WO2018020366A1

WO2018020366A1 - Crystalline (r)-mandelate salt of (1r,2s)-2-phenylcyclopropylamine

Info

Publication number: WO2018020366A1
Application number: PCT/IB2017/054403
Authority: WO
Inventors: Jeremiah David Powers
Original assignee: Glaxosmithkline Intellectual Property (No.2) Limited
Priority date: 2016-07-26
Filing date: 2017-07-20
Publication date: 2018-02-01

Abstract

Disclosed is a crystalline form of the (R)-mandelate salt of (1R, 2S)-2- phenylcyclopropylamine. Also disclosed is a method for resolving trans-2- phenylcyclopropylamine.

Description

CRYSTALLINE (R)-MANDELATE SALT OF (1 R,2S)-2-PHENYLCYCLOPROPYLAMINE

FIELD OF INVENTION

The present invention relates to a novel crystalline i?-mandelate salt of (\R, 2S)-2- phenylcyclopropylamine. This invention also relates to a process for resolving trans-2- phenylcyclopropylamine .

BACKGROUND OF THE INVENTION fr «5-2-Phenylcyclopropylamine, commonly known as tranylcypromine, is a well known monoamine oxidase (MAO) inhibitor used for the treatment of Parkinson's disease and depression {See U.S. Patent No. 4,331,687). trans-2 -Phenylcyclopropylamine enantiomers have markedly different pharmacological properties and inhibitory effects. For example, (+)-fra«s-2-Phenylcyclopropylamine has a fifteen to twenty times greater monoaminoxidase potency than the (-)-enantiomer {Id ). However, {-)-trans-2- phenylcyclopropylamine is a better inhibitor of noradrenaline and dopamine uptake than the (+)-enantiomer (A.S. Horn and S.H. Snyder, J. Pharmacol. Exp. Ther., 1972, 180:523- 530).

More recently, derivatives of fra«s-2-phenylcyclopropylamine have been identified as potent small molecule inhibitors of Lysine-specific demethylase 1 (LSD1; also known as BHC110) and as therapeutic agents for the treatment of diseases and conditions associated with LSD1 activity. International Patent Application Publication Number WO 2012/135113 A2 describes a series of fr ra-2-phenylcyclopropylamine derivatives as LSD 1 inhibitors, and which are indicated as being useful in the treatment of cancers. The series of compounds include optically active trans-2- phenylcyclopropylamine derivatives, of which {\R, 2<S)-2-phenylcyclopropylamine serves as a useful intermediate for the preparation of such compounds.

Several methods for the resolution of enantiomerically enriched trans-2- phenylcyclopropylamines already exist. For example, enantiomerically enriched trans-2- phenylcyclopropylamine can be obtained by forming a tartrate salt or by using chromatographic techniques. However, these known methods have some drawbacks. Enantiomerically enriched fra«s-2-phenylcyclopropylamine can be obtained from its racemic mixture by forming a tartrate salt, but the process requires four to five crystallizations to obtain a complete resolution (U.S. Patent No. 4,016,204). Chromatographic separation with high performance liquid chromatography (HPLC) using chiral stationary phases has been used to resolve fra«s-2-phenylcyclopropylamines, but the process requires prior derivatization (H.Y. Aboul-Enein and V. Serignese, 1995, Biomed. Chromatogr., 9:98-101). Chromatographic techniques that do not require derivatization of fr «5-2-phenylcyclopropylamine are not used preparatively, but are instead only used analytically to quantify enantiomeric ratios in analytical samples (Id.). Thus, an improved low cost method for resolving fra«s-2-phenylcyclopropylamine on a preparatory scale without multiple crystallizations is highly desirable.

SUMMARY OF THE INVENTION

The present invention relates to a crystalline form of the (i?)-mandelate salt of (\R, 2iS)-2-phenylcyclopropylamine (hereinafter "Compound A"). The compound of the invention is represented by Formul

(I)

The present invention also relates to a method for resolving a racemic mixture of fr «5-2-phenylcyclopropylamine, the method comprising reacting the racemic mixture of fr «5-2-phenylcyclopropylamine with either (R)- or (<S)-mandelic acid and precipitating the derived salt, followed by optional conversion to the enantiomerically enriched free base of fr «5-2-phenylcyclopropylamine .

The present invention also relates to a method for preparing a salt according to Formula (I),

comprising reacting fra«s-2-phenylcyclopropylamine with i?-(-)mandelic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows an X-ray powder diffraction pattern of Compound A - Form 1.

Fig. 2 shows a differential scanning calorimetry trace of Compound A - Form 1.

Fig. 3 shows a ¹³C solid state NMR spectrum of Compound A - Form 1.

DETAILED DESCRIPTION OF THE INVENTION

(i?)-Mandelate Salt of (lR, 2S)-2-Phenylcyclopropylamine

The present invention is directed to a (i?)-mandelate salt of (\R, 2S)-2- phenylcyclopropylamine (hereinafter "Compound A").

In one embodiment, a crystalline form of the (i?)-mandelate salt of (\R,2S)-2- phenylcyclopropylamine (Compound A - Form 1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six diffraction angles, when measured using Cu Κ_α radiation, selected from a group consisting of about 5.7, 11.4, 12.9, 16.2, 17.0, 20.1, 22.8, and 25.6 degrees 2Θ. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five diffraction angles or at least four diffraction angles, when measured using Cu K_a radiation, selected from a group consisting of about 5.7, 11.4, 12.9, 16.2, 17.0, 20.1, 22.8, and 25.6 degrees 2Θ. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Ka radiation, selected from a group consisting of about 5.7, 11.4, 12.9, 16.2, 17.0, 20.1, 22.8, and 25.6 degrees 2Θ. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Κ_α radiation, of about 5.7, 11.4, 17.0, 22.8, and 25.6 degrees 2Θ. In yet another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1.

In another embodiment, Compound A - Form 1 is characterized by a ¹³C solid state NMR spectrum comprising at least seven peaks selected from a group consisting of about 14.5, 22.4, 34.0, 77.4, 126.3, 128.1, 129.1, 138.8, 141.1 and 184.6 ppm. In another embodiment, Compound A - Form 1 is characterized by a ¹³C solid state NMR spectrum comprising at least six or at least five or at least four peaks selected from a group consisting of about 14.5, 22.4, 34.0, 77.4, 126.3, 128.1, 129.1, 138.8, 141.1 and 184.6 ppm. In another embodiment, Compound A - Form 1 is characterized by a ¹³C solid state NMR spectrum comprising at least three peaks selected from a group consisting of about 14.5, 22.4, 34.0, 77.4, 126.3, 128.1, 129.1, 138.8, 141.1 and 184.6 ppm.

In further embodiments, Compound A - Form 1 is characterized by a differential scanning calorimetry trace substantially in accordance with Fig. 2 and/or a ¹³ C solid state NMR spectrum substantially in accordance with Fig. 3.

In still further embodiments, as a person having ordinary skill in the art will understand, Compound A - Form 1 is characterized by any combination of the analytical data characterizing the aforementioned embodiments. For example, in one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a differential scanning calorimetry trace substantially in accordance with Fig. 2 and a ¹³C solid state NMR spectrum substantially in accordance with Fig. 3. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a differential scanning calorimetry trace substantially in accordance with Fig. 2. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1 and a ¹³C solid state NMR spectrum substantially in accordance with Fig. 3. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu K_a radiation, of about 5.7, 11.4, 17.0, 22.8, and 25.6 degrees 2Θ, and a differential scanning calorimetry trace substantially in accordance with Fig. 2. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Κ_α radiation, of about 5.7, 1 1.4, 17.0, 22.8, and 25.6 degrees 2Θ, and a ¹³C solid state NMR spectrum substantially in accordance with Fig. 3. In another embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu K_a radiation, of about 5.7, 1 1.4, 17.0, 22.8, and 25.6 degrees 2Θ, and a ¹³C solid state NMR spectrum comprising at least seven peaks selected from a group consisting of about 14.5, 22.4, 34.0, 77.4, 126.3, 128.1, 129.1, 138.8, 141.1 and 184.6 ppm.

An XRPD pattern will be understood to comprise a diffraction angle (expressed in degrees 2Θ) of "about" a value specified herein when the XRPD pattern comprises a diffraction angle within ± 0.1 degrees 2Θ of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an X-ray powder diffraction (XRPD) pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. An X-ray powder diffraction pattern that is "substantially in accordance" with that of Figure 1 provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of Figure 1. That is, the XRPD pattern may be identical to that of Figure 1, or more likely it may be somewhat different. Such an XRPD pattern may not necessarily show each of the lines of the diffraction pattern presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their XRPD patterns. For example, one skilled in the art can overlay an XRPD pattern of a sample of the (R)- mandelate salt of (-)-(li?,25)-2-phenylcyclopropylamine, with Fig. 1 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern of Compound A - Form 1. If the XRPD pattern is substantially in accordance with Fig. 1, the sample form can be readily and accurately identified as having the same form as Compound A - Form 1. A ¹³C solid state NMR spectrum will be understood to comprise a peak (expressed in ppm) of "about" a value specified herein when the ¹³C solid state NMR spectrum comprises a peak within ± 0.2 ppm of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining a ¹³C solid state NMR spectrum may cause some variability in the appearance, intensities, and positions of the lines in the spectrum. A ¹³C solid state NMR spectrum that is "substantially in accordance" with that of Figure 3 provided herein is a ¹³C solid state NMR spectrum that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the ¹³C solid state NMR spectrum of Figure 3. That is, the a ¹³C solid state NMR spectrum may be identical to that of Figure 3, or more likely it may be somewhat different. Such a ¹³C solid state NMR spectrum may not necessarily show each of the lines of the ¹³ C solid state NMR spectrum presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their ¹³ C solid state NMR spectrum. For example, one skilled in the art can overlay a ¹³C solid state NMR spectrum of a sample of the (i?)-mandelate salt of (-)- (li?,2<S)-2-phenylcyclopropylamine, with Fig. 3 and, using expertise and knowledge in the art, readily determine whether the ¹³C solid state NMR spectrum of the sample is substantially in accordance with the ¹³C solid state NMR spectrum of Compound A - Form 1. If the ¹³ C solid state NMR spectrum is substantially in accordance with Fig. 3, the sample form can be readily and accurately identified as having the same form as Compound A - Form 1.

"Compound of the invention" means the (i?)-mandelate salt of (\R,2S)-2- phenylcyclopropylamine, and in some embodiments, specifically the crystalline form defined herein as Compound A - Form 1. The present invention further includes a method for resolving a racemic mixture of fr «5-2-phenylcyclopropylamine. The present resolution method provides a solid (i.e. granular, powder, or crystalline) form of an optically active salt of trans-2- phenylcyclopropylamine. This salt may be optionally converted into the enantiomerically enriched free base of trans -2 -phenylcyclopropylamine.

In one embodiment, the method includes forming a precipitate of the i?-mandelate salt of (\R, 2iS)-2-phenylcyclopropylamine from a solution or a mixture comprising trans- 2-phenylcyclopropylamine and i?-(-)-mandelic acid. In another embodiment, the method includes forming a precipitate of the S-mandelate salt of (IS, 2R)-2- phenylcyclopropylamine from a solution or a mixture comprising trans-2- phenylcyclopropylamine and 5'-(+)-mandelic acid.

The precipitate of the mandelate salt of fra«s-2-phenylcyclopropylamine can be formed as follows. The concentrations in this embodiment are merely exemplary, and can be varied as determined by routine experimentation.

The free base of racemic or enantiomerically enriched trans-2- phenylcyclopropylamine can be dissolved in a solvent, such as ethanol. The free base of trans-2 -phenylcyclopropylamine in solvent may be stirred at a selected temperature, such as about 20-50 °C, in particular about 35 °C. To the free base of trans-2- phenylcyclopropylamine in solvent can be added either R-(-)- or 5'-(+)-mandelic acid as a mixture or solution in a solvent, such as ethanol, at a selected temperature, such as about 20-50 °C, in particular about 30-35 °C. For instance, the R-(-)- or 5^*-(+)-mandelic acid may be added as a 0.95 M solution in ethanol at about 30 °C. The resulting mixture or solution may be stirred at a selected temperature, such as about 20-50 °C, in particular about 30-35 °C, and then may be cooled to a lower selected temperature, such as about 0-25 °C, in particular about 15-20 °C. Alternatively, the resulting mixture or solution may be stirred at about 30 °C for a given period of time, such as about 1 hour, and then may be cooled to ambient temperature over a given period of time, such as about 1 hour. In another alternative, the mixture may be stirred for an additional 2-3 hours after cooling to ambient temperature. The solid can be collected by filtration, washed with a solvent, such as ethanol, and dried under vacuum at a selected temperature, such as about 20-50 °C, in particular about 35-45 °C to give a crude mandelate salt. Alternatively, the solid may be collected by filtration, washed with a solvent, such as ethanol, and dried under vacuum at a selected temperature, such as about 20-50 °C, in particular about 40 °C for a given period of time, such as about 24 hours to give the crude mandelate salt.

A mixture of crude mandelate salt of trans-2 -phenylcyclopropylamine in a solvent or solvent mixture, such as ethanol and/or water, may be heated to a selected temperature, such as about 30-100 °C, in particular about 60-70 °C, until the solid dissolves completely. In a particular embodiment, the ethanol-water ratio can be about 0.8: 1. In another particular embodiment, the ethanol-water ratio can be about 4: 1. This mixture may be heated to a selected temperature, such as about 30-100 °C, in particular about 70 °C for a given period of time, such as about 20 minutes. The solution can be cooled to a lower selected temperature, such as about 40-50 °C, and after a hold period, may be further cooled to a further lower selected temperature, such as about 15-20 °C and aged. Alternatively, the temperature may be reduced to a lower selected temperature, such as about 40-50 °C, in particular about 45 °C over a period of time, such as about 1.5 hours, and the mixture may be stirred for a period of time, such as about 2 hours at about 45 °C, after which the temperature may be further reduced to ambient temperature, and the mixture may be stirred for a period of time, such as about 2 hours at ambient temperature. The mixture can be filtered, and the solid may be washed with a solvent, such as ethanol, before drying under vacuum at a selected temperature, such as about 20-50 °C, in particular about 40-45 °C, to give the crystalline mandelate salt.

If the starting material is a salt of fra«s-2-phenylcyclopropylamine, such as a hemisulphate salt, rather than the free base of fra«s-2-phenylcyclopropylamine, the free base can be formed by any suitable technique known in the art. For example, a solution of fr «5-2-phenylcyclopropylamine hemisulphate salt in water may be adjusted to a pH of about 13 or greater with about 2M aqueous NaOH solution at about 15-25 °C and may be extracted with dichloromethane. The separated aqueous layer can be adjusted to a pH of about 13 or greater with about 2M aqueous NaOH solution. Organic materials can be extracted from the aqueous layer with dichloromethane. The combined organic phase may be washed with water and concentrated under reduced pressure to provide the free base form.

In one embodiment, the i?-mandelate salt of (-)-(li?, 2<S)-2-phenylcyclopropylamine is prepared by the above method using i?-(-)-mandelic acid. In another embodiment, the S- mandelate salt of (+)-(15^*, 2i?)-2-phenylcyclopropylamine is prepared by the above method using 5'-(+)-mandelic acid.

In one embodiment, the mandelate salt of fra«s-2-phenylcyclopropylamine, prepared by the above method, is further converted to enantiomerically enriched free base of fr «5-2-phenylcyclopropylamine by any suitable technique known in the art. In another embodiment, the i?-mandelate salt of (-)-(li?, 2<S)-2-phenylcyclopropylamine, prepared by the above method using i?-(-)-mandelic acid, is converted to the free base of (-)-(li?, 2S)-2- phenylcyclopropylamine by any suitable technique known in the art. In another embodiment, the S-mandelate salt of (+)-(15^*, 2i?)-2-phenylcyclopropylamine, prepared by the above method using 5'-(+)-mandelic acid, is converted to the free base of (+)-(15^*, 2R)- 2-phenylcyclopropylamine by any suitable technique known in the art.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Percent enantiomeric excess (% ee) was determined according to normal phase HPLC using a Shimadzu HPLC with a diode array dectector (DAD), or equivalent, equipped with a CHIRALCEL OJ-H 4.6 mm x 250 mm, 5 μπι column at 220 nm wavelength. The mobile phase used was a 3% ethanol: methanol (1 : 1) in hexanes with 0.01% diethylamine. The sample was prepared by adding about 30 mg of Compound A into a 25 mL volumetric flask. A diluent of ethanol methanol (50:50, v/v) was added to volume. The sample was sonicated to dissolve if necessary. The injection volume was 5 μΜ, and the flow rate was 1.0 mL/minute with a run time of 40 minutes. The retention time for (-)-(li?, 2<S)-2-phenylcyclopropylamine was 17.25 minutes. The retention time for (+)-(15^*, 2i?)-2-phenylcyclopropylamine was 18.02 minutes.

Proton nuclear magnetic resonance (¾ NMR) was recorded at 400 MHz using a Bruker AV 400 MHz spectrometer. DMSO-d6 is hexadeuteriodimethylsulfoxide. Chemical shifts are reported in parts per million (δ). The residual solvent resonance of DMSO-d6 was used as an internal reference at 2.50 ppm. Chemical shifts are reported in Abbreviations for NMR data are as follows: s = singlet, d = doublet, m = multiplet, ddd = doublet of doublets of doublets, br = broad. J indicates the NMR coupling constant measured in Hertz.

Carbon-13 nuclear magnetic resonance (¹³C NMR) spectrum was recorded at 101

MHz using a Bruker AV 400 MHz spectrometer. DMSO-de is

hexadeuteriodimethylsulfoxide. Chemical shifts are reported in parts per million (δ). The residual solvent resonance of DMSO-d6 was used as an internal reference at ppm 39.52. High resolution mass spectrometry (HRMS) was acquired using an Agilent G6224A TOF LC/MS system. Electrospray ionization was performed in positive ion mode. The solution for analysis was prepared by dissolving 2.596 mg of Compound A in 25 mL of diluent (0.1% formic acid in acetonitrile : 0.1% formic acid in water = 50:50 (v/v)) and then transferred to 1.0 mL of the solution into a 10 mL volumetric flask. The solution was diluted with the diluents and mixed well. A final concentration of 0.0104 mg/mL was obtained and analyzed.

EXAMPLE 1

Preparation of:

i?-mandelate salt of (li?,2<S)-2-phenylcyclopropylamine (Compound A) a) Procedure A - Detailed

A solution of fr ra-2-phenylcyclopropylamine (20 g, 150 mmol, 1 equivalent) in ethanol (410 mL) was stirred at 35 °C. To the solution was added a solution of R-(-)- mandelic acid (20 g, 131 mmol, 0.87 equivalent) in ethanol ( 137 mL). The mixture was sirred at 35 °C for 2 hours, cooled to ambient temperature over 1 hour, and stirred at ambient temperature for 2 hours. The solid was collected by filtration, washed with ethanol ( 137 mL), and dried under vacuum at 40 °C for 24 hours to give a crude product (24.25 g).

Crude product (24.0 g, 84.1 mmol) was suspended in ethanol (384 mL) and water (480 mL). The resulting mixture was heated at 70 °C for 15 minutes (until a solution was obtained). The temperature was reduced to 45 °C over 2 hours and stirred at 45 °C for 2.5 hours. The temperature was reduced to ambient temperature over 1 hour and stirred at ambient temperature for 2 hours. The solid was collected by filtration, washed with ethanol (54.8 mL), and dried under vacuum at 40 °C for 18 hours to yield crystalline mandelate salt ( 11.34 g, 27%). b) Procedure B - General

A solution of fra«s-2-phenylcyclopropylamine hemisulphate salt (1 wt) in water is adjusted to pH > 13 with 2M aqueous NaOH solution at 15-25 °C and extracted with dichloromethane. The separated aqueous layer is adjusted to pH > 13 with 2M aqueous NaOH solution. Organic material is extracted from the aqueous layer with dichloromethane. The combined organic phase is washed with water and concentrated under reduced pressure. Ethanol is added to the residue. (i?)-2-Hydroxy-2-phenylacetic acid in ethanol is added at 30-35 °C. The mixture is stirred at 30-35 °C and then cooled to 15-20 °C. The mixture is filtered, and the solid is rinsed with ethanol and dried under reduced pressure at 35-45 °C to afford crude product.

Ethanol (12.0- 12.6 wt) and water (4.0-4.1 wt) are added to the crude product. The mixture is heated to 60-70 °C and stirred until the solid is dissolved completely. The solution is cooled to 40-50 °C and after a hold period is cooled to 15-20 °C and aged. The mixture is filtered and the solid is rinsed with ethanol (0.5-1.0 wt). The residue is taken up in ethanol (3.1-3.2 wt) and water (0.21-0.25 wt), and the mixture is heated to 60-70 °C and stirred. The solution is then cooled to 40-50 °C and after a hold period is cooled to 15-20 °C and aged. The mixture is filtered, and the solid is rinsed with ethanol (0.1-0.4 wt) and is dried under reduced pressure at 45-50 °C to give a crystalline mandelate salt of (\R,2S)- 2-phenylcyclopropylamine. Data generated from Procedure B - General: (% ee > 99%); ¾ NMR (400 MHz, DMSO-de) δ 7.39 (m, 2 H), 7.25 (m, 4H), 7.18 (m, 1H), 7.17 (m, 1 H), 7.07 (m, 2 H), 5.71 (br s, 4 H), 4.67 (s, 1 H), 2.62 (ddd, J = 7.8, 4.1, 4.1 Hz, 1 H), 2.15 (ddd, J = 9.6, 6.1, 3.4 Hz, 1 H), 1.23 (ddd, J = 9.9, 5.6, 4.7, 1 H), 1.05 (ddd J = 7.6, 6.0, 6.0, 1 H); ¹³C NMR ( 101 MHz, DMSO-de) δ 175.0, 142.9, 140.4, 128.3, 127.5, 126.4, 125.9, 73.3, 31.9, 22.1, 14.6; HRMS (m/z): 134.0965 [M+l]⁺.

The X-ray powder diffraction (XRPD) pattern of this material (Compound A -

Form 1) is shown in Fig. 1. A summary of the diffraction angles and d-spacings is given in Table I below. The XRPD analysis was conducted on a PANanalytical X'Pert Pro powder diffractometer, model PW3040/60 using an X'Celerator dectector. The acquisition conditions included: Cu K_a radiation, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0° 2Θ, end angle: 40.0° 2Θ, step size: 0.0167° 2Θ, time per step: 95.25 seconds. The sample was prepared by dispersing a few milligrams of material on a silicon wafer (zero background plate), resulting in a thin layer of powder. TABLE I

The differential scanning calorimetry (DSC) thermogram of the title compound was recorded on a TA Q2000 Differential Scanning Calorimeter and is shown in Fig. 2. The experiment was conducted using a heating rate of 10 °C/min in a crimped aluminum pan. The DSC thermogram of Compound A - Form 1 exhibits an endotherm with an onset temperature at about 187 °C. A person skilled in the art would recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

The ¹³C Solid State NMR (ssNMR) spectrum is shown in Fig. 3. The ¹³C ssNMR is consistent with a salt and not a co-crystal. The ¹³C ssNMR comprises chemical shifts at about 14.48 ± 0.2, 22.39 ± 0.2, 33.97 ± 0.2, 77.43 ± 0.2, 126.32 ± 0.2, 128.07 ± 0.2, 129.12 ± 0.2, 138.83 ± 0.2, 141.07 ± 0.2 and 184.60 ± 0.2 ppm. ¹³C ssNMR data of the title compound was acquired using a Bruker Advance 360 triple-resonance spectrometer operating at a ¾ frequency of 360.13 MHz. The ¹³C ssNMR spectra was obtained using a cross-polarization pulse sequence with a Bruker 4-mm triple resonance magic-angle spinning probe at a rotor frequency of 8 kHz. A linear power ramp was used on the ¾ channel to enhance cross-polarization efficiency. Spinning sidebands were eliminated by a total sideband suppression sequence using 5 π pulses. ¾ decoupling was obtained using the Spinal-64 sequence. The ¹³ C chemical shift scale was referenced relative to tetramethylsilane at 0 ppm (parts per million) as the primary reference by using glycine as a secondary, where the carbonyl peak was referenced to 176 ppm.

Claims

What is claimed is:

1. A crystalline form of (i?)-mandelate salt of (IR, 2<S)-2-phenylcyclopropylamine. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu K_a radiation, selected from a group consisting of about 5.7, 1 1.4, 12.9, 16.

2, 17.0, 20.1, 22.8, and 25.6 degrees 2Θ.

3. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Ka radiation, of about 5.7, 1 1.4, 17.0, 22.8, and 25.6 degrees 2Θ.

4. The crystalline form of claim 2 or claim 3, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 1.

5. The crystalline form of any one of claims 2-4, wherein the crystalline form is characterized by a ¹³C solid state NMR spectrum comprising at least seven peaks selected from a group consisting of about 14.5, 22.4, 34.0, 77.4, 126.3, 128.1, 129.1, 138.8, 141.1 and 184.6 ppm.

6. The crystalline form of any one of claims 2-5, wherein the crystalline form is characterized by a ¹³C solid state NMR spectrum substantially in accordance with Fig. 3.

7. A method for resolving a racemic mixture of fra«s-2-phenylcyclopropylamine, the method comprising:

reacting the racemic mixture of fra«s-2-phenylcyclopropylamine with (i?)-mandelic acid;

precipitating a (i?)-mandelate salt of ( \R, 2<S)-2-phenylcyclopropylamine;

collecting the (i?)-mandelate salt of ( \R, 2<S)-2-phenylcyclopropylamine; and then optionally converting the mandelate salt into the free base form of (\R, 2S)-2- phenylcyclopropylamine .

8. The method of claim 7, wherein the (i?)-mandelate salt of ( IR, 2S)-2- phenylcyclopropylamine is precipitated from a solution or mixture comprising trans-2- cyclopropylamine, i?-(-)-mandelic acid, and ethanol.

9. A method for preparing a salt according to Formula (I):

comprising reacting fra«s-2-phenylcyclopropylamine with i?-(-)-mandelic acid.

10. The method of claim 9, further comprising precipitating the salt according to Formula (I) from a solution or mixture comprising fra«s-2-phenylcyclopropylamine, R-(-) mandelic acid, and ethanol.