DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10, rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR ALAFENAMIDE MONOFUMARATE”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

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

FIELD OF THE INVENTION:

The present invention generally relates to an improved process for the preparation of tenofovir alafenamide monofumarate.

BACKGROUND OF THE INVENTION:

Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine (GS-7340) and represented by the following structure:

U.S. Patent No. 7,390,791 discloses Tenofovir alafenamide or pharmaceutically acceptable salts thereof including tenofovir alafenamide monofumarate and methods for chemically synthesizing this prodrug. The disclosed process involves reaction of Tenofovir alafenamide with fumaric acid in acetonitrile solvent at reflux followed by cooling to 5°C for 16hrs to obtain Tenofovir alafenamide monofumarate.

U.S. Patent No. 8,754,065 discloses Tenofovir alafenamide hemifumarate and process for its preparation.

Other processes have been reported in the art for the preparation of tenofovir alafenamide monofumarate and its polymorphs, which are as follows: WO2015/040640, WO2015/107451, WO2017/134089, WO2017/037608, WO2017/211325, WO2019/130354, CN105646584B, CN107226826A, CN107663217A and CN105131038A.

Various processes existed for the preparation of tenofovir alafenamide monofumarate, but the known processes have difficulty in getting pure product and contamination of high levels of unreacted fumaric acid and other polymorphic forms. There remains still a need for improved processes for the preparation of tenofovir alafenamide monofumarate to circumvent the prior process difficulties and getting high yields and high purity, which is suitable on industrial scale.

Thus, the present invention provides an improved process for the preparation of tenofovir alafenamide monofumarate.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I.

In accordance with one embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I,

comprising treating tenofovir alafenamide with fumaric acid in a suitable solvent; wherein the particles of fumaric acid contains less than 120 µm.

In accordance with another embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:
a) dissolving tenofovir alafenamide in a suitable solvent;
b) combining the step a) solution with fumaric acid in a suitable solvent; and
c) isolating the tenofovir alafenamide monofumarate of formula I; wherein the particles of fumaric acid contains less than 120 µm.

In accordance with another embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:
a) dissolving tenofovir alafenamide in a suitable solvent,
b) suspending fumaric acid in a suitable solvent,
c) adding step a) solution to step b) reaction mass, and
d) isolating the tenofovir alafenamide monofumarate of formula I, wherein the particles of fumaric acid contains less than 120 µm.

In accordance with another embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:
a) dissolving tenofovir alafenamide in a suitable solvent at ambient to reflux temperature,
b) suspending fumaric acid in a suitable solvent,
c) adding step a) solution to step b) reaction mass at temperature below 60°C,
d) optionally cooling to a temperature of less than about 30°C, and
e) isolating the tenofovir alafenamide monofumarate of formula I; wherein the particles of fumaric acid contains less than 120 µm.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising Tenofovir alafenamide monofumarate prepared according to the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is the characteristic PXRD pattern of tenofovir alafenamide monofumarate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I. The improvement includes the step of saltification of Tenofovir alafenamide with predetermined particle size of fumaric acid to control the formation of impurities.

In the production of tenofovir alafenamide monofumarate of formula I, the present inventors have found that by using commercially available fumaric acid which typically has a D90 particle size of about 400 - 500 µm, the final tenofovir alafenamide monofumarate product always contaminated with hemifumarate of formula (B) in about 2-10% and unreacted fumaric acid in the range of about 25 to 30%, thus resulting in lower yield and purity.

Further, when following the reported literature, it was observed that due to high temperatures in the salt formation step the resultant tenofovir alafenamide monofumarate is always contaminated with PMPA of formula (A) in about 0.15 to 5% due to decomposition of tenofovir alafenamide thereby inevitably resulting in yield loss and lower purity of the product.

Therefore, improvement in the activity of fumaric acid that exhibits a higher conversion rate and high purity needs to be explored. Hence, the present inventors have tried to establish an improved process for the preparation of tenofovir alafenamide monofumarate of formula I without contamination with PMPA (A), fumaric acid and tenofovir alafenamide hemifumarate (B). The inventors of the present invention have tried to reduce the fumaric acid particle size between 200 and 300 µm and the results are more or less the same as like use of commercial grade fumaric acid and found effective and advantageous results when the fumaric acid particle size is still lower, of less than 120 µm.

In accordance with one embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I,

comprising treating tenofovir alafenamide with fumaric acid in a suitable solvent, wherein the particles of fumaric acid contains less than 120 µm.

In another embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:
a) dissolving tenofovir alafenamide in a suitable solvent,
b) combining the step a) solution with fumaric acid in a suitable solvent, and
c) isolating the tenofovir alafenamide monofumarate of formula I; wherein the particles of fumaric acid contains less than 120 µm.

In a preferred embodiment, the present invention provides an improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:
a) dissolving tenofovir alafenamide in a suitable solvent at ambient to reflux temperature,
b) suspending fumaric acid in a suitable solvent,
c) adding step a) solution to step b) reaction mass at a temperature below 60°C,
d) optionally cooling to a temperature of less than about 30°C, and
e) isolating the tenofovir alafenamide monofumarate of formula I; wherein the particles of fumaric acid contains less than 120 µm.

The starting tenofovir alafenamide is known in the art and can be prepared by any known methods, for example starting tenofovir alafenamide may be synthesized according to U.S. patent No’s: 7,390,791 and 8,664,386. Alternatively, the starting tenofovir alafenamide may be obtained as a solution directly from a reaction mixture in which tenofovir alafenamide is formed and used as such without isolation.

The step a) process involves dissolving tenofovir alafenamide in a suitable solvent which may optionally include heating to a temperature of about ambient temperature to reflux temperature of the solvent, preferably up to about 60°C and stirring for a period of time from about 5 mins to about 5 hrs. Suitable temperature depends on the amount of tenofovir alafenamide, solvent used and/or amount of solvent in the reaction mass.

Examples of suitable solvent for use in the foregoing process includes but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfoxides such as dimethylsulfoxide and the like, water and mixtures thereof. Preferably, the suitable solvent is selected from acetonitrile, water and mixtures thereof.

Once the solution containing tenofovir alafenamide is prepared, it may be added to the solution or suspension of fumaric acid in a suitable solvent of step b) at a temperature of less than 60°C; preferably at below 45°C more preferably less than 30°C. The resultant reaction mass may be stirred at a temperature of below 60°C, preferably at below 45°C and more preferably at below 30°C and allowed to stir for a period of time from about 5 hrs to until completion of the reaction, preferably 5- 20 hrs.

Examples of suitable solvent for use in step b) includes but are not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfoxides such as dimethylsulfoxide and the like, water and mixtures thereof; preferably acetonitrile, water and mixtures thereof.

In another embodiment, wherein the particles of fumaric acid used in the present invention is having less than 120 µm, preferably less than 100 µm; and more preferably less than 50 µm.

In another embodiment, wherein the particles of fumaric acid used in the present invention is having D90 less than 120 µm, preferably D90 less than 100 µm; and more preferably D90 less than 50 µm.

If the reaction is carried out at a temperatures of above 30°C; the resultant product may be precipitated by cooling the reaction solution to less than 30°C. The cooling step may be involved at any phase such as either sudden cooling or cooling with specific time interval.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant product may optionally be further dried. Drying may be performed at a temperature of about 100°C or less, preferably of about 80°C or less and more preferably of about 60°C or less. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably from about 6 to 18 hours.

The drying may be carried out using drying techniques known in the art for removal of solvent from the solvent containing products, for example solvates. Exemplary drying techniques include, but are not limited to tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

Thus, the use of fumaric acid with specific particle size distribution of less than 120 µm according to the present invention has significance during the preparation of tenofovir alafenamide monofumarate to minimize the content of PMPA (A), fumaric acid and tenofovir alafenamide hemifumarate (B) to less than about 0.15%.

In another embodiment, the present invention provides tenofovir alafenamide monofumarate having less than about 0.15% of PMPA (A) and/or fumaric acid.

Particle size reduction of fumaric acid can be carried out according to known methods such as the precipitation or the mechanical method. Typically, precipitation method involves dissolving the substance in an appropriate solvent and then is finely precipitated by the addition of another solvent; whereas the mechanical method involves subjecting the substance to mechanical forces using grinding equipment such as ball mill, roller mill, loop mill, jet mill, colloid mill, ultra-sonication, high speed homogenizer etc.

The particle size distribution of fumaric acid is measured utilizing: Instrument model: Malvern; Mastersizer 3000; particle refraction index of sample: 1.700; Absorption: 0.01 and Analysis model: general purpose, normal sensitivity, non-spherical particles.

Tenofovir alafenamide monofumarate obtained by the process of the present invention is characterized by X-ray powder diffraction (XRPD) pattern as per the below method:
PANalytical Empyrean Powder and X'Pert3 Powder
Source : Cu (1.5406Å)
Voltage : 45 KV
Current : 40 mA
Scanning axis : °2?
Measurement method : Continuous
Time per step/Scan speed : 50 Sec. (Net time per step 48.195s)
Step size : 0.01°
Angular range : 3-45 °2?

Tenofovir alafenamide monofumarate obtained according to the present invention is analyzed using the high performance liquid chromatography with the conditions described below:
Column and Packing : Kromasil C18
Column Oven Temperature : Room temperature
Mobile phase-A : Buffer and Methanol (85:15 v/v)
Mobile phase-B : Acetonitrile and Milli-Q water (80:20 v/v).
Flow rate : 1.0 mL/min
Detection : UV 260 nm
Injection volume : 20 µl

The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLES:

Reference Example:
Tenofovir alafenamide (1.294 Kg), fumaric acid (284 gms) and acetonitrile (24.6 Kg) were added in to round bottom flask equipped with reflux condenser and heated to reflux to dissolve the solids. The reaction mass was filtered while hot, cooled to 5°C and maintained for 16 hours. The product was isolated by filtration, rinsed with acetonitrile (707 gms), and dried under reduced pressure to get the title product (1.328 Kg). HPLC purity: 99.64% by HPLC, PMPA (A): 0.21%; Fumaric acid content: 20.4% (actual value 19.7%, but modified to 20.4%); The PXRD is set forth in Figure 1.

Reference Example:
Tenofovir alafenamide (10 gms), acetonitrile (180 ml) and water (4 ml) were added in to round bottom flask equipped with reflux condenser at 27-33°C. The resulting reaction mass was treated with carbon (0.5 gms) and filtered on hyflow. The filtrate was added to a suspension of fumaric acid (2.44 gms, PSD= 350µm) in mixture of acetonitrile (100 ml) and water (2 ml) at 9-15°C for 30 min and further stirred for 12 hrs at the same temperature. The precipitated solids were filtered, washed with chilled acetonitrile (2x20 ml) and dried under vacuum at 50-53°C for 18 hrs to afford the title compound as a white solid (9.03 gms). HPLC purity: 99.64%; PMPA (A): 0.03%; Fumaric acid content: 22.3%; The PXRD is set forth in Figure 1.

EXAMPLE-1:
Tenofovir alafenamide (10 gms), acetonitrile (180 ml) and water (4 ml) were added in to round bottom flask equipped with reflux condenser at 27-33°C. The resulting reaction mass was treated with carbon (0.5 gms) and filtered on hyflow. The filtrate was added to a suspension of fumaric acid (2.44 gms, PSD= less than 40µm) in mixture of acetonitrile (100 ml) and water (2 ml) at 9-15°C for 30 min and further stirred for 12 hrs at the same temperature. The precipitate solids were filtered, washed with chilled acetonitrile (2x20 ml) and dried under vacuum at 50-53°C for 18 hrs to afford the title compound as a white solid (10.2 gms). HPLC purity: 100%; PMPA (A): 0.03%; Fumaric acid content: 19.7%; The PXRD is set forth in Figure 1.

EXAMPLE-2:
Tenofovir alafenamide (10 gms), acetonitrile (180 ml) and water (4 ml) were added in to round bottom flask equipped with reflux condenser at 27-33°C. The resulting reaction mass was treated with carbon (0.5 gms) and filtered on hyflow. The filtrate was added to a suspension of fumaric acid (2.44 gms, PSD= less than 40µm) in mixture of acetonitrile (100 ml) and water (2 ml) at 0-6°C for 30 min and further stirred for 12 hrs at the same temperature. The precipitate solids were filtered, washed with chilled acetonitrile (2x20 ml) and dried under vacuum at 50-53°C for 18 hrs to afford the title compound as a white solid (9.12 gms). HPLC purity: 99.64%; PMPA (A): 0.03%; Fumaric acid content: 19.7%; The PXRD is set forth in Figure 1.

EXAMPLE-3:
Tenofovir alafenamide (10 gms), acetonitrile (180 ml) and water (4 ml) were added in to round bottom flask equipped with reflux condenser at 27-33°C. The resulting reaction mass was treated with carbon (0.5 gms) and filtered on hyflow. The filtrate was added to a suspension of fumaric acid (2.44 gms, PSD= less than 40µm) in mixture of acetonitrile (100 ml) and water (2 ml) at 37-43°C for 30 min and further stirred for 12 hrs at the same temperature. The reaction mass was further cooled to 22°C to 28°C and the precipitated solids were filtered, washed with chilled acetonitrile (2x20 ml) and dried under vacuum at 50-53°C for 18 hrs to afford the title compound as a white solid (10.2 gms). HPLC purity: 99.64%; PMPA (A): 1.29%; Fumaric acid content: 20.2%; The PXRD is set forth in Figure 1.

EXAMPLE-4:
Tenofovir alafenamide (10 gms), acetonitrile (180 ml) and water (4 ml) were added in to round bottom flask equipped with reflux condenser at 27-33°C. The resulting reaction mass was treated with carbon (0.5 gms) and filtered on hyflow. The filtrate was added to a suspension of fumaric acid (2.44 gms, PSD= less than 112µm) in mixture of acetonitrile (100 ml) and water (2 ml) at 9-15°C for 30 min and further stirred for 12 hrs at the same temperature. The precipitate solids were filtered, washed with chilled acetonitrile (2x20 ml) and dried under vacuum at 50-53°C for 18 hrs to afford the title compound as a white solid (9.03 gms). HPLC purity: 99.64%; PMPA (A): 0.03%; Fumaric acid content: 20.4%; The PXRD is set forth in Figure 1.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:WE CLAIM:

1. An improved process for the preparation of Tenofovir alafenamide monofumarate of formula I, comprising:

a) dissolving tenofovir alafenamide in a suitable solvent,
b) combining the step a) solution with fumaric acid in a suitable solvent, and
c) isolating the tenofovir alafenamide monofumarate of formula I; wherein the particles of fumaric acid contains less than 120 µm.

2. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising alcohols; ethers; ketones; halogenated hydrocarbons; aromatic hydrocarbons; nitriles; amides; sulfoxides; water and mixtures thereof.

3. The process as claimed in claim 2, wherein the suitable solvent is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1,4-dioxane, acetone, methyl isobutyl ketone, methyl ethyl ketone, dichloromethane, chloroform, toluene, xylene, acetonitrile, propionitrile, benzonitrile, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, water and mixtures thereof.

4. The process as claimed in claim 3, wherein the suitable solvent is a mixture of acetonitrile and water.

5. The process as claimed in claim 1, wherein the step a) is carried out at a temperature of up to about 60°C.

6. The process as claimed in claim 1, wherein the step b) comprises adding step a) solution to suspension of fumaric acid in a suitable solvent.

7. The process as claimed in claim 6, wherein the suitable solvent is a mixture of acetonitrile and water.

8. The process as claimed in claim 1, wherein the step b) is carried out at a temperature of below 45°C.

9. The process as claimed in claim 1, wherein the step c) further comprises optionally cooling to a temperature of less than 30°C.

10. The process as claimed in claim 1, wherein the particles of fumaric acid having D90 less than 120 µm.