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

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 substantially pure compound of Formula – IV.

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

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.

Atogepant of Formula – I' is chemically known as (3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-tri fluorophenyl)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.

The compound of Formula – IV, chemically known as 1-(tert-Butyl)-3-((5-chloro-3-(hydroxymethyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one is an useful intermediate for preparing Spiro acid compound of Formula – III, which is a common key advanced intermediate in both Ubrogepant and Atogepant.

US 8,912,210 disclosed a process for the preparation of Spiro acid compound of Formula – III by esterification and bromination of pyridine-2,3-dicarboxylic acid of Formula – III(a) to obtain dimethyl 5-bromopyridine-2,3-dicarboxylate of Formula III(b), which undergoes reduction to obtain (5-bromopyridine-2,3-diyl)dimethanol of Formula – III(c), then coupled with silyl protected azaoxindole of Formula – III(d) to obtain Spiro cycle compound of Formula – III(e), followed by palladium catalysed carbonylation and chiral resolution to obtain Spiro ester compound of Formula – III(f) as single enantiomer, then deprotecting by using hydrochloric acid followed by hydrolysis using sodium hydroxide to obtain spiro acid compound of Formula – III. The process is depicted below, as Scheme – I:

Scheme – I

The major disadvantage associated with the above-mentioned process is the possibility of potential isomers, dibromination compounds and use of tedious chromatographic procedures which leads to low yield and also makes the process more expensive and commercially non-viable.

The US ‘210 also discloses an alternate process for the preparation of Spiro acid compound by Diazotization of compound of Formula – III(h) followed by treatment with potassium iodide to obtain Formula - III(g), which undergoes palladium-catalyzed carbonylation in methanol to obtain Formula – III(f), which on hydrolysis with sodium hydroxide to obtain spiro acid compound of Formula – III. The process is depicted below, as Scheme – II:

Scheme – II

The major disadvantage associated with the above-mentioned process is the use of sodium nitrite for diazotization reaction, which is hazardous and unsafe for large scale operations.

The US ‘210 patent further disclosed a process for the conversion of Spiro acid compound of Formula – III to Ubrogepant of Formula – I and Atogepant of Formula – I' by coupling with corresponding Lactam compounds of Formula II and II’ (as HCl salts) respectively. The process is depicted below, as Scheme – III:
Scheme – III

US 9,174,989 disclosed a process for the preparation of Formula – IV by treating 2,3-dibromo-5-chloropyridine of Formula–IV(a) with isopropyl magnesium chloride lithium chloride solution followed by reduction to obtain Formula–IV(b), which is then protected with tetrahydropyran and treated with sulfuric acid to obtain Formula – IV(c), then coupled with azaoxindole of Formula – IV(d) in the presence of DBU to obtain Formula – IV(e), which further undergoes reduction to obtain in-situ intermediate of Formula – IV(f) followed by deprotection to obtain compound of Formula – IV. The process is depicted below, as Scheme – III:

Scheme – III

The above-mentioned process for the preparation of compound of Formula – IV leads to the formation of process related impurity i.e. 1-tert-butyl-3-((5-chloro-3-(tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)methyl)-3-hydroxy)-1H-pyrrolo[2,3-b]pyridine-2(3H)-one (THP hydroxy impurity) of Formula – IV'.

The above impurity is difficult to separate and results in low purity of compound of Formula - IV. The above process also requires more purification steps which ultimately results in poor yield.
In an attempt to improve the purity and yield of compound of Formula – IV, the inventors of the present invention found an improved process to prepare compound of Formula – IV to eliminate the formation of process related impurities such as THP hydroxy impurity. Further, the process of the present invention is less expensive, industrially feasible, overcomes the above disadvantages and provides compound of Formula – IV, which can be used as such to obtain Ubrogepant or Atogepant 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 substantially pure compound of Formula – IV.

The compound of Formula – IV is a key intermediate in the preparation of Ubrogepant and Atogepant of Formula – I and Formula – I' respectively.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of compound of Formula – IV or pharmaceutically acceptable salt thereof,

which comprises:

(i) treating a compound of Formula – IV(e) or pharmaceutically acceptable salt thereof with an acid to obtain a compound of Formula – IV(g);
;
(ii) treating the compound of Formula – IV(g) with a reducing agent to obtain the compound of Formula – IV;
(iii) purifying the compound of Formula – IV by using a solvent or mixture thereof;
(iv) optionally converting the compound of Formula – IV into its pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of Formula – IV(g) or pharmaceutically acceptable salt thereof,

Yet, in another embodiment, the present invention provides the use of compound of Formula – IV or pharmaceutically acceptable salt thereof obtained according to the process of the present invention as an intermediate for the preparation of Ubrogepant or Atogepant.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of compound of Formula – IV or its pharmaceutically acceptable salts.

The present invention relates to a compound of Formula – IV(g) or pharmaceutically acceptable salt thereof.

The process for preparation of compound of Formula – IV or its pharmaceutically acceptable salts comprises, treating a compound of Formula – IV(e) or pharmaceutically acceptable salt thereof with an acid to obtain a compound of Formula – IV(g), then treating with a reducing agent to obtain the compound of Formula – IV followed by purifying the compound of Formula – IV by using a solvent or mixture thereof which is then optionally converted to its pharmaceutically acceptable salt.

The acid used in the above reaction comprises hydrochloric acid, sulfuric acid, para toluene sulfonic acid, 1-propane sulfonic acid and like.

The reducing agent used in the above reaction comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride and like.

The above process can be carried out in the presence or absence of a solvent.

The solvent used for the above said reactions and purification step comprises water, alcohols, 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, heptane, 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.

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

The compound of Formula – IV or pharmaceutically acceptable salt thereof obtained according to the process of the present invention can be converted to Spiro acid compound of Formula - III, which is a common key advanced intermediate in both Ubrogepant and Atogepant. The Spiro acid compound of Formula - III from compound of Formula – IV can be produced by methods well known in the art or by process as disclosed in the patent reference US 9,174,989.

The compound of Formula – IV or pharmaceutically acceptable salt is used in the preparation of Ubrogepant / Atogepant as per the known methods in the art.

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 2-Bromo-5-chloropyridine-3-carbaldehyde

THF (500 ml) was added to 2,3-dibromo-5-chloropyridine (100 grams, 368 mmol) and a solution of isopropyl magnesium chloride lithium chloride in THF (1.3 molar, 341 ml) was added at -45 to -35°C for about 90 minutes and stirred for 20 minutes. Then DMF (79.2 grams) was added and the resulting solution was stirred for 60 minutes and then quenched with 1 N HCl (650 ml) and MTBE (200 ml). Organic layer was separated and concentrated under vacuum at 40°C. The resulting solid was added to a solution of sodium metabisulphite (100 grams, 526 mmol) in toluene (500 ml) and water (1000 ml) mixture. The solution was stirred for 15 minutes and the reaction mass pH was adjusted to 3.0-3.5 with acetic acid. Aqueous layer was separated and pH was adjusted to 10-11 with sodium hydroxide solution to obtain desired product as white solid (50 grams).

HPLC Purity: 99.8% purity

EXAMPLE - 2:
Preparation of 2-Bromo-5-chloropyridin-3-yl)methanol [Formula – IV(b)]

Methanol (300 ml) was added to 2-bromo-5-chloropyridine-3-carbaldehyde (50 grams, 227 mmol) and sodium borohydride (6.0 grams, 158 mmol) was added lot wise (1.5 grams each) slowly for about an interval of 15 minutes at 0-5oC. The reaction mixture was stirred for another 30 minutes followed by addition of water (210 ml). The resulting mixture was concentrated under vacuum to approximately 125 ml. Solids precipitated during the concentration were filtered and dried in vacuum oven over night at 60° C to obtain compound of Formula – IV(b) (45 grams, 90 % yield).

HPLC Purity: 99.8% purity

EXAMPLE - 3:
Preparation of 2-Bromo-5-chloro-3-((tetrahydro-2H-pyran-2-yloxy)methyl) pyridine:

MTBE (400 ml) was added to 2-bromo-5-chloropyridin-3-yl)methanol (100 grams, 449 mmol) then 3,4-dihydro-2H-pyran (56.7 grams, 588 mmol) and PTSA (4.0 grams) was added at 25-35oC. The reaction mass was stirred for 120 minutes and washed with saturated sodium bicarbonate solution (250 ml). Organic layer was separated and dried with sodium sulphate and concentrated to obtain title compound (140 grams).

HPLC Purity: 97.9% purity
EXAMPLE - 4:
Preparation of 5-chloro-3-((tetrahydro-2H-pyran-2-yloxy) methyl)pyridine-2-carbaldehyde [Formula – IV(c)]

To a precooled solution of 2-bromo-5-chloro-3-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine (140 grams, 457 mmol) in THF (300 ml), isopropyl magnesium chloride lithium chloride solution (600 ml, 777 mmol) was slowly added maintaining the temperature at -5 to 5°C. Then resulting solution was stirred at -5 to 5°C for 30 minutes and DMF (100 ml) was added for about 30 minutes at below 5°C. The resulting solution was stirred for another 1 hour at this temperature. MTBE (850 ml) was added to the reaction mixture followed by quenching with 15% aqueous citric acid (450 ml), followed by water (300 ml). The organic layer was separated and concentrated under vacuum at 50°C to obtain compound of Formula – IV(c) as reddish oil (84 grams, 80.2% HPLC purity).

EXAMPLE - 4:
Preparation of (E)-1-tert-butyl-3-((5-chloro-3-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)methylene)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one [Formula – IV(e)]

1-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (47 grams, 247 mmol) in isopropanol (1200 ml) and DBU (1.68 grams, 11 mmol) were added to crude compound of Formula – IV(c) (84 grams, 80% w/w and 262 mmol based on assay), at -5 to 0°C. The reaction mixture was stirred for 120 minutes at -5 to 0°C, and then temperature raised to 20-30°C and stirred for overnight. Further, the temperature was raised to 50-55°C and stirred for ~4 hours till the reaction complies by HPLC. The reaction mass cooled to 20-30oC and purified water (1000 ml) was slowly added over a period of 30 minutes and then product was filtered and washed with mixture of isopropanol (10 ml) and water (90 ml). The collected precipitate was dried in a vacuum oven over night at 50°C to obtain title compound of Formula – IV(e) as yellow solid (100 grams, 72 % yield).

HPLC Purity: 99.6 % purity

EXAMPLE - 5:
Preparation of (E)-1-tert-butyl-3-((5-chloro-3-(hydroxymethyl)pyridin-2-yl)methylene)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one [Formula – IV(f)]

Ethanol (800 ml) was added to a compound of Formula – IV(e) (100 grams, 234 mmol) and a mixture of HCl (80 ml) and IPA (80 ml) were slowly added for about a period of 30 minutes. Then the solution was stirred for about 180 minutes and water (2400 ml) was added for about a period of 45 minutes and then reaction mixture was stirred for 1 hour, followed by filtration to obtain title compound of Formula – IV(f) (72 grams, 90 % yield).

HPLC Purity: 99.84 % purity

EXAMPLE - 6:
Preparation of 1-(tert-Butyl)-3-((5-chloro-3-(hydroxymethyl)pyridin-2-yl) methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one [Formula – IV]

Ethanol (800 mL) was added to a compound of Formula – IV(f) (72 grams, 282 mmol) and then sodium borohydride (12.3 grams) was added in three equal lots for every 15 minutes. The resulting suspension was stirred at 0-5oC for 90 minutes. The reaction was quenched by adding purified water (200 mL) over a period of 30 minutes and stirred at 25-35oC for 60 minutes. The solid was filtered and washed with heptane (500 ml) to obtain the title compound of Formula – IV (60 grams, 83% yield).

HPLC Purity: 99.9 % purity ,CLAIMS:CLAIMS
We claim,

1. A process for the preparation of compound of Formula – IV or pharmaceutically acceptable salt thereof,

which comprises:
(i) treating a compound of Formula – IV(e) or pharmaceutically acceptable salt thereof with an acid to obtain a compound of Formula – IV(g);
;
(ii) treating the compound of Formula – IV(g) with a reducing agent to obtain the compound of Formula – IV;
(iii) optionally purifying the compound of Formula – IV by using a solvent or mixture thereof.

2. The process as claimed in claim 1, wherein the acid used in step (i) comprises hydrochloric acid, sulfuric acid, para toluene sulfonic acid, 1-propane sulfonic acid and like.
3. The process as claimed in claim 1, wherein the reducing agent used in step (ii) comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride and like.

4. The process according to claim 1, wherein the solvent used in step (iii) comprises water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulphoxides, nitriles, esters, ethers, ketones or mixtures thereof.

5. A compound of formula – IV(g) or pharmaceutically acceptable salt thereof,