3-CH2), 2.92-2.90 (1H, m, one of 7-CH2), 2.80-2.74 (3H, m, one of 1-CH2, one of 6-CH2, one of 7-CH2). Spectral data agreed with that reported previously [Ref 1]. The numbering system used for PZQamine here is in accordance with that paper.

References:
[1] Laurent, Sophie A.-L.; Boissier, Jerome; Cosledan, Frederic; Gornitzka, Heinz; Robert, Anne; Meunier, Bernard, Euro. J. of Org. Chem., 2008, 5, 895-913.
[2] Woelfe, M. et al. "The Resolution of Praziquantel". 2011. http://openwetware.org/wiki/Todd:PZQ_Resolution.
Attached Files
9th June 2011 @ 05:38
See also:
Hydrolysis of rac-PZQ (MW2-13)
Hydrolysis of rac-PZQ (MW2-14)
Optimizing the acid cleavage conditions II

MW2-13.png


Procedure:
rac-PZQ (10.0 g, 32.0 mmol) was dissolved in a mixture of EtOH (75 mL) and 1N HCl (300 mL) and heated to reflux for 24 h. The solution was cooled to room temperature, washed with EtOAc (4 x 10 mL) to remove the cyclohexane-1-carboxylic acid (Note 1). The aqueous layer was basified with NaOH solution (5 N) to ph 12, extracted with DCM (4 x 30 mL), washed with brine, dried over MgSO4 and evaporated under reduced pressure. The yellow oil solidified on standing at 3 oC overnight.

Purification:
The resulting solid was recrystallised from toulene to give PZQ amine as a yellow solid (4.81g 77%, m.p. 114-115 oC, lit. 118-119 oC.

Notes:
(1) The EtOAC appeared to be somewhat missable with the aqueous/EtOH phase and the initial extraction to remove the cyclohexane-1-carboxylic acid was not entirely successful, as evidenced by a prevailing odour of cough syrup. On this scale, it might be worthwhile to remove the EtOH under reduced pressure first.
Attached Files