Crystalline form of a 3-phenoxymethylpyrrolidine compound
The invention provides a crystalline hydrochloride salt of (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine. This invention also provides pharmaceutical compositions comprising the crystalline salt, processes and intermediates for preparing the crystalline salt, and methods of using the crystalline salt to treat diseases.
1. A crystalline salt of (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine and hydrochloric acid in a 1:1 molar ratio, characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.78±0.20, 15.26±0.20, 19.08±0.20, 20.36±0.20, 21.50±0.20, and 25.46±0.20.
2. The compound of claim 1 , characterized by having one or more additional diffraction peaks at 2θ values selected from 26.42±0.20, 30.65±0.20, 28.91±0.20, 24.77±0.20, 14.42±0.20, 16.74±0.20, and 5.20±0.20.
3. The compound of claim 1 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .
4. The compound of claim 1 , characterized by a differential scanning calorimetry trace which has a melting point of about 128° C.
5. The compound of claim 1 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
7. The pharmaceutical composition of claim 6 , further comprising a therapeutic agent selected from anti-Alzheimer's agents, anticonvulsants, antidepressants, anti-Parkinson's agents, dual serotonin-norepinephrine reuptake inhibitors, non-steroidal anti-inflammatory agents, norepinephrine reuptake inhibitors, opioid agonists, opioid antagonists, selective serotonin reuptake inhibitors, sodium channel blockers, sympatholytics, and combinations thereof.
8. A process for preparing the compound of claim 1 , comprising the step of:
(a) treating a hydrochloride salt of (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine with a polar solvent to form a first composition or deprotecting (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine-1-carboxylic acid t-butyl ester with hydrochloric acid in an inert diluent to form a first composition; and (b) adding a nonpolar solvent to form a second composition from which the compound of claim 1 is formed.
9. The process of claim 8 , wherein step (b) comprises:
(i) adding a non-polar solvent to form a second composition;
(ii) optionally cooling to effect crystallization; and
(iii) isolating the resulting solids to yield the compound of claim 1 .
10. The process of claim 8 , wherein the polar solvent is isopropanol.
11. The process of claim 8 , wherein deprotection is done with 3 M HCl and the inert diluent is cyclopentyl methyl ether.
12. The process of claim 8 , wherein the nonpolar solvent is diisopropyl ether.
13. A process for purifying (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine comprising forming the compound of claim 1 .
14. A method of treating a patient that is suffering from a pain disorder, a depressive disorder, an affective disorder, attention deficit hyperactivity disorder, a cognitive disorder, stress urinary incontinence, chronic fatigue syndrome, obesity, or vasomotor symptoms associated with menopause, comprising administering a therapeutically effective amount of the compound of claim 1 .
15. The method of claim 14 , wherein the pain disorder is selected from neuropathic pain, fibromyalgia, chronic low back pain, and osteoarthritis.