The present disclosure relates to cobicistat intermediates and processes for the conversion of intermediates to cobicistat with improved yield and quality.

Background: Cobicistat is a component of a four-drug, fixed-dose combination for HIV treatment elvitegravir/cobicistat/emtricitabine/tenofovir (known as the "Quad Pill" or Stribild). The Quad Pill/Stribild was approved by the FDA in August 2012 for use in the United States.

Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide fUmarate.

Cobicistat known by chemical name of 1 ,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)2-[(methyl{[2- (propan-2-yl)-1 ,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4yl)but anoyl]amino}-1 ,6- diphenylhexan-2-yl]carbamate (Formula I).

US 8148374 patent discloses cobicistat, its pharmaceutically acceptable salts and It ^' s pharmaceutical composition.

WO2010115000 discloses a process for the preparation of cobicistat using novel intermediates. According to WO2010115000 publication, process for the preparation of Cobicistat and their novel intermediates are prepared as depicted below synthetic scheme- B.

Preparation of Intermediate Formula IX: The process disclosed in the WO2010115000 publication utilizes sodium hydride, which is highly flammable, is difficult to handle in bulk production. The process also involves the use of the expensive reagent, trimethylsilyl iodide. Thus, there is a need for a cost effective process for the preparation of cobicistat that utilizes inexpensive, easily handled reagents.

Summary:

A first aspect of the disclosure relates cobicistat intermediates of formula 9, 4a and further conversion of the intermediates to cobicistat.

Another aspect relates to a process for the preparation of (S)-2-benzyl-N,N-dimethylaziridine-1- sulfonamide (aziridine formula 8), comprising the steps of; protecting L-phenylalaninol with Ν,Ν-Dimethylsulfamoylchloride in the presence of a base to give amino protected alcohol of formula 9, and cyclising amino protected alcohol of formula 9 to give aziridine formula 8.

Still another aspect relates to a process for the preparation of morpholine thiazole ester formula 3a comprising the steps of: reacting L-thiazole amino lactone formula 5a with trimethylsilyl bromide in the presence of an alcohol solvent to give bromothiazole ester formula 4a, reacting the bromothiazole ester formula 4a with morpholine to give morpholine thiazole ester formula 3a, and

optionally converting the morpholine thiazole ester formula 3a to its salt.

Yet another aspect is to provide a novel compound of formula 9.

Yet another aspect is to provide a novel compound of formula 4a.

Yet still another aspect relates to a process for the preparation of cobicistat as depicted in the following synthetic scheme (Scheme-C).

Preparation of intermediate 2: Preparation of intermediate 3a:

Preparation of Cobicistat:

Formula I ( Cobicistat)

Scheme-B

Detailed Description:

The present disclosure relates to an improved process for the preparation of cobicistat, wherein the process involves cost effective reagents and the process is feasible in large scale production. The present disclosure encompasses an improved process for the preparation of cobicistat using intermediates of formula 9 and 4a.

Yet another embodiment relates to process for the preparation of aziridine intermediate formula 8 comprising the steps of: protecting the amine of L-phenylalaninol of formula 10 with N,N-dimethylsulfamoyl chloride in the presence of base to give amino protected alcohol of formula 9, and

cyclising amino protected alcohol of formula 9, and to give aziridine formula 8.

Yet another embodiment relates to a process for the preparation of morpholine thiazole ester formula 3a comprising the steps: reacting L-thiazole amino lactone formula 5a with trimethylsilyl bromide in the presence of ROH to give bromothiazole ester formula 4a,

reacting the bromothiazole ester formula 4a with morpholine to give morpholine thiazole ester formula 3a, and

optionally converting the morpholine thiazole ester formula 3a into its salt. The quantity of the reagent (Ν,Ν-dimethylsulfomyl chloride) range is between 0.9 to 1.1 molar equivalents with respect to L-phenylalaninol, preferably 1.0 molar equivalent. The base used in this reaction may be, but is not limited to, triethylamine, diethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or combinations thereof.

The aziridine formula 8 may be prepared by reacting the compound of formula 9 with p- toluenesulfonyl chloride in the presence of base. The base may be, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, or combinations thereof. The reaction may be carried out, optionally, in the presence of a phase transfer catalyst. The phase transfer catalyst may be, but is not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabubutylammonium iodide, or mixtures thereof. The obtained compound of formula 8 may be crystallized in a solvent. In some embodiments, the solvent is selected from isopropyl alcohol, ethanol, methanol, acetone, heptanes, hexanes, and mixtures thereof.

The reaction of L-thiazole amino lactone formula 5a with trimethylsilylbromide is carried out in the presence of an alcohol, ROH (R=C ₁ -C ₈ alkyl), in a solvent. In some embodiments, the solvent is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, and mixtures thereof, give a corresponding bromothiazole ester formula 4a.

The bromothiazole ester formula 4a may be reacted with morpholine in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane, toluene, methyl tert-butyl ether, acetone, acetonitrile, tetrahydrofuran, and mixtures thereof to give morpholine thiazole ester formula 3a. The morpholine thiazole ester formula 3a may be optionally converted to a corresponding salt by treatment with an acid. In some embodiments, the acid is selected form oxalic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, formic acid, and citric acid.

As used herein, the term "solvent," unless otherwise indicated, refers to an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a chlorinated solvent, dimethyl formamide, dimethy!sulfoxide, alkyl ester, an alcohol, water, ketone solvent, a nitrile solvent, or an ether. Alcohol solvents include, but are not limited tomethanol, ethanol, propanol, isopropanol, n- butanol, sec-butanol, 2-butanol, t-butanol, pentanol, or mixtures thereof. The ether solvents include, but are riot limited to tetrahydrofuran, 1 ,4-dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixtures thereof. The chlorinated sol solvents include, but are not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof. The ketone solvents include, but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, or mixtures thereof. The alkyl ester solvents include, but are not limited to ethyl acetate, ethyl acetoacetate, methyl acetate, or mixtures thereof. The hydrocarbon solvents include, but are not limited to hexane, pentane, heptane, cyclohexane, xylene, toluene, or mixtures thereof. The nitrile solvents include, but are not limited to acetonitrile. The reaction may be carried out without isolating the bromo intermediate of compound of formula 4a and it is formed in-situ in the reaction.

Yet another embodiment is compound of formula 4a:

Yet another embodiment is a compound of formula 9:

Advantages over prior art:

1. The instant disclosed processes may be carried out with about one molare equivalents of N,N-dimethylsulfamoyl chloride.

2. The flammable reagent, sodium hydride, is' not used in the instant disclosed process step.

3. The instant disclosed process may utilize an optional phase transfer catalyst for faster

aziridine formation.

4. The instant disclosed process utilizes the trimethylsilyl bromide, a cheaper reagent than

trimethylsilyl iodide.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way.

Examples

Example-1 : Preparation of L-Phenylalaninol Formula 10:

Aqueous L-phenylalanine methyl ester hydrochloride formula 1 1 (100 gm, 0.463 mol) solution was added to a solution of sodium borohydride (53 gm, 1.4mol) in water at 0-5 °C over period of 3-4 hours. The reaction mixture was stirred at about the same temperature for about 12 hours and then the pH was adjusted to about 5.0 with concentrated hydrochloric acid, followed by a basification with a sodium hydroxide solution (300 ml of 30% aqueous). The reaction mixture was maintained at reflux for about 3 hours, and then the reaction mass was cooled to about 20-25 °C. The aqueous solution thus obtained was extracted with dichloromethane. Concentration of the dichloromethane layer under reduced pressure afforded L-phenylalaninol as a pale yellow solid. Recrystallisation from toluene gave an white to off white solid (50 gm). 1 H NMR (300 MHz, CDCI3) δ 2.49-2.56(m, 1 H), 2.78-2.83(m, 1 H), 3.08-3.16(m, 1 H), 3.36-3.42(m, 1 H) 3.61-3.66(m, 1 H), 7.18-7.37(m, 5H).

Example-2: Preparation of Ν,Ν-dimethylsulfamoyl amino alcohol Formula 9: Ν,Ν-Dimethylsulfamoyl chloride (63 gm, 0.438 mol) was added to L-phenylalaninol (63 gm, 0.417 mol) in a solution of dichloromethane and triethylamine (51 gm, 0.504 mol) at reflux. The reaction mixture was stirred at about the same temp for 20-24 hours. The reaction mixture was then washed with a 1 N hydrochloric acid solution and water. Evaporation of the dichlpromethane under reduced pressure gave of N,N- dimethylsulfamoyl amino alcohol (100 gm, 93 % yield, >95 % HPLC purity) as a gummy residue. 1 H NMR (300 MHz, CDCI3) δ 2.57(s, 6H), 2.82-2.87(m, 2H), 3.57-3.62(m, 2H), 3.76-3.81(m, 1 H) 4.81-4.83(d, 1 H), 7.22-7.34(m, 5H).

Example-3: Preparation of (S)-2-Benzyl-N,N-dimethylaziridirte-1-sulfonamide (Sulfamoyl Aziridine) Formula 8:

Tetrabutyl ammonium bromide (6 gm, 0.018 mol), potassium carbonate (217.3 gm, 1.575 mol) and p-toluenesulfonyl chloride (78.6 gm, 0.412 mol) were added to Ν,Ν-dimethylsulfamoyl amino alcohol (100 gm, 0.387 mol) in dichloromethane at 0-5 °C. The temperature of the reaction mass was raised to about 20-25 °C. The reaction mass was stirred at about same temperature for 12- 14 hours. The dichloromethane layer was then washed with water and concentrated under reduced pressure to afford (S)-2-benzyl-N,N-dimethylaziridine-1-sulfonamide (sulfamoyl aziridine) as pale yellow color residue. This residue was crystallized in isopropyl alcohol at about -20 °C to give (S)-2-benzyl-N,N-dimethylaziridine-1-sulfonamide (sulfamoyl aziridine) as a white solid. Yield: 75g (67.56%). 1 H NMR (300 MHz, CDCI3) δ =2.13-2.14(d, 1 H), 2.55-2.57(m, 1 H), 2.66(s, 6H), 2.69-2.75(m, 1 H), 2.80-2.97(m, 2H) 7.24-7.36(m, 5H).

Example-4: Preparation of (S)-2-Benzyl-N,N-dimethylaziridine-1 -sulfonamide (Sulfamoyl Aziridine) from L-phneylalanine hydrochloride Formula 8:

Aqueous L-phenylalanine methyl ester hydrochloride formula 1 1 (100 gm, 0.463 mol) solution was added to a solution of sodium borohydride (53 gm, 1.4 mol) in water at 0-5 °C for 3-4 hours. The reaction mixture was then stirred at about the same temperature for about 12 hours. Then the pH of the mixture was adjusted to 5.0 with concentrated hydrochloric acid followed by a basification with an aqueous sodium hydroxide solution (300ml of 30% aqueous). The reaction mixture was maintained at reflux for about 3 hours and then cooled to about 20-25 °C. The aqueous solution obtained was extracted with dichloromethane to give L-phenylalaninol formula 10 as a dichloromethane solution.

This dichloromethane solution was used as such in the next reaction without further purification. Ν,Ν-Dimethylsulfamoyl chloride (63 gm, 0.438 mol) was added to the above dichloromethane solution of L-phenylalaninol formula 10 and triethylamine (51 gm, 0.504 mol) at reflux. The reaction mixture was stirred at about the same temperature for 20-24 hours. The dichloromethane layer was then washed with a 1 N hydrochloric acid solution and water to give N,N- dimethylsulfamoyl amino alcohol formula 9 in dichloromethane (90 % yield based on HPLC). This dichloromethane layer was used without further purification by mixing with N,N-dimethylsulfamoyl amino alcohol, tetra butyl ammonium bromide (6 gm, 0.018 mol), potassium carbonate (217.3 gm, 1.575 mol) and p-toluenesulfonyl chloride (78.6 gm, 0.412 mol) at 0-5 °C. The temperature of the reaction mass was raised to about 20-25 °C, then the reaction mass was stirred the reaction mass at about the same temperature for 12-14 hours. The dichloromethane layer was then washed with water and concentrated under reduced pressure to afford (S)-2-benzyl-N,N- dimethylaziridine-1 -sulfonamide (sulfamoyl aziridine) formula 8 as a pale yellow color residue. This residue was crystallized in isopropyl alcohol at -20 °C to give (S)-2-benzyl-N,N- dimethylaziridine-1 -sulfonamide (sulfamoyl aziridine) formula 8 as a white solid. Yield: 75 gm (67.56 %). 1 H NMR (300 MHz, CDCI3) δ =2.13-2.14(d, 1 H), 2.55-2.57(m, 1 H), 2.66(s, 6H), 2.69- 2.75(m, 1 H), 2.80-2.97(m, 2H) 7.24-7.36(m, 5H).

Example-5: Preparation of L-thiazole amino lactone Formula 5a:

A stirred mixture of L-amino lactone formula 7a (92 gm) and dichloromethane (500 ml) was cooled to -5 to -8 °C. To this mixture was added carbonyl diimidazole (92 gm) lot wise. . Triethylamine (45 gm) was added drop wise with continued stirring until the starting material disappeared by TLC. To the mixture was added slowly methyl amino thiazole hydrochloride (100 gm) and triethylamine (92 gm). The reaction mixture was stirred at about at 20-25 °C for 15 hours. Water (200 ml) was added, and the organic layer was separated. The organic layer was washed with water (200 ml). The combined aqueous layers were back extracted with dichloromethane (100 ml). The collected the organic layers were washed with 20 % aqueous citric acid solution (40 gm). The combined organic layer was washed with water (200 ml). The organic layer was concentrated under reduced pressure at about 38-40 °C to obtain the crude L- thiazole amino lactone formula 5a (80 gm).

Example 6: Preparation of morpholine thiazole ethyl ester oxalate Formula 3a:

The solution of L-thiazole amino lactone formula 5a (100 gm) dichloromethane (500 ml) was stirred at room temperature and ethanol (100 ml) was added. Cooled the reaction mass to 0-5 °C and added slowly drop wise trimethylsilyl bromide (183 gm). Raise the reaction mass temperature to 19-25 °C and stirred until reaction was judged complete. The reaction mass was cooled to 0-5 °C and morpholine was added (230 gm) drop wise slowly. Raised the temperature to 19-25 °C and stirred the reaction mass over a period of 17 hours. The reaction mixture was then filtered to remove morpholine hydrobromide salt. The filter cake was rinsed with dichloromethane. The filtrates were washed with water and the combined organic layer was concentrated under vacuum to dryness to give a residue. The residue was dissolved in acetone (500 ml). Oxalic acid dihydrate (60 gm) in acetone (400 ml) was slowly added. The resulting slurry was refluxed for about one hour and cooled to 0-5 °C. The product was filtered and rinsed with acetone (200ml) and dried under vacuum at 40 °C to afford morpholine thiazole ethyl ester oxalate formula 3a as a white to off-white solid (122 gm). Example 7: Preparation of cobicistat silicon dioxide.

To the solution of thiazole ethyl ester oxalate formula -3a (150 gm) in water (250 ml) was charged dichloromethane (800 ml), followed by a slow addition of aqueous potassium bicarbonate (220 gm of potassium bicarbonate dissolved 1250 ml of water). The resulting mixture was stirred for about 1 hour and the layers were separated. The organic layer was washed with water. The organic layer was concentrated under vacuum until the reaction mass volume reached about 350 ml. The reaction mass was cooled to about 5 °C. To the cooled reaction mass was slowly added an aqueous potassium hydroxide solution (about 23 gm of KOH dissolved in 25 ml of water) while maintaining temperature at not more than about 10 °C. The mixture was then stirred for about 12 hours at the same temperature.To the mixture was added cobicistat intermediate-2 or its salt (100 gm) and dichloromethane (350 ml), and the temperature was adjusted to about -20 °C. To this mixture was added HOBT hydrate (about 25 gm). A pre-cooled solution (about -20 °C of N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ((80 gm) in dichloromethane (about 800 ml)) was added to the reaction mixture while the reaction mass temperature was maintained at not more than about -20 °C. The reaction mixture was then stirred at about the same temperature for 24 hours. The reaction mass temperature was then adjusted to about 5 °C and the reaction was quenched with an aqueous citric acid solution. The layers were separated and the organic layer was washed once with aqueous potassium bicarbonate solution and water. The organic layer was concentrated under reduced pressure to give cobicistat (about 160 gm) as a residue. The residue was dissolved in mixture of dichloromethane (160 ml) and n-hexane (160 ml) at room temperature. To this mixture silicon dioxide (150 gm) was added and stirred for 2-3 hours. The solution was concentrated, cooled, and filtered to give the cobicistat silicon dioxide product (300 gm).