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 UBROGEPANT

AUROBINDO PHARMA LTD 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 relates to a simple and cost effective process for the preparation of Lactam compound of Formula – II or pharmaceutically acceptable salt thereof.

Lactam compound of Formula – II is the key advanced intermediate of Ubrogepant of Formula – I.

BACKGROUND OF THE INVENTION

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 -hydrospiro[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 8,912,210 discloses CGRP (Calcium Gene-related Peptide) receptor antagonists such as Ubrogepant of Formula – I. This patent disclosed a process for the preparation of Ubrogepant by reductive amination followed by cyclization and epimerization of methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate of Formula – V to obtain tert-Butyl[(3S,5S,6R)-5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate of Formula IV primarily as a racemic mixture, which undergoes chiral resolution using normal-phased liquid chromatography, then deprotecting Formula – IV with Palladium on carbon followed by treating with hydrochloride to obtain Lactam compound of Formula – II as HCl salt, which is then coupled with a spiro acid compound of Formula – III to obtain Ubrogepant of Formula – I. The process is depicted in the below, as Scheme – I:
Scheme – I

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

The ‘210 patent further disclosed an alternative process for the preparation of Lactam compound of Formula – II as HCl salt which comprises hydrogenation of Formula – VI using platinum oxide under acidic conditions and chiral resolution to obtain Lactam compound of Formula – II as HCl salt. The process is depicted in the below, as Scheme – II:

Scheme – II

The major disadvantage associated with the above-mentioned process is the use of costly catalyst such as PtO2, which makes the process more expensive and not viable for large scale operations. Moreover the reaction requires high pressure for the reduction reaction.

US 9,174,989 disclosed a process for the preparation of Formula – II as HCl salt by using a transaminase enzyme for kinetic resolution with high diastereoselectivity at positions C5 and C6 of Formula – X to obtain tert-butyl (5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-ylcarbamate of Formula – IX, which undergoes deprotection to obtain (5S,6R)-3-amino-6-methyl-5-phenyl-1-(2.2.2-trifluoroethyl)piperidin-2-one of Formula – VIII followed by treating with p-toluic acid in the presence of aryl aldehyde derivative to obtain (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-aminium-4-methylbenzoate of Formula – VII which is then treated with hydrochloric acid to obtain Lactam compound of Formula – II as HCl salt. The process is depicted below, as Scheme – III:

Scheme – III

The above-mentioned process requires custom based transaminase enzyme for dynamic kinetic reaction. The process also requires additional steps for epimerization reaction via schiff base which involve the usage of aldehyde.

Hence, there is a need of a simple, cost-effective alternative process for the preparation of Lactam compound of Formula – II or pharmaceutically acceptable salt thereof which is the key intermediate in the preparation of Ubrogepant of Formula – I.

The inventors of the present invention found an improved process to prepare Lactam compound of Formula – II or pharmaceutically acceptable salt thereof. The process of the present invention is less expensive, industrially feasible, overcomes the above disadvantages and provides Lactam compound of Formula – II which results Ubrogepant with high purity and higher yields.

OBJECTIVE OF THE INVENTION

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

Lactam compound of Formula – II is the key advanced intermediate of Ubrogepant of Formula – I.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a Lactam Chiral acid salt compound of Formula – IIb,

In specific embodiment, the present invention provides a Lactam (R)-Ibuprofen salt compound of Formula – IId,

In another embodiment, the present invention provides a process for the preparation of Lactam Chiral acid salt compound of Formula – IIb,
which comprises:

(i) treating racemic lactam compound of Formula – IIc or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof to obtain Lactam chiral acid salt of Formula – IIb;
;
(ii) purifying Lactam chiral acid salt of Formula – IIb by using a solvent or mixture thereof.

Yet, in another embodiment, the present invention provides a process for the preparation of Lactam compound of Formula – II or pharmaceutically acceptable salt thereof,

which comprises:
(i) treating Lactam chiral acid salt of Formula – IIb with a base to obtain Lactam compound of Formula – II;

(ii) optionally converting Lactam compound of Formula – II into its pharmaceutically acceptable salt thereof.

Still, in another embodiment, the present invention provides a process for the preparation of Ubrogepant of Formula – I from Lactam compound of Formula – II or pharmaceutically acceptable salt thereof prepared by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a Lactam chiral acid salt of Formula – IIb.

The chiral acid comprises (R)-ibuprofen, (R)-ibuprofen (R)-(+)-phenyl ethyl amine, (S)-ibuprofen, (S)-ibuprofen (S)-(+)-phenyl ethyl amine, mandelic acid, camphor sulphonic acid, tartaric acid.

The present invention specifically encompasses a Lactam (R)-Ibuprofen salt compound of Formula – IId,

The present invention also relates to a process for the preparation of Lactam chiral acid salt of Formula – IIb, comprising, treating racemic lactam compound of Formula – IIc or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof to obtain Lactam chiral acid salt compound of Formula – IIb, followed by purifying Lactam chiral acid salt of Formula – IIb by using a solvent or mixture thereof.

The reaction of racemic lactam compound of Formula – IIc or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof 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 – IIb is recovered from mother liquors of isolation and purification steps.

Lactam chiral acid salt compound of Formula – IIb is isolated or proceeded to the next step without isolation.

The process for preparation of Lactam compound of Formula – II or its pharmaceutically acceptable salts comprises, treating the Lactam chiral acid salt compound of Formula – IIb with a base to obtain Lactam compound of Formula – II which is then converted to its pharmaceutically acceptable salts thereof.

The base used to obtain Lactam compound of Formula – II 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 reaction comprises hydrochloride, hydrobromide, sulphate, bisulphate, para toluene sulphonate and methane sulphonate.

A process for the preparation of racemic Lactam compound of Formula – IIc or pharmaceutically acceptable salt thereof comprises deprotecting racemic N-Boc Lactam compound of Formula – XI with an acid in the presence of solvent to obtain pharmaceutically acceptable salt of racemic Lactam compound of Formula – IIc.

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 and like.

The racemic N-Boc Lactam compound of Formula – XI can be prepared by methods well known in the art, as disclosed in the patent reference US 9,174,989.

A process for the preparation of Ubrogepant of Formula – I comprises reacting Lactam compound of Formula – II or pharmaceutically acceptable salt thereof with a spiro compound of Formula – III in a known method in the art, as disclosed in the patent reference US 8,912,210.

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 Racemic Lactam hydrochloride [Formula – IIc. HCl]:
Concentrated hydrochloric acid solution (115 ml, 1.293 mmol) was added to a solution of N-Boc Lactam compound (100 grams, 0.258 mmol) in ethyl acetate (1000 ml), at 20-30°C and stirred for 4 hours. The solid was filtered and washed with ethyl acetate (200 ml). The compound was dried under vacuum at 55-60°C to obtain lactam hydrochloride of Formula – IIc. HCl (80 grams).

HPLC Purity: 99.8 %.

EXAMPLE – 2:
Preparation of (R)-Ibuprofen-(R)-Phenyl ethylamine salt:
Racemic Ibuprofen (100 grams) and methylene chloride (2000 ml) were charged at 20-25°C and heated to 33-40°C, a solution of (R)-(+)-1-Phenyl ethylamine (58.8 grams, 0.485 mmol) in methylene chloride (500 ml) was slowly added at 33-40°C and stirred for 30 minutes. The reaction mass was then cooled to 20-30°C and stirred for 60 minutes. The obtained solid was filtered and washed with methylene chloride (200 ml).

The obtained wet filtered mass (170 grams) was suspended in methylene chloride (2000 ml) at 20-30°C, heated to 30-40°C and stirred for 30 minutes. The suspension was cooled to 20-30°C and stirred for 60 minutes. The obtained solid was filtered and washed with methylene chloride (200 ml). (The process is repeated 2-3 times for lowering the content of unwanted (S)-Ibuprofen)

The obtained wet filtered mass (50 grams) was suspended in methylene chloride (300 ml) and purified water (300 ml) was added at 20-30°C and then stirred for 5-10 minutes. The pH of the reaction mass was adjusted to 1.8 ± 0.3 by adding 6 N hydrochloric acid (30 ml) at 20-30°C. The layers were separated, and the organic layer was washed with purified water (200 ml) and then concentrated under vacuum at a temperature below 40°C (weight of concentrated mass: 20 grams).

The concentrated mass (20 grams, 0.097 mmol) was dissolved in methylene chloride (400 ml) and heated to 30-40°C. The solution of (R)-(+)-1-Phenyl ethylamine (10.59 grams, 0.087 mmol) in methylene chloride (100 ml) was slowly added to the above reaction mass and stirred for 30 minutes. The reaction mass was then cooled to 20-30°C and stirred for 60 minutes. The obtained solid was filtered, washed with methylene chloride (40 ml) and dried under vacuum at below 35°C to obtain (R)-Ibuprofen-(R)-phenyl ethylamine salt (30 grams).

Chiral HPLC Purity: 99.63 : 0.37 (R:S)

Preparation of Lactam (R)-Ibuprofen salt [Formula – IIb]:
Aqueous sodium hydroxide solution (13.6 grams, 0.34 mmol, dissolved in 100 ml water) was added to a solution of racemic Lactam hydrochloride (100.0 grams, 0.309 mmol) in methylene chloride (1000 ml) and DM water (1000 ml) at 20-30°C and stirred for 30 minutes. The organic layer was separated and washed with DM water (1000 ml) (racemic lactam organic layer).

(R)-Ibuprofen-(R)-phenyl ethylamine salt (101.4 grams, 0.309 mmol), methylene chloride (1000 ml) and purified water (1000 ml) were charged to another flask at 20-30°C and stirred for 15±5 minutes. Then, concentrated hydrochloric acid (36.0 grams, 0.342 mmol) was added at 20-30°C and stirred for 15 minutes. The organic layer was separated and washed with purified water (1000 ml).

The above racemic lactam organic layer was combined with (R)-Ibuprofen organic layer and concentrated under vacuum at below 35°C. Then, methanol (1200 ml) was added and heated to 50-55°C and stirred for 60 minutes. The above reaction mass was concentrated under reduced pressure at a temperature below 40°C till the volume of the reaction mass reaches to 300-350 ml. Then the reaction mass cooled to 20-30°C and methyl t-butyl ether (1500 ml) was added at 20-30°C.The reaction mass was then heated to 50-55°C and stirred for 45±5 min and was maintained for 4 hours at 20-25°C. The product was filtered and washed with mixture of Methanol: MTBE (1:9 ratio) (100 ml) to obtain Lactam (R)-Ibuprofen as wet compound (weight: 53 grams).
Chiral HPLC Purity: 96.95 : 3.05
HPLC purity: 99.79 %
Methylene chloride (500 ml) and purified water (500 ml) were added to the above wet solid (53 grams), followed by addition of aqueous sodium hydroxide solution (4.6 grams, 0.115 mmol, dissolved in 50 ml water) and stirred for 30 minutes. The organic layer was separated and washed with DM water (500 ml) (Lactam organic layer).

(R)-Ibuprofen.(R)-phenyl ethylamine salt (35 grams), methylene chloride (350 ml) and purified water (350 ml) were charged to another flask at 20-30°C and stirred for 15±5 minutes. Then, concentrated Hydrochloric acid (12.5 grams) was added at 20-30°C and stirred for 15 minutes. Separated the organic layer and washed with DM water (350 ml).

The above lactam organic layer was combined with (R)-Ibuprofen organic layer and concentrated under vacuum at below 35°C. Then, methanol (700 ml) was added and heated to 50-55°C and stirred for 60 minutes. The above reaction mass was concentrated under reduced pressure at a temperature below 40°C till the volume of the reaction mass reaches to 120 to 150 ml. Then the reaction mass cooled to 20-30°C and methyl t-butyl ether (750 ml) was added at 20-30°C. The reaction mass was heated to 50-55°C and stirred for 45±5 minutes and then maintained for 4 hours at 20-25°C. The product was filtered and washed with mixture of methanol: methyl t-butyl ether (1:9 ratio) (50 ml) and then dried under vacuum to obtain Lactam (R)-Ibuprofen salt (weight: 30 grams).

Chiral HPLC Purity: 99.82%
HPLC purity: 99.87 %

EXAMPLE – 3:
Preparation of Lactam (R)-Ibuprofen salt [Formula – IIb]:
Racemic Lactam Hydrochloride (100.0 g, 0.309 mmol) was added to purified water (1000 ml) at 20-30°C. Aqueous solution of potassium carbonate (51.38 grams of potassium carbonate in 200 ml of purified water) was added to the reaction mass and stirred at 20-30°C for 2 hours. The obtained solid was filtered, washed with purified water (2 x 200 ml) and dried under vacuum at 45-50°C to obtain Racemic Lactam free amine (weight: 75 grams).

(R)-Ibuprofen-(R)-Phenyl ethylamine salt (96.38 grams, 0.294 mmol), methylene chloride (500 ml) and purified water (500 ml) were charged to another flask at 20-30°C and stirred for 15±5 minutes. The pH of the reaction mass was adjusted to 1.0 to 2.0 by using concentrated hydrochloric acid solution (36.0 grams, 0.346 mmol). The organic layer was washed with purified water (500 ml) and concentrated to obtain (R)-Ibuprofen as thick oily mass product. The obtained (R)-Ibuprofen was dissolved in MTBE (1500 ml) at 20-30°C.

Racemic lactam free amine (75 grams, 0.2622 mmol) was added to ethanol (300 ml) in another flask and stirred at 20-30°C for 30 ±5 minutes to obtain a clear solution. Then, the above reaction mass of R-Ibuprofen in MTBE was added and stirred at 20-30°C for 3 hours. The solid was filtered and washed with MTBE (200 ml) to obtain Lactam (R)-Ibuprofen salt as wet compound. (Weight: ~55 grams).

Chiral HPLC Purity: 95.48 %

The obtained Lactam (R)-Ibuprofen salt (55 grams) was added to the mixture of Ethanol: MTBE (3:15 ratio) at 20-30°C. The reaction mass was stirred at 20-45°C for 3-4 hours. The solid was filtered and washed with MTBE (55 ml) to obtain Lactam (R)-Ibuprofen salt. (Weight: ~40 grams)

Chiral HPLC Purity: 99.95%
EXAMPLE - 4:
Preparation of Lactam hydrochloride [Formula – II. HCl]
Lactam (R)-Ibuprofen salt (10 grams, 0.020 mmol) was added in DM water (100 ml) at 20-30°C. The pH of the reaction mass was adjusted to 11-12.0 using 10% aqueous NaOH solution (9 ml, 1.1 m.eq) at 20-30°C. The reaction mass was extracted with methylene chloride (100 ml) and concentrated under vacuum at below 35°C to obtain Lactam compound (as concentrated mass).

MTBE (100 ml) and concentrated hydrochloric acid (3.62 ml, 0.04 mmol) were added to the above obtained concentrated mass at 20-30°C and stirred for 1 hour at 20-30°C. The obtained solid was filtered, washed with MTBE (10 ml) and dried under vacuum at 50 to 55°C to obtain Lactam hydrochloride of Formula – II (weight: 6.1 grams).

Chiral HPLC Purity: 99.71%
HPLC purity: > 99.75 %

EXAMPLE - 5:
Preparation of Ubrogepant [Formula – I]
Lactam hydrochloride (3.0 grams, 0.0092 mmol) was added in DM water (15 ml) at 20-30°C. The pH of the reaction mass was adjusted to 11-12.0 using 10% aqueous sodium hydroxide solution (4 ml) at 20-30°C. The reaction mass was extracted with methylene chloride (15 ml), separated and concentrated the organic layer under vacuum at below 35°C to obtain Lactam compound as concentrated mass. Acetonitrile (25 ml), DM water (10 ml) and Spiro acid compound (2.1 grams, 1 mmol) were added to the above concentrated mass at 20-30°C, stirred for 10 minutes. EDC.HCl (1.8 grams, 0.0094 mmol) and HOPO (hydroxy pyridine-N-oxide; 85 gram, 0.00094 mmol) were added at 20-30°C and stirred the reaction mass for 12 hours. After completion of the reaction, DM water (10 ml) and MDC (20 ml) were added to the reaction mass at 20-30°C and stirred for 10 minutes. Organic layer was separated and concentrated under vacuum at below 35°C and co-distilled with ethanol (10 ml) at 40-45°C. MTBE (30 ml) was added to the concentrated mass at 20-30°C and stirred for 1 hour. Filtered the solid, washed with MTBE (10 ml) and dried under vacuum at below 35°C to obtain Ubrogepant [weight: 3grams]
HPLC purity: more than 99% ,CLAIMS:CLAIMS
We claim,

1. A compound of formula - IIb,

2. The compound as claimed in claim 1, wherein the chiral acid comprises of (R)-ibuprofen, (R)-ibuprofen (R)-(+)-phenyl ethyl amine, (S)-ibuprofen, (S)-ibuprofen (S)-(+)-phenyl ethyl amine, mandelic acid, camphor sulphonic acid, tartaric acid.

3. A compound of formula - IId,

4. A process for the preparation of lactam chiral acid salt compound of formula – IIb,

which comprises:
(i) treating racemic lactam compound of formula – IIc,

or pharmaceutically acceptable salt thereof with a chiral acid or pharmaceutically acceptable salt thereof to obtain lactam chiral acid salt of formula – IIb;
(ii) purifying lactam chiral acid salt of formula – IIb by using a solvent or mixture thereof.

5. A process for the preparation of lactam compound of formula – II or pharmaceutically acceptable salt thereof,

which comprises:
(i) treating lactam chiral acid salt of formula – IIb, which is prepared as claimed in claim 3, with a base to obtain lactam compound of formula – II;
(ii) optionally converting lactam compound of formula – II into its pharmaceutically acceptable salt thereof.

6. 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 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.

7. The process as claimed in claim 4, wherein the pharmaceutically acceptable salt of step (ii) comprises hydrochloride, hydrobromide, sulphate, bisulphate, para toluene sulphonate and methane sulphonate.

8. The process as claimed in claim 4, wherein preparation of Ubrogepant of formula – I,

by using lactam compound of formula – II or its pharmaceutically acceptable salt thereof.