METHOD FOR THE PRODUCTION OF LUMATEPERONE AND ITS SALTS

Abstract

Method for the production of formula (I) lumateperone or its acid addition salts so that the enantiomer compound with stereochemistry 6bR,10aS

##STR00001##

is separated form the cis racemate using resolution and the formula (II) stereoisomer is alkylated with 4-halo-4′-fluoro butyrophenone (X = I, Br, Cl) to produce the formula (I) lumateperone, or optionally its acid addition salt. The object of the invention also relates to the amorphous form of the morphologically uniform p-toluenesulfonic acid salt of lumateperone and to the naphthalene-2-sulfonic acid salt of lumateperone, to the 1:2 stoichiometry salt of lumateperone formed with naphthalene-2-sulfonic acid.

Claims

1-47. (canceled)

48. The crystalline form of the formula ##STR00026## (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline base, preferably characterised by that the positions of its characteristic the x-ray powder diffraction lines are [(Cu Kα) °2θ(±0.2 °2θ)]: 9.99; 16.03; 20.87, more preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 9.99; 13.17; 15.25; 16.03; 20.32, 20.87, most preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 7.46; 9.99; 13.17; 15.25; 16.03; 16.38; 20.32; 20.87; 21.35; 23.18, or salt of formula ##STR00027## (VI) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline formed with (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), preferably characterised by that the positions of x-ray powder diffraction lines are [(Cu Kα) °2θ(±0.2 °2θ)]: 6.17; 19.88; 23.58, more preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 6.17; 9.89; 13.56; 18.66; 19.88; 23.58, most preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 6.17; 9.89; 10.37; 11.72; 12.94; 13.56; 14.92; 18.66; 19.88; 23.58, or a salt of the formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline formed with hydrochloric acid, preferably its formula ##STR00028## (II).Math.2HCl salt formed with 2 mol hydrochloric acid, preferably characterized by that the positions of characteristic the x-ray powder diffraction lines of [(Cu Kα) °2θ(±0.2 °2θ)]:13.43; 16.52; 22.19, more preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 6.75; 13.43; 16.52; 17.79; 20.26; 22.19, most preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 6.75; 9.40; 13.43; 16.52; 17.79; 18.20; 18.86; 20.26; 22.19; 27.02; or the salt of the formula (I) lumateperone formed with naphthalene-2-sulfonic acid, preferably in form of the structural formula of which is a.) ##STR00029## (X), in which salt the molar ratio of the lumateperone and the naphthalene-2-sulfonic acid is 1:1, or b.) ##STR00030## (VIII), in which salt the molar ratio of the lumateperone and the naphthalene-2-sulfonic acid is 1:2, more preferably formula (VIII) compound ischaracterised by positions of its characteristic x-ray powder diffraction lines of [(Cu Kα) °2θ(±0.2 °2θ)]: 3.87; 15.09; 20.71, more preferably [(Cu Kα) °2θ(±0.2 °2θ)]: 3.87; 5.82; 15.09; 17.38; 20.71; 27.20, most [(Cu Kα) °2θ(±0.2 °2θ)]: 3.87; 5.82; 7.76; 13.63; 15.09; 15.57; 17.38; 18.52; 20.26; 20.71; 21.04; 27.20, or the amorphous form of the ##STR00031## ##STR00032## formula (III) lumateperone salt, in which salt the molar ratio of the formula (I) lumateperone and the p-toluenesulfonic acid is 1:1.

49. Compounds according to claim 48, characterised by that the enantiomer purity of the formula (II) and/or (I) compounds, in which formula (II) or (I) compounds the configuration of the chiral carbon atoms is 6bR, 10aS, or of their salts is greater than 97%, preferably greater than 99%, even more preferably greater than 99.5%.

50. Compounds according to claim 48, characterised by that the chemical purity of the formula (II) and/or (I) compounds or of their salts, in which formula (II) or (I) compounds the configuration of the chiral carbon atoms is 6bR,10aS, is greater than 97%, preferably greater than 99%, even more preferably greater than 99.5%.

51. Method for the production of the crystalline form of the formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline base according to claim 48, characterised by that a.) reacting the formula (VI) salt formed with (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), or the formula (II).Math.2HCl salt formed with hydrochloric acid with a base, and the released formula (II) compound is brought into crystalline form, or b.) reacting the formula (IV) compound with a chiral acid, preferably the formula (V) (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), then the salt of the formula (II) compound formed with chiral acid, in which formula of the formula (II) compound the configuration of the chiral carbon atoms is 6bR, 10aS, is isolated from the reaction mixture and then transformed into the formula (II) base, or c.) reacting the formula (IV) compound with chiral acid, then the salt of the formula (II/A) compound formed with a chiral acid, wherein the configuration of the chiral carbon atoms in the formula of the compound is 6bS,10aR, is separated from the reaction mixture, and the formula (II) compound that has been enriched in this way in the reaction mixture, wherein the configuration of the chiral carbon atoms in its formula is 6bR,10aS, is isolated, then the formula (II) compound obtained in this way is crystallized; or for the production of the formula (VI) salt of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline formed with (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), characterised by that a.) the formula (IV) compound is reacted with the formula (V) (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), then the formula (VI) compound obtained in this way is isolated from the reaction mixture, or b.) the formula (IV) compound is reacted with a chiral acid, preferably the formula (V/A) (-)-dibenzoyl-L-tartaric acid mono(dimethylamide), then the salt of compound (II/A) formed with chiral acid, in which the configuration of the chiral carbon atoms is 6bS, 10aR, preferably the formula (VI/A) salt formed with (-)-dibenzoyl-L-tartaric acid mono(dimethylamide) is isolated from the reaction mixture, and the formula (II) compound enriched in the reaction mixture in this way is reacted with the formula (V) (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), then the formula (VI) compound formed is isolated; or for the production of the formula (II).Math.2HCl salt of the formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline formed with hydrochloric acid, characterised by that the formula (VI) salt of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline formed with (+)-dibenzoyl-D-tartaric acid mono(dimethylamide), or the formula (II) base is stirred in an organic solvent, preferably ethyl acetate, then hydrochloric acid dissolved in an organic solvent, preferably in ethyl acetate, even more preferably hydrogen chloride gas dissolved in ethyl acetate is added to the reaction mixture, then the formula (II).Math.2HCl salt formed is separated.

52. The use of the crystalline form of formula (II) according to claim 48 (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline, of the formula (VI) (+)-dibenzoyl-D-tartaric acid mono(dimethylamide) salt, or of the formula (II).Math.2HCl salt with hydrochloric acid for the production of lumateperone or of its salts, preferably the lumateperone p-toluenesulfonic acid salt, the naphthalene-2-sulfonic acid salt, most preferably the formula (III) amorphous form of the p-toluenesulfonic acid salt, or the formula (VIII) naphthalene-2-sulfonic acid salt.

53. Method for the production of the salt of lumateperone formed with p-toluenesulfonic acid according to claim 48, characterised by that the lumateperone base is reacted with an amount of p-toluenesulfonic acid equal to 0.7 to 1.2 times the molar amount of the lumateperone base, preferably 0.9 to 1.1 times the amount, more preferably 0.95 to 1.05 times the amount, most preferably with an equivalent amount, then the salt obtained a.) is isolated in amorphous form, more preferably the salt formation is carried out in a solvent mixture of water and a nitrile type solvent, preferably water and acetonitrile, preferably in the solvent mixture to be lyophilised the volumetric ratio of the water and the nitrile type solvent, preferably the water and acetonitrile at room temperature (20° C.) is 40:1-10:1, preferably 30:1-15:1, more preferably 25:1-19:1, then the formula (III) lumateperone p-toluenesulfonic acid salt solution obtained in this way is lyophilised in such a way that the ratio of the mass of the used tosylate salt with respect to the volume of the solvent (tosylate salt mass [g]/solvent volume [litre]) is preferably 0.2-100, more preferably 0.2-50, even more preferably 0.25-10, most preferably 0.3-1, most preferably in the course of the salt formation the temperature of the mixture is maintained at between 0 to 50° C., preferably between 20 to 25° C., most preferably at room temperature, then the solution made of lumateperone monotosylate with water and a nitrile type solvent, preferably acetonitrile is cooled to a temperature lower than 0° C., preferably to between 0° C. and -200° C., even more preferably to between -60° C. and -200° C., most preferably to a temperature between -70° C. and -100° C., then the solution obtained in this way is lyophilised at a decreased pressure under 6.117 mbar, preferably 0.01 to 6 mbar, even more preferably 0.1 to 5 mbar, most preferably 1 to 5 mbar or b.) the formula (III) lumateperone p-toluenesulfonic acid salt formed, which consists of morphologically uniform crystals, or consists of several crystals of different morphology, or of a mixture of crystalline and amorphous tosylate salts of various morphology is isolated, then dissolving it in a mixture of water and a nitrile type solvent, preferably in a mixture of acetonitrile and water and then lyophilising it.

54. Method for the production of the salt of lumateperone produced with naphthalene-2-sulfonic acid according to claim 48, characterised by that the formula (I) lumateperone base is reacted with naphthalene-2-sulfonic acid, preferably the amount of naphthalene-2-sulfonic acid used is a.) 0.7 to 1.2 times, preferably 0.9 to 1.1 times, even more preferably 0.95 to 1.05 times, most preferably in an equivalent amount to the molar amount of the lumateperone base for the preparation of the compound of the formula (X), or b.) 1.5 to 2.5 times, preferably 1.8 to 2.2 times, even more preferably 1.9 to 2.1 times, most preferably two times the molar amount of the lumateperone base for the preparation of the compound of the formula (VIII).

Description

BRIEF DESCRIPTION OF DRAWING

[0241] FIG. 1.) The x-ray powder diffractogram of the crystalline form of the formula (II) compound.

[0242] FIG. 2.) The x-ray powder diffractogram of the crystalline form of the formula (VI) salt.

[0243] FIG. 3.) The chiral HPLC chromatogram of the lumateperone base produced according to example 9 of the invention.

[0244] FIG. 4.) The chiral HPLC chromatogram of the lumateperone tosylate produced according to example 12 of the invention.

[0245] FIG. 5.) The x-ray powder diffractograms of the formula (III) amorphous salt produced according to example 13, where curve “A” is the XRD curve of the finished product after manufacture, while curve “B” shows the XRD curve, with displacement, after 3 months of storage at room temperature in a sealed vessel.

[0246] FIG. 6.) The XRD curve of the formula (II).Math.2HCl compound produced according to example 4.b. of the invention.

[0247] FIG. 7.) The x-ray powder diffractogram of the formula (VIII) salt produced according to example 14 of the invention.

[0248] FIG. 8.) The chiral HPLC chromatogram of the formula (VIII) salt produced according to example 14 of the invention.

[0249] FIG. 9.) The structural formulae of the starting materials, intermediates and products used in the methods according to the invention.

[0250] FIG. 10.) The x-ray powder diffractogram of the formula (IX) salt produced according to example 16 of the invention.

[0251] FIG. 11.) Illustrates Reaction Scheme 1.

[0252] FIG. 12.) Illustrates Reaction Scheme 2.

[0253] FIG. 13.) Illustrates Reaction Scheme 3.

[0254] The invention is presented via the following examples without restricting the scope of the patent application to these examples:

[0255] During the experiments the structures of the samples were confirmed with infrared (IR) spectra, with .sup.1H-NMR, .sup.13C-NMR measurements, and the crystal structure using x-ray powder diffractograms. The enantiomer purity was determined using chiral HPLC. The specific rotation of the intermediates and products confirmed to be pure was also determined. The rotation was measured using a Jasco P-2000 polarimeter. The melting points of the crystalline samples were determined using a Büchi B-540 melting point measurement device.

[0256] The IR-spectra were recorded using a Bruker Vector 22 FT spectrometer.

[0257] The .sup.1H-NMR and the .sup.13C-NMR recordings were made using Bruker Avance III HD and Bruker Avance III NMR devices.

TABLE-US-00007 The thermogravimetric measurement conditions Device TA Instruments Discovery TGA thermogravimetric analyser Atmosphere: flowing N.sub.2: 25 mL/min (furnace) 10 mL/min (balance) Sampling frequency: 0.5 seconds/point Temperature program: 30° C. - 250° C. 10° C./min Crucible: Platinum 100 .Math.L

TABLE-US-00008 Differential scanning calorimeter measurement conditions Device TA Instruments Discovery DSC differential scanning calorimeter Atmosphere: flowing N.sub.2 (50 mL/min) Sampling frequency: 0.1 seconds/point Temperature program: 30° C. - 230° C. 10° C./min Crucible: Standard Al closed

TABLE-US-00009 Differential scanning calorimeter (DSC) (conditions prevailing in the case of the testing of the formula III amorphous tosylate) Device TA Instruments Discovery DSC differential scanning calorimeter Atmosphere: flowing N.sub.2 (50 mL/min) Sampling frequency: 0.1 seconds/point Temperature program: 30° C. - 190° C. 10° C./min Crucible: Standard Al open

TABLE-US-00010 The x-ray powder recordings were made with the following instrument and measurement method 1.1 Device: PANalytical Empyrean X-ray powder diffractometer Measuring mode: Transmission X-ray tube Type: Empyrean Long Fine Focus High Resolution tube Anode: Cu Wavelength: Kα (1.541874 Å) Focus: line focus

TABLE-US-00011 Source side optical elements Divergence slit: Fixed slit ½ ° Mirror: Elliptical focussing mirror Soller slit: 0.04 rad Diffusion inhibitor slit: Fixed slit ½ °

TABLE-US-00012 Diffracted side optical elements Diffusion inhibitor slit: Programmable slit in fixed mode: ½ ° Soller slit: 0.04 rad

TABLE-US-00013 Sample table Type: Reflection-transmission, with rotatable sample holders Sample rotation speed: 1 rps Direct ray blocker (“beam knife”): Transmission

TABLE-US-00014 Detector Type: PIXcel 3D 1×1 area detector Detecting mode: Scanning line detector (1D) mode Active detector window size: 3.3473°

[0258] Sample preparation: The unpowdered samples are placed between two Mylar sheets.

TABLE-US-00015 Measurement conditions Temperature: room temperature Accelerating voltage: 45 kV Anode heating current: 40 mA Scanning mode: continuous (θ/θ) scanning Measurement range: 2.0000 - 34.9964 °2θ Step gap: 0.0131 °2θ Step duration: 109.650 s Number of measurement cycles: 1 Measurement time: ~20 min

[0259] Chiral HPLC method:

TABLE-US-00016 The methods used to test the formula (II) and (IV) compounds Device: Agilent 1100 Column: Lux Amylose-2.5 .Math.m, 150 mm × 4.6 mm Eluent: ethanol / ethanolamine = 100/0.1 Flow rate: 0.6 ml/min Temperature: 25° C. Detection: DAD 230 nm Retention times: II (6bR,10aS): 11.5 min, II/A (6bS,10aR): 6.0 min

[0260] The chiral HPLC method used to test the lumateperone and its salts (formula (I), (III) and (VIII) compounds):

TABLE-US-00017 Device: HP 1100 Column: Lux Amylose-2.5 .Math.m, 150 mm × 4.6 mm Eluent: ethanol / acetonitrile / diethylamine = 85/15/0.1 Flow rate: 0.3 ml/min Temperature: 25° C. Detection: DAD 232 nm Retention times: eutomer (6bR,10aS): 9.5 min, distomer (6bS,10aR): 11.0 min.

Example 1

The Formula (VI) Salt of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Formed with (+)-dibenzoyl-D-tartaric Acid Mono(dimethylamide)

[0261] ##STR00019##

34.40 g (150 mmol) formula (IV) cis racemate is dissolved in 100 ml methanol in a flask rinsed with argon. Over the course of approx. 1 minute a solution of (+)-dibenzoyl-D-tartaric acid mono(dimethylamide) (40.47 g, 105 mmol) made with 150 ml methanol is poured into the yellow solution stirred at room temperature. Crystallization starts from the bright yellow solution within a few minutes. The yellow suspension is stirred for a further 3 hours in an argon atmosphere at room temperature. The precipitated crystalline material is filtered, washed with methanol (80 ml) then dried at room temperature. The 43.65 g of yellow crystalline material obtained in this way is suspended in methanol (1200 ml) in an argon atmosphere and boiled. Further methanol (220 ml) is added until full dissolution. The hot solution is left to cool to room temperature, then stirred for a further 17 hours. The precipitated crystalline material is filtered, then washed with methanol (40 ml) and with ether (30 ml), in this way 31.98 g (35%, 69% calculated for the eutomer cis compound) formula (VI) compound is obtained. According to chiral HPLC measurement the product obtained contains 99.82% formula (VI) compound, 0.04% diastereomer salt and a further 3 contaminants (0.14% in total).

[0262] Mp: 203-207° C. (decomposes).

[0263] [α].sub.D.sup.25 = +28 (c = 0.40, methanol)

[0264] IR (KBr): 3583, 3420, 3066, 2617, 1720, 1672, 1652, 1111, 717 cm.sup.-1.

[0265] .sup.1H-NMR (DMSO-d.sub.6, 600 MHz): 9.38 (b, 2H), 7.97 (m, 2H), 7.97 (m, 2H), 7.66 (m, 1H), 7.64 (m, 1H), 7.53 (m, 2H), 7.52 (m, 2H), 6.55 (m, 1H), 6.39 (m, 1H), 6.38 (m, 1H), 6.10 (d, J=3.6 Hz, 1H), 5.49 (d, J=3.5 Hz, 1H), 3.43 (m, 1H), 3.34 (m, 1H), 3.28 (m, 1H), 3.17 (m, 1H), 3.17 (m, 1H), 3.16 (s, 3H), 3.08 (m, 1H), 3.07 (m, 1H), 2.83 (m, 1H), 2.79 (s, 3H), 2.79 (s, 3H), 2.63 (m, 1H), 2.41 (m, 1H), 1.99 (m, 1H), 1.92 (m, 1H) ppm.

[0266] .sup.13C-NMR (DMSO-d.sub.6, 150 MHz): 167.88; 166.32; 165.37; 165.31; 137.52; 135.32; 133.79; 133.35; 130.42; 129.54; 129.49; 128.97; 128.81; 127.64; 120.59; 112.56; 109.35; 72.77; 72.10; 62.88; 49.97; 44.48; 43.83; 38.85; 37.79; 37.20; 36.66; 35.62; 21.15 ppm.

Example 2

The Production of Lumateperone (I) From (VI)

(Method 1)

[0267] 6.15 g (10 mmol) formula (VI) compound is dissolved in 20 ml 5% NaOH solution and then the solution is extracted with toluene (20 ml, 2 × 15 ml). The unified toluene phase is dehydrated using azeotropic distillation. 3.01 g (15 mmol) 4-chloro-4′-fluoro butyrophenone, 5.86 ml (42.5 mmol) triethylamine and 2.49 g (15 mmol) dried potassium iodide is added to the 20 ml toluene solution obtained in this way. The reaction mixture is boiled for 14 hours in an argon atmosphere, then cooled and filtered. The filtrate is extracted with 10 ml water and 10 ml conc. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue to cleaned with flash chromatography on silica gel with a CH.sub.2Cl.sub.2—MeOH eluent. 2.68 g (68%) lumateperone (brown oil) is obtained.

[0268] [α].sub.D.sup.24 = -36,8 (c = 0.853, CHCl.sub.3).

[0269] IR (film): 1737, 1686, 1616, 1597, 1504, 1326, 1156 cm.sup.-1.

[0270] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.00 (~dd, J.sub.1= 5.5 Hz, J.sub.2= 8.9 Hz, 2H), 7.12 (~t, J = 8.7 Hz, 2H), 6.64 (m, 1H), 6.51 (m, 1H), 6.40 (m, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 3.26 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 2.98 (t, J= 7.2 Hz, 2H), 2.86 (s, 3H), 2.84 (m, 1H), 2.82 (m, 1H), 2.65 (m, 1H), 2.39 (m, 2H), 2.24 (m, 1H), 1.98 (m, 1H), 1.95 (m, 2H), 1.89 (m, 1H), 1.82 (m, 1H) ppm.

Example 3

The Production of Lumateperone (I) From (VI)

(Method 2)

[0271] 922 mg (1.5 mmol) formula (VI) salt is suspended in 20 ml toluene. 0.88 ml triethylamine (6.3 mmol), 0.375 g potassium iodide (2.25 mmol) and 0.45 g (2.25 mmol) 4-chloro-4′-fluoro butyrophenone is added to it. It is then boiled in an argon atmosphere for 14 hours, the cooled reaction mixture is filtered. The filtrate is extracted with 1 × 10 ml water and 1 × 10 ml saturated NaCl solution, dried on sodium sulphate, filtered and evaporated. The raw product obtained is cleaned using flash chromatography, 0.20 g (34%) lumateperone (brown oil) is obtained.

Example 4a

The Formula (II).Math.2HC1 Salt of Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline

[0272] ##STR00020##

18.44 g (30 mmol) formula (VI) salt is suspended in 180 ml ethyl acetate, then 53.5 ml 1.4 mol hydrochloric acid ethyl acetate solution (2.73 g HCl, 75 mmol) is added to the yellow suspension stirred in a 25° C. water bath in an argon atmosphere. Following this the suspension is stirred for 1 hour, in an argon atmosphere at room temperature. The precipitated product is filtered, washed with ethyl acetate (30 ml), dried in the air at room temperature for 1.5 hours, thereby 8.97 g (98.9%) bone coloured powder is obtained.

[0273] According to chiral HPLC measurement the product contains 99.83 % formula (II).Math.2HCl compound, 0.06 % (6bS,10aR) absolute configuration enantiomer and one further contaminant (0.12%).

[0274] .sup.1H-NMR (DMSO-d.sub.6, 600 MHz): 9.54 (b, 1H), 9.31 (b, 1H), 6.83 (b, 3H), 3.3-3.7 (bm, 6H), 3.17 (bm, 1H), 3.11 (bm, 1H), 2.95 (b, 4H), 2.58 (bm, 1H), 2.17 (bm, 2H) ppm.

Example 4b

The Production of the Formula (II).Math.2HCl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Dihydrochloride Salt From the Formula (II) Base

[0275] ##STR00021##

631 mg (2.75 mmol) enantiomer-pure base (II) is dissolved in 5 ml ethyl acetate, the airspace above the solution is rinsed with argon. 5.0 ml 1.4 M hydrochloric acid ethyl acetate (7 mmol HCl, 2.54 equiv.) is added drop by drop to the tape water-cooled, intensively stirred yellow solution. The precipitation of the product starts immediately. The thick off white suspension is stirred for 1 hour at room temperature in an argon atmosphere. The product is filtered, and washed with a little ethyl acetate (1.5 ml + 1 ml). After vacuum drying at room temperature 825 mg (99%) formula (II).Math.2HCl light grey crystalline dihydrochloride salt is obtained.

[0276] mp 199-203° C. (decomposes)

[0277] IR (KBr): 3058, 1964, 1420, 1128, 756 cm.sup.-1.

[0278] .sup.1H-NMR (DMSO-d.sub.6, 600 MHz): 9.54 (b, 1H), 9.31 (b, 1H), 6.83 (b, 3H), 3.3-3.7 (bm, 6H), 3.17 (bm, 1H), 3.11 (bm, 1H), 2.95 (b, 4H), 2.58 (bm, 1H), 2.17 (bm, 2H).

[0279] Element analysis: calculated C 55.64; H 7.00; N 13.90; Cl 23.46%; measured C 55.40; H 7.06; N 13.81; Cl 23.48%.

Example 5

The Production of Formula (I) Lumateperone From (II).Math.2HCl

[0280] 1.82 g (6.0 mmol) formula (II).Math.2HCl substance is suspended in 20 ml toluene, then 1.81 g (9.0 mmol) 4-chloro-4′-fluoro butyrophenone, 5.04 ml (36.1 mmol) triethylamine and 1.50 g (9.0 mmol) dried potassium iodide are added to it. The suspension reaction mixture is then boiled for 14 hours in an argon atmosphere. After cooling the reaction mixture is filtered and the filtered out solid material is washed with toluene. The organic phase is extracted with 20 ml water, then with 20 ml saturated NaCl solution, dried over MgSO.sub.4, filtered and evaporated. The raw product obtained is cleaned on silica gel using flash chromatography and dichloromethane eluent. 0.93 g (39%) formula (I) substance is obtained (light brown oil).

Example 6

The Production of Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Crystalline Base From the Formula (VI) Salt

[0281] ##STR00022##

Method A

[0282] 4 ml 5 m/m% aqueous sodium hydroxide solution (200 mg NaOH, 5 mmol) is added drop by drop to an aqueous suspension of 1.23 g (2.0 mmol) formula (VI) salt (10 ml). The alkaline yellow solution is extracted with 3 × 15 ml toluene. The combined organic phase is dried (Na.sub.2SO.sub.4), then evaporated until dry in a vacuum, thereby with quantitative yield the formula (II) compound is obtained. Mp: 79-81° C. (diisopropyl ether).

[0283] Chiral HPLC: 99.31% (II) + 0.08% (II/A) (+ 3 contaminants, total 0.61%)

Example 7

The Production of Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Crystalline Base From the Formula (VI) Salt

Method B

[0284] 4 ml 5 m/m% aqueous sodium hydroxide solution (200 mg NaOH, 5 mmol) is added drop by drop to an aqueous suspension of 1.23 g (2.0 mmol) formula (VI) salt (10 ml). The alkaline yellow solution is extracted with 3 × 15 ml ethyl acetate. The combined organic phase is dried (Na.sub.2SO.sub.4), then evaporated until dry in a vacuum, thereby with quantitative yield the formula (II) compound is obtained. Mp: 79-81° C. (diisopropyl ether).

Example 8

The Production of Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Crystalline Base From its Formula (II).Math.2HCl Salt

[0285] ##STR00023##

8.46 g (28 mmol) formula (II).Math.2HCl compound is dissolved in 40 ml distilled water and to the solution at 20° C. 27.5 ml concentrated aqueous ammonia solution (24.7 g 25 m/m% solutions, 6.19 g ammonia, 364 mmol) is added to it drop by drop over a few minutes. Precipitation occurs immediately. The oily product precipitating from the strong alkaline solution (pH > 12) is extracted with toluene (2 × 50 ml, then 30 ml). The combined toluene phases are evaporated in a vacuum. The residue is 6.95 g light brown oil, which crystalizes from diisopropyl ether (12 ml). In this way 4.86 g (76%) off-white crystalline material is obtained.

[0286] According to chiral HPLC measurement the product contains 99.85% formula (II) compound and a further two contaminants (a total of 0.15%). (6bS,10aR) absolute configuration enantiomer contamination (II/A) could not be detected.

[0287] Mp: 79-81° C.

[0288] [α].sub.D.sup.25 = -132 (c = 0.40, methanol).

[0289] IR (KBr): 3329, 1614, 1503, 1326, 730 cm.sup.-1.

[0290] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6.65 (m, 1H), 6.51 (m, 1H), 6.41 (m, 1H), 3.59 (m, 1H), 3.33 (m, 1H), 3.30 (m, 1H), 3.28 (m,1H), 3.06 (m, 1H), 3.01 (m, 1H), 2.87 (s, 3H), 2.84 (m, 1H), 2.83 (m, 2H), 2.64 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H) ppm.

[0291] .sup.13C-NMR (CDCl.sub.3, 100 MHz): 138.06; 134.98; 120.94; 120.13; 112.67; 108.80; 64.81; 50.59; 48.93; 44.07; 41.80; 41.78; 37.54; 25.70 ppm.

Example 9

The Production of the Formula (I) Lumateperone From the Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline

Method A

[0292] 4.58 g (20 mmol) formula (II) compound is dissolved in 50 ml toluene, to which 6.02 g (30 mmol) 4-chloro-4′-fluoro butyrophenone, 11.72 ml (84 mmol) triethylamine and 4.98 g (30 mmol) dried potassium iodide is added. The suspension reaction mixture is boiled for 14 hours in an argon atmosphere. After cooling it is filtered, and the filtered out solid substance is washed with toluene. The organic phase is extracted with 25 ml water, then with 25 ml saturated NaCl solution, dried on MgSO.sub.4, filtered and evaporated. The raw product obtained is cleaned on silica gel using flash chromatography using a dichloromethane-methanol eluent. 5.58 g (71%) formula (I) substance is obtained (light brown oil). The purity of the product measured with chiral HPLC is 99.41%, contaminants: distomer: 0.000%, other contaminants (3 contaminants): 0.10%; 0.16% and 0.32%. (FIG. 3)

Example 10

The Production of the Formula (I) Lumateperone From the Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline

Method B

[0293] 0.459 g (2.0 mmol) formula (II) compound is dissolved in 15 ml acetonitrile, then, to this, 1.303 g (4.0 mmol) caesium carbonate and 0.876 g (3.0 mmol) 4-iodo-4′-fluoro butyrophenone is added. The reaction mixture is stirred for 24 hours at room temperature. Then it is filtered and evaporated. The evaporation residue is dissolved in 20 ml dichloromethane and then extracted with 10 ml water, than with 10 ml saturated NaCl solution. The organic phase is dried on Na.sub.2SO.sub.4, filtered and evaporated. The 1.06 g raw product obtained is cleaned on silica gel with flash chromatography using CH.sub.2Cl.sub.2—MeOH as eluent. 0.66 g (84%) formula (I) compound is obtained (light brown oil).

Example 11

The Production of Formula (II) (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pirrolo[1,2,3-de]quinoxaline Crystalline Base From the Formula (IV) Racemic Cis Compound With a Two-Step Resolution Process

Step A

The Separation of the Formula (VI/A) L-DBMA Salt From the Formula (IV) Racemic Cis Compound

[0294] 2.29 g (10 mmol) cis racemate is dissolved in 12 ml methanol. A thin stream of a colourless solution of 2.70 g (7 mmol, 0.7 equiv.) (-)-dibenzoyl-L-tartaric acid mono(dimethylamide) (L-DBMA) made with 13 ml methanol is poured into the brownish solution stirred in an argon atmosphere in a 25° C. water bath, the Erlenmeyer flask is rinsed with a further 2 ml methanol. After 2 minutes the yellow solution starts to become cloudy, and after another 1 minute a thick yellow suspension is obtained, which is then stirred for 3 hours in an argon atmosphere at room temperature. The precipitated product is filtered, then washed with methanol (5 + 2.5 ml) and diethyl ether (2 × 3 ml). The raw product dries to constant weight in 1 hour in air.

[0295] The distomer raw product: 2.717 g light yellow powder, mp 210-213° C. (decomposes) (yield: 88.5%, theoretical yield: 3.07 g, 5 mmol)

[0296] chiral HPLC: 98.26% (VI/A) + 1.39% (VI) (+ 2 contaminants, total 0.35%)

Step B

The Purification Step of the Methanol Mother Liquor, in the Course of Which the Excess L-DBMA is Removed

[0297] The methanol mother liquor formed in the resolution step A is evaporated in a vacuum.

[0298] The 2.60 g oily residue is dissolved in 20 ml toluene, then the brown solution is washed with 10 ml 5 m/m% aqueous NaOH solution. The aqueous phase (pH = 14) is washed with 2 × 10 ml toluene, then the combined organic phases are evaporated in a vacuum. 1.48 g brown oily residue is obtained.

Step C

The Isolation of the Formula (VI) D-DBMA Salt From an Approx. 10:1 Ratio (II) / (II/A) Base Mixture

[0299] The 1.48 g oily extract obtained in step B (approx. 10:1 (II) / (II/A) isomer mixture) is dissolved in 6 ml methanol. A thin stream of a colourless solution of 1.93 g (5 mmol, appr. 0.91 equiv.) (+)-dibenzoyl-D-tartaric acid mono(dimethylamide) (D-DBMA) made with 8 ml methanol is poured into the brownish solution stirred in an argon atmosphere in a 25° C. water bath, with a further 2 ml methanol the residue is rinsed from the Erlenmeyer flask. The precipitation of the product starts immediately resulting in a thick yellow suspension, which is then stirred for 3 hours at room temperature in an argon atmosphere. The precipitated product is filtered, then washed with methanol (5 + 2.5 ml) and diethyl ether (2 × 3 ml). The raw product dries to constant weight in 10 minutes in air.

[0300] The formula (VI) raw product: 2.785 g light yellow powder, mp (192-) 204-207° C. (decomposes), (yield: 90.7 %) (theoretical yield: 3.07 g, 5 mmol)

[0301] chiral HPLC: 98.98 % (VI) + 0.71 % (VI/A) (+ 3 contaminants, total 0.31%)

[0302] 2.65 g eutomer raw product is recrystallized from 100 ml methanol in an argon atmosphere. The thin yellow suspension cooled to room temperature is stirred at room temperature in an argon atmosphere for 16 hours. The precipitated product is filtered, washed with methanol (5 + 3 ml), and then with diethyl ether (2 × 5 ml). The product dries to constant weight in 1 hour in the air.

[0303] The formula (VI) product: 1.837 g light yellow crystals, mp 203-209° C. (decomposes) chiral HPLC: 99.74% (VI) + 0.00 % distomer (VI/A) (+ 2 contaminants, total 0.26%)

Example 12

The Production of the Lumateperone (I) P-toluenesulfonic Acid Salt Polymorph “A”

[0304] ##STR00024##

The production of the lumateperone monotosylate salt (on the basis of WO2009/114181 patent example A2)

[0305] The 2.75 g (7.0 mmol) formula (I) lumateperone base produced according to example 9 is dissolved in 20 ml 2-propanol, then 1.20 g (6.3 mmol, 0.9 equiv.) p-toluenesulfonic acid monohydrate dissolved in 9 ml 2-propanol is added to this in one portion at room temperature in an argon atmosphere. If crystallization does not start even after 15 minutes, then the solution is seeded with the previously produced lumateperone monotosylate salt. After the crystals have precipitated the solution is stirred for another 24 hours at room temperature. (after 1-2 hours with filtration it was not usually possible to obtain 1:1 ratio tosylate salt.) After the one day of stirring the white crystalline material is filtered, washed with a little 2-propanol, then dried over P.sub.2O.sub.5 until constant weight at 40° C. 3.20 g white crystalline material is obtained, 78% yield. White crystalline substances, not a solvate and not a hydrate. Melting point 181-184° C. (2-propanol). [α].sub.D.sup.24 = -10.6 (c = 1.00, acetone). According to XRPD polymorph “A” (identified according to WO2009/114181 A2).

[0306] IR (KBr): 2611, 1687, 1598, 1508, 1325, 1228, 1159, 1010, 683 cm.sup.-1.

[0307] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 9.18/9.42 (b, 1H), 8.04 (~dd, J.sub.1=5.6 Hz, J.sub.2=8.8 Hz, 2H), 7.50 (~d, J= 8.1 Hz, 2H), 7.36 (~t, J=8.8 Hz, 2H), 7.11 (~d, J=8.0 Hz, 2H), 6.60 (m, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 3.58 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.40 (m, 1H), 3.33 (m, 1H), 3.31 (m, 1H), 3.20 (m, 1H), 3.12 (m, 2H), 3.11 (t, J= 7.0 Hz, 2H), 3.03 (m, 1H), 2.81 (s, 3H), 2.56 (m, 1H), 2.27 (s, 3H), 2.23 (m, 1H), 2.12 (m, 1H), 2.01 (m, 2H) ppm.

[0308] .sup.13C-NMR (DMSO-d.sub.6, 100 MHz): 197.36; 165.24 (d, J=251.6 Hz); 145.58; 138.00; 137.47; 135.37; 133.28 (d, J= 2.7 Hz); 131.07 (d, J= 9.5 Hz); 128.30; 126.92; 125.65; 120.76; 115.89 (d, J=22.0 Hz); 112.68; 109.52; 62.38; 55.73; 52.71; 49.97; 47.92; 43.91; 38.71; 37.17; 35.07; 21.85; 20.93; 18.19 ppm.

[0309] Element analysis: calculated C: 65.82%, H: 6.41 %, N: 7.43%, S: 5.64%. Measured C: 65.67%, H: 6.29%, N: 7.54%, S: 5.93%.

[0310] On the basis of chiral HPLC the desired enantiomer, no distomer contamination, HPLC purity: 99.76% (Chiral HPLC: FIG. 4)

Example 13

The Production of Lumateperone (I) P-Toluenesulfonic Acid Amorphous Salt

[0311] The 80 mg ITI-007 monotosylate produced according to example 12 is dissolved in a mixture of 250 ml water and 12.5 ml acetonitrile. The solution obtained was distributed among two 500 ml flasks, and then these were lyophilised. The content of the flasks was frozen using an acetone dry ice bath. Following this the two flasks were connected to the lyophilising device and the freeze drying was carried out at -80° C., at a pressure of 3.6 mbar until constant weight was achieved. A loose structured, white substance was obtained.

[0312] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 9.18/9.42 (b, 1H), 8.04 (~dd, J.sub.1=5.6 Hz, J.sub.2=8.8 Hz, 2H), 7.50 (~d, J= 8.1 Hz, 2H), 7.36 (~t, J=8.8 Hz, 2H), 7.11 (~d, J=8.0 Hz, 2H), 6.60 (m, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 3.58 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.40 (m, 1H), 3.33 (m, 1H), 3.31 (m, 1H), 3.20 (m, 1H), 3.12 (m, 2H), 3.11 (t, J= 7.0 Hz, 2H), 3.03 (m, 1H), 2.81 (s, 3H), 2.56 (m, 1H), 2.27 (s, 3H), 2.23 (m, 1H), 2.12 (m, 1H), 2.01 (m, 2H) ppm.

[0313] .sup.13C-NMR (DMSO-d.sub.6, 100 MHz): 197.36; 165.24 (d, J=251.6 Hz); 145.58; 138.00; 137.47; 135.37; 133.28 (d, J = 2.7 Hz); 131.07 (d, J = 9.5 Hz); 128.30; 126.92; 125.65; 120.76; 115.89 (d, J=22.0 Hz); 112.68; 109.52; 62.38; 55.73; 52.71; 49.97; 47.92; 43.91; 38.71; 37.17; 35.07; 21.85; 20.93; 18.19 ppm.

Example 14

The Formula (VIII) Salt of Lumateperone Formed With Naphthalene-2-sulfonic Acid, in Which the Molar Ratio of Lumateperone to Naphthalene-2-sulfonic Acid is 1:2

[0314] 1.5 g (3.81 mmol) of the formula (I) lumateperone base according to example 9 is dissolved in 12 ml acetone. The acetone solution of naphthalene-2-sulfonic acid monohydrate (1.726 g, 7.62 mmol) is prepared separately using 2 ml acetone. The acetone solution of naphthalene-2-sulfonic acid monohydrate is added drop by drop at room temperature to the lumateperone base solution in an argon atmosphere. A white crystalline substance precipitates. The suspension is stirred for 1 day at room temperature, then cooled in a ice and water bath, then the crystalline substance is filtered out. The product is then washed on the filter with a little cold acetone. The filtered lumateperone dinapsylate salt is dried until constant weight at 40° C., 2.5 g (83%). The raw product can be further purified using acetonitrile recrystallization (250 ml). 1.8 g (60%) white crystals, mp: 188-192° C. [α].sub.D.sup.25 = 4.4 (c = 1.00, DMF). HPLC purity: 99.628% (FIG. 8)

[0315] IR (KBr): 3006, 2621, 2400, 1678, 1599, 1482, 1237, 1167, 1086, 1026, 676 cm.sup.-1.

[0316] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 9.10 (b, 1H), 8.14 (bs, 2*1H), 8.04 (~dd, J.sub.1=5.6 Hz, J.sub.2= 8.8 Hz, 2H), 7.97 (m, 2*1H), 7.90 (m, 2*1H), 7.86 (d, J= 8.5 Hz, 2*1H), 7.71 (dd, J.sub.1= 1.7 Hz, J.sub.2 = 8.5 Hz, 2*1H), 7.53 (m, 2*1H), 7.51 (m, 2*1H), 7.37 (~t, J = 8.8 Hz, 2H), 6.61 (m, 1H), 6.53 (m, 1H), 6.44 (m, 1H), 3.60 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.45 (m, 1H), 3.41 (m, 1H), 3.35 (m, 1H), 3.33 (m, 1H), 3.23 (m, 1H), 3.13 (m, 2H), 3.11 (m, 1H), 3.08 (m, 1H), 3.03 (m, 1H), 2.81 (m, 3H), 2.70 (m, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 2.00 (m, 1H) ppm.

[0317] .sup.13C-NMR (DMSO-d.sub.6, 100 MHz): 197.37; 165.25 (d, J= 251.6 Hz); 145.74; 137.67w; 135.46w; 133.27 (d, J= 2.9 Hz); 132.90; 132.32; 131.06 (d, J= 9.5 Hz); 128.63; 127.63; 127.49; 127.12w; 126.61; 126.47; 124.21; 124.14; 120.87w; 115.92 (d, J= 22.0 Hz); 113.42w; 110.07w; 62.30; 55.72; 52.66; 50.07; 47.93; 43.74; 37.56w; 35.02; 21.88; 18.20 (w: weak) ppm.

[0318] COSY: 8.14-7.71-7.86, 8.04-7.37, 7.97-7.51-7.53-7.90, 6.53-6.61-6.44, (3.60, 2.57)-3.33-3.23-(2.26, 2.06)-(3.45, 3.03), (3.46, 3.35)-(3.41, 2.70), 3.13-(2.03, 2.00)-(3.11, 3.08).

[0319] HSQC (140 Hz): 8.14-124.21, 8.04-131.06, 7.97-128.63, 7.90-127.63, 7.86-127.49, 7.71-124.14, 7.53-126.61, 7.51-126.47, 7.37-115.92, 6.61-120.87, 6.53-113.42, 6.44-110.07, 3.60-52.66, 3.46-50.07, 3.45-47.93, 3.41-43.74,3.35-50.07, 3.33-38.81, 3.23-62.30, 3.13-35.02, 3.11-55.72, 3.08-55.72, 2.81-37.56, 2.70-43.74, 2.57-52.66, 2.26-21.88, 3.03-47.93, 2.06-21.88, 2.03-18.20, 2.00-18.20.

[0320] HMBC (140 Hz, 8 Hz): 8.14-(132.90, 128.63, 124.14), 8.04-(197.37, 165.25, 131.06), 7.97-(132.90, 126.61), 7.90-(132.32, 126.47), 7.86-(145.74, 132.32), 7.71-(132.90, 124.21), 7.53-(132.90, 128.63), 7.51-(132.32, 127.63), 7.37-(165.25, 133.27, 115.92), 6.61-135.46, 6.53-110.07, 6.44-137.67, 3.13-(197.37, 18.20), (3.11, 3.08)-18.20.

[0321] X-ray powder diffractogram: FIG. 7

The Thermal Characterisation of the Lumateperone Dinapsylate Salt (TG, DSC)

[0322] The crystalline form of the lumateperone dinapsylate salt may be characterised using thermoanalysis techniques. In the course of thermogravimetric testing (TG) a maximum of 0.2% mass loss may be observed in the course of heating up to 190° C., on the basis of which the crystalline form of lumateperone dinapsylate salt is a water and solvent-free form. In the course of differential scanning calorimetry testing (DSC) in the course of heating up to 200° C. an endothermic peak may be detected with an onset value around 189.0° C., and with a peak value of 192.2° C., on the basis of which the melting point of the crystalline form of lumateperone dinapsylate salt is around 189.0° C.

Example 15

The Formula (X) Salt of Lumateperone Formed With Naphthalene-2-sulfonic Acid, in Which the Molar Ratio of Lumateperone to Naphthalene-2-sulfonic Acid is 1:1

[0323] 1.00 g (2.54 mmol) formula (I) lumateperone base according to example 9 is dissolved in 6 ml acetone and in an argon atmosphere 0.575 g (2.54 mmol) naphthalene-2-sulfonic acid monohydrate is added to this in a single portion. The salt precipitates almost immediately after the acid has been dissolved. The suspension is stirred at room temperature for 24 hours, then cooled for 30 minutes in an ice and water bath. The salt is filtered using a glass filter, then washed with about 0.5 ml cold acetone. 1.10 g mononapsylate is obtained, which is purified further by recrystallization from 60 ml isopropanol. 0.92 g white crystalline product is obtained, mp: 165-172° C.

[0324] .sup.1HNMR (DMSO-d.sub.6, 400 MHz): 8.14 (d, J= 0.6 Hz, 1H), 8.04 (~dd, J.sub.1= 5.5 Hz, J.sub.2= 9.0 Hz, 2H), 7.97 (m, 1H), 7.90 (m, 1H), 7.86 (d, J= 8.6 Hz, 1H), 7.71 (dd, J.sub.1= 1.6 Hz, J.sub.2= 8.5 Hz, 1H), 7.52 (m, 2H), 7.37 (~t, J= 8.9 Hz, 2H), 6.60 (m, 1H), 6.52 (m, 1H), 6.43 (m, 1H), 3.60 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.41 (m, 1H), 3.32 (m, 1H), 3.31 (m, 1H), 3.23 (m, 1H), 3.12 (m, 2H), 3.10 (m, 1H), 3.08 (m, 1H), 3.03 (m, 1H), 2.81 (s, 3H), 2.71 (m, 1H), 2.57 (m, 1H), 2.25 (m,1H), 2.06 (m, 1H), 2.02 (m, 2H) ppm.

Example 16

The Production of the Formula (IX) Lumateperone P-toluenesulfonic Acid Salt, in Which the Molar Ratio of the Lumateperone and the p-toluenesulfonic Acid Is 1:2

[0325] ##STR00025##

[0326] 250 mg (0.636 mmol) lumateperone base is dissolved in 1.5 ml acetone, then 241.8 mg (1.271 mmol) p-toluenesulfonic acid monohydrate is added to this in an argon atmosphere. White crystals are formed approx. 1 minute after the p-toluenesulfonic acid has been dissolved. The reaction mixture is stirred at room temperature for 24 hours. Following this it is cooled to 0° C. and the white crystalline substance is filtered out, then washed with cold acetone. The product obtained is recrystallized from 21 ml 2-propanol and dried at 40° C. in a vacuum until constant weight. 270 mg of product is obtained, mp: 193-196° C. [α].sub.D.sup.25 = 5.0 (c = 1.00, DMF) Chiral HPLC: 99.56% (distomer contamination 0%)

Element Analysis

[0327] Calculated: C, 61.85; H, 6.01; N, 5.69; S, 8.69.

[0328] Measured: C, 61.68; H, 6.01; N, 5.69; S, 8.72.

[0329] IR (KBr): 3000, 2274, 1684, 1601, 1482, 1241, 1165, 1030, 1008, 683, 568 cm.sup.-1.

[0330] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 8.04 (~dd, J.sub.1= 5.6 Hz, J.sub.2= 8.8 Hz, 2H), 7.49 (~d, J= 8.1 Hz, 4H), 7.37 (-t, J= 8.8 Hz, 2H), 7.12 (~d, J= 7.9 Hz, 4H), 6.61 (b, 1H), 6.53 (b, 1H), 6.21 (b, 1H), 3.58 (m, 1H), 3.46 (m, 1H), 3.45 (m, 1H), 3.40 (m, 1H), 3.33 (m, 1H), 3.31 (m, 1H), 3.20 (m, 1H), 3.12 (m, 4H), 3.03 (m, 1H), 2.85 (b, 3H), 2.71 (m, 1H), 2.56 (m, 1H), 2.30 (m, 1H), 2.29 (s, 6H), 2.05 (m, 1H), 2.01 (m, 2H) ppm.

[0331] .sup.13C-NMR (DMSO-d.sub.6, 100 MHz): 197.38; 165.25 (d, J= 251.7 Hz); 145.60; 137.99; 137.82; 134.24; 133.29 (d, J= 2.8 Hz); 131.08 (d, J= 9.5 Hz); 128.30; 127.46; 125.67; 120.79; 115.92 (d, J= 21.8 Hz); 113.90; 110.75; 62.40; 5.74; 52.62; 50.26; 47.89; 43.43; 38.71; 37.95; 35.06; 21.86; 20.96; 18.19 ppm.