PRIORITY:

This application claims the benefit of Indian complete application number 202221029766 dated 24/05/2022 and bearing title “A DEUTERATED AMINE COMPOUNDS AND PROCESS FOR SYNTHESIS THEREOF” the contents of which are incorporated herein by reference.

FIELD OF INVENTION:

The present invention relates to a process for synthesis of a deuterated compound. Most particularly, it relates to synthesis of a deuterated amine compounds of formula (I) and salts thereof. The said compound is an important key intermediate in the synthesis of deuterated drugs and/or chemical compounds.

BACKGROUND OF INVENTION:

Deuterium (deuterium), a stable isotope of hydrogen (H), also known as deuterium, is commonly denoted by the symbol D or 2H. The deuterium nucleus consists of one proton and one neutron, has twice the relative atomic weight of ordinary hydrogen, and has substantially the same shape and volume as hydrogen in a drug molecule. That is, hydrogen in the drug molecule is selectively replaced by deuterium, and the original biological activity and selectivity are generally retained.

Moreover, due to deuterium has very low toxicity. In recent years, several deuterated drugs have entered clinical trials and have been approved for use. Currently, there are two main routes for introducing deuterium into a compound: one is by proton exchange with hydrogen; and secondly, the synthesis is carried out by using deuterated raw materials. Deuterated methylamine and salt thereof as important key intermediates play significant roles in the preparation of deuterated drugs and pesticides.

Several deuterated methyl amine (CD3NH2) containing drugs have been undergoing Phase III clinical studies (Deucravacitinib- BMS-986165; Enzalutamide-d3- HC 1119; Donafenib- CM-4307). Recently FDA has approved Deucravacitinib- BMS-986165 to treat plaque psoriasis.

(Methyl-d3) amine is used during the preparation of sorafenib derivatives. However, the synthetic steps or the current preparation processes are relatively complex, or the cost is high.

US8748666B2 and EP2548859 discloses preparation methods of methyl- d3-amine and salts thereof. The said method involves the following steps: (i) nitromethane is subjected to react with deuterium oxide in the present of bases and phase-transfer catalysts to form nitromethane-d3, which is subsequently subjected to reduction in an inert solvent to form methyl-d3- amine, and optionally, methyl-d3-amine reacts subsequently with acids to form salts of methyl-d3-amine; or (ii) N-(1,1,1-trideuteriomethyl) phthalimide is subjected to react with acids to form salts of methyl-d3- amine.

CN111302951 describes N-deuterium methylamine compound and a preparation method thereof. The preparation method comprises the following steps: mixing an amine compound, a deuterium source and a photocatalyst, and carrying out a reaction in an inert gas atmosphere under a light source to obtain the N-deuterium methylamine compound. In the said preparation method, deuterium water and deuterated methanol are used as deuterium sources, the deuterated methanol is used as a deuterium methyl source. The photocatalyst is selected from Pd/PCN, Pt/PCN, Au/PCN, Pd/TiO ₂ , Pt/TiO ₂ , Au/TiO ₂ , Pd/ZnCdS, Pt/ZnCdS or Au/ZnCdS.

Current manufacturing process of deuterated methylamine HCI has the following issues (a) Isotopic enrichment; (b) workup and isolation; and (c) not cost effective

Therefore, it is urgently needed to develop a simple, efficient and inexpensive method for preparing deuterated methylamine salt.

OBJECTS OF INVENTION

One of the objects of the present invention is to provide a process for synthesis of methyl amine compound, specially deuterated methyl amine compound.

Another object of the present invention is to provide deuterated methylamine as a key starting material that can be used in the synthesis of deuterated drugs and chemicals.

Anther embodiment of the present invention is to provide a process for synthesis deuterated methyl amine salts.

Yet another embodiment of the present invention is to provide a process for synthesis of deuterated methyl amine, wherein the said process can be carried out in minimum steps with higher yield.

Yet another embodiment of the present invention is to provide easy, high efficient, and low cost process for synthesis of deuterated methyl amine. SUMMARY OF INVENTION

One of the aspects of the present invention is to provide a deuterated amine compound represented by formula (I)

Wherein R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl.

Another aspect of the present invention is to provide a process for synthesis of deuterated amine compounds of formula (I), the process comprising the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D) respectively; and b) treating the compound of formula (C) or formula (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art.

The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

It must also be noted that as used herein, the singular forms "a", "an," and "the" include plural references unless the context clearly dictates otherwise. Although any systems and methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred, systems are now described.

The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

The term “including” is used to mean “including but not limited to”. The terms “Including” and “including but not limited to” are used interchangeably.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.

Detailed embodiments of the present invention are disclosed herein, however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific functional and structural details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure.

The term “compound” used herein, is also intended to include any salts, solvates, or hydrates thereof. Thus, it is to be understood that when any compound is referred to herein by name and structure, salts, solvates, and hydrates thereof are included.

The term “solvent” used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).

The term ‘desired reaction conditions’ used herein refers to the conditions that may be applied to synthesis of product. The reaction conditions includes such as but not limited to temperature, pressure, time, concentration of reactants, the physical state of reactants and their dispersion, the solvent, and the presence of a catalyst.

One of the embodiments of the present invention provides a deuterated amine compound represented by formula (I)

Wherein R is selected from deuterated C1-C10 alkyl and C1-C20 aryl, wherein the alkyl and aryl optionally substituted with halo, -OH, aryl and alkyl; and

X is OMs, OTf, OTs, ONs or halogen selected from fluorine, chlorine, bromine, and iodine.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), the process comprises the steps of: a) reacting a compound of formula (A) or formula (B) with a compound of formula (b) (R-X) at desired reaction conditions in a solvent to obtain a compound of formula (C) or formula (D); and b) treating the compound of formula (C) or (D) obtained from step (a) with an acid at desired reaction conditions in a solvent to obtain a salt of the compound of formula (I).

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (A) is represented by: wherein R in the compound of formula (I) is alkyl, tolyl or aryl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (A) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (B) is represented by: wherein R is alkyl, tolyl or aryl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl group (R) in the compound of formula (B) may be selected from methyl, ethyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-propyl, iso-propyl, pentyl, isopentyl, neopentyl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) is represented by R-X, wherein R is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group; and X is any leaving group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein X group in the compound of formula (b) (R-X) including but not limited to OMs, OTf, OTs, ONs or halogen.

Yet another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the halogen in the compound of formula (b) (R-X) is selected from the group consisting of fluorine, chlorine, bromine, and iodine.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (C) is represented by formula wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; wherein the alkyl group (R) in the compound of formula (C) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated pentyl, deuterated isopentyl, deuterated neopentyl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (D) is represented by formula wherein R in the compound of formula (C) is alkyl, tolyl or aryl group; and wherein R group in the compound of formula (D) is selected from methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, secondary butyl, tertiary butyl, n- pentyl, isopentyl, neopentyl; and deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated iso-propyl, deuterated butyl, deuterated isobutyl, deuterated secondary butyl, deuterated tertiary butyl, deuterated n-pentyl, deuterated isopentyl, deuterated neopentyl group.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated amine compounds of formula (I) are deuterated aliphatic amines and/or aromatic amines, preferably deuterated methyl amine (D3C-NH2.HX). Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the acid can be organic and/or inorganic acid.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic or camphorsulphonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid).

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the alkyl halide (R-X) is deuterated alkyl halide.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the deuterated alkyl halide (R-X) is selected from deuterated methyl iodide, deuterated methyl chloride, deuterated methyl bromide and deuterated methyl fluoride.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (A) or formula (B) including but not limited to t-butylsulfinamide, t-butylsulfonamide, p-toluenesulfinamide and p-toluenesulfonamide.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the compound of formula (b) (R-X) including but not limited to methyliodide-D3 methanol-d4 containing leaving groups like methylbromide-d3, methylchloride-d3, CD3OTs, CD3OMs, CD3OTf, CD3ONs.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein methanol-d4 can also be directly coupled with t-butylsulfinamide using Mitsunobu reaction (PPh3, DEAD or PPh3, DIAD).

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base including such as but not limited to organic and inorganic bases.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the base may be selected from inorganic base including but not limited to sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; and wherein the base is selected from organic base including such as but not limited to pyridine, triethyl amine, dimethyl amino pyridine, diethyl amine.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be polar or nonpolar solvent and/or deuterated polar or non-polar solvents. The solvent including but not limited to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein salt of deuterated amine compound of formula (I) may be prepared by adding HCI gas in an organic solvent.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the solvent used in the present invention can be deuterated solvents.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compound of formula (I), wherein the deuterated amine compound of formula (I) can be further purified or recrystallized by known conventional methods.

Another embodiment of the present invention provides a process for synthesis of deuterated amine compounds of formula (I), wherein the said amine compounds can be used as intermediate in the synthesis of drug compounds and/or chemical compounds.

The details of the present invention are provided in the examples given below to illustrate the invention only and therefore they should not be construed to limit the scope of invention.

EXAMPLES

I. Synthesis of compound of formula (C) or formula (D): To a 100 mL three neck RB flask were added 2 g of t-butylsulfinamide, 10 mL of THF and 2.78g of powdered KOH, cooled the reaction mass to - 10°C using ice salt and stirred for 15 min, then added 3.12g of CD3I drop wise, and stirred at same temperature for 2h, quench the reaction with 10 ml of water and extracted with chloroform for three times, the combined organic layer dried over sodium sulphate, and evaporated under reduced pressure, the crude reaction mass directly used for the next step without further purification 2.1g Mass: 139 (M+1).

II. Synthesis of deuterated methyl amine hydrochloride (compound of formula I):

To a 25 mL RB flask was added 2.1g of compound of example I (step-1), 5 mL of IPA and 3 mL of 6M-IPA.HCI at room temperature, stirred the reaction mass at room temperature for 1h, filtered the solid and recrystallized using chloroform and Ethanol to obtain 0.5g of pure Methyl- D3 Amine Hydrochloride, 43% overall yield after two steps (Chemical purity: 100% by ELSD, D%:99.89% by Q-NMR) 13C NMR: 23.412 (septet, 21.58Hz).