WO2017203395A1 - Crystalline forms of tenofovir alafenamide hemi fumarate - Google Patents

Crystalline forms of tenofovir alafenamide hemi fumarate Download PDF

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WO2017203395A1
WO2017203395A1 PCT/IB2017/052896 IB2017052896W WO2017203395A1 WO 2017203395 A1 WO2017203395 A1 WO 2017203395A1 IB 2017052896 W IB2017052896 W IB 2017052896W WO 2017203395 A1 WO2017203395 A1 WO 2017203395A1
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Prior art keywords
tenofovir alafenamide
preparation
acid
tenofovir
solvent
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PCT/IB2017/052896
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French (fr)
Inventor
Sriram RAMPALLI
Paradesi Naidu PENTAKOTA
Bhavani Sankar MANCHUPALLI
Vijaya Murali Mohan Rao SESHAGIRI
Chaturvedi AKSHAY KANT
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Shilpa Medicare Limited
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Publication of WO2017203395A1 publication Critical patent/WO2017203395A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel crystalline forms of L-alanine, N-[(S)-[[( ⁇ R)-2-
  • Tenofovir Alafenamide hemi fumarate Plasma exposure to Tenofovir Alafenamide hemi fumarate allows for permeation into cells and then Tenofovir Alafenamide hemi fumarate is intracellularly converted to Tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite Tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain- termination.
  • Tenofovir specifically shows activity towards human immunodeficiency virus and hepatitis B virus.
  • Cell culture studies have shown that both Emtricitabine and Tenofovir can be fully phosphorylated when combined in cells.
  • Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase ⁇ and there is no evidence of toxicity to mitochondria in cell culture.
  • Tenofovir Alafenamide hemi fumarate was approved by USFDA in 2015 and is marketed under the brand name GENVOYA®, is a four-drug combination of Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), Cobicistat, a CYP3A inhibitor, and Emtricitabine and Tenofovir Alafenamide (TAF), both HIVl nucleoside analog reverse transcriptase inhibitors (NRTIs) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 R A less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.
  • INSTI HIV-1 integrase strand transfer inhibitor
  • Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both Emtricitabine and Tenofovir can be fully phosphorylated when combined in cells. Tenofovirdiphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase ⁇ and there is no evidence of toxicity to mitochondria in cell culture.
  • Tenofovir Alafenamide hemi fumarate is chemically known as L-alanine, N-[(S)-[[(1R)- 2-(6-amino-9H-purin-9-yl)-lmethylethoxy]methyl]phenoxy phosphinyl]-,l-methylethyl ester, (2E)-2-butenedioate).
  • Tenofovir Alafenamide hemi fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20°C. It has a molecular formula of C2 3 H 3 i0 7 N 6 P and a molecular weight of 534.5.
  • WO2015/040640 discloses a process for the preparation of Tenofovir Alafenamide comprises
  • WO2015/079455 discloses a process for racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of Tenofovir Alafenamide, said method comprising treating the (R,R,S)-diastereomer or the mixture having (R,S,S) & (R,R,S)- diastereomer with a suitable base in a suitable organic solvent.
  • WO 2015/107451 discloses a process for the purification of Tenofovir Alafenamide, comprising the steps of
  • acid is selected from chiral acid such as of (S)-(+)-mandelic acid, (R)-(-)-mandelic Acid, (lS)-(+)-10- camphor sulfonic acid, (lR)-(-)-10-camphor sulfonic acid, (D)-(-)-tartaric acid, (L)-(+)-Tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (L)-(-)-malic acid, (D)-(+)-malic acid, (+)-dibenzoyl-D-tartaric acid, (-)- dibenzoyl-L-tartaric acid, (1R, 3S)-(+)-camphoric acid, (I S, 3R)-(-)-camphoric acid, L-pyroglutamic acid, and D- pyl
  • the present invention provides an improved process for the preparation of substantially pure novel crystalline forms of Tenofovir Alafenamide hemifumarate, wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines.
  • Tenofovir Alafenamide hemifumarate crystalline material obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.
  • the main objective of the invention relates to new stable crystalline polymorphic forms of Tenofovir Alafenamide hemifumarate.
  • Yet another objective of the invention relates to process for the preparation of new stable crystalline polymorphic forms of Tenofovir Alafenamide hemifumarate.
  • Yet another objective of the invention relates to a process for the preparation of highly pure Tenofovir Alafenamide hemifumarate, which is stable and thermodynamically stable.
  • the present invention relates to Tenofovir Alafenamide hemifumarate characterized by X-ray powder diffraction pattern comprising characteristic 2Q° peaks selected from 5.2, 7.3, 10.3, 1 1.1 , 18.5, 19.4, 21.1, 22.2, 26.5 ⁇ 0.2°2 ⁇ .
  • the present invention further relates to a process for the preparation of Tenofovir Alafenamide hemifumarate comprising the steps of:
  • the present invention relates to a process for the preparation of Tenofovir Alafenamide or its pharmaceutically acceptable salt thereof, comprising the steps of:
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Tenofovir Alafenamide hemi fumarate Form -STA obtained according to the process of the present invention.
  • XRPD X-ray powder diffraction
  • Fig. 2 is an example of example of DSC endotherm of Tenofovir Alafenamide hemi fumarate Form -STA obtained according the present invention.
  • aspects of the present invention relates to the new stable polymorphic forms of Tenofovir Alafenamide hemi fumarate designated as Form-STA.
  • Tenofovir Alafenamide hemi fumarate crystalline Form-STA characterized by X-ray powder diffraction pattern comprising characteristic 2 ⁇ ° peaks selected from 5.2, 7.3, 10.3, 11.1, 18.5, 19.4, 21.1, 22.2, 26.5 ⁇ 0.2°2 ⁇ .
  • Tenofovir Alafenamide hemi fumarate crystalline Form-STA was further characterized by X-ray powder diffraction pattern comprising characteristic 29° peaks selected from 10.9, 12.2, 12.8, 14.2, 14.8, 15.3, 15.7, 16.5, 17.6, 18.8, 21.7, 24.4, 26.9 ⁇ 0.2°2 ⁇ .
  • the present invention provides Tenofovir
  • the present invention provides Tenofovir Alafenamide hemi fumarate contains fumaric acid content ranging from 10.40-11.4 % w/w.
  • the present invention relates to a process for the preparation of Tenofovir Alafenamide hemi fumarate comprising, dissolving Tenofovir Alafenamide in a solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, amylalcohol; nitrile solvents such as acetonitrile or propionitrile or mixtures thereof; at a temperature ranging between 0°C to 65°C. Adding fumaric acid, wherein fumaric acid was added in the range of 0.4-0.6 moles to obtain desired Tenofovir Alafenamide hemi fumarate. The obtained crystalline material was recovered and dried the crystalline material at 60-65°C to yield highly pure Tenofovir Alafenamide hemi fumarate.
  • the present invention further relates to a process for the preparation of Tenofovir
  • Alafenamide or its pharmaceutically acceptable salts such as mono fumarate, hemi fumarate comprising adding (R)-((-l-(6-amino-9H-purin-9-yl)propan-2-yloxy)methylphosphonic acid in a solvent selected from alcohols, such as C2-C6 alcohols like ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 1 -butanol, 2-butanol, t-butyl alcohol; or nitriles, such as acetonitrile or propionitrile; amides such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl a
  • reaction mass phenol was added.
  • base which was selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate.
  • the obtained reaction mass was heated to 80-120°C and maintained stirring for 4 hours to 8 hours.
  • the solvent was removed at atmospheric pressure under nitrogen at 80°C; the reaction mixture was washed with toluene twice at atmospheric pressure under nitrogen at 80°C, cooled to 25°C, diluted with dichloromethane. The reaction mass as such was used for next stage.
  • the prior art process disclosed in prior art involves the stirring for longer hours (92 hours) for chiral enhancement.
  • the present inventors surprisingly found that the reaction will complete with in the 3 hours.
  • the chiral purity is around 65-80%.
  • the present inventors are able to prepare the Tenofovir Alafenamide having a purity of greater than 99.5 % and free of diastereomeric impurities using the process as described in the present invention.
  • the prior art process involves the use of high volumes (5 volumes) of halogenating agent for completion of the reaction, which leads to the formation of highly chlorinated byproducts/impurities.
  • the present inventors surprisingly found that the reaction will complete with the use of 2.5 equivalents of halogenating agent for completion of the reaction, which yields in a highly pure Tenofovir Alafenamide free of highly halogenated impurities.
  • a mixture of L-alanine isopropyl ester hydrochloride was dissolved in a solvent selected from alcohols, such as C2-C6 alcohols like ethanol, 1-propanol, 2- propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol; or nitriles, such as acetonitrile or propionitrile; amides such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate;
  • alcohols such as
  • reaction mass base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate was added slowly and maintained reaction mass at room temperature for 5 h. The obtained reaction mass was filtered to remove solids and filtrate was cooled to -30°C to -10°C.
  • organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole
  • inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate
  • hydroxides such
  • the obtained racemic Tenofovir Alafenamide having a diastereomeric purity of around 65- 80% was dissolved in a solvent, wherein solvent is selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof.
  • solvent is selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-
  • reaction mass Heated the reaction mass to a temperature ranging between 60-85°C and maintained the reaction mass under stirring for a period of 30 min to 1 hour to get clear solution. Cooled the reaction mass to 45-50°C and charge solvent if necessary, wherein solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof.
  • solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether,
  • reaction mass Cooled the reaction mass to room temperature and stirred the reaction mass for 12 hours to 14 hours at same temperature Further, cooled the reaction mass to 0-5°C and stirred the mass for 4-5 h. Filtered the reaction mass and washed withabove used solvent. The wet compound was taken into flask and charged Isopropyl alcohol. Heated the reaction mass to 70-75°C and maintained for 30 min to 1 hour to get clear solution.
  • reaction mass Cooled the reaction mass to 45-50°C and charged solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 .4- dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof. Cooled the reaction mass to room temperature and stirred for 3-4 h at same temperature. Filtered the reaction mass and washed with same solvent and dried the solid under vacuum at 50°C for 6 hours to 8 hours to yield pure Tenofovir Alafenamide.
  • solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl
  • the above disclosed process may be performed by using seeding process, Tenofovir Alafenamide obtained in the above stage having chiral purity of above 99% may be used for performing seeding.
  • the present inventors surprisingly performed this process by using a single solvent.
  • Tenofovir Alafenamide hemi fumarate obtained by the present invention is having an enantiomerically purity of greater than 99.5% and substantially free of diastereomeric impurities.
  • Tenofovir Alafenamide was dissolved in amyl alcohol and methanol and 0.4 moles to 0.6 moles of Fumaric acid was added and stirred for 30 min at room temperature.
  • the above mass was passed through micron filter and washed with methanol.
  • the filtrate mass was distilled out below 3 volumes with respect to batch size under reduced pressure at below 50°C.
  • the reaction mass was heated to 60-65 °C, maintained for 30 min and cooled to room temperature. Cyclohexane was added in to reaction mass and cooled to 0-5°C and maintained for 5 h.
  • the product was isolated by filtration, washed with Cyclohexane and dried the compound at 60-65 °C for 10-12 h under reduced pressure to yield Tenofovir Alafenamide Fumaric acid salt.
  • Tenofovir Alafenamide Fumaric acid salt in another embodiment of the present invention relates to substantially pure Tenofovir Alafenamide hemi fumarate having enantiomeric purity of greater than 99.5% and total impurities A to J and diastereomeric impurity collectively less than 0.5% by HPLC.
  • Impurit -J Diastereomeric Impurity The word “Substantially pure” means Tenofovir Alafenamide hemi fumarate having a purity of greater than 99.5 % by HPLC and less than 0.05 % of diastereomeric impurities or the impurity levels within the limits as per the ICH guidelines.
  • the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.5 % and meeting the ICH guidelines.
  • the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.6 % and meeting the ICH guidelines. In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.7 % and meeting the ICH guidelines.
  • the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.8 % and meeting the ICH guidelines.
  • the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.9 % and meeting the ICH guidelines.
  • the process related impurities that appear in the impurity profile of the Tenofovir is having a purity of greater than 99.9 % and meeting the ICH guidelines.
  • Alafenamide hemi fumarate may be substantially removed by the process of the present invention resulting in the formation of highly pure material.
  • the process of the present invention is as summarized below:
  • the Tenofovir Alafenamide or its hemi fumarate obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising Tenofovir Alafenamide hemi fumarate obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like.
  • diluents such as starch
  • compositions derived from Tenofovir Alafenamide hemi fumarate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Phenol (6.54 g, 0.069 mol), and 1 -methyl 2-pyrrolidinone (NMP) (30.0 mL) was charged in to reaction flask containing anhydrous ((-l-(6-amino-9H-purin-9-yl)propan-2- yloxy)methylphosphonic acid (10.0 g 0.034mol), The reaction mixture was heated to 85°C. and Triethylamine (TEA) (4.35 g, 0.043 mol) was added slowly.
  • TEA Triethylamine
  • the pH of the aqueous solution was adjusted to 2 to 3 with Conc.HCl.
  • the crude solid was isolated by filtration and washed with methanol (8.7 mL).
  • the wet cake was slurred in methanol (40.0 mL).
  • Solids were isolated by filtration and washed with methanol (6.0 mL). The resulting solid was dried under reduced pressure to yield title compound.

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Abstract

The present invention relates to novel crystalline forms of L-alanine,N-[(S)-[[(lR)-2-(6- amino-9H-purin-9-yl)-1methylethoxy]methyl]phenoxyphosphinyl]-1-methylethyl ester, (2E)- 2-butenedioate or Tenofovir Alafenamide hemi fumarate(I). The present invention further relates to a process for the enantiomerically pure Tenofovir Alafenamide hemi fumarate having an enantiomeric purity of greater than 99.5%

Description

CRYSTALLINE FORMS OF TENOFOVIR ALAFENAMIDE HEMI FUMARATE
FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of L-alanine, N-[(S)-[[(\R)-2-
(6-amino-9H-purin-9-yl)- 1 methylethoxy]methyl]phenoxyphosphinyl]-, 1 -methylethyl ester hemi fumarate or Tenofovir Alafenamide hemi fumarate of Formula (I).
Figure imgf000003_0001
BACKGROUND OF THE INVENTION
L-alanine, N-[(S)-[[(lR)-2-(6-amino-9H-purin-9-yl)-lmethylethoxy]methyl]phenoxy phosphinyl]-,l -methylethyl ester, (2E)-2-butenedioate (2: 1) or Tenofovir Alafenamide hemi fumarate ( Hemi fumarate). Tenofovir Alafenamide hemi fumarate is a phosphonoamidate prodrug of Tenofovir (2 'deoxy adenosine monophosphate analog). Plasma exposure to Tenofovir Alafenamide hemi fumarate allows for permeation into cells and then Tenofovir Alafenamide hemi fumarate is intracellularly converted to Tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite Tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain- termination.
Tenofovir specifically shows activity towards human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both Emtricitabine and Tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture. Tenofovir Alafenamide hemi fumarate was approved by USFDA in 2015 and is marketed under the brand name GENVOYA®, is a four-drug combination of Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), Cobicistat, a CYP3A inhibitor, and Emtricitabine and Tenofovir Alafenamide (TAF), both HIVl nucleoside analog reverse transcriptase inhibitors (NRTIs) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 R A less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.
Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both Emtricitabine and Tenofovir can be fully phosphorylated when combined in cells. Tenofovirdiphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Tenofovir Alafenamide hemi fumarate is chemically known as L-alanine, N-[(S)-[[(1R)- 2-(6-amino-9H-purin-9-yl)-lmethylethoxy]methyl]phenoxy phosphinyl]-,l-methylethyl ester, (2E)-2-butenedioate). Tenofovir Alafenamide hemi fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20°C. It has a molecular formula of C23H3i07N6P and a molecular weight of 534.5.
Tenofovir Alafenamide mono fumarate is generically and specifically disclosed in US
7390791. US '791disclose a process for the preparation of Tenofovir Alafenamide mono fumarate starting from Tenofovir. The process is as demonstrated below:
Figure imgf000004_0001
US 8664386 discloses process for the preparation of Tenofovir Alafenamide comprises diastereomeric separation of 9-{(R)-2-[((R,S)-{[(S)-l-(isopropoxycarbonyl)ethyl] amino }phenoxyphosphinyl) methoxyjpropyl} adenine. The process is as demonstrated below:
Figure imgf000005_0001
US 8754065 (which were also issued as US8697675) disclose Tenofovir Alafenamide hemi fumarate. Mainly this patent discloses crystalline polymorphic form of Tenofovir Alafenamide hemi fumarate having an X-ray powder diffraction (XRPD) pattern comprises values at 6.9and 8.6±0.2°2theta. WO2014195724 discloses a process for preparing 9-[(R)-2-[[(R)-[[(S)-l-
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine or 9-[(R)-2- [[(S)-[[(S)-l-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] adenine reacting phenyl (R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yloxy)methylphosphonochloridate with 2-amino propionic acid isopropyl ester in presence of chiral organic acid.
WO2015/040640 discloses a process for the preparation of Tenofovir Alafenamide comprises
(i) reacting PMPA with phenol in presence of a base and a condensing agent in a suitable organic solvent to obtain [(R)-2-(Phenylphosphonomethoxy) propyl] adenine (ii) reacting the [(R)-2-(Phenylphosphonomethoxy)propyl] adenine or a reactive derivative with L-alanine isopropyl ester in presence of a base to obtain Tenofovir Alafenamide. WO2015/079455 discloses a process for racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of Tenofovir Alafenamide, said method comprising treating the (R,R,S)-diastereomer or the mixture having (R,S,S) & (R,R,S)- diastereomer with a suitable base in a suitable organic solvent..
WO 2015/107451 discloses a process for the purification of Tenofovir Alafenamide, comprising the steps of
(i) reacting racemic Tenofovir Alafenamide with an acid to produce an acid salt; and
(ii) desaltification of the acid salt to get Tenofovir Alafenamide.
wherein acid is selected from chiral acid such as of (S)-(+)-mandelic acid, (R)-(-)-mandelic Acid, (lS)-(+)-10- camphor sulfonic acid, (lR)-(-)-10-camphor sulfonic acid, (D)-(-)-tartaric acid, (L)-(+)-Tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (L)-(-)-malic acid, (D)-(+)-malic acid, (+)-dibenzoyl-D-tartaric acid, (-)- dibenzoyl-L-tartaric acid, (1R, 3S)-(+)-camphoric acid, (I S, 3R)-(-)-camphoric acid, L-pyroglutamic acid, and D- pyroglutamic acid; or an achiral acid such as orotic acid, fumaric acid, oxalic acid, maleic acid, benzoic acid, p-toluenesulphonic acid, succinic acid, orthophosphoric acid, and malonic acid.
In view of the above it is pertinent to note that there exists an inherent need to develop stable crystalline form of Tenofovir Alafenamide hemifumarate having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process/crystallization process for the preparation of Tenofovir Alafenamide hemi fumarate, which may further improve the characteristics of drug Tenofovir Alafenamide hemifumarate and in developing the substantially pure stable crystalline forms of Tenofovir Alafenamide hemifumarate consistently obtainable and amenable to scale up.
As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability. Exploring new polymorphic form for developing a stable and pure form of Tenofovir Alafenamide hemifumarate, which are amenable to scale up for pharmaceutically active useful compounds in the preparation of Tenofovir Alafenamide hemifumarate may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a new polymorphic form, which is a stable and substantially pure form of Tenofovir Alafenamide hemifumarate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions. The present invention provides an improved process for the preparation of substantially pure novel crystalline forms of Tenofovir Alafenamide hemifumarate, wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines. Tenofovir Alafenamide hemifumarate crystalline material obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.
In view of the above and to overcome the prior-art problems the present inventors had now developed a new polymorphic forms of Tenofovir Alafenamide hemifumarate, which are substantially pure, stable produced by using industrially friendly solvents, which does not include tedious work up and time lagging steps.
OBJECTIVE OF THE INVENTION
The main objective of the invention relates to new stable crystalline polymorphic forms of Tenofovir Alafenamide hemifumarate.
Yet another objective of the invention relates to process for the preparation of new stable crystalline polymorphic forms of Tenofovir Alafenamide hemifumarate.
Yet another objective of the invention relates to a process for the preparation of highly pure Tenofovir Alafenamide hemifumarate, which is stable and thermodynamically stable.
SUMMARY OF THE INVENTION
The present invention relates to Tenofovir Alafenamide hemifumarate characterized by X-ray powder diffraction pattern comprising characteristic 2Q° peaks selected from 5.2, 7.3, 10.3, 1 1.1 , 18.5, 19.4, 21.1, 22.2, 26.5±0.2°2Θ. The present invention further relates to a process for the preparation of Tenofovir Alafenamide hemifumarate comprising the steps of:
a) dissolving Tenofovir Alafenamide in a solvent;
b) adding fumaric acid;
c) recover the crystalline material; and
d) drying the crystalline material between 60-65°C.
The present invention relates to a process for the preparation of Tenofovir Alafenamide or its pharmaceutically acceptable salt thereof, comprising the steps of:
Figure imgf000008_0001
comprising the steps of:
a) reacting [(R)-2-(Phenylphosphonomethoxy) propyl] adenine with halogenating agent to provide Phosphono chloridic acid, P-[[(lR)-2-(6-amino-9-H-purin-9-yl)-l- methylethoxy] methyl] -phenyl ester of Formula (IV);
Figure imgf000008_0002
(HI) (IV) b) reacting compound of Formula IV with L- Alanine Isopropyl Ester to provide racemic
Tenofovir Alafenamide(V);
Figure imgf000008_0003
c) reacting racemic Tenofovir Alafenamide(V) with a solvent to provide greater than 95% diasteromerically pure Tenofovir Alafenamide (I)
Figure imgf000009_0001
d) optionally treating with salt forming acid to obtain Tenofovir Alafenamide salt.
In yet another aspect of the present invention relates to substantially pure Tenofovir Alafenamide hemi fumarate having enantiomeric purity of greater than 99.5% and total impurities A to J and diastereomeric impurity (R, R, S) collectively less than 0.3% by Chiral HPLC.
Figure imgf000009_0002
Impurity-J Diastereomeric Impurity BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Tenofovir Alafenamide hemi fumarate Form -STA obtained according to the process of the present invention.
Fig. 2 is an example of example of DSC endotherm of Tenofovir Alafenamide hemi fumarate Form -STA obtained according the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Aspects of the present invention relates to the new stable polymorphic forms of Tenofovir Alafenamide hemi fumarate designated as Form-STA.
In one aspect of present invention, it relates to Tenofovir Alafenamide hemi fumarate crystalline Form-STA characterized by X-ray powder diffraction pattern comprising characteristic 2Θ° peaks selected from 5.2, 7.3, 10.3, 11.1, 18.5, 19.4, 21.1, 22.2, 26.5±0.2°2Θ.
Tenofovir Alafenamide hemi fumarate crystalline Form-STA was further characterized by X-ray powder diffraction pattern comprising characteristic 29° peaks selected from 10.9, 12.2, 12.8, 14.2, 14.8, 15.3, 15.7, 16.5, 17.6, 18.8, 21.7, 24.4, 26.9 ±0.2°2Θ.
In another aspect of present invention, the present invention provides Tenofovir
Alafenamide hemi fumarate crystalline Form-STA characterized by DSC isotherm comprising endothermic peak ranging between 109 to 1 14°C.
In another aspect of present invention, the present invention provides Tenofovir Alafenamide hemi fumarate contains fumaric acid content ranging from 10.40-11.4 % w/w.
Further aspect of the present invention relates to process for the preparation of Tenofovir Alafenamide hemi fumarate comprising the steps of:
a) dissolving Tenofovir Alafenamide in a solvent;
b) adding fumaric acid;
c) recover the crystalline material; and
d) drying the crystalline material between 60-65°C. The present invention relates to a process for the preparation of Tenofovir Alafenamide hemi fumarate comprising, dissolving Tenofovir Alafenamide in a solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, amylalcohol; nitrile solvents such as acetonitrile or propionitrile or mixtures thereof; at a temperature ranging between 0°C to 65°C. Adding fumaric acid, wherein fumaric acid was added in the range of 0.4-0.6 moles to obtain desired Tenofovir Alafenamide hemi fumarate. The obtained crystalline material was recovered and dried the crystalline material at 60-65°C to yield highly pure Tenofovir Alafenamide hemi fumarate. The present invention further relates to a process for the preparation of Tenofovir
Alafenamide or its pharmaceutically acceptable salts such as mono fumarate, hemi fumarate comprising adding (R)-((-l-(6-amino-9H-purin-9-yl)propan-2-yloxy)methylphosphonic acid in a solvent selected from alcohols, such as C2-C6 alcohols like ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 1 -butanol, 2-butanol, t-butyl alcohol; or nitriles, such as acetonitrile or propionitrile; amides such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; organic solvents such as dimethyl formamide, n-hexane, n-heptane, cyclohexane, cycloheptane; hetero aromatic solvents such as pyridine, dimethyl amino pyridine; water or mixtures thereof. To the reaction mass phenol was added. The reaction mass was heated to 60-90°C and then base was added, which was selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate. The obtained reaction mass was heated to 80-120°C and maintained stirring for 4 hours to 8 hours. The reaction mass was cooled to 45°C, water was added and further cooled to room temperature. The reaction mass was filtered and washed with water. The obtained reaction mass was filtered through the Celite bed and washed with dichloromethane twice. The crude solid was isolated by filtration and washed with methanol. The wet cake was slurred and washed with methanol. The resulting solid was dried under reduced pressure to yield Phenyl hydrogen((R)-l-(6-amino-9H-purin-9- yl)propan-2-yloxy)methylphosphonate
Phenyl hydrogen((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yloxy)methylphosphonate obtained above under halogenations using a halogenating agent selected from Iodine, Bromine, Chlorine, thionyl chloride, oxalyl chloride, Phosphorous tri-chloride, Phosphorous penta-chloride, Phosphorous oxy chloride; at a temperature ranging from 75°C to 80°c for 3 hrs. The solvent was removed at atmospheric pressure under nitrogen at 80°C; the reaction mixture was washed with toluene twice at atmospheric pressure under nitrogen at 80°C, cooled to 25°C, diluted with dichloromethane. The reaction mass as such was used for next stage.
The prior art process disclosed in prior art involves the stirring for longer hours (92 hours) for chiral enhancement. The present inventors surprisingly found that the reaction will complete with in the 3 hours. However, the chiral purity is around 65-80%. Even after preparing the Tenofovir Alafenamide with low diastereomeric purity, the present inventors are able to prepare the Tenofovir Alafenamide having a purity of greater than 99.5 % and free of diastereomeric impurities using the process as described in the present invention.
The prior art process involves the use of high volumes (5 volumes) of halogenating agent for completion of the reaction, which leads to the formation of highly chlorinated byproducts/impurities. The present inventors surprisingly found that the reaction will complete with the use of 2.5 equivalents of halogenating agent for completion of the reaction, which yields in a highly pure Tenofovir Alafenamide free of highly halogenated impurities.
In a second flask a mixture of L-alanine isopropyl ester hydrochloride was dissolved in a solvent selected from alcohols, such as C2-C6 alcohols like ethanol, 1-propanol, 2- propanol (isopropyl alcohol), 1-butanol, 2-butanol, t-butyl alcohol; or nitriles, such as acetonitrile or propionitrile; amides such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; organic solvents such as dimethyl formamide, n-hexane, n-heptane, cyclohexane, cycloheptane; water; or any mixtures. To the reaction mass base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate was added slowly and maintained reaction mass at room temperature for 5 h. The obtained reaction mass was filtered to remove solids and filtrate was cooled to -30°C to -10°C. To the reaction mass above obtained, acid chloride reaction mass was added slowly for a period of 10 to 15 min. The reaction mixture was stirred for 30 min to 1 hour at same temperature (-30°C to -10°C), raised to room temperature. The organic layer was washed with water, 10% sodium di hydrogen orthophosphate solution twice. Followed by treatment with 10% potassium bi carbonate solution and with water. The organic layer was concentrated and co-distilled with acetonitrile under reduced pressure to obtain 9-[(R)-2-[{(S)-[{(S)-l-(isopropoxycarbonyl) ethyl] amino] phenoxyPhosphinyl] methoxy] propyl] adenine (Racemic Tenofovir Alafenamide in the ratio of R,S,S:R,R.S=65-80:35-20).
The obtained racemic Tenofovir Alafenamide having a diastereomeric purity of around 65- 80% was dissolved in a solvent, wherein solvent is selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof. Heated the reaction mass to a temperature ranging between 60-85°C and maintained the reaction mass under stirring for a period of 30 min to 1 hour to get clear solution. Cooled the reaction mass to 45-50°C and charge solvent if necessary, wherein solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof. Cooled the reaction mass to room temperature and stirred the reaction mass for 12 hours to 14 hours at same temperature Further, cooled the reaction mass to 0-5°C and stirred the mass for 4-5 h. Filtered the reaction mass and washed withabove used solvent. The wet compound was taken into flask and charged Isopropyl alcohol. Heated the reaction mass to 70-75°C and maintained for 30 min to 1 hour to get clear solution. Cooled the reaction mass to 45-50°C and charged solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 .4- dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof. Cooled the reaction mass to room temperature and stirred for 3-4 h at same temperature. Filtered the reaction mass and washed with same solvent and dried the solid under vacuum at 50°C for 6 hours to 8 hours to yield pure Tenofovir Alafenamide.
The above disclosed process may be performed by using seeding process, Tenofovir Alafenamide obtained in the above stage having chiral purity of above 99% may be used for performing seeding. The present inventors surprisingly performed this process by using a single solvent.
However, the prior art process involves the use of saltification technique, which is difficult and involves tedious work up to remove the unwanted impurities/by products and salts.
Even after the diastereomeric purity of Tenofovir Alafenamide is around 70%.The present inventors successfully removed the diastereomeric impurity by following the process as disclosed in the present invention to yield highly pure Tenofovir Alafenamide hemi fumarate free of diastereomeric impurities. Tenofovir Alafenamide hemi fumarate obtained by the present invention is having an enantiomerically purity of greater than 99.5% and substantially free of diastereomeric impurities.
The above obtained Tenofovir Alafenamide was dissolved in amyl alcohol and methanol and 0.4 moles to 0.6 moles of Fumaric acid was added and stirred for 30 min at room temperature. The above mass was passed through micron filter and washed with methanol. The filtrate mass was distilled out below 3 volumes with respect to batch size under reduced pressure at below 50°C. The reaction mass was heated to 60-65 °C, maintained for 30 min and cooled to room temperature. Cyclohexane was added in to reaction mass and cooled to 0-5°C and maintained for 5 h. The product was isolated by filtration, washed with Cyclohexane and dried the compound at 60-65 °C for 10-12 h under reduced pressure to yield Tenofovir Alafenamide Fumaric acid salt. In another embodiment of the present invention relates to substantially pure Tenofovir Alafenamide hemi fumarate having enantiomeric purity of greater than 99.5% and total impurities A to J and diastereomeric impurity collectively less than 0.5% by HPLC.
Figure imgf000015_0001
Impurity- A Impurity-B
Impurity-F
Impurity-I
Figure imgf000015_0002
Impurit -J Diastereomeric Impurity The word "Substantially pure" means Tenofovir Alafenamide hemi fumarate having a purity of greater than 99.5 % by HPLC and less than 0.05 % of diastereomeric impurities or the impurity levels within the limits as per the ICH guidelines.
In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.5 % and meeting the ICH guidelines.
In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.6 % and meeting the ICH guidelines. In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.7 % and meeting the ICH guidelines.
In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.8 % and meeting the ICH guidelines.
In one embodiment the substantially pure Tenofovir Alafenamide hemi fumarate is having a purity of greater than 99.9 % and meeting the ICH guidelines. The process related impurities that appear in the impurity profile of the Tenofovir
Alafenamide hemi fumarate may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:
Figure imgf000016_0001
In another embodiment, the Tenofovir Alafenamide or its hemi fumarate obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Tenofovir Alafenamide hemi fumarate obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Tenofovir Alafenamide hemi fumarate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
The following examples 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. EXAMPLES
Example 1
Process for the preparation of Phenylhydrogen((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yloxy)methylphosphonate mono hydrate:
Phenol (6.54 g, 0.069 mol), and 1 -methyl 2-pyrrolidinone (NMP) (30.0 mL) was charged in to reaction flask containing anhydrous ((-l-(6-amino-9H-purin-9-yl)propan-2- yloxy)methylphosphonic acid (10.0 g 0.034mol), The reaction mixture was heated to 85°C. and Triethylamine (TEA) (4.35 g, 0.043 mol) was added slowly. To the obtained reaction mass 1,3-dicyclohexylcarbodiamide (DCC) (1 1.69 g, 0.056 mol) in 1-methyl -2- pyrrolidinone (NMP) (1.1 mL) was added for a period of 6 hours at 100°C. The reaction mixture was stirred for 16 hours and then cooled to 45°C. To the obtained reaction mass, water (20.0 mL) was added slowly, and cooled to 25°C. pHof the reaction mass was adjusted not less than 10 with 25% sodium hydroxide in water. The reaction mass was filtered through the Celite bed and washed with water (3.0 mL). The filtrate was extracted with dichloromethane (20.0 mL) twice. The pH of the aqueous solution was adjusted to 2 to 3 with Conc.HCl. The crude solid was isolated by filtration and washed with methanol (8.7 mL). The wet cake was slurred in methanol (40.0 mL). Solids were isolated by filtration and washed with methanol (6.0 mL). The resulting solid was dried under reduced pressure to yield title compound.
Yield:5.0 g
Chromatographic Purity (By HPLC): 95.05 %
Example 2
Preparation of Racemic Tenofovir Alafenamide:
Thionylchloride (4.09 g, 0.0343 mol ) was charged in to reaction flask containing [(R)-2- (Phenylphosphonomethoxy) propyl] adenine ( 5 g, 0.01376 mol) in Toluene (50 ml) solution. The obtained reaction mass was heated to 75°C to 80°C for 3 hr. The solvent was removed at atmospheric pressure under nitrogen below 80°C, the reaction mixture was washed with (10.0 mL ) of toluene twice at atmospheric pressure under nitrogen below 80°C, cooled to 25°C, diluted with Toluene (15.0 mL) dichloromethane (60.0 mL). In a second reaction flask a mixture of L-alanine isopropyl ester hydrochloride (8.09 g , 0.04815mol) and potassium bicarbonate (5.51 g , 0.0550mol) in dichloromethane (70 ml) was stirred at room temperature for 5 h. Solids formation were observed. The reaction mass was and washed with dichloromethane (10 mL), to remove salts. The filtrate was cooled to -30°C to -10°C. The above obtained acid chloride reaction mass in dichloromethane was added slowly to filtrate mass cooled at -30°C to -10°C (L-alanineisopropyl ester reaction mass in dichloromethane at -30°C to -10°C). The reaction mixture was maintained for lh at same temperature (-30°C to - 10°C). Raised the reaction mass temperature to room temperature. The organic layer was washed with water (25 mL) then aqueous layer and organic layer were separated. The organic layer was washed with 10% sodium di hydrogen orthophosphate solution (2x 25 mL), followed by with 10% potassium bi carbonate solution (25 mL) and water (25 mL). The organic layer was concentrated and strip off with acetonitrile (2x 10 mL) under reduced pressure below 60°C to give residue compound (Racemic R,S,S:R,R.S=65-80:35-20). Acetonitrile (10.0 mL) was charged in to above residue and heated the reaction mass to 60- 65°C and cooled to 0-5°C for 3 hrs. Filtered the reaction mass and washed with chilled acetonitrile (1.0 mL). The above wet cake was taken into 4 neck RBF Acetonitrile (10.0 mL) was charged in to above wet cake and heated the reaction mass to 60-65°C and cooled to 0- 5°C for 3 hrs. Filtered the reaction mass and washed with chilled acetonitrile (1.0 mL) and dried the compound at50-60°C for 8 h under reduced pressure to yield Tenofovir Alafenamide
Yield: 2.0 g
Chromatographic Purity (By HPLC): 99.70%
Chiral purity by HPLC: 99.80 %
Example 3
Preparation ofcrystalline Tenofovir Alafenamide hemi fumarate Form-STA
To a solution of 9-[(R)-2-[{(S)-[{(S)-l-(isopropoxycarbonyl)ethyl]amino] phenoxy phosphinyl] methoxy] propyl] adenine (5 g , 0.0104 mol) in Amyl alcohol (15.0 mL), Methanol (45.0 mL) charged Fumaric acid (0.609 g) and stirred for 30 min at room temperature . The above mass was passed through micron filter and washed with Methanol (5.0 mL). The filtrate mass was distilled out below 3 volumes with respect to batch size under reduced pressure at below 50°C. The reaction mass was heated to 60-65 °C, maintained for 30 min and cooled to room temperature. Cyclohexane (75.0 mL) was added in to reaction mass and cooled to 0-5 °C and maintained for 5 h. The product was isolated by filtration, washed with Cyclohexane (2.5 mL) and dried the compound at 60-65 °C for 10 h under reduced pressure to yield Tenofovir Alafenamide hemifumarate.
Yield: 5.0 g
Chemical Purity HPLC: 99.88%
Chiral purity by HPLC: 99.97 %
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not 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 be interpreted as illustrative of the invention and not in a limiting sense.

Claims

Claims:
1) Tenofovir Alafenamide hemifumarate characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 26° peaks selected from 5.2, 7.3, 10.3, 11.1, 18.5, 19.4, 21.1, 22.2, 26.5±0.2°2Θ.
2) Tenofovir Alafenamide hemifumarate according to claim 1 , further characterized by X-ray powder diffraction pattern comprising at 2θ° peaks selected from 10.9, 12.2, 12.8, 14.2, 14.8, 15.3, 15.7, 16.5, 17.6, 18.8, 21.7, 24.4, 26.9 ±0.2°2Θ. 3) Tenofovir Alafenamide hemifumarate according to claim 1, further characterized by DSC isotherm comprising endothermic peak ranging between 109 to 1 14°C.
4) Tenofovir Alafenamide hemifumarate according to claim 1, wherein Tenofovir Alafenamide hemifumarte contain fumaric acid content ranging from 10.4-11.4 % w/w.
5) A process for the preparation of Tenofovir Alafenamide hemifumarate comprising the steps of:
a) dissolving Tenofovir Alafenamide in a solvent;
b) adding fumaric acid;
c) recover the crystalline material; and
d) drying the crystalline material between 60-65°C.
6) A process for the preparation of Tenofovir Alafenamide hemifumarate according to claim- 5, wherein solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol,amylalcohol; nitrile solvents such as acetonitrile or propionitrile or mixtures thereof.
7) A process for the preparation of Tenofovir Alafenamide (I) according to claim-5; wherein the addition of fumaric acid requires 0.4- 0.6 moles of fumaric acid w.r.t to Tenofovir Alafenamide.
8) A process for the preparation of Tenofovir Alafenamide or its pharmaceutically acceptable salt thereof,comprising the steps of:
Figure imgf000021_0001
comprising the steps of:
a) reacting phenyl hydrogen ((R)-l-(6-amino-9H-purin-9-yl) propan-2-yloxy) methylphosphonate (III) with halogenating agent to provide Phosphonochloridic acid, P-[[(lR)-2-(6-amino-9-H-purin-9-yl)-l-methylethoxy]methyl]-phenyl ester of Formula (IV);
Figure imgf000021_0002
(III) (IV)
b) reacting compound of Formula (IV) with L- Alanine Isopropyl Ester to provide racemic
Tenofovir Alafenamide (V);
Figure imgf000021_0003
c) reacting racemic Tenofovir Alafenamide (V) with a solvent to provide greater than 95% diastereomerically pure Tenofovir Alafenamide (I);
Figure imgf000021_0004
d) optionally treating with acid forming salt to obtain Tenofovir Alafenamide salt. A process for the preparation of Tenofovir Alafenamide according to claim 8, wherein solvent used in step c) is selected from alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol; ether such as diethyl ether, diisopropyl ether, methyl t- butyl ether, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, anisole or nitrile solvents such as acetonitrile or propionitrile or mixtures thereof.
10) A process for the preparation of Tenofovir Alafenamide; wherein Tenofovir Alafenamide or its pharmaceutically acceptable salt thereof is substantially pure having enantiomeric purity of greater than 99.5% and total impurities A to J and diastereomeric impurity collectively less than 0.5% by HPLC.
Figure imgf000022_0001
Impurity-J Diastereomeric Impurity
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Cited By (10)

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CN107522743A (en) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method
CN108623632A (en) * 2018-08-17 2018-10-09 上海麦步医药科技有限公司 A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine
WO2019130354A1 (en) 2017-12-30 2019-07-04 Cipla Limited Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1- (isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof
CN111484527A (en) * 2019-01-25 2020-08-04 上海清松制药有限公司 Preparation method of tenofovir alafenamide intermediate
CN111943981A (en) * 2019-05-14 2020-11-17 博瑞生物医药泰兴市有限公司 Preparation method of fosaprevir
CN112782311A (en) * 2020-12-30 2021-05-11 南京百泽医药科技有限公司 HPLC (high performance liquid chromatography) determination method of L-isopropyl alanine in tenofovir disoproxil fumarate
CN113185552A (en) * 2021-04-29 2021-07-30 天地恒一制药股份有限公司 Preparation method of propane fumarate tenofovir disoproxil degradation impurity
CN113501846A (en) * 2021-06-10 2021-10-15 江苏豪森药业集团有限公司 Almenopterine tenofovir hemifumarate compound, crystal form, preparation method and application thereof
CN113549111A (en) * 2020-04-24 2021-10-26 北京康派森医药科技有限公司 Preparation method of tenofovir alafenamide fumarate impurity
CN114671915A (en) * 2021-12-31 2022-06-28 浙江车头制药股份有限公司 Preparation method of high diastereoisomer phosphonyl chloride

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WO2013025788A1 (en) * 2011-08-16 2013-02-21 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
WO2014195724A1 (en) * 2013-06-07 2014-12-11 Cipla Limited An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine

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WO2013025788A1 (en) * 2011-08-16 2013-02-21 Gilead Sciences, Inc. Tenofovir alafenamide hemifumarate
WO2014195724A1 (en) * 2013-06-07 2014-12-11 Cipla Limited An efficient process for separation of diastereomers of 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl] methoxy]propyl]adenine

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522743A (en) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method
WO2019130354A1 (en) 2017-12-30 2019-07-04 Cipla Limited Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1- (isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof
CN108623632A (en) * 2018-08-17 2018-10-09 上海麦步医药科技有限公司 A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine
CN111484527A (en) * 2019-01-25 2020-08-04 上海清松制药有限公司 Preparation method of tenofovir alafenamide intermediate
CN111943981A (en) * 2019-05-14 2020-11-17 博瑞生物医药泰兴市有限公司 Preparation method of fosaprevir
CN113549111A (en) * 2020-04-24 2021-10-26 北京康派森医药科技有限公司 Preparation method of tenofovir alafenamide fumarate impurity
CN112782311A (en) * 2020-12-30 2021-05-11 南京百泽医药科技有限公司 HPLC (high performance liquid chromatography) determination method of L-isopropyl alanine in tenofovir disoproxil fumarate
CN113185552A (en) * 2021-04-29 2021-07-30 天地恒一制药股份有限公司 Preparation method of propane fumarate tenofovir disoproxil degradation impurity
CN113501846A (en) * 2021-06-10 2021-10-15 江苏豪森药业集团有限公司 Almenopterine tenofovir hemifumarate compound, crystal form, preparation method and application thereof
CN114671915A (en) * 2021-12-31 2022-06-28 浙江车头制药股份有限公司 Preparation method of high diastereoisomer phosphonyl chloride
CN114671915B (en) * 2021-12-31 2024-04-09 浙江车头制药股份有限公司 Preparation method of high diastereoisomer phosphonochloride

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