DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“IMPROVED PROCESS FOR THE PREPARATION OF (R)-1-(TERT-BUTOXYCARBONYL)-2-METHYLPYRROLIDINE-2-CARBOXYLIC ACID”

We, ZYDUS LIFESCIENCES LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Corporate Park, Scheme No. 63, Survey No. 536, Khoraj (Gandhinagar), Nr. Vaishnodevi Circle, Sarkhej – Gandhinagar Highway, Ahmedabad – 382481, Gujarat, India,

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
Present invention provides an improved process for the preparation of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid of formula (I).
BACKGROUND OF THE INVENTION
(R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid is an important intermediate for preparation of some important NOD-like receptor family (NLR) protein NLRP3 modulators disclosed in WO2020148619.
The patent application WO2020148619 discloses the use of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid as an intermediate (4) for certain sulfonyl urea compounds that are considered as NLRP3 modulators as explained below scheme 1:
Process for preparation of NLRP3 modulators:

NLRP3 modulators are useful in the treatment of the diseases or conditions mediated by NLRP3 or conditions in which interleukin 1ß activity is implicates. This includes inflammation, cryopyrin-associated periodic syndrome (CAPS), gouty arthritis, multiple sclerosis, inflammatory bowel diseases, Parkinson’s and Alzheimer’s diseases and other diseases related to Central Nervous System. NLRP3 modulators preferably useful as therapeutics in treatment of a variety of pathological condition including but not limited to lymphoma, auto-immune diseases, cancer, inflammatory diseases, neurodegenerative diseases or conditions.
Compound of formula (I) is a useful intermediate in the field of medicinal chemistry and has been used as an intermediate of many Active pharmaceutically ingredients. Lawrence Kolaczkowski et al. has described synthesis of 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide using compound of formula (I) of present invention. However, being a chiral compound, purity of this compound is always an issue for scientists. In present invention inventors provide a process to obtain a compound of formula (I) with 100% chiral purity in cost effective manner.
SUMARY OF THE INVENTION
The present invention relates to an improved process for preparation of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (Formula (I)). Further the present invention provides a process to obtain compound of formula (I) with 100% chiral purity and higher yields.
EMBODIMENTS OF THE INVENTION
The main aspect of the invention is provided a process of compound of formula (I) with 100% chiral purity.

BRIEF DESCRIPTION OF DRAWING
Figure 1 is a HPLC chromatogram of compound of formula (I).
Figure 2 is a chiral HPLC chromatogram of compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Following is the list of abbreviations used in description:
CDCl3: Deuterated chloroform
DCM: Dichloromethane
NMR: Nuclear Magnetic Resonance
GC: Gas chromatography
h: Hour
Kg: Kilogram
L: Liter
MeOD: Deuterated methanol
MS: Mass Spectrometry
MTBE: Methyl tert-butyl ether
NMR: Nuclear Magnetic Resonance
SOR: Specific Rotation
SSR: Stainless Steel Reactor
ESI-MS: Electrospray Ionization Mass Spectrometry
Instrument details:
HPLC and Chiral HPLC chromatograms were recorded on Agilent 1260 series.
Mass spectra were recorded with Waters, XevoG2a-ToF LCMS instrument.
NMR was recorded with Bruker 400 MHZ instrument
Specific rotation of chiral compounds were recorded with Jasco Polarimeter , Digital Polarimeter P-2000
The above main aspect of present invention are attained by improved process for the preparation of compound of formula (I) and other intermediates of process described herein.
In one embodiment of the present invention is provided a process of compound of formula (I) with 100% chiral purity.

In another embodiment of the present invention is provided a process of compound of formula (I) as provided in scheme 2.

The process comprises five steps to obtain compound of formula (I) with 100% chiral purity.
The process comprises following steps:
Step 1: reacting starting material L-alanine

in presence of thionyl chloride and suitable solvents at appropriate temperature to obtain compound of formula (II).

Step 2: compound of formula (II) namely ethyl L-alaninate hydrochloride further reacts to 1-bromo-3-chloropropane in presence of diisopropylethyl amine and tetrabutylammoniumbromide to obtain compound of formula (III). Methyl tert-butyl ether used as a solvent for step 2.

Step 3: reacting compound of formula (III) namely ethyl (3-chloropropyl)-L-alaninate in solvent methyl tert-butyl ether reacted with protecting agent di-tert-butyl dicarbonate at appropriate temperature to obtain compound of formula (IV).

Step 4: reacting compound of formula (IV) namely ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate was reacted with potassium hydroxide to get cyclized product -compound of formula (V). Dimethylsulfoxide was used as a solvent for step 4.

Step 5: reacting compound of formula (V) namely 1-(tert-butyl) 2-ethyl (R)-2-methylpyrrolidine-1,2-dicarboxylate to get de-esterified in presence of potassium hydroxide and ethanol as solvent at appropriate temperature to obtain crude product of compound of formula (I). The reaction mass further dumped in water and washed with DCM. Then aqueous layer acidified with 5N aqueous HCl solution and pH was brought between 3 to 4. Product in aqueous layer was further extracted using ethyl acetate;
Step 6: purifying the crude product by recrystallizing in suitable solvent to get pure compound of formula (I).
Thus obtained solid product was filtered and dried at 50-55 oC for 16 hours.

In general, the suitable solvent used in step (i) may be selected from one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropylether, diethylether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in dimethylformamide and acetonitrile.
In general, the suitable solvent used in step (vi) is one or more of hydrocarons selected from pentane, hexane, heptane, and cyclohexane or mixture thereof.
In one of the embodiment of the present invention is provided that the product obtained using this process, possess 99.54% purity by HPLC.
In another embodiment of present invention is provided that the product obtained using this process possess 100% chiral purity by chiral HPLC.
Following are non-limiting examples of present invention; representing the preferred modes of carrying out the invention. The scope of invention is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge that are within the general understanding of a person skilled in the art.
Examples:
Example 1: Process for preparation of ethyl L-alaninate hydrochloride - compound of formula (II).
L-alanine (3.0 Kg, 33.67 mol) was added in ethanol (30 L) in a 100 L glass assembly at room temperature. Reaction mixture was cooled to 0 to 5° C. Thionyl chloride (12.02 Kg, 101 mol) was added carefully at 0 to 5 oC over a period of 45 minutes. Heated the reaction mixture to 80 to 85 ºC for 3 h. Concentrated the reaction mixture in vacuum below at 65 °C to get oily residue which cool to 35 to 45 °C. Diisopropyl ether (15 L x 2) was added in to oily residue to get off white colored solid and decant solvent. Dry the solid in vacuum to get ethyl L-alaninate hydrochloride compound of (II) 5.10 Kg.
Yield: 98.6%
Appearance: Off white colored solid.
MS (ESI-MS): m/z 118.10 (M-HCl+H)+.
1H NMR (400 MHz, DMSO-d6): d 1.22 (t, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 3.98 (q, J = 14 Hz, 7.2 Hz, 1H), 4.21-4.13 (m, 2H), 8.75 (s, 3H).
Example 2: Process for Preparation of ethyl (3-chloropropyl)-L-alaninate - compound of formula (III)
Ethyl L-alaninate hydrochloride (II) (5.1 Kg, 33.2 mol), Diisopropylethyl amine (12.86 kg, 99.60 mol), 1-Bromo-3-chloropropane (18.29 kg, 116.20 mol) and Tetrabutylammonium bromide (0.535 Kg, 1.660 mol) were added in acetonitrile (20.4 L) in 150 L SSR at room temperature. Reaction mixture was stirred for 72 h at room temperature and further quenched with 20% aqueous citric acid solution (127.5 L) to bring pH 3 to 4. Reaction mixture was then washed with n-Heptane (20.4 L x 2) and aqueous layer was then basify with 4 N sodium hydroxide solution (95 L) to bring pH 9 to 10. Aqueous layer was extracted with MTBE (25.5 L x 2). Organic layer was washed with 10% aqueous sodium bicarbonate solution (15.5 L) and 10% sodium chloride solution (10.2 L). Organic layer containing ethyl (3-chloropropyl)-L-alaninate (III) was used in next reaction without any further purification.
Example 3: Process for Preparation of ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate - compound of formula (IV)
Organic layer obtained from stage 2 was charged in a 150 L SSR, at room temperature. Boc anhydride (6.81 kg, 31.2 mol) was added and the reaction mixture was stirred for 16 h at room temperature. Imidazole (0.565 Kg, 8.30 mol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was washed with aqueous 1 N hydrochloric acid solution (11.2 L x 3). Organic layer was washed with 5% aqueous sodium bicarbonate solution (11.25 L) followed by water (11.25 L) and 10% brine solution (11.25 L). Concentrated solvents in vacuum to get ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate (IV) 7.51 Kg.
Yield: 77% (two steps yield)
Appearance: Pale yellow colored oil
MS (ESI-MS): m/z 194.09 (M-Boc+H)+
1H NMR (400 MHz, CDCl3): d 1.24 (d, J = 6.8 Hz, 3H), 1.42-1.38 (m, 12H), 2.08-2.00 (m, 2H), 3.20 (d, J= 6.0 Hz, 1H), 3.65-3.43 (m, 3H), 4.17-4.09 (m, 2H)
Example 4: Process for Preparation of 1-(tert-butyl) 2-ethyl (R)-2-methylpyrrolidine-1,2-dicarboxylate - compound of formula (V)
Ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate (IV) (5 Kg, 17.01 mol) was added in dimethyl sulfoxide (25 L) in a 50 L SSR, at room temperature. Reaction mixture was cooled at 20 to 25 oC and potassium hydroxide (2.86 Kg, 51.05 mol) was added at 20 to 25oC and further reaction mixture was stirred for 3 h at room temperature. The reaction mixture was dump in to water (125 L) and aqueous layer was extracted with ethyl acetate (25 L x 3). Organic layer was washed with 10% aqueous sodium chloride solution (25 L) and concentrated in vacuum to get 1-(tert-butyl) 2-ethyl (R)-2-methylpyrrolidine-1, 2-dicarboxylate (V) 4.160 Kg.
Yield: 95%
Appearance: Oily compound
MS (ESI-MS): m/z 280.16 (M+Na)+
1H NMR (CDCl3): d 1.29-1.22 (m, 3H), 1.43 (d, J = 14Hz, 9H), 1.54 (d, J = 18.8 Hz, 3H), 1.95-1.85 (m, 3H), 2.19-2.14 (m, 1H), 3.60-3.48 (m, 2H), 4.23-4.08 (m, 2H)
Example 5: Process for Preparation of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid - compound of formula (I)
1-(tert-butyl) 2-ethyl (R)-2-methylpyrrolidine-1, 2-dicarboxylate (V) (6.2 Kg, 24.093 mol) was added to the mixture of ethanol (12.4 L) and water (12.4 L) in 150 L SSR at room temperature and the reaction mixture was further cooled at 15 to 20 oC. Potassium hydroxide powder (13.5 Kg, 240.93 mol) was added at 15 to 35 oC and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with water (124 L) and aqueous layer was washed with DCM (31 L x 2) and then aqueous layer was acidifying with 5 N aqueous hydrochloric acid (52.7 L) to bring pH 3 to 4. Aqueous layer was extracted with ethyl acetate (62 L x 1 and 31 L x 2). Combined all organic layer was concentrated in vacuum to get crude solid product which was recrystallized with n-heptane (25.6 L) followed by cyclohexane (24 L). Filter the solid and dry it at 50-55 ºC for 16 h to get (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (I) 4.255 Kg.
Yield: 77%
Description: Off white colored solid
MS (ESI-MS): m/z 228.11 (M-H)
1H NMR (400 MHz, MeOD): d 1.45 (d, J = 7.6 Hz, 9H), 1.53 (d, J = 10.4 Hz, 3H), 2.02-1.89 (m, 3H), 2.27-2.18 (m, 1H), 3.56-3.47 (m, 2H)
HPLC Purity: 99.54 %
Chiral Purity: 100.00%
SOR: +5.41° (0.5 % in Methanol at 20°C)
Melting Point: 134.1 oC
XRPD: Crystalline Form, peaks at about 10.7 + 0.2, 12.8 + 0.2, 14.2 + 0.2, 16.5 + 0.2, 17.9 + 0.2 , 24.1 + 0.2 and 26 + 0.2 degrees 2 – theta.
,CLAIMS:We claim:
1. Process for the preparation of compound of formula (I) comprising:

(i) reacting starting material L-alanine

in presence of thionyl chloride and suitable solvents at appropriate temperature to obtain compound of formula (II);

(ii) reacting compound of formula (II) namely ethyl L-alaninate hydrochloride with 1-bromo-3-chloropropane in presence of diisopropylethyl amine and tetrabutylammoniumbromide in solvent methyl tert-butyl ether to obtain compound of formula (III);

(iii) reacting compound of formula (III) namely ethyl (3-chloropropyl)-L-alaninate in solvent methyl tert-butyl ether in presence of protecting agent di-tert-butyl dicarbonate at appropriate temperature to obtain compound of formula (IV);

(iv) reacting compound of formula (IV) namely ethyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-L-alaninate with potassium hydroxide in solvent dimethylsulfoxide to get cyclized product -compound of formula (V);

(v) reacting compound of formula (V) to get de-esterified in presence of potassium hydroxide and ethanol at appropriate temperature to obtain crude product of compound of formula (I);
(vi) purifying the crude product by recrystallizing in a suitable solvent to get pure compound of formula (I).

2. The process as claimed in claim 1, wherein suitable solvent in step (i) is one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropylether, diethylether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably the solvent is diisopropylether.

3. The process as claimed in claim 1, wherein solvent in step (vi) is one or more of hydrocarons selected from pentane, hexane, heptane, and cyclohexane or mixture thereof.

4. The process as claimed in claim 1, wherein compound of formula (I) obtained is having at least 99.54 % purity by HPLC.

5. The process as claimed in claim 1, wherein compound of formula (I) obtained is having 100% chiral purity by chiral HPLC.

Dated this 15th day of February 2023.

(HARIHARAN SUBRAMANIAM)
IN/-PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS