DESC:PROCESS FOR THE PREPARATION OF CABOTEGRAVIR
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN201941032186 filed on August 08, 2019.
FIELD OF THE INVENTION
The present invention relates generally to the pharmaceutical arts, and more particularly to a process for the preparation of cabotegravir or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Cabotegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) currently under development for the treatment of HIV-1 infection in combination with other antiretroviral agents. It is chemically designated as (3S,11aR)-N[2,4- Difluorophenyl)methy1]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo [3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide and can be represented by the following chemical structure according to Formula (I).

Formula-I
PCT Publication No. WO2006/116764A1 discloses cabotegravir and a process for the preparation of cabotegravir.
The present invention provides a process for the preparation of cabotegravir and pharmaceutically acceptable salts thereof.

OBJECT OF THE INVENTION
The main object of the present invention is to provide novel process for the preparation of cabotegravir utilizing alkenylamine intermediates.

SUMMARY OF THE INVENTION
In one aspect, the present invention encompasses a process for the preparation of cabotegravir, having the steps of:
a) condensing the compound of formula 4 with 2,4-difluorobenzylamine to obtain a compound of formula 3;

b) oxidizing the compound of formula 3 to obtain a compound of formula 2;

c) reacting the compound of formula 2 with L-alaninol to obtain a compound of formula 1; and

d) converting the compound of formula 1 to cabotegravir.

The condensing step (i.e., step a)) may be carried out in the presence of a base, which may be N-methylmorpholine (NMM), diisopropylethylamine, triethylamine, N,N’-dimethylpiperazine, N-methylpiperidine, pyridine, or mixtures thereof. In certain embodiments, the base used in this step is N-methylmorpholine. The condensing step may also be carried out in the presence of a coupling agent, which may be isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-y 1-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxyIate-2-oxime, o-(6-chloro-l-hydroxybenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(l H-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU), or mixtures thereof. In certain embodiments, the coupling agent used in this step is isobutyl chloroformate.
The condensing step may also be carried out in the presence of an additive such as, for example, hydroxyl benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), imidazole or its salts, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), dimethylaminopyridine (DMAP), or mixtures thereof.
The oxidizing step in this method (i.e., step b)) may be carried out using an oxidizing agent, such as, for example, ozone, ozonized oxygen, periodic acid, osmium tetroxide-periodate, ruthenium trichloride-periodate, sodium metaperiodate, sodium orthoperiodate, ruthenium trichloride/potassium peroxymonosulfate, bis(acetonitrile)dichloropalladium(II), bis(benzonitrile)palladium(II)chloride, or mixtures thereof. In certain embodiments, the oxidizing agent used in this step is ozone or ozonized oxygen.
The step where the compound of formula 2 is reacted with L-alaninol to obtain a compound of formula 1 (i.e., step c)) may be conducted in the presence of a solvent and an acid. The solvent may be an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, an ester solvent, a polar aprotic solvent, or mixtures thereof. The acid used in this step may be acetic acid, methane sulfonic acid, p-toluenesulfonic acid, or mixtures thereof. In certain embodiments, the solvent used in this step is acetonitrile and the acid is acetic acid.
This process may also include the step of converting cabotegravir to a pharmaceutically acceptable salt of cabotegravir.
DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention.

One embodiment of the present invention provides a process for the preparation of cabotegravir or pharmaceutically acceptable salts thereof.
According to an embodiment of the present invention, cabotegravir may be prepared by the following steps:
a) condensing the compound of formula 4 with 2,4-difluorobenzylamine to obtain a compound of formula 3;

b) oxidizing the compound of formula 3 to obtain a compound of formula 2;

c) reacting the compound of formula 2 with L-alaninol to obtain a compound of formula 1; and

d) converting the compound of formula 1 to cabotegravir.


According to this embodiment of the present invention, a compound of formula 4 may then be condensed with 2,4-difluorobenzylamine to obtain a compound of formula 3. This reaction may occur in presence of a base and a coupling agent in a suitable solvent. Optionally, an additive may be also be used in this reaction. Within the context of this embodiment of the invention, the additive may enhance the reaction, for example, to increase the rate of the reaction or to control the product distribution.
Within the context of this embodiment of the present invention, the base may be, for example, N-methylmorpholine (NMM), N,N-diisopropylethylamine, triethylamine, N,N’-dimethylpiperazine, N-methylpiperidine, pyridine, or mixtures thereof. In particularly useful embodiments of the present invention, N-methylmorpholine is used as a base. One of skill in the art will recognize numerous bases that may be useful for this reaction.
Within the context of this embodiment of the present invention, the coupling agent may be, for example, isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-y 1-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxyIate-2-oxime, o-(6-chloro-l-hydroxybenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(l H-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU), or mixtures thereof. In particularly useful embodiments of the present invention, isobutyl chloroformate is used as a coupling agent. One of skill in the art will recognize numerous additional coupling agents that may be useful for this reaction.
Within the context of this embodiment of the present invention, examples of suitable solvents include esters such as ethyl acetate, ethers such as tetrahydrofuran, chlorinated hydrocarbons such as methylene dichloride, and mixtures thereof. In particularly useful embodiments of the present invention, methylene dichloride is used as a solvent.
Within the context of this embodiment of the present invention, the additive may be, for example, hydroxyl benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), imidazole or its salts, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), dimethylaminopyridine (DMAP), or mixtures thereof. Within the context of the present invention, the additive may be utilized to enhance the reaction, for example, to increase the rate of the reaction, or to control the product distribution.
One of skill in the art will recognize numerous other additives that may be useful within the context of the present invention.
According to this embodiment of the present invention, a compound of formula 3 may then be oxidized to get a compound of formula 2. Within the context of the present invention, this reaction may be performed by reacting the compound of formula 3 with an oxidizing agent in the presence of a solvent. The oxidizing agent may be, for example, ozone, ozonized oxygen, periodic acid, osmium tetroxide-periodate, ruthenium trichloride-periodate, sodium metaperiodate, sodium orthoperiodate, rutheniumtrichloride/potassiumperoxymonosulfate, bis(acetonitrile)dichloropalladium(II), bis(benzonitrile)palladium(II)chloride, or mixtures thereof. In particularly useful embodiments of the present invention, a mixture of osmium tetroxide and sodium metaperiodate is used as an oxidizing agent. In other particularly useful embodiments of the present invention, the oxidizing agent is rutheniumtrichloride/potassiumperoxymonosulfate. In yet other particularly useful embodiments of the present invention, ozone gas or ozonized oxygen is used as an oxidizing agent. One of skill in the art will recognize numerous additional oxidizing agents that may be useful for oxidizing compound of formula 3 to result in a compound of formula 2.
Within the context of this embodiment of the present invention, examples of suitable solvents include alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, ketones such as acetone or methyl isobutyl ketone, other polar aprotic solvents such as acetonitrile, and mixtures thereof. In particularly useful embodiments of the present invention tetrahydrofuran is used as a solvent.
A compound of formula 2 may then be reacted with L-alaninol to obtain a compound of formula 1. This reaction may be performed in a suitable solvent and an acid.
Within the context of this embodiment of the present invention, examples of suitable solvents include alcohols such as methanol or ethanol, aromatic hydrocarbons such as toluene, ethers such as tetrahydrofuran, esters such as ethyl acetate, polar aprotic solvents such as acetonitrile, and mixtures thereof. In particularly useful embodiments of the present invention, acetonitrile is used as a solvent.
Within the context of this embodiment of the present invention, examples of suitable acids include acetic acid, methane sulfonic acid, p-toluenesulfonic acid, and mixtures thereof. In particularly useful embodiments of the present invention, acetic acid is used. One of skill in the art will recognize numerous other acids that may be useful to convert formula 2 to formula 1.
A compound of formula 1 may then be converted to cabotegravir. This reaction may be performed in the presence of a suitable reagent and a solvent.
Examples of suitable reagents include metal bromides, for example, magnesium bromide or lithium bromide.
Examples of suitable solvents include tetrahydrofuran, acetonitrile, N-methyl pyrrolidone, dimethyl formamide, and mixtures thereof. In particularly useful embodiments of the present invention, lithium bromide is used as a reagent and tetrahydrofuran is used as solvent.
Within the context of the present invention, the compound of formula 4 can be prepared according to process disclosed in PCT publication WO 2016125192, which is as shown below:

Within the context of the present invention, cabotegravir may be optionally converted into a pharmaceutically acceptable salt of cabotegravir.
The term “pharmaceutically acceptable salt” is well known and understood in the art and refers to salts of pharmaceutically active agents which are suitable for use in contact with the tissues of humans and lower animals without undue adverse effects (e.g., toxicity, irritation, allergic response). Examples of pharmaceutically acceptable salts may be found in S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), in which all information pertaining to the pharmaceutically acceptable salts and processes for preparation thereof are hereby incorporated by reference.
Preparation of a pharmaceutically acceptable salt of an active pharmaceutical agent is well known in the art. For example, the salts can be prepared in situ during the final isolation and purification of the compounds taught herein or separately by reacting a free base or free acid moiety on the active pharmaceutical agent with a suitable reagent. For example, a free base moiety on cabotegravir can be reacted with a suitable acid to obtain a pharmaceutically acceptable basic salt of cabotegravir. In another example, a free acid moiety on cabotegravir may be reacted with a suitable base to obtain a pharmaceutically acceptable acid salt of cabotegravir.
Pharmaceutically acceptable salts of cabotegravir include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts. In some embodiments, the sodium salt of cabotegravir is particularly useful.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions, and formulations according to the present invention. All references made to these examples for the purpose of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present invention.
Example 1: Preparation of Methyl-1-allyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate
N-methyl morpholine (9.6 g) was added to the suspension of 1-allyl-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (23 g) in methylene dichloride (138 mL) and the solution was cooled to -10 to -15°C. A solution of Isobutyl chloroformate (11.8 g) in methylene dichloride (46 mL) was added to the reaction mass slowly over 20-30 minutes and stirred at -10 to -15°C for 1 hour. Thereafter, a solution of 2,4-difluorobenzylamine (12.32 g) in methylene dichloride (23 mL) was added at -10 to -15°C and maintained at the same temperature for 2 hours after which the temperature of the reaction mass was raised to 25-35°C to complete reaction. The reaction mass was then washed with 5% (w/v) aqueous potassium carbonate solution (138 mL) twice, 10% (w/v) aqueous NaCl solution (92 mL), 5% (w/v) aqueous citric acid solution (138 mL), and finally with 5% (w/v) aqueous NaCl solution (92 mL). The organic layer was dried over anhydrous sodium sulfate (3 g) and concentrated under reduced pressure. The residue was further treated with methanol under reflux and cooled to obtain Methyl-1-allyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (30 g).
Example 2: Preparation of Methyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate
Methyl-1-allyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (25 g) was dissolved in THF (500 mL). The solution was cooled to -10°C and ozone gas was passed through the solution by maintaining temp until the ozonolysis reaction is complete. The solution was purged with nitrogen to remove excess of dissolved ozone. Temperature of reaction was adjusted to 25-35°C. Water (625 mL) and Ethyl acetate (250 mL) was charged to it and layers separated. Organic layer was washed with 5% sodium metabisulphite solution (250 ml) followed by 10% NaCl solution (250 ml). Hexane (750ml) was added to the organic layer and stirred at 25-35°C. material filtered and dried to get Methyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate (28 g).
Example 3: Preparation of (3S,11aR)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Methyl-5-(2,4-difluorobenzylcarbamoyl)-3-methoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate (40g) was mixed with acetonitrile (200ml) and Acetic acid (9.14g). It was heated to 58±3°C. L-alaninol solution (10.7g dissolved in 40 ml acetonitrile) was slowly added to the reaction and maintained for 2 hours. Reaction mass was concentrated under vacuum at below 50°C to get residue. Isopropyl alcohol (200 mL) was charged to the residue and heated to 60±2°C. Reaction mass was cooled to 25±3°C and filtered, bed washed with Isopropyl alcohol (40ml) and dried to get (3S,11aR)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (37 g).
Example 4: Preparation of Cabotegravir.
(3S,11aR)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11ahexahydro oxazolo [3,2-a] pyrido [1,2-d]pyrazine-8-carboxamide (30g) was charged into Tetrahydrofuran (450ml). Lithium bromide (13.7g) was charged to it and heated to 64±2°C. Reaction mass was maintained for 6 hours and gradually cooled to 20°C. Sulfuric acid solution (16.1g diluted in 450ml water) was added slowly. Reaction mass was stirred for 1 hour and filtered off, dried under vacuum to get Cabotegravir (25 g).
Example 5: Preparation of Cabotegravir Sodium.
Cabotegravir (10 g) was slurried in ethanol (360ml), Sodium hydroxide solution (0.98g dissolve in 20 ml water) was added slowly to the reaction mass and stirred for 1 hour. Diisopropyl ether (100ml) was added to it and stirred for 30 min. Filtered and dried under vacuum to get Cabotegravir Sodium (9.8 g).

,CLAIMS:1. A process for the preparation of cabotegravir, which comprises:
a) condensing the compound of formula 4 with 2,4-difluorobenzylamine to obtain a compound of formula 3;

b) oxidizing the compound of formula 3 to obtain a compound of formula 2;

c) reacting the compound of formula 2 with L-alaninol to obtain a compound of formula 1; and

d) converting the compound of formula 1 to cabotegravir.

2. The process as claimed in claim 1, wherein the condensing step a) is carried out in the presence of a base selected from the group consisting of N-methylmorpholine (NMM), diisopropylethylamine, triethylamine, N,N’-dimethylpiperazine, N-methylpiperidine, pyridine, and mixtures thereof.

3. The process as claimed in claim 1, wherein the condensing step a) is carried out in the presence of a coupling agent selected from the group consisting of isobutyl chloroformate, carbonyldiimidazole (CDI), pivaloyl chloride, o-benzotriazole-l-yl-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-y 1-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-l-yl-oxy-tris(pyrrolidino) phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxyIate-2-oxime, o-(6-chloro-l-hydroxybenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(l H-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU), and mixtures thereof.

4. The process as claimed in claim 1, wherein the condensing step a) is carried out optionally in the presence of an additive selected from the group consisting of hydroxyl benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), imidazole or its salts, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), dimethylaminopyridine (DMAP), and mixtures thereof.

5. The process as claimed in claim 1, wherein the oxidizing step b) is carried out using an oxidizing agent selected from the group consisting of ozone, ozonized oxygen, periodic acid, osmium tetroxide-periodate, ruthenium trichloride-periodate, sodium metaperiodate, sodium orthoperiodate, ruthenium trichloride/potassium peroxymonosulfate, bis(acetonitrile)dichloropalladium(II), bis(benzonitrile)palladium(II)chloride, and mixtures thereof.

6. The process as claimed in claim 1, wherein step c) is conducted in the presence of a solvent, which is selected from the group consisting of alcohol solvent, aromatic hydrocarbon solvent, ether solvent, ester solvent, polar aprotic solvent, and mixtures thereof; and an acid, which is selected from the group consisting of acetic acid, methane sulfonic acid, p-toluenesulfonic acid, and mixtures thereof.

7. The process as claimed in claim 1, wherein step d) is conducted in the presence of metal bromides, which is magnesium bromide or lithium bromide; and a solvent which is selected from tetrahydrofuran, acetonitrile, N-methyl pyrrolidone, dimethyl formamide, and mixtures thereof.

8. The process as claimed in claim 1, further comprising converting cabotegravir to a pharmaceutically acceptable salt of cabotegravir.