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WO2015040640A2 - Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci - Google Patents

Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci Download PDF

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Publication number
WO2015040640A2
WO2015040640A2 PCT/IN2014/000614 IN2014000614W WO2015040640A2 WO 2015040640 A2 WO2015040640 A2 WO 2015040640A2 IN 2014000614 W IN2014000614 W IN 2014000614W WO 2015040640 A2 WO2015040640 A2 WO 2015040640A2
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WIPO (PCT)
Prior art keywords
tenofovir alafenamide
acid
formula
isopropyl ester
mixtures
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PCT/IN2014/000614
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English (en)
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WO2015040640A3 (fr
Inventor
Suresh Thatipally
Venkata Lakshmi Narasimha Rao Dammalapati
Venkata Siva Ramakrishna Reddy KALLAM
Seeta Rama Anjaneyulu GORANTLA
Satyanarayana Chava
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Laurus Labs Private Limited
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Publication of WO2015040640A2 publication Critical patent/WO2015040640A2/fr
Publication of WO2015040640A3 publication Critical patent/WO2015040640A3/fr

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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
    • 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

Definitions

  • the present invention relates to an improved process for the preparation of Tenofovir alafenamide or salts thereof, pharmaceutical compositions and methods of using Tenofovir alafenamide or salts thereof to treat or prevent diseases or disorders such as antiretroviral infections.
  • Tenofovir alafenamide is chemically known as 9-[(R)-2-[[(S)-[[(S)-l-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine; and represented by the following structure:
  • U.S. Patent No 7,390,791 discloses prodrugs of methoxyphosphonate nucleotide analogs, in particular Tenofovir alafenamide or pharmaceutically acceptable salts thereof exhibiting potent anti-HTV activity and enhanced ability to deliver parent tenofovir into peripheral blood mononuclear cells (PBMCs) and other lymphatic tissues in vivo.
  • PBMCs peripheral blood mononuclear cells
  • the obtained tenofovir alafenamide was purified by simulated moving bed chromatography (SMB) over Chiralpak AS column by eluting with 30% methanol in acetonitrile provided 98.7% diastereomeric purity and the resultant required diastereomer was converted into tenofovir alafenamide fumarate.
  • SMB simulated moving bed chromatography
  • Nucleosides, Nucleotides & Nucleic acids, 20 (4-7), 621-628 (2001) disclosed a process for the preparation of L-alanine isopropyl ester by esterification of L-alanine with isopropanol in the presence of trimethyl silyl chloride to provide L-alanine isopropyl ester as a hydrochloride salt which was further treated with DABCO in THF and isolating L-alanine isopropyl ester as oil which was used immediately in the next step.
  • reaction of the thus formed L-alanine isopropyl ester with [(i?)-2-(Phenylphosphonomethoxy) propyl] adenine resulted in contamination of the product, tenofovir alafenamide, with isopropyl ester of [(i?)-2-(Phenylphosphonomethoxy) propyl] adenine which happened because of the presence of residual isopropanol in L-alanine isopropyl ester.
  • PCT Publication No. 2013/11 16730 discloses a process for the preparation of tenofovir alafenamide by treating L-alanine isopropyl ester hydrochloride salt with potassium bicarbonate in DCM for 10-14 hrs followed by filtration and drying the filtrate over a bed of 4A molecular sieves until water content was ⁇ 0.05% to obtain a stock solution of L- alanine isopropyl ester.
  • the present invention fulfills the need in the art and provides an improved process for the preparation of tenofovir alafenamide or salts thereof that circumvents disadvantages associated with the prior art process, proved to be advantageous from industrial point of view and also fulfill purity criteria.
  • the new process has a further advantage in separation of the diastereomers which is achieved by Simulated moving bed chromatography or preparative high performance liquid chromatography ("Prep HPLC") resulting in >99% purities of individual diastereomer in contrast to the prior art process which involves more time-cycles and less efficient separation of diastereomers.
  • the present invention encompasses an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof.
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof;
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof; comprising the steps of:
  • step (iii) adding a base to the aqueous layer of step (ii) to adjust the pH of the reaction mixture to about 9 to 12,
  • step (iv) adding an acid to the aqueous layer of step (iv) to adjust the pH of the reaction mixture to about 2 to 4 for precipitation of solid,
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof; comprising the steps of:
  • step (iii) adding a base to the aqueous layer of step (ii) to adjust the pH of the reaction mixture to about 9 to 12,
  • step (iv) adding an acid to the aqueous layer of step (iv) to adjust the pH of the reaction mixture to about 2 to 4 for precipitation of solid,
  • step viii) adding a second solvent to the solid obtained from step viii) and co-distilling the solvent completely to obtain L-alanine isopropyl ester hydrochloride
  • the suitable organic solvent is selected from the group consisting of ethers, ketones, halogenated solvents, cyclic hydrocarbons, aromatic hydrocarbons, nitriles and the like and mixtures thereof.
  • the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof, comprising:
  • step c) adding a second solvent to the solid obtained from step b) and co-distilling the solvent completely to obtain L-alanine isopropyl ester hydrochloride, and d) treating the L-alanine isopropyl ester ⁇ hydrochloride with 1,4- diazabicyclo[2.2.2]octane (DABCO) in an organic solvent to. obtain L-alanine isopropyl ester of Formula IV, and
  • the present invention provides a process for separation of diastereomers of tenofovir alafenamide, comprising subjecting diastereomeric mixtures of tenofovir alafenamide to a simulated moving bed chromatography or Preparative HPLC using suitable eluent comprising an alcohol, an ester solvent and mixtures thereof.
  • the present invention provides an acid addition salt of tenofovir alafenamide, which may have greater stability, bioavailability, and having desired pharmacological, pharmacokinetic and pharmacodynamic effects; wherein the salts includes an organic acid such as acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, p- hydroxy benzoic acid, vanillic acid, syringic acid, 4-
  • an organic acid such as
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tenofovir alafenamide or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of tenofovir alafenamide as obtained according to Example -3.
  • Figure 2 is the characteristic PXRD pattern of tenofovir alafenamide fumarate.
  • Figure 3 is the characteristic PXRD pattern of tenofovir alafenamide ferulate.
  • Figure 4 is the characteristic PXRD pattern of tenofovir alafenamide phosphate
  • Figure 5 is the characteristic PXRD pattern of tenofovir alafenamide succinate.
  • Figure 6 is the characteristic PXRD pattern of tenofovir alafenamide citrate.
  • Figure 7 is the characteristic PXRD pattern of tenofovir alafenamide tartarate.
  • Figure 8 is the characteristic PXRD pattern of tenofovir alafenamide lactate.
  • Figure 9 is the characteristic PXRD pattern of tenofovir alafenamide mesylate.
  • the present invention provides an improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof.
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof;
  • the suitable organic solvent is selected from the group consisting of ethers, ketones, halogenated solvents, cyclic hydrocarbons, aromatic hydrocarbons, nitriles and the like and mixtures thereof.
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof; comprising the steps of:
  • step (iii) adding a base to the aqueous layer of step (ii) to adjust the pH of the reaction mixture to about 9 to 12,
  • step (iv) adding an acid to the aqueous layer of step (iv) to adjust the pH of the reaction mixture to about 2 to 4 for precipitation of solid,
  • step viii) adding a second solvent to the solid obtained from step viii) and co-distilling the solvent completely to obtain L-alanine isopropyl ester hydrochloride
  • the suitable organic solvent is selected from the group consisting of ethers, ketones, halogenated solvents, cyclic hydrocarbons, aromatic hydrocarbons, nitriles and the like and mixtures thereof.
  • the starting compound PMPA of Formula II is known in the art and can be prepared by any known methods, for example starting compound of Formula II may be synthesized according to U.S. patent No's: 4,808,716; 5,922,695 and 6,653,296.
  • the step a) of the fore going process may include reacting PMPA of Formula II with phenol in the presence of a base and a condensing agent in a suitable organic solvent.
  • bases include but are not limited to primary, secondary or tertiary amines such as methyl amine, tri ethyl amine, diisopropyl amine and the like, preferably triethyl amine.
  • Suitable organic solvent include but are not limited to ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert. butyl ether, cyclopentyl methyl ether and the like; ketones such as acetone, methyl isobutyl ketone and the like; halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride and the like; hydrocarbon solvents such as cyclohexane and the like; aromatic hydrocarbon solvents such as toluene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like or mixtures thereof; preferably cyclopentyl methyl ether, 1,4-dioxane, methylene chloride, toluene and acetonitrile and mixtures thereof; more preferably cyclopentyl methyl ether.
  • ethers such as te
  • Suitable condensing agents include but are not limited to N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-[3-dimethyIaminopropyl]-carbodiimide (EDC), 1,1-carbonyl diimidazole (CDI) and the like, preferably ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC).
  • DCC N,N'-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-[3-dimethyIaminopropyl]-carbodiimide
  • CDI 1,1-carbonyl diimidazole
  • the reaction may typically be carried out at a suitable temperature such as 40°C to reflux temperature of the solvent.
  • a suitable temperature such as 40°C to reflux temperature of the solvent.
  • the reaction temperature is about 60°C to about 130°C.
  • the reaction is allowed to stir for a period of time from about 5 hrs to until completion of the reaction, preferably 8 - 20 hrs.
  • the resultant reaction mass may be diluted with water and the by-products formed, if any, during the reaction were separated by filtration.
  • the resultant mother liquor may be either concentrated by normal vacuum or the organic and aqueous layers are may be separated; preferably organic and aqueous layers are separated.
  • the product containing aqueous layer may be basified with a suitable base to adjust pH of the solution to about 9 to 12.
  • suitable bases include but are not limited to sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate and the like; preferably the suitable base is sodium hydroxide and is in the aqueous solution medium.
  • the aqueous layer may be washed with a suitable water immiscible organic solvent which include but are not limited to ethyl acetate, toluene or methylene chloride and the like; preferably ethyl acetate. Then, pH of the resultant product containing aqueous layer may be readjusted back to about 2 to 4 with an acid such as hydrochloric acid and the like to precipitate out the [(i?)-2-(Phenylphosphonomethoxy) propyl] adenine of Formula III.
  • a suitable water immiscible organic solvent include but are not limited to ethyl acetate, toluene or methylene chloride and the like; preferably ethyl acetate.
  • 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 can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 50°C to about 90°C, preferably from about 65°C to about 75°C.
  • the reported literature, U. S. patent No. 7,390791 employed high boiling N-methyl-2- pyrrolidone solvent, which is water soluble and requires high vacuum distillation (HVD) for extended period of time to remove the solvent from the reaction medium.
  • Step b) of the aforementioned process involves reaction of [(i?)-2- (Phenylphosphonomethoxy) propyl] adenine of formula III with a chlorinating agent such as thionyl chloride, phosphorous oxychloride, oxalyl chloride or phosphorous pentachloride and the like, preferably thionyl chloride to obtain a reactive derivative of formula III, which is then reacted with L-alanine isopropyl ester in presence of a suitable base in an organic solvent to obtain tenofovir alafenamide of formula I.
  • a chlorinating agent such as thionyl chloride, phosphorous oxychloride, oxalyl chloride or phosphorous pentachloride and the like, preferably thionyl chloride to obtain a reactive derivative of formula III, which is then reacted with L-alanine isopropyl ester in presence of a suitable base in an organic solvent to obtain ten
  • suitable base for use in step b) includes but are not limited to primary, secondary or tertiary amine such as triethyl amine, diisopropyl amine and the like, preferably triethyl amine.
  • the Organic solvent for use in step b) includes but are not limited to ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone and the like; halogenated solvents such as dichloromethane, chloroform and the like; amides such as dimethyl formamide and the like; hydrocarbon solvents such as cyclohexane, methyl cyclohexane and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like or mixtures thereof.
  • the solvent used for chlorination and subsequent phosphoramidation may be same or different. More preferably, the solvent for chlorination is acetonitrile and the solvent for phosphoramidation is dichloromethane.
  • the chlorination reaction is typically carried out at a suitable temperature such as 50°C to 90°C. Preferably the reaction temperature is about 70°C to about 80°C and is allowed to stir for a period of time from about 30 mins until completion of the reaction, preferably 1-3 hrs.
  • the phosphoramidation reaction is typically carried out at a suitable temperature such as about -40°C to about 50°C. Preferably the reaction temperature is about -20°C to about 40°C and is allowed to stir for a period of time from about 30 mins until completion of the reaction, preferably 1-3 hrs.
  • the resultant tenofovir alafenamide of formula I can be isolated by known techniques, for example, conventional separation of the organic layer from the reaction mixture.
  • the solvent from the organic layer may be concentrated under vacuum to get residue by any method known in the art, at the end of the reaction, such as distillation, evaporation, rotational drying (such as with the Buchi Rotavapor), preferably distillation under vacuum.
  • additional purification may be carried out by process such as crystallization, solvent slurry techniques or any chromatography techniques.
  • the present invention provides a process for crystallization of tenofovir alafenamide, comprising a) stirring the tenofovir alafenamide as obtained from the above process in ether solvent such as tetrhydrofuran, methyl tert. butyl ether, diethyl ether and the like; preferably methyl tert. butyl ether at a temperature of about 25°C to about reflux, preferably at about 25 °C to about 35° and b) isolating the tenofovir alafenamide by filtration.
  • ether solvent such as tetrhydrofuran, methyl tert. butyl ether, diethyl ether and the like
  • preferably methyl tert. butyl ether at a temperature of about 25°C to about reflux, preferably at about 25 °C to about 35°
  • isolating the tenofovir alafenamide by filtration comprising a) stirring the tenofo
  • the tenofovir alafenamide recovered using process of the present invention is in crystalline form and characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 01
  • XRD X-Ray diffraction
  • the present invention provides an improved process for the preparation of tenofovir alafenamide of Formula I or pharmaceutically acceptable salts thereof; comprising:
  • step c) adding a second solvent to the solid obtained from step b) and co-distilling the solvent completely to obtain L-alanine isopropyl ester hydrochloride,
  • Step a) of the foregoing process involves reacting L-alanine with isopropanol in the presence of trialkyl silyl chloride to obtain L-alanine isopropyl ester as hydrochloride salt.
  • trialkyl silyl chlorides include but are not limited to trimethyl silyl chloride, triethyl silyl chloride, tribuyl silyl chloride and the like, preferably trimethyl silyl chloride.
  • the reaction is typically carried out at a suitable temperature such as 40°C to reflux temperature of the solvent employed.
  • a suitable temperature such as 40°C to reflux temperature of the solvent employed.
  • the reaction temperature is about 75°C to about 85°C.
  • the reaction is allowed to stir for a period of time from about 2 hrs until completion of the reaction, preferably 6-9 hrs.
  • Step b) of the foregoing process involves removal of solvent by distillation under atmospheric pressure to get the residue at temperature of about 90°C to about 140°C.
  • the distillation temperature is about 110°C to about 120°C.
  • Step c) of the foregoing process involves removal of traces of isopropanol by adding a second solvent and co-distilling it under atmospheric pressure at a temperature of about 40°C to about 80°C, preferably at 60-65°C. This process of adding second solvent and co- distillation is repeated if necessary until complete removal of residual isopropanol.
  • the suitable second solvent includes but is not limited to tetrahydrofuran, dichloromethane and the like, preferably tetrahydrofuran.
  • Step d) of the foregoing process involves treating the L-alanine isopropyl ester hydrochloride salt with DABCO in an organic solvent to obtain L-alanine isopropyl ester.
  • the reaction is typically carried out at a suitable temperature such as 20°C to 60°C.
  • the reaction temperature is about 25°C to about 50°C.
  • the reaction is allowed to stir for a period of time from about 10 mins until completion of the reaction, preferably 15- 40 mins.
  • the organic solvent for use in step d) includes but are not limited to ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether, cyclopentyl methyl ether and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; halogenated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as cyclohexane, pentane, hexane and the like; aromatic hydrocarbon solvents such as toluene, benzene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like or mixtures thereof, preferably tetrahydrofuran.
  • ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether, cyclopentyl methyl ether and the like
  • Isolating isopropyl L-alanine ester of the foregoing process may be carried out by conventional techniques such as distillation, evaporation, rotational drying (such as with the Buchi Rotavapor), preferably distillation under vacuum.
  • the step e) of converting the L-alanine isopropyl ester of Formula IV into tenofovir alafenamide or pharmaceutically acceptable salts thereof is carried out by the procedure described just as above.
  • the process according to the present invention involves complete removal of isopropanol by carrying out distillation at high temperatures and by co-distilling with a second solvent, thereby improving purity and yield of the resulting tenofovir alafenamide.
  • the present invention provides tenofovir alafenamide of Formula I, obtained by the process described herein with a chemical purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC as a mixture of diasteromers and substantially free of isopropyl ester of [(i?)-2-(Phenylphosphonomethoxy) propyl] adenine impurity by HPLC.
  • the term "substantially free” refers to tenofovir alafenamide of Formula I having less than the detectable levels of its isopropyl ester impurity or its enantiomeric form as measured by HPLC, preferably less than 0.05% of its isopropyl ester impurity or its enantiomeric form as measured by HPLG.
  • the present invention provides a process for separation of diastereomers of tenofovir alafenamide of Formula I, comprising subjecting diastereomeric mixtures of tenofovir alafenamide to a simulated moving bed chromatography or Preparative HPLC technique using suitable eluent comprising an alcohol, an ester solvent and mixtures thereof.
  • the present invention provides a process for the separation of diastereomers of tenofovir alafenamide of formula I; comprising subjecting the crude product of diastereomeric mixtures of tenofovir alafenamide to a simulated moving bed chromatography using suitable stationary chiral phase and suitable eluent.
  • the suitable eluent comprising an alcohol, an ester solvent and mixtures thereof; preferably the eluent is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate and mixtures thereof; more preferably a mixture of ethanol and ethyl acetate.
  • Suitable chiral stationary phases are in particular those which contain the derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates or optically active network polymers and which are optionally and preferably applied to a support material.
  • the suitable chiral stationary phases are in particular those which contain the derivatives of polysaccharides including the preferred ranges mentioned and are applied to a support material such as silica gel.
  • Such chiral phases are commercially available, for example, under the name CFflRALPAK® (IA, IB, IC, ID, IE, IF, AD, AS, AY, AZ)TM or CFflRALCEL® (OA, OB, OC, OD, OF, OG, OJ, OK, OX, OZ)TM from Daicel.
  • CFflRALPAK® IA, IB, IC, ID, IE, IF, AD, AS, AY, AZ
  • CFflRALCEL® OA, OB, OC, OD, OF, OG, OJ, OK, OX, OZ
  • the particles of the support material advantageously have an average diameter (based on the particle size) of 5 ⁇ to 500 ⁇ , preferably ⁇ to 100 ⁇ , more preferably 20 ⁇ .
  • the present invention provides a process for separation of diastereomers of tenofovir alafenamide of Formula I, comprising subjecting the crude product to a Preparative HPLC technique using a suitable eluent.
  • the present invention provides a process for the separation of diastereomers of tenofovir alafenamide of formula I; comprising subjecting the crude product of diastereomeric mixtures of tenofovir alafenamide' to a Preparative HPLC.
  • the Preparative HPLC can be performed using preparative chiral column and an eluent.
  • the Preparative HPLC column may be selected by any chiral columns known in the art, for example, preferably chiral columns as described just as above for simulated moving bed chromatography can be used; preferably Chiral Pak IA (500x50) mm, 20 ⁇ .
  • the suitable eluent comprising an alcohol, an ester solvent and mixtures thereof; preferably the eluent is selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, methyl acetate, propyl acetate and mixtures thereof.
  • Flow rate of the mobile phase may be selected from about 30 ml to 150ml per minute, preferably about 40 ml to 100 ml per minute, more preferably about 60 ml per minute.
  • Conditions for the Preparative HPLC are known to the person skilled in the art.
  • the present invention provides tenofovir alafenamide of Formula I, obtained by the processes described herein, having individual diastereomeric purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC, more preferably at least about 99.5% as measured by HPLC.
  • the present invention provides an acid addition salt of tenofovir alafenamide, wherein the acid addition salts are selected from either organic acid or an inorganic acid.
  • the organic acid may be selected from the group consisting of acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, p-hydroxy benzoic acid, vanillic acid, syringic acid, 4-(4- phenoxybenzoyl) benzoic acid, gentisic acid, protocatechuic acid, gallic acid, lipoic acid, aspartic acid and the like.
  • the inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid and the like.
  • the ratio of tenofovir alafenamide to the organic or inorganic acid compound may be stoichiometric or non-stoichiometric according to the present invention. For example, 1:1, 1.5:1, 1 :1.5, 2:1 and 1 :2 ratios of tenofovir alafenamide to organic or inorganic acid compound are acceptable.
  • salt forms may be in the form of solvates, hydrates, polymorphs of salts, co-crystals, or polymorphs of co-crystals.
  • the present invention provides a process for the preparation of acid addition salts of tenofovir alafenamide, comprising:
  • step a) of providing a solution of tenofovir alafenamide in one or more solvents includes but are not limited to alcohols, esters, ethers, ketones, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, amides, nitroalkanes and the like; water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n- butanol, isobutanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbon
  • the reaction may be heated to . dissolve or suspend the tenofovir alafenamide in the one or more solvents.
  • the temperature suitable for dissolving or suspending the tenofovir alafenamide in the one or more solvents depends on the solvent used and the amount of tenofovir alafenamide in the solution.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • Step b) of the foregoing process includes adding a suitable organic or inorganic acid to the solution obtained in step a).
  • the organic or inorganic acid can be selected, but not limited to fumaric acid, ferulic acid, phosphoric acid, succinic acid, citric acid, tartaric acid, lactic acid, methane sulfonic acid and the like.
  • the organic or inorganic acid may be added from about 0.5 to about 2 mole equivalents per mole of starting tenofovir alafenamide, preferably about 0.8 to about 1.5 moles.
  • the suitable acid can be added either as a solution in one or more solvents defined above or it may be added directly to the solution of tenofovir alafenamide in one or more solvents.
  • the sequence of addition of the suitable acid is not particularly critical. Additionally, the salt formation can be carried out in any known manner, for example, the suitable acid can be added into tenofovir alafenamide or tenofovir alafenamide may be added to the suitable acid.
  • the isolation of pharmaceutically acceptable salts of tenofovir alafenamide may be carried out by crystallization, solvent precipitation, concentration by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like.
  • the reaction may be cooled to a temperature from about 25°C or less such that the pharmaceutically acceptable salts of tenofovir alafenamide can be recovered by conventional techniques, for example filtration.
  • the resultant pharmaceutically acceptable salts of tenofovir alafenamide may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 80°C for a time period ranging from about 1 hour to about 10 hours.
  • the present invention provides tenofovir alafenamide fumarate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 02.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide ferulate.
  • the present invention provides tenofovir alafenamide ferulate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 03.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide phosphate.
  • the present invention provides tenofovir alafenamide phosphate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 04.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide succinate.
  • the present invention provides tenofovir alafenamide succinate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide citrate. In another embodiment, the present invention provides tenofovir alafenamide citrate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 06.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide tartarate.
  • the present invention provides tenofovir alafenamide tartarate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 07.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide lactate.
  • the present invention provides tenofovir alafenamide lactate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 08.
  • XRD X-Ray diffraction
  • the present invention provides tenofovir alafenamide mesylate. In another embodiment, the present invention provides tenofovir alafenamide mesylate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09.
  • XRD X-Ray diffraction
  • the pharmaceutically acceptable salts of tenofovir alafenamide as described above may have greater stability, bioavailability, and having desired pharmacological, pharmacokinetic and pharmacodynamic effects as compared to the tenofovir alafenamide fumarate.
  • the present invention provides characterization of pharmaceutically acceptable salts of tenofovir alafenamide of the present invention characterized by X-ray powder diffraction (XRD) pattern and/or melting point.
  • XRD X-ray powder diffraction
  • the present invention provides tenofovir alafenamide or pharmaceutically acceptable salts thereof, obtained by the process of the present invention, as analyzed diastereomeric purity using high performance liquid chromatography ("HPLC") with the conditions described below:
  • the present invention provides tenofovir alafenamide or pharmaceutically acceptable salts thereof, obtained by the process of the present invention, as analyzed chemical purity using high performance liquid chromatography (“HPLC”) with the conditions described below:
  • the present invention provides a pharmaceutical composition comprising at least substantially pure tenofovir alafenamide or a salt thereof disclosed herein and at least one pharmaceutically acceptable excipient.
  • a slurry of DABCO in THF (113 gms of DABCO in 178 gms of THF) was added to the reaction mass at 25 to 30°C and stirred for 15 minutes. Filtered the solids, washed with THF (178 gms) and the filtrate was concentrated under reduced pressure at below 40°C to get L-Alanine isopropyl ester as an oil.
  • the reaction mass was cooled to 35°C, diluted with water (150 gms), filtered the resulting. solids and washed with water (50 gms).
  • the aqueous phase was separated and pH was adjusted to 1 1 with 25% aq. NaOH and the aqueous phase was washed with ethyl acetate.
  • the pH of the aqueous phase was adjusted back to 3 with aq HC1 and the precipitated crude was isolated by filtration and washed with methanol.
  • the wet product obtained was further slurried in methanol, isolated, washed with methanol and dried at 70-75°C to yield the title compound (75 gms) as white powder.
  • Acetone (237 gms) was charged to the residue and die mixture concentrated under reduced pressure. Acetone (237 gms) was again charged to the residue, purified by chromatography over 1 100 gms of silica gel by eluting the column with acetone (7100 gms). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile (2 X 157 gms) was charged to the residue and the mixture was distilled under reduced pressure and then charged methyl tert butyl ether (200 ml) to the obtained residue and stirred for 1 hour at 25°C to 35°C. The solid crystals obtained was filtered and washed with methyl tert butyl ether (50 ml) to get title compound (75 gms). HPLC Purity (chemical): 99.80 %
  • the XRPD is set forth in Figure 01.
  • the XRPD is set forth in Figure 02.
  • the XRPD is set forth in Figure 04.
  • the XRPD is set forth in Figure 05.
  • the XRPD is set forth in Figure 06.
  • the XRPD is set forth in Figure 07.
  • the XRPD is set forth in Figure 08.
  • the XRPD is set forth in Figure 09.

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Abstract

La présente invention concerne un procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci avec un rendement et une pureté élevés. L'invention concerne également un procédé pour la séparation de diastéréomères de ténofovir alafénamide par chromatographie à lit mobile simulé ou chromatographie liquide haute performance préparative.
PCT/IN2014/000614 2013-09-20 2014-09-22 Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci WO2015040640A2 (fr)

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CN104926872A (zh) * 2015-05-12 2015-09-23 杭州和泽医药科技有限公司 替诺福韦艾拉酚胺半酒石酸盐
WO2016192692A1 (fr) * 2015-06-05 2016-12-08 Zentiva K.S. Formes solides d'alafénamide de ténofovir
CN106414466A (zh) * 2014-05-20 2017-02-15 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途
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WO2017134089A1 (fr) 2016-02-02 2017-08-10 Sandoz Ag Formes cristallines du monofumarate de ténofovir alafénamide
CN107179355A (zh) * 2016-03-11 2017-09-19 广东东阳光药业有限公司 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法
CN107226826A (zh) * 2016-03-25 2017-10-03 江苏奥赛康药业股份有限公司 替诺福韦艾拉酚胺富马酸盐化合物及其药物组合物
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CN107488195A (zh) * 2016-06-13 2017-12-19 广东东阳光药业有限公司 一种磷酸酯的制备方法
WO2017221189A1 (fr) * 2016-06-22 2017-12-28 Laurus Labs Limited Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
CN107655987A (zh) * 2017-09-08 2018-02-02 安徽灵药业有限公司 一种替诺福韦艾拉酚胺及其异构体的hplc检测方法
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN107793451A (zh) * 2016-08-30 2018-03-13 江苏奥赛康药业股份有限公司 替诺福韦艾拉酚胺半富马酸盐化合物及其药物组合物
TWI620754B (zh) * 2015-08-26 2018-04-11 Method for preparing amino phosphate derivative and preparation method thereof
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
JP2018524308A (ja) * 2015-06-17 2018-08-30 ギリアード サイエンシーズ， インコーポレイテッド テノホビルアラフェナミドの共結晶、塩および結晶形態
WO2018153977A1 (fr) 2017-02-24 2018-08-30 Hexal Ag Composition stable de ténofovir alafénamide
CN110590844A (zh) * 2019-09-21 2019-12-20 江西农业大学 一种两步法合成替诺福韦艾拉酚胺的制备方法
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CN111650290A (zh) * 2020-04-16 2020-09-11 江苏艾立康药业股份有限公司 一种替诺福韦艾拉酚胺半富马酸盐有关物质的分析方法
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
CN112782311A (zh) * 2020-12-30 2021-05-11 南京百泽医药科技有限公司 一种富马酸丙酚替诺福韦中l-丙氨酸异丙酯的hplc测定方法
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
CN113552265A (zh) * 2021-09-17 2021-10-26 天地恒一制药股份有限公司 一种富马酸丙酚替诺福韦合成原料中杂质的检测方法及应用
CN113777186A (zh) * 2021-08-12 2021-12-10 北京鑫开元医药科技有限公司 一种富马酸丙酚替诺福韦中杂质的检测方法
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2023282698A1 (fr) * 2021-07-08 2023-01-12 동아에스티 주식회사 Formulation à libération immédiate contenant du ténofovir alafénamide présentant une stabilité de formulation améliorée
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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EP2046792B1 (fr) * 2006-07-12 2015-02-25 Mylan Laboratories Limited Procédé pour la préparation de ténofovir
JP5651275B2 (ja) * 2011-08-16 2015-01-07 ギリアード サイエンシス インコーポレーテッド テノホビルアラフェナミドヘミフマレート

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US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN106414466A (zh) * 2014-05-20 2017-02-15 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途
CN111205325A (zh) * 2014-05-20 2020-05-29 四川海思科制药有限公司 替诺福韦艾拉酚胺复合物及其制备方法和用途
CN104926872A (zh) * 2015-05-12 2015-09-23 杭州和泽医药科技有限公司 替诺福韦艾拉酚胺半酒石酸盐
WO2016192692A1 (fr) * 2015-06-05 2016-12-08 Zentiva K.S. Formes solides d'alafénamide de ténofovir
JP2018524308A (ja) * 2015-06-17 2018-08-30 ギリアード サイエンシーズ， インコーポレイテッド テノホビルアラフェナミドの共結晶、塩および結晶形態
TWI620754B (zh) * 2015-08-26 2018-04-11 Method for preparing amino phosphate derivative and preparation method thereof
WO2017134089A1 (fr) 2016-02-02 2017-08-10 Sandoz Ag Formes cristallines du monofumarate de ténofovir alafénamide
CN107179355A (zh) * 2016-03-11 2017-09-19 广东东阳光药业有限公司 一种分离检测替诺福韦艾拉酚胺及其有关物质的方法
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CN107488196B (zh) * 2016-06-13 2021-05-11 广东东阳光药业有限公司 一种磷酸酯的制备方法
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WO2017221189A1 (fr) * 2016-06-22 2017-12-28 Laurus Labs Limited Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
CN107793451A (zh) * 2016-08-30 2018-03-13 江苏奥赛康药业股份有限公司 替诺福韦艾拉酚胺半富马酸盐化合物及其药物组合物
CN106478725A (zh) * 2016-10-14 2017-03-08 上海礼泰医药科技有限公司 高纯度膦丙替诺福韦中间体的制备方法及其应用
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018153977A1 (fr) 2017-02-24 2018-08-30 Hexal Ag Composition stable de ténofovir alafénamide
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
CN107655987A (zh) * 2017-09-08 2018-02-02 安徽灵药业有限公司 一种替诺福韦艾拉酚胺及其异构体的hplc检测方法
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
CN110590844A (zh) * 2019-09-21 2019-12-20 江西农业大学 一种两步法合成替诺福韦艾拉酚胺的制备方法
CN110746461A (zh) * 2019-11-20 2020-02-04 江苏科本药业有限公司 一种替诺福韦衍生物盐及其制备方法和一种药物组合物
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
CN111650290A (zh) * 2020-04-16 2020-09-11 江苏艾立康药业股份有限公司 一种替诺福韦艾拉酚胺半富马酸盐有关物质的分析方法
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US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide
WO2023282698A1 (fr) * 2021-07-08 2023-01-12 동아에스티 주식회사 Formulation à libération immédiate contenant du ténofovir alafénamide présentant une stabilité de formulation améliorée
CN113777186A (zh) * 2021-08-12 2021-12-10 北京鑫开元医药科技有限公司 一种富马酸丙酚替诺福韦中杂质的检测方法
CN113777186B (zh) * 2021-08-12 2023-06-13 北京鑫开元医药科技有限公司 一种富马酸丙酚替诺福韦中杂质的检测方法
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