Crystal forms and synthetic methods of (2r,6r)-hydroxynorketamine and (2s,6s)-hydroxynorketamine
A technology of methylketamine crystallization, methylketamine, applied in bipolar depression, severe depression, standard treatment of selective 5-hydroxyl, and other depression and anxiety, recrystallization of 2R, 6R-HNK hydrochloride , the crystal form field of hydrochloride, which can solve problems such as no response
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Embodiment 1
[0157] Example 1. Chiral resolution of (S)-(+)-norketamine (14)
[0158]
[0159] Racemic norketamine (22.7 g, 101 mmol) (Cayman Chemicals, Ann Arbor, MI, USA, prepared as described in Hong, S.C. & Davisson, J.N., J.Pharm.Sci. (1982) 71:912-914) Dissolve in 1.1L ethanol. Then (D)-(R)-(+)-pyroglutamic acid solid (15.8 g, 0.5 equiv, 121 mmol) was added. The reaction was stirred and heated to reflux for 5 minutes. A white suspension formed while heating. Once the suspension reached reflux, it was allowed to cool to room temperature while stirring for 16 hours. The reaction was filtered and the white solid was collected. The resulting white solid was then resuspended in 0.9 L of ethanol, and the suspension was heated to reflux for 5 minutes. The suspension was allowed to cool to room temperature over 2 hours while stirring. The solid was collected by filtration, then suspended a third time in ethanol (0.8 L), heated to reflux for 5 minutes, and then allowed to cool to roo...
Embodiment 2
[0160] Example 2. (R)-(-)-norketamine (14 A ) chiral resolution
[0161]
[0162] (R)-(-)-norketamine (14 A ) was produced in a similar manner to (S)-(+)-norketamine (2), except that (L)-(S)-(-)-pyroglutamic acid was used as the chiral resolving reagent instead of (D) -(R)-(+)-Pyroglutamic acid. Chiral HPLC: 98% ee. (Chiralpak AD, 60% ethanol in hexane, 1 mL / min, rt: 6.8 min.) [α] D 20 : (-)-75°(c1.0, H 2 O, L-pyroglutamate salt).
Embodiment 3
[0163] Example 3. Synthesis of (S)-tert-butyl(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate (15)
[0164]
[0165] To a solution of (S)-(+)-norketamine (14) (1.85 g, 8.27 mmol) in toluene (100 mL) was added potassium carbonate (3.43 g, 24.8 mmol) and BOC-anhydride (2.71 g, 12.4 mmol) mmol). The reaction was heated to 80°C and stirred for 16 hours. The reaction was then cooled, extracted with ethyl acetate and washed with water. The organic layer was extracted and the solvent was removed in vacuo to give the crude product. Purification by silica gel chromatography (0% to 60% ethyl acetate in hexanes) gave the final product (15) as a white solid.
[0166] 1 H NMR (400MHz, CDCl 3 )δ7.83(d, J=8.0Hz, 1H), 7.42-7.28(m, 2H), 7.28-7.13(m, 1H), 6.59(s, 1H), 3.83(d, J=14.3Hz, 1H) ), 2.45-2.36 (m, 1H), 2.36-2.25 (m, 1H), 2.04 (ddq, J=11.5, 5.5, 3.0Hz, 1H), 1.89-1.56 (m, 4H), 1.29 (s, 9H) ).
[0167] 13 C NMR (101 MHz, CDCl 3 ) delta 209.0, 153.4, 135.1, 133.7, 131.5, 130.9, 1...
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