DESC:FORM 2

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

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF KEY INTERMEDIATE OF CGRP RECEPTOR ANTAGONISTS

APITORIA PHARMA PRIVATE LIMITED HAVING CORPORATE
OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention provides a simple and cost-effective process for the preparation of enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof.

wherein, X is halogen and n = 0 to 5.

The Lactam compound of Formula (II) is a key intermediate in the preparation of CGRP (Calcium Gene-related Peptide) receptor antagonists such as Atogepant of Formula (I), Ubrogepant of Formula (I') and likewise.

BACKGROUND OF THE INVENTION

Atogepant of Formula (I) is chemically known as s (3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide. Atogepant is approved by FDA under the brand name Qulipta® in the form of oral Tablets. Atogepant is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of episodic migraine in adults.
Ubrogepant of Formula (I') is chemically known as (3'S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetra-hydro- spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3b]pyridine]-3-carboxamide. Ubrogepant is approved by FDA under the brand name Ubrelvy® in the form of oral Tablets. Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults.

US 8,754,096 discloses CGRP (Calcium Gene-related Peptide) receptor antagonists such as Atogepant of Formula (I). This patent disclosed a process for the preparation of Lactam compound of Formula (II) by Suzuki coupling of compound of Formula (A) with boronic acid derivative to obtain compound of Formula (B) followed by reduction to obtain compound of Formula (C). This compound is reacted with trisyl azide to obtain compound of Formula (D), which undergoes reduction, Boc protection followed by chiral resolution and to obtain Boc protected Lactam compound of Formula (E), which is then treated with hydrochloric acid to obtain Lactam hydrochloride of Formula (IIa). This compound is further converted to Atogepant of Formula (I). The process is shown in below scheme:

Scheme – I
The major disadvantage associated with the above-mentioned process is the use of trisyl azide which is not suitable for industrial manufacturing due to the safety hazards associated with azides. Further, the products at every stage are purified using column chromatography which is laborious, expensive and are not suitable for commercialization. Use of bis(tri-tert-butylphosphine)palladium and palladium carbon are expensive and not viable for large scale operations. Finally, the enantiomers are isolated by Chiralcel® AD column which is not viable for large scale operations.

The US ‘096 also discloses an alternate process for the preparation of Lactam hydrochloride of Formula (IIa) comprising alkylation of aryl acetone of Formula (F) with iodo alanine derivative to obtain keto ester of Formula (G). This compound is reacted with trifluoro amine derivative, then undergoes cyclization and resolution using chiral chromatography to obtain Boc protected Lactam compound of Formula (E), which is deprotected with hydrochloric acid to obtain Lactam hydrochloride of Formula (IIa). The process is shown in below scheme:

Scheme – II
The major disadvantage associated with the above-mentioned process is the use of tedious chromatographic procedure for chiral resolution of racemic compound of Formula (E) which leads to low yield, makes the process more expensive and commercially non-viable.

US 9,174,989 discloses a process for the preparation of Lactam compound of Formula (IIb) by enzymatic cyclization of compound of Formula (G) to obtain compound of Formula (H) followed by treating with trifluoro ethyl derivative to obtain Boc protected cis / trans isomer of lactam compound of Formula (E1), which is then treated with araldehyde derivative to obtain Lactam compound of Formula (IIb). The process is shown in below scheme:

Scheme – III

The major disadvantage associated with the above-mentioned process is the use of transaminase enzyme which tends to be more unstable in the organic solvents and high pH of the reaction broth. Therefore, they are used in high stoichiometric quantities, which makes the process costlier, tedious and also generate lot of waste.

Hence, there is a need for a simple, cost-effective alternative process for the preparation of enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof.

In an attempt, to improve the purity and yield of the compound of Formula (II), the inventors of the present invention found an improved process to prepare enantiomerically pure Lactam compound of Formula (II), which is less expensive, industrially feasible, involves simple chemical conversion. The present invention overcomes the above disadvantages and provides Lactam compound of Formula – II, which can be used to obtain CGRP receptor antagonists such as Atogepant, Ubrogepant and likewise with high purity and yield.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a simple and cost-effective process for the preparation of enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof.

wherein, X is halogen and n = 0 to 5.

The compound of Formula (II) is a key intermediate in the preparation of CGRP receptor antagonists such as Atogepant, Ubrogepant and likewise.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a Lactam Chiral acid salt compound of Formula (III),

wherein, X is halogen and n = 0 to 5.

In another embodiment, the present invention provides a Lactam (R)-Naproxen salt compound of Formula (IIIa),

wherein, X and n are same as defined above,

In another embodiment, the present invention provides a process for the preparation of enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof, which comprises:

wherein, X and n are same as defined above,
(i) reating racemic Lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof to obtain Lactam chiral acid salt of Formula (III);
;
wherein, X and n are same as defined above,

(ii) isolating the Lactam chiral acid salt of Formula (III);
(iii) treating the Lactam chiral acid salt of Formula (III) with a base to obtain the Lactam compound of Formula (II);
(iv) isolating the enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof.

Yet, in another embodiment, the present invention provides a process for the preparation of CGRP receptor antagonist compounds such as Atogepant of Formula (I), Ubrogepant of Formula (I') and likewise, which comprises:

(i) providing enantiomerically pure Lactam compound of Formula (II);

wherein, X and n are same as defined above,
(ii) reacting enantiomerically pure Lactam compound of Formula (II) with spiro acid compound of Formula (V) to obtain the CGRP receptor antagonist compounds;

(iii) isolating the CGRP receptor antagonist compound.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a Lactam chiral acid salt of Formula (III).

The chiral acid comprises (R)-Naproxen, (S)-Naproxen, (R)-Ibuprofen, (R)-Ibuprofen (R)-(+)-phenyl ethyl amine, (S)-Ibuprofen, (S)-Ibuprofen (S)-(+)-phenyl ethyl amine, mandelic acid, camphor sulphonic acid, tartaric acid, binaphtyl-2,2'-diyl hydrogen phosphate, shikmic acid, dibenzoyl-L-tartaric acid, diacetyl-L- tartaric acid, malic acid, di-p-toluoyl-L-tartaric acid, methoxy acetic acid, Mosher’s acid, camphoric acid, tartranilic acid, mandelic acid, quinic acid or hydratropic acid.

The present invention specifically encompasses a Lactam (R)-Naproxen salt compound of Formula (IIIa).

The present invention provides a process for preparation of enantiomerically pure Lactam compound of Formula (II) or its pharmaceutically acceptable salts comprises, treating the racemic lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof with a chiral acid or a pharmaceutically acceptable salt thereof to obtain Lactam chiral acid salt compound of Formula (III) and then the obtained Lactam chiral acid salt compound of Formula (III) is treated with a base to obtain the enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salts thereof.

The reaction of racemic lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof in the above process is carried out in the presence or absence of a solvent.

The solvent used for the above reaction and purification steps comprises water, alcohols, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol or mixtures thereof; nitrile solvent selected from acetonitrile, propionitrile or mixtures thereof; halogenated hydrocarbons comprises methylene chloride, ethylene chloride, chloroform or mixtures thereof; hydrocarbons comprises hexane, cyclohexane, toluene, xylene or mixtures thereof; amides comprises dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone or mixtures thereof; sulfoxides such as dimethyl sulfoxide; nitriles comprises acetonitrile, propionitrile and the like; esters comprises, ethyl acetate and butyl acetate or mixtures thereof; ethers comprises diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran or mixtures thereof; ketones comprises acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl tertiary butyl ketone or mixtures thereof.

Lactam chiral acid salt compound of Formula (III) is recovered from mother liquors by isolation followed by purification.

The base used in the above process comprises an organic base selected from lithium methoxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethylamine, diisopropyl methyl amine, methyl amine, dimethyl amine or mixtures thereof or an inorganic base selected from alkaline or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or mixtures thereof; alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate and similar or mixtures thereof.

The pharmaceutically acceptable salts thereof in above process comprises hydrochloride, hydrobromide, sulphate, bisulphate, para toluene sulphonate and methane sulphonate.

The present invention provides the enantiomerically pure Lactam compound of Formula (II), which reacts with spiro acid compound of Formula (V) to obtain CGRP receptor antagonist compounds or pharmaceutically acceptable salt.

The present invention also provides a process for the preparation of racemic Lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof comprises deprotecting racemic N-Boc Lactam compound of Formula (VI) with an acid in the presence of solvent to obtain racemic Lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof.

wherein, X and n are same as defined above.

The acid used in the above reaction comprises an inorganic acid selected from HCl, HBr and like or an organic acid selected from methanesulfonic acid, formic acid, para toluene sulfonic acid and like. The solvent used in the above reaction is defined as above.
The racemic N-Boc Lactam compound of Formula (VI) can be prepared in a similar manner as known in the art or as disclosed in the patent reference US 9,174,989.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE - 1:
Preparation of (3S,5S,6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)-6-methylpiperidin-2-one hydrochloride and its enantiomer (racemic compound):
Ethyl acetate hydrochloride (300 ml, 10-12% HCl assay) was added to a solution of tert-butyl (3S,5S,6R)-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)-6-methyl-2-oxopiperidin-3-ylcarbamate and its enantiomer mixture (100 grams, 0.227 moles) in ethyl acetate (500 ml). The resulting mixture was maintained at room temperature for 12 hours. The desired product was filtered and washed with ethyl acetate (50 ml) after completion of reaction, to obtain (3S,5S,6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)-6-methyl-piperidin-2-one hydrochloride and its enantiomer mixture.

Yield: 88 %
Purity: > 99.93%

EXAMPLE - 2:
Preparation of (3S,5S,6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)-6-methylpiperidin-2-one. (R)-Naproxen:
Triethyl amine (30 grams) was added to a solution of (3S,5S,6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)-6-methylpiperidin-2-one hydrochloride and its enantiomer mixture (100 grams, 0.265 moles) in methylene chloride (500 ml). The resulting mixture was maintained at room temperature for 120 minutes. Water was charged to the reaction mixture and layers were separated after completion of the reaction. The organic layer was concentrated under reduced pressure at 20-30oC. Isopropyl alcohol (500 ml) followed by (R)-Naproxen (40 grams) were charged to the reaction mixture and the reaction mass was maintained for 6-8 hours at 20-30oC. The product was filtered and washed with isopropyl alcohol (50 ml) to obtain (3S, 5S, 6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)-6-methylpiperidin-2-one (R)-Naproxen.

Yield: 26.4 %
Purity: > 99%

EXAMPLE - 3:
Preparation of (3S,5S,6R)-3-amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)-6-methylpiperidin-2-one hydrochloride (Atogepant Lactam compound):
(3S,5S,6R)-3-Amino-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)-6-methyl piperidin-2-one- R-Naproxen (40 grams, 0.07 moles) was suspended in methylene chloride (200 ml). Potassium carbonate (9.6 grams, 0.14 moles) in water (200 ml) was added to the suspension for about 30 minutes. The reaction mass was allowed to settle, and then organic layer was separated. The organic layer was treated with conc. HCl (5 ml) followed by solvent evaporated and trituration was carried out with n-heptane to obtain Atogepant Lactam compound.

Yield: 68 %
Purity: >99.9 % ,CLAIMS:CLAIMS
We claim,

1. A lactam chiral acid salt compound of Formula (III),

wherein, X is halogen and n = 0 to 5.

2. The compound as claimed in claim 1, wherein the chiral acid comprises (R)-Naproxen, (S)-Naproxen, (R)-Ibuprofen, (R)-Ibuprofen (R)-(+)-phenyl ethyl amine, (S)-Ibuprofen, (S)-Ibuprofen (S)-(+)-phenyl ethyl amine, mandelic acid, camphor sulphonic acid, tartaric acid, binaphtyl-2,2'-diyl hydrogen phosphate, shikmic acid, dibenzoyl-L-tartaric acid, diacetyl-L- tartaric acid, malic acid, di-p-toluoyl-L-tartaric acid, methoxy acetic acid, Mosher’s acid, camphoric acid, tartranilic acid, mandelic acid, quinic acid or hydratropic acid.

3. A lactam (R)-Naproxen salt compound of Formula (IIIa),

wherein, X is halogen and n = 0 to 5.

4. A process for the preparation of enantiomerically pure Lactam compound of Formula (II) or pharmaceutically acceptable salt thereof, which comprises:

wherein, X and n are same as defined above,
(i) treating racemic lactam compound of Formula (IV) or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof to obtain lactam chiral acid salt of Formula (III);
;
(ii) isolating the lactam chiral acid salt of Formula (III);
(iii) treating the lactam chiral acid salt of Formula (III) with a base to obtain the enantiomerically pure Lactam compound of Formula (II);
(iv) isolating the enantiomerically pure lactam compound of Formula (II) or pharmaceutically acceptable salt thereof.

5. The process as claimed in claim 4, wherein the base used in step (i) comprises an organic base selected from triethylamine, diisopropyl methyl amine, methyl amine, dimethyl amine or mixtures thereof or an inorganic base selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate or mixtures thereof.

6. A process for the preparation of CGRP receptor antagonist compounds Atogepant of Formula (I) and Ubrogepant of Formula (I'), which comprises:

(i) providing enantiomerically pure lactam compound of Formula (II);

wherein, X and n are same as defined above,
(ii) reacting lactam compound of Formula (II) with spiro acid compound of Formula (V) to obtain the CGRP receptor antagonist compounds;

(i) isolating the CGRP receptor antagonist compound.