DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

“Process for the preparation of Dolutegravir Key intermediate”

AKTINOS Pharma Private Limited
4th and 5th floor, Sri Lakshmi Spaces, Plot no 7, Kavuri hills, Phase 1
Madhapur, Hyderabad, Telangana State, India- 500033

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

“Process for the preparation of Dolutegravir Key intermediate”

Field of the Invention:
The present invention relates to the preparation of Key intermediate of Dolutegravir, more specifically a new method for the synthesis of 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid.

Background of the Invention:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid is an important key intermediate of Dolutegravir, which is useful as HIV integrase inhibitors. Compared with the existing HIV integrase inhibitors Raltegravir and Ritonavir, the drug has improved safety and compared with Merck’s anti-HIV/AIDS drug. Dolutegravir not only achieved comparable efficacy in phase III clinical trials, but also did not need to be combined with drug accelerators, and at the same time, it has very strong resistance.
At present, most of the synthetic process of Dolutegravir requires the use of the core intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydro pyridine-3-carboxylic acid.
Chinese patent application CN110294705 discloses a method for the synthesis of key intermediates of Dolutegravir, involving the field of Dolutegravir compound synthesis. The present invention includes the synthesis of key intermediate of Dolutegravir 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid.
The invention uses Methyl 4-methoxy-2-methoxymethylene acetoacetate or Methyl 4-methoxy-2-ethoxymethylene acetoacetate as raw materials. Substitution, cyclization followed by hydrolysis reaction yields the target product Dolutegravir key intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid.

This method has high yield and low cost, but there is still a lot of room for improvement in purity.
Chinese patent application CN108101838 discloses a method for the synthesis of Dolutegravir intermediates and the detection method of related substances. Using methyl 4-chloroacetoacetate and benzyl alcohol as starting materials, Dolutegravir intermediate can be obtained in only four steps, as shown below.

Above synthesis of this intermediate generally has problems such as low yield, high cost, high pollution, and high industrialization difficulty.
WO2011119566 discloses a method for the synthesis of Dolutegravir intermediate using Methyl 4-methoxyacetoacetate as raw material.

The raw materials are expensive, which leads to high production costs. EP2602260 discloses the synthesis of Dolutegravir intermediate using Methyl 4-methoxyacetoacetate as starting material.

The yield of this method is very low, among which the two-step comprehensive yield of the second and third steps is only 22%, resulting in high raw material utilization as well as huge costs.
CN104557686 discloses a preparation method using 1,4-dihydro-3-methoxy-4-oxo-2,5-pyrandicarboxylic acid as raw material.

The method is not easy to prepare the starting materials, which leads to long synthetic routes, complicated operations and high raw material costs.
At present, the synthesis of this Dolutegravir key intermediate generally has problems such as low yield, high cost, high pollution, and high commercialization difficulty. The purpose of the present invention is to provide a method to prepare 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, which is simple in steps, mild in conditions, and environmental friendly in view of the deficiencies of the prior art. More importantly, the raw materials are cheap and easy to obtain and the supply is stable, which creates favorable conditions for reducing the raw material cost of Dolutegravir.

Summary of the invention:
An embodiment of the present invention is to provide a method for preparing Dolutegravir core intermediate of formula IX.

Another embodiment of the present invention provides the technical scheme of the present invention is as follows:
In one Aspect, the present invention is a method comprising contacting a compound of formula I in presence of base, and solvent to obtain compound of formula II.

In second Aspect, the present invention is a method comprising contacting a compound of formula II

with Dimethylformamide dimethyl acetal of formula III

which undergo condensation reaction to obtain compound of formula IV.

In third Aspect, without isolating the compound of formula IV

with Aminoacetaldehyde dimethyl acetal compound of formula V

under substitution reaction to obtain compound of formula VI.

In fourth Aspect, without isolating the compound of formula VI under cyclization reaction with dimethyl oxalate compound of formula VII

to obtain compound of formula VIII.

In fifth Aspect, the compound of formula VIII without isolating which undergo hydrolysis to obtain compound of formula IX.

The beneficial effects of adopting the technical solution of the present invention are:
The method for synthesizing Dolutegravir intermediate of the present invention has
• Simple steps, mild conditions, and relatively eco-friendly process ,
• More importantly, the raw materials are cheap and easily available,
• Low cost, which creates favorable conditions for reducing the raw material cost of Dolutegravir,
• High product yield and quality
The present invention avoids the commonly used reagents sodium hydride, lithium hydride, etc. for ring-closure reactions, and utilizes safer sodium methoxide with mild conditions. Using calcium hydroxide to selectively hydrolyze ester groups, with higher selectivity and lower cost.
The simple and most frequently used method for the hydrolysis of methyl ester is saponification with aqueous alkali, mostly in the presence of varying amounts of organic solvents such as 1,4-dioxane, methanol, ethanol, acetone, dimethylformamide etc. More specifically lithium hydroxide in methanol is used frequently for the hydrolysis of methyl esters in peptide chemistry.
The method provided by the present invention has high yield and low pollution and is especially suitable for industrial production.

Detailed description:
The present invention will be further described below in conjunction with specific embodiments. The examples are only preferred embodiments of the present invention and are not intended to limit the present invention.
To make the technical means, creative features, objectives and effects of the present invention easy to understand, the following examples are combined to further illustrate the present invention. However, the following embodiments are only preferred embodiments of the present invention.
The above mentioned content of the present invention will be further described in detail through below examples.
All technologies implemented based on the above-mentioned content of the present invention belong to the scope of the present invention.
The following scheme illustrates a general process for the preparation of the compound of formula IX, 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydro pyridine-3-carboxylic acid. Scheme 1

In the above scheme, Ethyl 4-chloroacetoacetate in presence of a base and solvent to form Ethyl 4-methoxyacetoacetate. Ethyl 4-chloroacetoacetate and sodium methoxide are used as raw materials, Acetonitrile and toluene used as a solvent. Tetrahydrofuran, Methyl tert-butyl ether are also used as solvent to get selectivity.
In one embodiment, the compound of formula II reacted with N,N-Dimethylformamide dimethyl acetal (III) in presence of solvent to form (E)-Ethyl-2-((dimethylaminomethylene)-4-methoxy-3-oxobutanoate (IV). Solvent is selected from Toluene, Acetonitrile, Acetic acid and dichloromethane. Most preferably acetic acid.
Ethyl 4-methoxyacetoacetate is used as the starting material for the synthesis of Dolutegravir intermediate. Its quality and price have a great influence on the further synthesis of Dolutegravir.
In another embodiment, the compound of formula IV without isolating further reacted with aminoacetaldehyde dimethyl acetal (V) in presence of solvent to form (E)-ethyl-2-((2,2-dimethoxyethylamino)methylene)-4-methoxy-3-oxobutanoate (VI). The solvent is selected from methanol, ethanol, propanol, tetrahydrofuran, acetonitrile. More preferably methanol.
In an embodiment, the compound of formula VI without isolating further reacted with Dimethyl oxalate (VII) in presence of base and solvent to form Ethyl 1-(2,2-dimethoxyethyl)- 5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (VIII). Base selected from sodium methoxide, potassium methoxide, and potassium tertiary butoxide. Most preferably sodium methoxide. Solvent selected from methanol, ethanol, isopropanol, ethyl acetate. Most preferably methanol.
In other embodiment, the compound of formula VIII selectively hydrolyzed with strong base and solvent to form desired intermediate 1-(2,2-dimethoxyehtyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (IX). Strong base is selected from calcium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide. Most preferably calcium hydroxide. Solvent is selected from alcoholic solvent, preferably methanol.
In an additional embodiment, the compound of formula VIII selectively hydrolyzed with lithium hydroxide monohydrate to obtain desired intermediate 1-(2,2-dimethoxyehtyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (IX).
Scheme 2

In one embodiment, Methyl 4-methoxyacetoacetate (1A), reacted with Dimethylformamide dimethyl acetal under condensation reaction in presence of acetic acid to form (E)-methyl-2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate (1B). Without isolation of compound of formula 1B, reacted with aminoacetaldehyde dimethyl acetal in presence of methanol to form (E)-methyl-2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate (1C).
In another embodiment, (E)-methyl-2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate (1C) without isolation further reacted with dimethyl oxalate under cyclization in presence of sodium methoxide and methanol to form Dimethyl 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (1D).
In an embodiment, compound of formula 1D without isolation undergo hydrolysis in presence of lithium hydroxide monohydrate to form desired intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (IX).
In another embodiment, compound of formula 1D without isolation undergo hydrolysis in presence of calcium hydroxide to form desired intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (IX).

Examples:
Preparation of Ethyl 4-methoxyacetoacetate (II):
Example 1:
To the mixture of Sodium methoxide (70.0 g, 1.29 moles) in Acetonitrile (100.0 mL, 1.0 vol), Ethyl 4-chloroacetoacetate (100.0 g, 0.607 moles) was added at below 70°C. The reaction mass was stirred for 60 minutes at 65-70°C. After reaction completion, reaction mass was cooled to 25°C and diluted with Toluene (200.0 mL, 2.0 vol). The reaction mass was neutralized with aqueous Hydrochloric acid and the organic layer was separated. The organic layer was concentrated under reduced pressure and purified by fractional distillation to get Ethyl 4-methoxyacetoacetate (72.0 g).

Example 2:
To the mixture of Sodium methoxide (70.0 g, 1.29 moles) in Methyl tert.butyl ether (500.0 mL, 5.0 vol), Ethyl 4-chloroacetoacetate (100.0 g, 0.607 moles) was added at below 60 °C. The reaction mass was stirred for 60 minutes at 55-60 °C. After reaction completion, reaction mass was cooled to 25 °C. The reaction mass was neutralized with aqueous Hydrochloric acid and the organic layer was separated. The organic layer was concentrated under reduced pressure and purified by fractional distillation to get Ethyl 4-methoxyacetoacetate (71.0 g).

Example 3:
To the mixture of Sodium methoxide (70.0 g, 1.29 moles) in Acetonitrile (100.0 mL, 1.0 vol), Ethyl 4-chloroacetoacetate (100.0 g, 0.607 moles) was added at below 70°C. The reaction mass was stirred for 60 minutes at 65-70 °C. After reaction completion, reaction mass was cooled to 25 °C and diluted with Toluene (200.0 mL, 2.0 vol). The reaction mass was neutralized with Sulphuric acid and undissolved salts was separated by filtration. The filtrate was concentrated under reduced pressure and purified by fractional distillation to get Ethyl 4-methoxyacetoacetate (71.5 g).

Preparation of Methyl 4-methoxyacetoacetate (1A):
To the mixture of Sodium methoxide (70.0 g, 1.29 moles) in methanol (400.0 mL, 4.0 vol), Ethyl 4-chloroacetoacetate (100.0 g, 0.607 moles) was added at below 65°C. The reaction mass was stirred for 6 hours at 60-65°C. After reaction completion, the reaction mass was concentrated under reduced pressure and cooled to 25°C. The reaction mass was diluted with Toluene (200.0 mL, 2.0 vol) and neutralized with aqueous Hydrochloric acid. Organic layer was separated and concentrated under reduced pressure. The crude product was purified by fractional distillation to get Methyl 4-methoxyacetoacetate (65.0 g).
Preparation of 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (IX):
Example 1:
Acetic acid (3.1 mL, 0.062 vol) was charged into Ethyl 4-methoxyacetoacetate (50.0 g, 0.312 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass was heated to 33-37°C and maintained for 5 hours. The reaction mixture was diluted with Methanol (100.0 mL, 2.0 vol) and Aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C. The reaction mass was stirred for 90-120 minutes at 22-28°C.
The reaction mass was concentrated under vacuum at below 40 °C. The concentrated mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate (101.0 g, 0.855 moles) was added at 19-25°C. 30% Sodium methoxide solution (132.5 mL, 2.65 vol) was added into the reaction mass at 0-6°C and stirred for 5 hours at 38-44°C. After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane-water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid. After layer separation, solvent was distilled out up to 50% of the total volume. Reaction mass was diluted with Methanol (25.0 mL, 0.5 vol) and cooled to -5 to 5°C.
Lithium hydroxide monohydrate (15.75 g, 0.375 moles) was added into the reaction mass in lots at -5 to 5°C and stirred for 60 minutes. After completion of reaction, reaction mass was quenched into dilute hydrochloric acid at 0-10°C. Organic layer was separated and concentrated under reduced pressure. To the concentrated mass, water (350.0 mL, 7.0 vol) was added and the product was filtered. The wet material was dried at 50°C to yield 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (80.0 g).

Example 2:
Acetic acid (3.1 mL, 0.062 vol) was charged into Ethyl 4-methoxyacetoacetate (50.0 g, 0.312 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass was heated to 33-37°C and maintained for 5 hours. The reaction mixture was diluted with Methanol (100.0 mL, 2.0 vol) and aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C.
The reaction mass was stirred for 90-120 minutes at 22-28°C. The reaction mass was concentrated under vacuum at below 40°C. The concentrated mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate 101.0 g (0.855 moles) was added at 19-25°C. 30% Sodium methoxide solution (132.5 mL, 2.65 vol) was added into the reaction mass at 0-6°C and stirred for 5 hours at 38-44°C.
After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane-water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid. After layer separation, solvent was distilled out up to 50% of the total volume. Reaction mass was diluted with Methanol (25.0 mL, 0.5 vol) and cooled to 15-20°C. Calcium hydroxide (32.5 g, 0.375 moles) and water (22.5 mL, 0.45 vol) were added simultaneously into the reaction mass in lots at 15-20°C and stirred for 60 minutes.
After completion of reaction, reaction mass was quenched into dilute hydrochloric acid at 0-10°C. Organic layer was separated and concentrated under reduced pressure. To the concentrated mass, water (350.0 mL, 7.0 vol) was added. The product was collected by filtration and washed with chilled methanol. The wet material was dried at 50°C to yield 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (78.0 g).

Example 3:
Acetic acid (3.1 mL, 0.062 vol) was charged into Methyl 4-methoxyacetoacetate (50.0 g, 0.342 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass temperature was raised to 33-37°C and maintained for 5 hours. The reaction mixture was diluted with Methanol (100.0 mL, 2.0 vol) and aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C. The reaction mass was stirred for 90-120 minutes at 22-28°C.
The solvent was distilled out under vacuum at below 40°C. The reaction mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate (101.0 g, 0.855 moles) was added at 19-25°C. Sodium methoxide solution (30%) (132.5 mL, 2.65 vol) was added into reaction mass at 0-6°C and stirred for 5 hours at 38-44°C.
After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane-water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid. After layer separation, solvent was distilled out up to 50% of the total volume. The reaction mass was diluted with Methanol (25.0 mL, 0.5 vol) and cooled to -5 to 5°C. Lithium hydroxide monohydrate (15.75 g, 0.375 moles) was added in lots at -5 to 5°C into the reaction mass. The reaction mass was stirred for 60 minutes at -5 to 5°C.
After completion of reaction, reaction mass was quenched into dilute hydrochloric acid at 0-10°C. Organic layer was separated and concentrated under reduced pressure and then water (350.0 mL, 7.0 vol) was added.
The product was filtered and washed with chilled methanol. The wet material was dried at 50°C to yield 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (78.0 g).
Example 4:
Acetic acid (3.1 mL, 0.062 vol) was charged into Methyl 4-methoxyacetoacetate (50.0 g, 0.342 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass temperature was raised to 33-37°C and maintained for 5 hours. The reaction mixture was diluted with Methanol (100.0 mL, 2.0 vol) and aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C.
The reaction mass was stirred for 90-120 minutes at 22-28°C. The solvent was distilled out under vacuum at below 40°C. The reaction mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate (101.0 g, 0.855 moles) was added at 19-25°C. Sodium methoxide solution (30%) (132.5 mL, 2.65 vol) was added into reaction mass at 0-6°C and stirred for 5 hours at 38-44°C. After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane and water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid.
After layer separation, solvent was distilled out up to 50% of the total volume. Reaction mass was diluted with Methanol (25.0 mL, 0.5 vol) and cooled to 15-20°C. Calcium hydroxide (32.5 g, 0.375 moles) and water (22.5 mL, 0.45 vol) were added simultaneously into the reaction mass in lots at 15-20°C. The reaction mass was stirred for 60 minutes at 15-20°C. After completion of the reaction, reaction mass was quenched into dilute hydrochloric acid at 0-10°C. Organic layer was separated and concentrated under reduced pressure and water (350.0 mL, 7.0 vol) was added.
The product was collected by filtration and washed with chilled methanol. The wet material was dried 50°C to yield 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (78.0 g).

Preparation of Dimethyl 1-(2,2-dimethoxyethyl)-5-methoxy-4-oxo-pyridine-3,5-dicarboxylate-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (1D):
Acetic acid (3.1 mL, 0.062 vol) was charged into Methyl 4-methoxyacetoacetate (50.0 g, 0.342 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass temperature was raised to 33-37°C and maintained for 5 hours. The reaction mixture was cooled to 0-5 °C and diluted with Dichloromethane (100.0 mL, 2.0 vol) followed by water (100.0 ml, 2.0 vol). The reeaction mixture was stirred for 10-20 minutes and the layers were separated. To the organic layer, water (100.0 mL, 2.0 vol) was added and the pH was adjusted between 7.0 and 7.5 with saturated Sodium bicarbonate solution. Both organic and aqueous layers were separated. Organic layer was concentrated under reduced pressure. The obtained residue was diluted with Methanol (100.0 mL, 2.0 vol) and aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C.
The reaction mass was stirred for 90-120 minutes at 22-28°C. The solvent was distilled out under vacuum at below 40°C. The reaction mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate (101.0 g, 0.855 moles) was added at 19-25°C. Sodium methoxide solution (30%, 132.5 mL, 2.65 vol) was added into reaction mass at 0-6°C and stirred for 5 hours at 38-44°C. After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane and water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid.
After layer separation, solvent was distilled out completely to yield Dimethyl 1-(2,2-dimethoxyethyl)-5-methoxy-4-oxo-pyridine-3,5-dicarboxylate-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (1D).
Yield: 190.0 g
HPLC purity: > 97 %

Preparation of Ethyl 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-pyridine-3-carboxylate (VIII):
Acetic acid (3.1 mL, 0.062 vol) was charged into Ethyl 4-methoxyacetoacetate (50.0 g, 0.312 moles) followed by Dimethylformamide dimethyl acetal (49.0 g, 1.20 moles) at -2 to 2°C. The reaction mass was heated to 33-37°C and maintained for 5 hours. The reaction mixture was cooled to 0-5 °C and diluted with Dichloromethane (100.0 mL, 2.0 vol) followed by water (100.0 ml, 2.0 vol). The reeaction mixture was stirred for 10-20 minutes and layers were separated. To the organic layer, water (100.0 mL, 2.0 vol) added and the pH was adjusted between 7.0 and 7.5 with saturated Sodium bicarbonate solution. Both organic and aqueous layers were separated. Organic layer was concentrated under reduced pressure. The obtained residue was diluted with Methanol (100.0 mL, 2.0 vol) and Aminoacetaldehyde dimethyl acetal (39.4 g, 0.374 moles) was added at -3 to 3°C. The reaction mass was stirred for 90-120 minutes at 22-28°C.
The reaction mass was concentrated under vacuum at below 40 °C. The concentrated mass was diluted with Methanol (225.0 mL, 4.5 vol) and Dimethyl oxalate (101.0 g, 0.855 moles) was added at 19-25°C. Sodium methoxide solution (30%, 132.5 mL, 2.65 vol) was added into the reaction mass at 0-6°C and stirred for 5 hours at 38-44°C. After reaction completion, the reaction mass was cooled to 20-30°C and quenched into the mixture of dichloromethane-water. The reaction mass pH was adjusted to 4.5-5.5 using acetic acid. After layer separation, solvent was distilled out completely to yield Ethyl 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-pyridine-3-carboxylate (VIII).
Yield: 185.0 g
HPLC purity: > 95 %.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein may be interpreted as mere illustrative of the invention and not in a limiting sense.

Dated this 28th day of September 2022


Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636
VP, Legal/IPR/Portfolio Management
AKTINOS Pharma Private Limited
RK Pharma subsidiaire

,CLAIMS:WE CLAIM:
1. A process for the preparation of Dolutegravir intermediate of formula IX;

Formula IX
comprising the steps of:
a) reacting the compound of formula I in presence of base and organic solvent to obtain compound of formula II;

I II
b) treating the compound of formula II with N, N-dimethyl formamide dimethyl acetal in presence of acid to obtain a compound of formula IV, which is proceeded to further step without any isolation.

II III IV

c) condensing the compound of formula IV with amino acetaldehyde dimethyl acetal in presence of organic solvent to obtain a compound of formula VI, which is proceeded to further step without any isolation.

IV V VI

d) cyclization of compound of formula VI in presence of dimethyl oxalate (VII), and a base to obtain a compound of formula VIII with 95% of purity, which is proceeded to further step without any isolation.

VI VII VIII

e) hydrolysing the compound of formula VIII in presence of base to give Dolutegravir intermediate compound of formula IX;

VIII IX

2. The process as claimed in claim 1 wherein step a) the reaction is carried out in presence of base selected from the group sodium methoxide, sodium ethoxide, sodium tertiary butoxide. The reaction temperature of the substitution reaction is 65-70°C.

3. The process as claimed in claim 1 wherein step a) the organic solvent is selected from the group comprising of ethanol, methanol, toluene, acetonitrile, ethyl acetate.

4. The process as claimed in claim 1 wherein step b) acid is selected from the group of acetic acid, formic acid, hydrochloric acid. The reaction temperature of the condensation reaction is 33-37°C.

5. The process as claimed in claim 1 wherein step c) alcoholic solvent is selected from methanol, ethanol, propanol. The reaction temperature of the condensation reaction is 22-28°C.

6. The process as claimed in claim 1 wherein step d) base is selected from sodium methoxide, sodium ethoxide, sodium hydroxide. The reaction temperature of the condensation reaction is 38-44°C.

7. The process as claimed in claim 1 wherein step e) base is selected from calcium hydroxide, sodium hydroxide, lithium hydroxide. The reaction temperature of the condensation reaction is -5 to 5°C.

Dated this 28th day of September 2022