DESC:FIELD OF THE INVENTION:
The present invention relates a novel process for the preparation lumateperone of formula I, pharmaceutically acceptable salts thereof via novel intermediates. Over and above that, the present invention relates to providing an economical and technically facile process for the preparation of lumateperone, pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:
Lumateperone (ITI-007; ITI-722) is approved as its tosylate salt for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy (with lithium or valproate). Lumateperone tosylate, sold under the brand name Caplyta, is an atypical antipsychotic medication of the butyrophenone class and it was developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb.

Lumateperone tosylate is chemically known as 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate (CAS Number: 1187020-80-9) and is structurally represented as below:

Lumateperone acts as a receptor antagonist of 5-HT2A receptor and antagonizes several dopamine receptors (D1, D2, and D4) with lower affinity. It has moderate serotonin transporter reuptake inhibition. It has additional off-target antagonism at alpha-1 receptors, without appreciable antimuscarinic or antihistaminergic properties, limiting side effects associated with other atypical antipsychotics.
After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 1–2 hours and has a terminal elimination half-life of 18 hours. Lumateperone is a substrate for numerous metabolic enzymes, including various glucuronosyltransferase (UGT) isoforms (UGT1A1, 1A4, and 2B15), aldo-keto reductase (AKR) isoforms (AKR1C1, 1B10, and 1C4), and cytochrome P450 (CYP) enzymes (CYP3A4, 2C8, and 1A2).

Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.

Lumateperone and related compounds have been first disclosed in US Patent Numbers 6,548,493; 7,238,690; 6,552,017; 6,713,471; USRE39,680, and USRE39,679.

US8648077 reported toluenesulfonic acid addition salt crystals of lumateperone. It also reports tosylate salt of lumateperone in solid form.
US8309722 disclosed a process for the preparation of lumateperone as follows:


SCHEME-1
The draw backs associated with the above process are that the final product is a brown liquid, hence it is tedious to isolate the lumateperone free base and the process is difficult to reproduce, less convenient to upscaling due to the involvement of multiple synthetic steps.

IN201911022605 disclosed a process for the preparation of lumateperone tosylate, as depicted below:


SCHEME-2

The draw back associated with the above process is the use of sodium cyanoborohydride for reduction. Sodium cyanoborohydride is hazardous, which liberates very toxic gas when reacts with acids and highly flammable gas when reacts with water. Hence, the above process is industrially not viable.
Thus, there is an unmet need of an improved industrially advantageous, cost effective as well as environment-friendly process for the preparation of lumateperone, pharmaceutically acceptable salts thereof.

Hence, the inventors of the present invention have developed an alternative improved process but yet simple, efficient and industrially advantageous for the preparation of lumateperone, pharmaceutically acceptable salts thereof with high yield and high purity by using novel intermediates.
The process of the present invention fulfills the above need and overcomes the prior-art disadvantages by avoiding the hazardous reagents.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide a novel process for the preparation of lumateperone, pharmaceutically acceptable salts thereof by using novel intermediates.
Another objective of the present invention is the preparation of novel intermediates and their further conversion into lumateperone, pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION:
In an embodiment the present invention provides a process for the preparation of lumateperone of formula I, pharmaceutically acceptable salts thereof,
,
which comprises:
(a) condensing compound of formula XII with compound of formula XIII to obtain a compound of formula X;
,
(b) reducing the compound of formula X to obtain a compound of formula IX;
,
(c) resoluting the compound of formula IX to obtain a compound of formula VIII;
,
(d) reacting the compound of formula VIII with protecting group to obtain a compound of formula VII;
,
(e) reducing the compound of formula VII to obtain a compound of formula VI;
,
(f) cyclizing the compound of formula VI to obtain a compound of formula V;
,
(g) reducing the compound of formula V to obtain compound of formula IV;
,
(h) de-protecting the compound of formula IV to obtain compound of formula III;
,
(i) coupling of compound of formula III with compound of formula XI to obtain compound of formula II;
,
(j) converting the compound of formula II to lumateperone of formula I;
,
(k) converting lumateperone of formula I to its pharmaceutically acceptable salts.

Another aspect of the present invention also provides novel intermediates to prepare lumateperone Tosylate are as follows:
.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include Di-p-toluoyl-D-tartaric acid [DPTTA], p-toluene sulfonic acid [PTSA], adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

One embodiment of the present invention relates to a novel process for the preparation of lumateperone, pharmaceutically acceptable salts thereof of formula I by using novel intermediates comprising the steps as below:
(a) condensing compound of formula XII with compound of formula XIII to obtain a compound of formula X;
(b) reducing the compound of formula X to obtain a compound of formula IX;
(c) resoluting the compound of formula IX to obtain a compound of formula VIII;
(d) reacting the compound of formula VIII with a protecting group to obtain a compound of formula VII;
(e) reducing the compound of formula VII to obtain a compound of formula VI;
(f) cyclizing the compound of formula VI to obtain a compound of formula V;
(g) reducing the compound of formula V to obtain compound of formula IV;
(h) de-protecting compound of formula IV to obtain compound of formula III;
(i) coupling the compound of formula III with compound of formula XI to obtain compound of formula II;
(j) converting compound of formula II to lumateperone of formula I;
(k) converting lumateperone of formula I to its pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, the present invention also provides novel intermediates to prepare lumateperone Tosylate are as follows:

.

Solvent used in the above reaction system include but is not limited to alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides, include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ester include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures there.

Condensing agent used in step (a) comprises, acids such as organic acid, inorganic acid but are not limited to acetic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid, hydrochloric acid, nitric acid, sulfuric acid, the like and mixtures there.

The suitable reducing agent used in step (b) comprises but is not limited to Palladium on carbon, Iron in HCl, Iron/NH4Cl, SnCl2, Sodium hydrosulfite, Titanium (III) chloride, Zinc/NH4Cl, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel, sodium borohydride, lithium aluminium hydride and the like.

Resolving agent used in step (c) comprises, but are not limited to (+)-tartaric acid, (-)-malic acid, (-)-mandelic acid and (+)-camphor-10-sulfonic acid and the like and mixtures there.

The suitable base used in the above reaction system comprises, inorganic base selected from but not restricted to alkaline or alkaline earth metal hydride, alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or mixtures thereof and organic base selected from but not restricted to sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride, lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethyl amine. methyl amine, diisopropyl methyl amine, diisopropyl ethyl amine, methyl amine, dimethyl amine

The suitable coupling agent used in step (i) comprises metal halides but are not limited to sodium iodide, sodium bromide, sodium chloride, potassium iodide, potassium bromide, potassium chloride, lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium iodide, calcium bromide, calcium chloride, copper iodide, copper bromide, copper chloride or mixture thereof; Dicyclohexylcarbodiimide/1-Hydroxybenzotriazole (DCC/HoBt), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium/N,N-diisopropylethylamine (HATU/DIPEA), Propylphosphonic anhydride/triethyl amine (T3P/TEA), 3-Dimethylamino-propyl)-ethyl-carbodiimide Hydrochloride (EDC.HCl) and the like.

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

CLAIMS:We claim

1. A process for the preparation of lumateperone of formula I, pharmaceutically acceptable salts thereof,
,
which comprises:
(a) condensing compound of formula XII with compound of formula XIII to obtain a compound of formula X;
,
(b) reducing the compound of formula X to obtain a compound of formula IX;
,
(c) resoluting the compound of formula IX to obtain a compound of formula VIII;
,
(d) reacting the compound of formula VIII with protecting group to obtain a compound of formula VII;
,
(e) reducing the compound of formula VII to obtain a compound of formula VI;
,
(f) cyclizing the compound of formula VI to obtain a compound of formula V;
,
(g) reducing the compound of formula V to obtain compound of formula IV;
,
(h) de-protecting the compound of formula IV to obtain compound of formula III;
,
(i) coupling of compound of formula III with compound of formula XI to obtain compound of formula II;
,
(j) converting the compound of formula II to lumateperone of formula I;
,
(k) converting lumateperone of formula I to its pharmaceutically acceptable salts by reaction of Lumateperone with p-Toluenesulfonic acid.

2. The process claimed in claim-1 step (a) comprising condensing agent selected form acid such as organic acid, inorganic acid but is not limited to acetic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid, hydrochloric acid, nitric acid, sulfuric acid, the like and mixtures thereof.

3. The process claimed in claim-1 step (b), (e), and (g) comprising reducing agent selected from but is not limited to Palladium on carbon, H2 (Pd/C, H2), Iron in HCl, Iron/NH4Cl, SnCl2, Sodium hydrosulfite, Titanium (III) chloride, Zinc/NH4Cl, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel, sodium borohydride, lithium aluminium hydride, the like and mixtures thereof.

4. The process claimed in claim-1 step (c) comprising resolving agent selected form but is not limited to (-)-mandelic acid, (+)-tartaric acid, (-)-malic acid, and (+)-camphor-10-sulfonic acid and the like and mixtures thereof in presence of suitable base includes but is not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and suitable solvent selected from C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol, the like and the mixtures thereof.

5. The process claimed in claim-1 step (d) comprising protecting agent ethyl chloroformate in presence of suitable base includes but is not limited to triethyl amine, sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride, lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, methyl amine, diisopropyl methyl amine, diisopropyl ethyl amine, methyl amine, dimethyl amine and the like and mixtures thereof, and suitable solvent includes but is not limited to tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, and the like and the mixtures therof.

6. The process claimed in claim-1 step (f) comprising cyclizing agent chloroacetaldehyde in presence of suitable base includes but is not restricted to triethyl amine, sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride, lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, methyl amine, diisopropyl methyl amine, diisopropyl ethyl amine, methyl amine, dimethyl amine and the like and mixtures thereof and suitable solvent includes but is not limited to from C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like.

7. The process claimed in claim-1 step (h) comprising de-protection using base includes but is not limited to potassium hydroxide, sodium hydroxide and suitable solvents includes but is not limited to n-butanol, Isopropanol, ethanol or methanol or mixture thereof.

8. The process claimed in claim-1 step (i) comprising coupling agent in metal halides but is not limited to sodium iodide, sodium bromide, sodium chloride, potassium iodide, potassium bromide, potassium chloride, lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium iodide, calcium bromide, calcium chloride, copper iodide, copper bromide, copper chloride or mixture thereof; dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HoBt), hexafluorophosphate azabenzotriazole tetramethyl uronium/N,N-diisopropylethylamine (HATU/DIPEA), propylphosphonic anhydride/triethyl amine (T3P/TEA), 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (EDC.HCl), the like and mixtures thereof.

9. The process claimed in claim-1 step (j) comprising preparation of Lumateperone by reaction of formula II with methyl iodide in presence of base includes but is not limited to alkaline earth metal hydride like sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride, lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, and solvent includes but is not limited to amides like dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, the like and the mixtures thereof.

10. A novel intermediates and pharmaceutically acceptable salt thereof are as follows,

.