FIELD OF THE APPLICATION
The present application relates to novel acid addition salts of Lumateperone and processes for their preparation thereof. It further relates to crystalline forms including its solvates and hydrates of Lumateperone novel acid addition salts. The application further concerns pharmaceutical compositions comprising the novel acid addition salts of the Lumateperone, useful as 5-HT2 receptor agonists and antagonists in treatment of disorders of the central nervous system.
The drug compound is having the adopted name “Lumateperone” and it has chemical name: 1-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl] 1-Butanone; and a structure depicted by Formula I.

Formula I
International Patent Application Publication Nos. WO2000077002A1, WO2009145900A1 and WO2013155504A1 which are incorporated herein in their entirety reported Lumateperone and its related compounds. These compounds have been found to be useful as 5-HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including a disorder associated with 5HT2C or 5HT2A receptor modulation selected from obesity, anorexia, bulemia, depression, anxiety, psychosis, schizophrenia, migraine, obsessive-compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility. International Patent Application Publication No. WO2008112280A1 disclose process(es) for preparing Lumateperone and its salts.
International Patent Application Publication No. WO2009114181A2 disclose crystalline forms of the p-Tosylate salt of compound of Formula (I).
Use of a substance for pharmaceutical purposes places high demands on the substance quality. The most efficient purification operation is crystallization. In the case of preparation of substances in amorphous form it is very difficult to achieve internationally appreciated quality criteria defined by the ICH guidelines. In those cases purification by way of preparation of acid addition salts could be very useful which on neutralization will lead to substances with improved purity. Therefore, various Lumateperone salt forms could be used to enhance the purity of Lumateperone or its p-tosylate salt. Furthermore being a chiral molecule, preparation of chiral acid addition salts offer added advantage of resulting in resolution and/or improving the chiral purity of molecule.
Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. In addition, polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphic forms of the same pharmaceutically active moiety also differ in their physical properties such as melting point, solubility, etc.
Pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors are the sizes of the crystals, shape of the crystals, water content, residual solvents and impurities. Towards this end, it has been the endeavor of pharmaceutical scientists to provide novel salts and stable forms of drug substances, which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.
Therefore there remains a need to provide and characterize new Lumateperone salts and their polymorphs. Further, it would be desirable to have reliable processes for producing these Lumateperone salt forms.

SUMMARY
In the first embodiment, the present application provides novel acid addition salts of Lumateperone with acids selected from hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid.
In the second embodiment, the present application provides crystalline forms including hydrates or solvates of the acid addition salts of Lumateperone with acids selected from hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid.
In the third embodiment, the present application provides a process for the preparation of acid addition salts of Lumateperone, comprising:
a) providing a mixture of Lumateperone free base or its salt in a suitable solvent;
b) adding free acid or a source of anion to the mixture of step a);
c) isolating and recovering the salt of Lumateperone from the mixture of step b); and
d) optionally drying the resulting salt of Lumateperone.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising one of the acid addition salts of Lumateperone with acids selected from hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid; and one or more pharmaceutically acceptable excipients. These acid addition salts can be crystalline or amorphous in nature.

BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone hydrochloride prepared according to example 12.
FIG. 2 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone hydrobromide prepared according to example 13.
FIG. 3 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone citrate prepared according to example 14.
FIG. 4 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone phosphate prepared according to example 15.
FIG. 5 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone oxalate prepared according to example 16.
FIG. 6 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Lumateperone L-DPTTA prepared according to example 17.

DETAILED DESCRIPTION
In the first embodiment, the present application provides novel acid addition salts of Lumateperone with hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid.
In the second embodiment, the present application provides crystalline forms including hydrates or solvates of these novel acid addition salts of Lumateperone.
In yet preferred aspects of second embodiment, Lumateperone salts can be characterized by Figures provided therein. For example,
Lumateperone hydrochloride that can be characterized by its PXRD pattern, as illustrated in Figure 1.
Lumateperone hydrobromide that can be characterized by its PXRD pattern, as illustrated in Figure 2.
Lumateperone citrate that can be characterized by its PXRD pattern, as illustrated in Figure 3.
Lumateperone phosphate that can be characterized by its PXRD pattern, as illustrated in Figure 4.
Lumateperone oxalate that can be characterized by its PXRD pattern, as illustrated in Figure 5.
Lumateperone L-DPTTA that can be characterized by its PXRD pattern, as illustrated in Figure 6.
In the third embodiment, the present application provides a process for the preparation of acid addition salts of Lumateperone, comprising:
a) providing a mixture of Lumateperone free base or its salt in a suitable solvent;
b) adding free acid or a source of anion to the mixture of step a);
c) isolating and recovering the salt of Lumateperone from the mixture of step b); and
d) optionally drying the salt.
The mixture comprising Lumateperone free base or its salt in step a) may be a suspension or a solution. The mixture of step a) may be obtained, for example, by providing free base or a salt of Lumateperone of any form in a solvent. The said base or salt may be obtained by a previous step of the process which can be a final reaction and/or purification. If it is intended to obtain a clear solution of Lumateperone free base or its salt, the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the Lumateperone free base or its salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent.
If Lumateperone salt is employed in step a) as an input material then it will be different from the finally obtained Lumateperone salt of step c) and step d).
Solvents employed for preparation of salts of Lumateperone include, but are not limited to: alcohols, such as, for example, methanol, ethanol, or 2-propanol; esters, such as, for example, ethyl acetate, isopropyl acetate, or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, THF, or methyl THF; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, or the like; hydrocarbons, such as, for example, toluene, xylene, or cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like; water; or any mixtures thereof.
Appropriate solvents or non-solvents may be determined by solubility tests in various solvents.
Step b) involves addition of free acid or source of anion to the mixture of step a). The free acid employed could be inorganic or organic. Inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, phosphoric acid and like; and organic acids include but are not limited to citric acid, oxalic acid, di-para-tolyl tartaric acid and like. Source of anion employed in step b) could be inorganic salts or organic salts. Such salts include but are not limited to potassium phosphate, ammonium chloride, ammonium bromide, ammonium oxalate, ammonium citrate or the like. The source of anion or free acid can be directly added as solid/liquid or its mixture in a solvent can be employed. Suitable solvents are same as that employed in step a). Non-dissolved particles from a mixture of step b) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.
The acids are employed in salt preparation-depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired-in an equimolar quantitative ratio or one differing therefrom.
Thus, within the acid addition salts of this invention the acid and the free compound may be substantially in 1:1 stoichiometry or one differing therefrom, such as e.g. from about 1:2 to about 2:1 stoichiometry. Non-stoichiometric ratios may also be possible, such as e.g. 1:1.5 or 1.5:1.
The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for a time from about 10 minutes to about 5 hours or longer. Suitable temperatures for crystallization are from about 0°C to about 50°C, from about 10 to about 30°C, or any other temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.
Step c) involves isolation and recovery of Lumateperone salts from the reaction mixture. The isolation of salts of Lumateperone may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying including ATFD, freeze-drying, or the like. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique includes but is not limited to tray drying, spray drying, fluidized bed drying, thin film drying under reduced pressure, or thin film drying at atmospheric pressure. The recovery of salts of Lumateperone can be done by decantation, centrifugation, gravity filtration, suction filtration and like.
Particularly, crystalline forms may also be obtained by heating or melting a form obtained followed by gradual or fast cooling; in this manner one polymorph or one crystalline form may be converted to another.
The salts of the present invention if desired can be purified by re-crystallization from an appropriate re-crystallization solvent or mixture of solvents by methods customary to one of skill in the art. If required, the process further comprises, at a suitable stage, removing or separating any undesired material or impurities, and finally, optionally, the salts may be washed and/or dried.
The resulting solid may be optionally further dried. Drying may be suitably carried out by using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
Once obtained, crystals of Lumateperone salts may be used as the nucleating agent or “seed” crystals for subsequent crystallizations of salts of Lumateperone from solutions.
Salts of the present invention can be converted to another salts, e.g. by reaction with an appropriate acid or by means of a suitable ion exchanger. Likewise, salts obtained can be converted into the free compounds (e.g. via neutralization with a suitable base, with or without isolation of the free base, e.g. by extraction), which can in turn be converted into salts, by acidification. In this manner, formation of the selected Lumateperone salts of the application might be an efficient way of purifying Lumateperone free base and further, physiologically unacceptable salts can be converted into physiologically acceptable salts.
In a further aspect, the present invention relates to salts of the invention (including their solvates and hydrates) in solid forms, including amorphous, semi-amorphous, polymorphous, semi-crystalline and crystalline forms, as well as mixtures thereof. In a preferred aspect, salts of the present invention are Lumateperone hydrochloride, Lumateperone hydrobromide, Lumateperone phosphate, Lumateperone citrate, Lumateperone oxalate, Lumateperone di-para-tolyl tartrate as characterized by PXRD in Figures 1 to 6.
The solid form of Lumateperone salts of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
Lumateperone employed as a starting material for preparation of Lumateperone salt can be obtained by any processes known in the art, including processes disclosed in US7183282, US8309722 and US9315504 which are incorporated herein by reference in their entireties, as well as by other processes known in the art.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuK? radiation, having the wavelength 1.5406 Å and were obtained using a PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9?" means "having a diffraction peak at a diffraction angle (2?) of 7.7? to 8.1?”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
Optionally Lumateperone salts of the present invention can be subjected to particle size reduction by conventional techniques like jet-milling, micronization and like to obtain suitable particle size distribution. The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50, and D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising novel acid addition salts of Lumateperone and one or more pharmaceutically acceptable excipients.
Such further excipients and adjuvants are known to the person skilled in the art and may include one or more fillers; diluents, for example microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate, pregelatinized starch and the like; binders such as PVP, HPMC, HPC and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, peppermint, methyl salicylate, orange flavoring and the like; colorants; preservatives; buffers; and/or other excipients depending on the dosage form used.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
The pharmaceutical dosage form according to the present invention may be is coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation “MC” mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.
“Crystalline form” as used herein refers to a solid state wherein the crystalline content with in the said solid state is at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Where this document refers to a material, such as in this instance, Lumateperone acid addition salt, and their solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
As used herein, the term "room temperature" refers to a temperature of from about 20oC to about 35oC, from about 25oC to about 35oC, from about 25oC to about 30oC, or for example, about 25oC.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "polymer" or “carrier” or “excipient” as used herein interchangeably refers to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
As used herein, the terms "salt(s) of Lumateperone," "Lumateperone salt(s)" and other similar phrases encompass crystalline and amorphous forms, solvates, hydrates, stereoisomers, both individual and in mixtures thereof.

EXAMPLES
Example 1: Preparation of 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride
A flask was charged with 2-bromophenylhydrazine hydrochloride (500 g), isopropanol (1500 mL) at room temperature. To this mixture, piperidin-4-one hydrochloride (364 g) and Conc. Hydrochloric acid (500 mL) were added. The resulting mixture was stirred at ~80oC for overnight and reaction progress was monitored by TLC. The mixture was cooled to room temperature and resulting solid was filtered and washed with isopropanol (3x500 mL) followed by n-hexane (3x500 mL) followed by drying at 40-45oC for ~4 hours to afford the title compound.

Example 2: Preparation of 6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole
A flask was charged with 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (400 g) and trifluoroacetic acid (4800 mL). The reaction mixture was cooled to 15oC followed by drop-wise addition of triethyl silane (1018.9 g) at 15-20oC. The resulting mixture was stirred at room temperature for 19 hours and reaction progress was monitored by TLC. After completion of reaction, the mixture was concentrated and the resultant crude was slurried with hexane (4400 mL, 2000 mL). The resulting residue was basified with aqueous sodium hydroxide (2N, 5000 mL) to pH of about 10.0. The solid obtained was filtered and washed with water (1000mL). The obtained solid was dissolved in dichloromethane (6000 mL), dried over sodium sulfate followed by filtration and removal of solvent under reduced pressure to afford the title compound as brown solid.

Example 3: Preparation of (4aS,9bR)-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole
A flask was charged with 6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (320 g), methanol (3840 mL) and mixture was stirred at 50oC for 10 minutes followed by addition of S-(+)-Mandelic acid (201.95 g) and further maintenance for 10 minutes. Then diethyl ether (2880 mL) was drop-wise added to the above mixture at 50 oC. The mixture was cooled to room temperature and stirred for 24 hours at which point solid precipitated out. The obtained solid was filtered and washed with diethyl ether (640 mL). The solid was dissolved in water (640 mL) and pH was adjusted with 2N aqueous sodium hydroxide solution up to ~9.0 at below 20oC. The above mixture was extracted with dichloromethane (2 x 1280mL) and the combined organic layers after drying with sodium sulfate were concentrated under vacuum to afford the title compound as white solid.

Example 4: Preparation of ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate
A flask was charged with (4aS,9bR)-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (98 g), triethyl amine (47 g) and THF (980 mL) followed by cooling to 10oC. To this mixture, ethyl chloroformate (50.41 g) was added drop-wise at 10-15oC and then mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered through celite bed and washed with THF (2 x 245 mL). The filtrate was distilled off under reduced pressure at 50oC followed by addition of hexane (392 mL) to the crude and maintenance for 15 minutes. The solid was filtered and washed with hexane (98 mL) followed by drying at 40-45oC to afford the title compound as an off white solid.

Example 5: Preparation of ethyl (4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate
A flask was charged with (ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (117 g), 1,4-dioxane (585 mL), potassium iodide (89.59 g), diisopropylethyl amine (93 g), N-methyl chloro acetamide (32.74 g) at room temperature. The mixture was stirred at 100oC for 24 hours. After completion of reaction, the mixture was cooled to room temperature and poured into ice cold water (1000 mL). The aqueous solution was extracted with dichloromethane (2 x 1000 mL) and combined organic layers were washed with brine solution and then subjected to evaporation under reduced pressure at 45oC. Then hexane (468 mL) was added to the crude obtained and stirred for 15 minutes. The resulting solid was filtered and washed with 10% ethyl acetate-hexane (234 mL) to afford the title compound as an off white solid.

Example 6: Preparation of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate
A flask was charged with ethyl (4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (274.50 g), 1,4-dioxane (1372 mL), potassium carbonate (239.18 g), Cuprous iodide (65.96 g) and dimethyl ethylenediamine (91.59 g). The resulting mixture was stirred at 100oC for 36 hours followed by cooling of the mixture at room temperature, filtration through silica gel bed and washed with ethyl acetate (4x1000 mL). The filtrate was concentrated under reduced pressure at 50oC followed by addition of hexane (823 mL) to the crude compound and mixture was further stirred at room temperature for 20 minutes. The resulting compound was filtered and washed with hexane (2x274 mL) to afford the title compound as an off white solid.

Example 7: Preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate
A flask was charged with ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (194 g), THF (970 mL), Borane-THF complex in THF (132.16 g, 1537 mL). The mixture was stirred at 70oC for 3 hours. After completion of reaction, the mixture was cooled to 10oC followed by drop-wise addition of 6N HCl (1552 mL) to the reaction mixture at 10-15oC and further stirred for 15 minutes. The pH of the resulting mixture was adjusted with 2N sodium hydroxide up to ~9.0 and then extracted with ethyl acetate (2x1500 mL). The combined organic layers were washed with brine solution (1000 mL), and then organic layer was subjected to evaporation under reduced pressure at 45oC to afford the crude compound which was purified by column chromatography using 40% ethyl acetate-hexane to afford the title compound as pale yellow liquid.

Example 8: Preparation of (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline
A flask was charged with ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (152 g), n-butanol (912 mL) and potassium hydroxide (113.19 g). The mixture was stirred at 120oC for 16 hours. After completion of reaction, the mixture was cooled to room temperature and then cold water (1000 mL) was added to the mixture and desired compound was extracted with ethyl acetate (2x500 ml). The combined organic layers were washed with brine solution (500 mL), dried with sodium sulphate followed by evaporation under reduced pressure at 50oC to afford the title compound as brown color liquid.

Example 9: Preparation of Lumateperone free base
A flask was charged with (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (114 g), 3-pentanone (1140 mL), 4-chloro-1-(4-fluorophenyl)butan-1-one (149.61 g), potassium iodide (123.79 g), diisopropylethylamine (96.38 g) at room temperature. The reaction mixture was stirred at 100oC for 16 hours. After completion of reaction, the mixture was cooled to room temperature and poured into 5% aqueous sodium hydroxide solution (1140 mL). The mixture was extracted with ethyl acetate (2x1000 mL), the combined organic layers were filtered through silica gel bed and washed with ethyl acetate (2x500 mL). The filtrate was concentrated under reduced pressure at 50 oC, the resulting crude compound was dissolved in ethyl acetate (700 mL) and washed with 1.5N HCl solution (2x500 mL). The organic layer was discarded and the aqueous layer was cooled to 10oC. The pH of the aqueous layer was adjusted to ~9.0 at 10-15oC with 20% sodium hydroxide solution followed by extraction with ethyl acetate (2x800 mL), the combined organic layers were washed with brine solution (500 mL), dried with sodium sulphate and then subjected to concentration under reduced pressure at 50oC to afford the title compound as brown liquid.

Example 10: Preparation of Lumateperone p-tosylate
A flask was charged with Lumateperone (132.5 g), isopropanol (530 mL), charcoal (19.87 g) and mixture was stirred at room temperature for 30 minutes. Then it was filtered through celite bed and washed with isopropanol (265 mL). The filtrate was charged in another flask and p-toluene sulfonic acid monohydrate (56.34 g) was added in one portion at room temperature. The reaction mixture was cooled to 15oC followed by addition of heptane (795 mL) and further maintenance for 2 hours. The solid obtained was isolated by filtration and washed with n-heptane (265 mL). The crude solid was taken in acetone (2100 mL) and DCM (280 mL) and the mixture was stirred at room temperature for 10 minutes. Then heptane (4200 mL) was drop-wise added to the mixture at room temperature and stirred for 1hour. The solid obtained was filtered and washed with heptane (2x200 mL) followed by drying at 40oC for 2 hours to afford the title compound.

Example 11: Preparation of 2-chloro-N-methylacetamide
A flask was charged with 40% methylamine solution (611 mL), water (2800 mL) and then it was cooled to 0-5oC followed by drop-wise addition of 2-chloroacetyl chloride (200 g) and further stirring for 1hour at the same temperature. After completion of the reaction, the reaction mixture was extracted with DCM (6x1000mL) and the combined organic layers were concentrated under reduced pressure at 45oC to afford the title compound.

Example 12: Preparation of Lumateperone Hydrochloride
A flask was charged with Lumateperone (1 g), acetone (5 mL) and the mixture was cooled to 10oC. To this mixture, 4M HCl in dioxane (0.097g) was added at 10oC followed by addition of MTBE (10 mL). The mixture was stirred at room temperature for 16 hours followed by filtration of solid and washing with MTBE (5 mL). The solid was dried under vacuum for 2 hours to afford the title compound as pale brown solid, as depicted in Figure 1.

Example 13: Preparation of Lumateperone Hydrobromide
A flask was charged with Lumateperone (1 g), acetone (5 mL), 47% HBr solution (0.216 g) at room temperature. The mixture was stirred for 30 minutes followed by addition of MTBE (10 mL) and further stirring for 16 hours at the same temperature. The obtained solid is isolated by filtration and washed with MTBE (5 mL). The solid was dried under vacuum for 2 hours to afford the title compound as an off white solid, as depicted in Figure 2.

Example 14: Preparation of Lumateperone Citrate
A flask was charged with Lumateperone (0.5 g) and acetone (3 mL) at room temperature. To this mixture, a solution of citric acid in acetone (0.256 g in 3 mL) was drop-wise added and then the mixture was further maintained for 45 minutes. Then MTBE (5 mL) was added and the mixture was further stirred for 16 hours at room temperature. The obtained solid was isolated by filtration and washed with MTBE (5 mL), followed by drying under vacuum to afford the title compound as an off white solid, as depicted in Figure 3.

Example 15: Preparation of Lumateperone Phosphate
A flask was charged with Lumateperone (1 g) and ethyl acetate (5 mL) at room temperature. To this mixture, phosphoric acid (0.261 g) was added and mixture was heated to 60oC. Then mixture was stirred at 60-65oC for 30 minutes and then cooled to room temperature. Then MTBE (10 mL) was added and the mixture was further stirred for 16 hours at room temperature. The obtained solid was isolated by filtration and washed with MTBE (5 mL), followed by drying under vacuum to afford the title compound as a light brown solid, as depicted in Figure 4.

Example 16: Preparation of Lumateperone Oxalate
A flask was charged with Lumateperone (1 g) and ethyl acetate (5 mL) at room temperature. To this mixture, oxalic acid (0.24 g) was added and then the mixture was heated to 70-75oC. The mixture was stirred at the same temperature for 1hour and then cooled to room temperature. Then MTBE (10 mL) was added and the mixture was further stirred for 16 hours at room temperature. The obtained solid was isolated by filtration and washed with MTBE (5 mL), followed by drying under vacuum to afford the title compound as an off white solid, as depicted in Figure 5.

Example 17: Preparation of Lumateperone DPTTA
A flask was charged with Lumateperone free form (1 g) and methanol (10 mL) at room temperature. The mixture was heated to about 60oC followed by addition of Di-p-toluyl-L-tartaric acid (1.03 g). The mixture was stirred at the same temperature for 1hour and then cooled to room temperature. Then heptane (15 mL) was added and the mixture was further stirred for 24 hours at room temperature. The obtained solid was isolated by filtration and washed with heptane (5 mL), followed by drying under vacuum to afford the title compound as light brown solid, as depicted in Figure 6.
,CLAIMS:Claims

Claim 1: A process for preparation of pharmaceutically acceptable salt of Lumateperone selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid, the process comprising,
a) providing a mixture of Lumateperone free base or its salt in a suitable solvent;
b) adding free acid or a source of anion to the mixture of step a);
c) isolating and recovering the salt of Lumateperone from the mixture of step b); and
d) optionally drying the salt.
Claim 2: The process of claim 1, wherein the suitable solvent in step a) comprises is selected from alcohols, esters, ketones, hydrocarbons, water or mixtures thereof.

Claim 3: The process of claim 3 wherein suitable solvent in step a) is selected from C1-C5 alcohols like methanol, ethanol, isopropanol, ethyl acetate and acetone.

Claim 4: The process of claim 1, wherein isolation in step c) is done by crystallization, addition of suitable anti-solvent, cooling, evaporation and like.

Claim 5: The process of claim 4, wherein isolation is done by addition of suitable anti-solvent selected from the group consisting of ethers, hydrocarbons and thereof.

Claim 6: A pharmaceutical composition comprising acid addition salts of Lumateperone wherein the acids is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, oxalic acid and di-para-tolyl tartaric acid; and one or more pharmaceutically acceptable excipients.