DESC:FIELD OF THE INVENTION
The present application provides improved process for the preparation of 3-aminopiperidine-2,6-dione hydrochloride in high yields and purity and suitable for manufacturing in commercial scale which is a potential intermediate involved in the preparation of Lenalidomide and pomalidomide.

BACKGROUND OF THE INVENTION
Lenalidomide chemically is a non-polypeptide compound which decrease the levels of TNF (alpha). Lenalidomide, a thalidomide analogue, was initially intended for use as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but it has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes (MDS). The exact mechanism of the immunomodulatory drugs (e.g. thalidomide, CC-4047/actimid and lenalidomide) is not known.
Lenalidomide was approved by the U.S. Food and Drug Administration on December 27, 2005, for treating patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. The drug is commercially marketed in products sold by Celgene Corporation under the brand name REVLIMID™ in the form of capsules having the strengths 5 mg, 10 mg, 15 mg, and 25 mg. It also plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrocystic reaction. Lenalidomide inhibits tumour angiogenesis, tumour secreted cytokines and tumour proliferation through the induction of apoptosis. Lenalidomide has also shown efficacy in the class of haematological disorders known as myelodysplasia syndromes (MDS), and whose chemical structure is the following.

Several processes have been discussed in the literature for the preparation of Lenalidomide and their pharmaceutically acceptable salts, which are disclosed in US5635517A, WO2009114601 A2, WO2010056384A1, WO2011027326A1, WO2013005229A1, US8946265B2, WO2010100476A1, CN107337667A, IN201641022825A, WO2019227968A1, CN111196800 A, WO2021036922 A1 and WO2022144924 A1.

Pomalidomide (Pomalyst) is a thalidomide analogue used for the treatment of multiple myeloma, and AIDS-related and HIV-negative Kaposi sarcoma. Pomalidomide can be used in combination with almost all existing antimyeloma drugs because of its favourable safety profile, and whose chemical structure is the following.

Several processes have been discussed in the literature for the preparation of pomalidomide and their pharmaceutically acceptable salts, which are disclosed in WO9803502 A1, WO2002064083A2, US20070004920A1, WO2012149299A2, WO2012177678A2, CN103497174A, WO2014018866A1, WO2017134476A1, IN201641021533A, IN201641022827A, WO2018154516A1, WO2022092774A1.
Several synthetic methods have been reported in the literature to prepare 3-aminopiperidine-2,6-dione hydrochloride compound of formula (I)
(I)
WO2006/028964 describes processes for the preparation of substituted 2-(2,6-dioxopiperidin3-yl)-l-oxo-isoindolines. The process described therein for preparing lenalidomide involves the preparation of the nitro intermediate by first coupling of an L-glutamine methyl ester withmethyl 2-bromomethyl-3-nitro-benzoate in acetonitrile and cyclising the resultant N-(l-oxo-4-nitro-isoindol-2-yl)-L-glutamine methyl ester. The nitro compound is then hydrogenated with10% Pd/C catalyst in methanol at 50 psi of hydrogen. The solid was slurried in hot ethyl acetate and dried, resulting in a yield of 51% lenalidomide.
IN47/CHE/2006 discloses a process for the preparation of lenalidomide comprising hydrogenating 3-(4-Nitro-l-oxo-l,3-dihydro-2/7-isoindol-2-yl)piperidine-2,6-dione using 10% Pd on carbon in a mixture of solvents comprising methanol and N,N-dimethylformamide. This publication also discloses a process for the preparation of a-amino glutarimide hydrochloride, However, in the above process product obtained with less purity and very low yields.
WO2009/114601 discloses a process for the preparation of lenalidomide comprising hydrogenating 3-(4-Nitro-l-oxo-l,3-dihydro-2//-isoindol-2-yl)piperidine-2,6-dione using 10% Pd on carbon in the presence of an acid and solvent mixture. However, this process is very lengthy and the product yield is also very low.
WO2005028436A2 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

WO2010056344A1 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN109305935A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

CN111675648A discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, extreme reaction conditions invariably resulting in the formation of low pure intermediates. Accordingly, there remains a need for the industrial preparation of substantially pure 3-aminopiperidine-2,6-dione hydrochloride which is free of impurities with high yield. Therefore, still there is need for the development of commercially viable, cost-effective process for the preparation of lenalidomide and pomalidomide intermediate of a compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, cost-effective, and industrially feasible process for the preparation of substantially pure 3-aminopiperidine-2,6-dione hydrochloride a potential intermediate of Lenalidomide and pomalidomide.

SUMMARY OF THE INVENTION
The improved process for the preparation of substantially pure 3-aminopiperidine-2,6-dione hydrochloride disclosed herein has the following advantages over the processes described in the prior arts:
i) Prior art applications process involves expensive reagents, especially in deprotection of Cbz, disclosed expensive reagent/catalyst like Pd/C with hydrogen pressure reactor;
ii) using pyrophoric reagent i.e., Pd/C filtering and concentrating is involving tedious workup to get free amine residue;
iii) the present invention provides significantly improved, cost-effective process which is simple and eco-friendly process for deprotection of Cbz by using very cheap acids like formic acid, acetic acid, hydrochloric acid and hydrobromic acid;
iv) intramolecular cyclization reaction with CDI in acetone solvent dilutions significantly enhances the reaction and at lower temperature leads to high yield and high quality;
v) using mixture of strong alkali hydroxides and weak carbonate bases improves the reactivity benzyl chloroformate in protection reaction;
vi) the present invention provides not only eco-friendly commercial adoptable but also provides high yield with high pure compound with any impurities not more than 0.1 %;
vii) reactions carried out at low temperatures reduced additional energy;
viii) acetone has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
ix) solvent recovery is a form of waste reduction eco-friendly and alternative to improving the greenness of industrial processes and which makes the process economic cost effective and environment friendly.
The present invention provides a process for preparation of 3-aminopiperidine-2,6-dione hydrochloride compounds which is faster and cost-effective and the overall yield of the product is increased also it is substantially pure.
The present invention provides an improved process for the preparation of substantially pure 3-aminopiperidine-2,6-dione hydrochloride a Lenalidomide and pomalidomide intermediate compound of formula (I).

Formula (I)
In an aspect of the present application provides process for preparation of a compound of formula (I)

Formula (I)
a) L-Glutamine reacts with benzyl chloroformate in presence of a mixture of strong alkali hydroxide and weak carbonate or bicarbonate base in an aqueous medium gives ((benzyloxy)carbonyl)-L-glutamine compound of formula (II);

Formula (II)
b) compound of formula (II) undergoes intramolecular cyclodehydration reaction in presence of suitable dehydrating agent in appropriate solvent gives compound of formula (III);

Formula (III)
c) compound of formula (III) undergoes Cbz deprotection reaction in presence of acidic medium gives compound of formula (I);

d) optionally purifying the compound of formula (I) in a suitable solvent and the % of any impurity is not more than 0.1%.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indicates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.

All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.

It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.

In one embodiment the present invention particularly describes improved process for the preparation of substantially pure 3-aminopiperidine-2,6-dione hydrochloride a lenalidomide and pomalidomide intermediate compound of formula (I).
In one embodiment the following Scheme-1 describes the process for the preparation of 3-aminopiperidine-2,6-dione hydrochloride compound of formula (I)

Scheme 1
In one embodiment, stage (a) of the present process Cbz protection carried out in presence of hydroxy strong base for benzyl chloroformate protection reaction is selected from sodium hydroxide, potassium hydroxide, barium hydroxide caesium hydroxide, strontium hydroxide, rubidium hydroxide, calcium hydroxide and weak carbonate base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or mixture thereof in water to give compound of formula (II);
In another embodiment, stage (b) of the present process involves cyclization in presence of N, N'-Carbonyl diimidazole, Di cyclohexyl carbodiimide, N-(3-dimethylaminopropyl)-N-ethyl carbodiimide in suitable solvents gives compound of formula (III); wherein solvent is selected from toluene, acetone, xylene, benzene, dioxane gives compound of formula (III);
In another embodiment, stage (c) of the present process involves compound of formula (III) undergoes deprotection reaction in presence of acidic medium gives compound of formula (I); wherein acid is selected from formic acid, trifluoracetic acid, methane sulphonic acid, acetic acid, propanoic acid, butanoic acid, pentatonic acid hydrochloric acid, hydrobromic acid more preferably formic acid, hydrochloric acid, hydrobromic acid or mixture thereof;
In certain embodiment, the compound of formula (I) optionally purifying in a suitable solvent.
In specific embodiment, the process for the preparation of 3-aminopiperidine-2,6-dione hydrochloride compound of formula (I);

Formula (I)
which comprises
compound of formula (III) undergoes deprotection reaction in presence of acidic medium gives compound of formula (I); wherein acid is selected from formic acid, trifluoracetic acid, methane sulphonic acid, acetic acid, propanoic acid, butanoic acid, pentatonic acid hydrochloric acid, hydrobromic acid more preferably formic acid, hydrochloric acid, hydrobromic acid or mixture thereof; wherein the solvents are selected from methanol, ethanol, isopropyl alcohol, tert-butanol, dichloroethane, isopropyl acetate, ethyl acetate, acetonitrile, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, toluene or mixture thereof to form compound of formula (I).
In one embodiment, the reaction duration employed in the process of deprotection is carried in presence acids selected from formic acid, hydrochloric acid, acetic acid, hydrobromic acid, or mixture thereof to afford said compound of formula (I).
In one embodiment the solvent for coupling reaction is selected from acetone or mixture thereof to afford said compound of formula (III).
In another embodiment, the base for protection reaction is selected from sodium carbonate, sodium hydroxide, sodium carbonate and sodium hydroxide or mixture thereof to afford said compound of formula (II).
In further embodiment, acid for deprotection reaction is selected from formic acid, acetic acid, hydrochloric acid, hydrobromic acid, trifluoracetic acid, methane sulphonic acid, propanoic acid, butanoic acid, pentatonic acid or mixture thereof.
In specific embodiment, the said acid for Cbz deprotection reaction is selected from formic acid, acetic acid and hydrochloric acid or mixture thereof.
In another embodiment, The process as claimed in claim 1, the % of any impurity is not more than 0.1%.
In further specific embodiment, the solvent for purification is selected form ethyl acetate, isopropyl acetate, iso propyl alcohol, methanol, ethanol. territory butanol, toluene, acetone, dioxane or mixture thereof.
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
In an embodiment, the below are the abbreviations are used in the specification.
CDI- 1,1' Carbonyldiimidazole, HCOOH-formic acid, HCl- Hydrochloric acid, AcOH-acetic acid, DCM-Dichloromethane, TEA- Triethyl amine, DIPEA- Di isopropyl ethylamine, KOH-Potassium hydroxide, NaOH- Sodium Hydroxide, Na2CO3-Sodium Carbonate, NaH-Sodium hydride, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography Oleum- sulphur trioxide in sulfuric acid, THF-Tetrahydrofuran, 2-Methyl-THF- 2-Methyltetrahydrofuran, MDC- Methylene Dichloride, H2SO4- sulfuric acid, , MeOH- Methanol, EtOAc-Ethyl acetate, H2O-Water, ACN-acetonitrile, Monoglyme-Dimethoxyethane , Diglyme- 1-Methoxy-2-(2-methoxyethoxy)ethane, ND-not detected, SM-starting material and SMI-Single maximum impurity.

EXAMPLES
Example-1: Synthesis of ((benzyloxy)carbonyl)-L-glutamine

To a 1000 ml round bottom flask Charge 500 ml of water, 100 g of L-glutamine 50 ml of sodium hydroxide solution. The mixture is stirred until dissolved. Then cool to a temperature of 5°C for 60 minutes. After stirring charge sodium carbonate 100.0gm and then add 530.0mlof benzylchloroformate. Upon completion, slowly raise temperature up to 25-30°C and adjust the pH reaction mass in the region of 1-3. The precipitated product was filtered and dried to get the title product of 180.0gm (93.5%) with HPLC purity: 99.4%
Example-2: Synthesis of Benzyl (2,6-dioxopiperidin-3-yl)carbamate

100.0g of ((benzyloxy)carbonyl)-L-glutamine and 200ml of acetone to the reaction flask, stir for10 minutes, then add 160.0g of N,N'-carbonyldiimidazole, after the addition reaction mass temperature raise to reflux temperature and stir for completion of reaction After the reaction was completed, after cooling, it was rotary evaporated to dryness at a bath temperature of 40°C. Charge 100ml of water was added to the residue and stirred for 2 hours, filtered and washed with an appropriate amount of water, and dried to obtain 88.0g of white powder with a purity of, 99.8%, yield 94.2%
Example-3: Synthesis of 3-aminopiperidine-2, 6-dione hydrochloride.

100.0g of Benzyl (2,6-dioxopiperidin-3-yl) carbamate charged into the formic acid(400.0ml) under nitrogen atmosphere. The reaction mass cooled and purge the HCl gas and maintain the reaction up to completion by analytical method of HPLC. After completion of reaction mass charge Methanol and cool to 0-5°C and filter the reaction mass then dried to get the Tittle compound of yield 95.1%, purity 99.9%.
,CLAIMS:1. A process for preparation of a compound of formula (I), or a salt thereof

Formula (I)
which comprises
a) L-Glutamine reacts with benzyl chloroformate in presence of a mixture of strong alkali hydroxide and weak carbonate or bicarbonate base in an aqueous medium gives ((benzyloxy)carbonyl)-L-glutamine compound of formula (II);

Formula (II)
b) compound of formula (II) undergoes intramolecular cyclization reaction in presence of suitable dehydrating agent in appropriate solvent gives compound of formula (III);

Formula (III)
c) compound of formula (III) undergoes Cbz deprotection reaction in presence of acidic medium gives compound of formula (I);

d) optionally purifying the compound of formula (I) in a suitable solvent and any impurity is not more than 0.1%.
2. A process for the preparation of compound of formula (I), or a salt thereof

formula (I)
which comprises:
compound of formula (III) undergoes Cbz deprotection reaction in presence of a acid is selected form formic acid, acetic acid and hydrochloric acid, hydrobromic acid or mixture thereof to give compound of formula (I).
3. The process as claimed in claim 1, wherein the said alkali hydroxide strong base for benzyl chloroformate protection reaction is selected from sodium hydroxide, potassium hydroxide and weak carbonate base is selected from sodium carbonate, potassium carbonate, bicarbonate base is selected from sodium bicarbonate, potassium bicarbonate or mixture thereof.
4. The process as claimed in claim 1, wherein the said solvent for intramolecular cyclization reaction is selected from toluene, xylene, benzene, acetone, Ethyl acetate dioxane or mixture thereof.
5. The process as claimed in claim 1, wherein the said solvent for intramolecular cyclization reaction is selected from acetone or mixture thereof.
6. The process as claimed in claim 1, wherein the said dehydrating agent is selected from N, N'-Carbonyl diimidazole, Di cyclohexyl carbodiimide, N-(3-dimethylaminopropyl)-N-ethyl carbodiimide.
7. The process as claimed in claim 1 and 2, wherein the said acid for deprotection reaction is selected from formic acid, acetic acid, hydrochloric acid, hydrobromic acid, trifluoracetic acid, methane sulphonic acid, propanoic acid, butanoic acid, pentatonic acid or mixture thereof.
8. The process as claimed in claim 1 and 2, wherein the said acid for Cbz deprotection reaction is selected from formic acid, acetic acid and hydrochloric acid, hydrobromic acid or mixture thereof.
9. The process as claimed in claim 1, the % of any impurity is not more than 0.1%.

10. The process as claimed in claim 1, the solvent for purification is selected form ethyl acetate, isopropyl acetate, iso propyl alcohol, methanol, ethanol. territory butanol, toluene, acetone, dioxane or mixture thereof.