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WO2022256490A9 - Synthèse améliorée de phosphoramidates pour le traitement du virus de l'hépatite b - Google Patents

Synthèse améliorée de phosphoramidates pour le traitement du virus de l'hépatite b Download PDF

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Publication number
WO2022256490A9
WO2022256490A9 PCT/US2022/031904 US2022031904W WO2022256490A9 WO 2022256490 A9 WO2022256490 A9 WO 2022256490A9 US 2022031904 W US2022031904 W US 2022031904W WO 2022256490 A9 WO2022256490 A9 WO 2022256490A9
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compound
formula
acid
ati
reaction
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WO2022256490A2 (fr
WO2022256490A3 (fr
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Mark Andrew LOCKWOOD
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Antios Therapeutics Inc
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Antios Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12

Definitions

  • Embodiments disclosed herein relate to the synthesis of phosphoramidate prodrugs useful in the treatment of viral infections. Specifically, embodiments relate to an improved synthesis of phosphoramidate nucleotides useful in the treatment of Hepatitis B virus.
  • Hepatitis B virus is an infectious disease that targets the liver resulting in either an acute infection, with symptoms arising in 45 to 160 days, or a chronic infection, which 350 million people worldwide are affected by. Estimates indicate that 600,000 deaths occur each year as a result of consequences related to HBV infection.
  • HBV possesses a 3.2- kb relaxed circular DNA (rcDNA) genome that is used to form covalently closed circular DNA (cccDNA) in a host cell.
  • the cccDNA is then transcribed by RNA polymerase II, a host DNA-dependent RNA polymerase, to produce pregenomic RNA (pgRNA).
  • pgRNA pregenomic RNA
  • the pgRNA is then used by the virally encoded reverse transcriptase to form rcDNA.
  • the goals of current treatments for chronic HBV infections are to reduce HBV replication and reduce liver damage.
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • Clevudine is an NRTI that is no longer being developed for the treatment of chronic HBV because of drug-related skeletal myopathy that was a result of mitochondrial dysfunction in patients.
  • clevudine triphosphate has been shown to be a competitive nonsubstrate inhibitor of the HBV encoded polymerase, and due to its long intracellular half-life, is able to suppress HBV replication for an extended period of time after drug withdrawal.
  • the discovery and synthesis of the (S,S) and (S,R) diastereomers of clevudine phosphoramidate has been previously reported. These studies were undertaken to address the myopathy concerns associated with clevudine. The phosphoramidate moiety was utilized to deliver clevudine, as its 5 '-monophosphate, to the liver reducing 1) systemic exposure to clevudine and 2) the possibility of skeletal myopathy. Both phosphoramidates showed anti-HBV activity similar to clevudine with the (S,S) diastereomer being slightly more potent.
  • WO20 16099982 discloses compounds having the general formula: where R 1 is any one of several phosphoramidate groups. Specifically, they discovered the pro-drug compound referred to as EIDD-2173; also known as ATI-2173. See U.S. Patent No. 10,683,319.
  • ATI-2173 is able to effectively and selectively deliver clevudine 5' monophosphate to the liver, bypassing the first systemic phosphorylation and thus reducing systemic exposure to clevudine allowing for the improved treatment of HBV.
  • WO20 17223421 discloses that clevudine phosphoramidate compounds, such as
  • ATI-2173 are additive or synergistic when combined with other antivirals such as lamivudine, adefovir, tenofovir, telbivudine, entecavir, or combinations thereof.
  • the synthesis begins with commercially available clevudine, herein referred to as Compound-D, that is reacted with t-BuMgCl in THF solution in the presence of an excess of the pentafluoro compound SM-3, herein referred to as Compound-3.
  • the reaction yields both ATI- 2173 and the clevudine 3', 5 '-bis phosphoramidate, as well as unreacted clevudine.
  • Table 1 Summary of impurities from 1kg and 3kg batches [0017] Thus, what are needed are methods of more efficient, specific and selective synthesis for the clevudine phosphoramidates useful for the treatment of HBV.
  • the present disclosure provides materials and methods of synthesizing clevudine phosphoramidates useful for the treatment of HBV infections. Specifically, disclosed are more efficient, specific and selective syntheses for the clevudine phosphoramidates that avoid the use of expensive and difficult to obtain starting materials, yield fewer impurities, provide greater stereoselectivity, are relatively stable under routine conditions allowing for the reaction to be performed at larger scales, and allow isolation by recrystallization.
  • FIG. 1 is the X-Ray Powder Diffraction (XRPD) spectra of ATI-2173.
  • FIG. 2 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with l.Oeq of TMSOTf.
  • FIG. 3 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with 0.5eq of PhCOOH.
  • FIG. 4 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with l.Oeq of PhCOOH.
  • FIG. 5 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with 0.5eq of PhCOOH at 30g scale.
  • FIG. 6 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with 0.5eq of PhCOOH at 30g scale, as the wet cake isolate.
  • FIG. 7 is the high performance liquid chromatography (HPLC) spectra for the preparation of Compound-6 with 0.5eq of PhCOOH at 30g scale, recrystallized from EtOH.
  • reduce or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., viral infection). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces viral infection” means decreasing the amount of viral load relative to a standard or a control.
  • an event or characteristic e.g., viral infection
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. [0039] As used herein, “treatment” refers to obtaining beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms (such as infection), diminishment of extent of infection, stabilized (i.e., not worsening) state of infection, preventing or delaying spread of the infection, preventing or delaying occurrence or recurrence of infection, and delay or slowing of infection progression.
  • symptoms such as infection
  • stabilized i.e., not worsening
  • the term “patient” may refer to a human in need of treatment with an antibiotic or treatment for any purpose, such as a human in need of such a treatment to treat viral infection.
  • the term “patient” can also refer to non-human animals, including but limited to, mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with an antibiotic or treatment for any purpose, such as with an antiviral compound.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the mixture.
  • a weight percent (wt.%) of a component unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas-chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • NMR nuclear magnetic resonance
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • GC-MS gas-chromatography mass spectrometry
  • a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable and has the desired pharmacological properties. Such salts include those that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g., sodium, potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric and hydrobromic acids) and organic acids (e.g., acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid).
  • inorganic acids e.g., hydrochloric and hydrobromic acids
  • organic acids e.g., acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid.
  • acetic acid e.g., citric acid, maleic acid
  • alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid.
  • “Pharmaceutically acceptable excipient” refers to an excipient that is conventionally useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
  • a “pharmaceutically acceptable carrier” is a carrier, such as a solvent, suspending agent or vehicle, for delivering the disclosed compounds to the patient.
  • the carrier can be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutical carrier.
  • carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the present disclosure provides materials and methods of synthesizing clevudine phosphoramidates useful for the treatment of HBV infections.
  • the methods disclosed herein are more efficient, specific and provide for the more selective synthesis for the clevudine phosphoramidates.
  • the methods disclosed avoid the use of expensive commercially available starting materials, yield fewer impurities, provide greater stereoselectivity, are stable under routine conditions allowing for the reaction to be performed at larger scales, and allow isolation by recrystallization.
  • Table 2 depicts the designated name used throughout the current specification for each of the respective compounds and intermediates. The table also shows the standard IUPAC (International Union of Pure and Applied Chemistry) name for each as well as the structure.
  • IUPAC International Union of Pure and Applied Chemistry
  • Certain embodiments disclosed herein provide a process for the preparation of ATI-
  • reaction temperature is cooled to 25 °C or less
  • the fluorinating agent of step (A-2) is selected from, but not limited to, trihydrofluorine trimethylamine, HF pyridine complex, bis(2-methoxy- ethyl)aminosulfur trifluoride (BAST, also called Deoxo-Fluor®), diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride, morpholinosulfur trifluoride, (diethylamino)difluorosulfonium tetrafluoroborate, 2-pyridinesulfonyl fluoride, N-fluorobenzenesulfonimide, perfluoro- 1 -butanesulfonyl fluoride, 2-thiophenesulfonyl fluoride, l-chloromethyl-4-fluoro-l,4-diazoniabicyclo- [2.2.2]octane bis(tetrafluoroborate), or
  • step (A-3) can be raised continuously up to 75 °C-85 °C or carried out incrementally in a step-wise fashion.
  • the temperature of step (A-3) is first raised to 40 °C-50 °C, the raised 75 °C-85 °C.
  • the reaction at step (A-3) is stirred at 75 °C-85 °C for 15-20 hours.
  • the reaction at step (A-3) is stirred at 75 °C-85 °C until Compound-SM-1 is consumed by HPLC.
  • the reaction in step (A-4) is cooled to 15 °C-25 °C.
  • the NaHCCh aqueous solution of step (A-5) is a 7% NaHCOs aqueous solution.
  • the NaHCOs of step (A-5) is added slowly.
  • the NaHCOs solution of step (A-5) is added dropwise.
  • the reaction mixture is first diluted with additional EtOAc and MeOH.
  • the organic solvent fraction of step (A-6) may be washed one or more time. In embodiments, the organic solvent fraction of step (A-6) may be washed one, two, three, four, five, six, seven, eight, nine, or even ten times. In embodiments, the organic solvent fraction of step (A-6) may be washed more than ten times.
  • the EtOAc of step (A-7) is reduced to about 2 volumes at a temperature of not more than 45 °C. In an embodiment the EtOAc of step (A-7) is removed entirely except for a trace quantity at a temperature of not more than 45 °C. In an embodiment the EtOAc of step (A-7) is removed entirely at a temperature of not more than 45 °C.
  • step (A-8) before charging with EtOH and warming, the reaction is charged with an separate initial amount of EtOH. This initial EtOH may then be distilled off at a temperature of not more than 45 °C to about 2 volumes; then, the reaction mixture may be charged with the EtOH to be warmed. In an embodiment the reaction mixture of step (A-8) is warmed from about 70 °C to about 80 °C for 1-2 hours.
  • step (A-9) the reaction is cooled to ⁇ 5 °C.
  • the mixture of step (A-9) is stirred at the cooled temperature for 8-14 hours.
  • the mixture of step (A-9) is stirred at the cooled temperature for 9 hours.
  • the filtration of step (A-9) is carried out in a centrifuge.
  • the filtrate of step (A- 10) is warmed to about 45 °C while drying under vacuum.
  • Certain embodiments disclosed herein provide a process for the preparation of ATI- 2173 involving the preparation of Compound-5, where Compound-5 is prepared from the reaction of Compound-4 in hydrogen bromide (HBr), acetic acid (AcOH), and dichloromethane (DCM).
  • HBr hydrogen bromide
  • AcOH acetic acid
  • DCM dichloromethane
  • reaction mixture is diluted with additional dichloromethane and quenched with sodium bicarbonate solution to a pH of about 6 to about 7;
  • the temperature of step (B-l) is adjusted between about 10 °C and about 20 °C.
  • the temperature of step (B-l) may be adjusted between about 11 °C and about 19 °C, between about 12 °C and about 18 °C, between about 13 °C and about 17 °C, or between about 14 °C and about 16 °C.
  • step (B-3) is stirred for about 12 hours to about 20 hours. In another embodiment, the mixture of step (B-3) is stirred for about 15 hours. In an embodiment, step (B-3) is monitored for completeness by HPLC. In an embodiment, in step (B-3) additional portions of HBr/acetic acid can be added with additional time spent stirring until the starting material is consumed.
  • the sodium bicarbonate solution of step (B-4) is a 7% sodium bicarbonate solution.
  • the temperature during step (B-4) is maintained below 25 °C.
  • the mixture of step (B-4) is cooled to between about 15 °C and about 20 °C with stirring.
  • the sodium sulfate solution of step (B-5) is a 5% sodium sulfate solution.
  • the organic layer of step (B-5) is washed more than once. In an embodiment, the organic layer of step (B-5) is washed twice.
  • the filtrate of step (B-7) is reduced to about 1-2 volumes.
  • Compound-B has a purity of greater than about 95% or greater based on the potency of the product solution.
  • Certain embodiments disclosed herein provide a process for the preparation of ATI- 2173 involving the preparation of Compound-6, where Compound-6 may be prepared by the reaction of Compound-5 with Compound-2 in the presence of A,O-bis(trimethylsilyl)acetamide (BSA), benzoic acid and 1,4-di oxane.
  • BSA A,O-bis(trimethylsilyl)acetamide
  • the preparation of Compound-6 may be carried out where: [0097] (C-l) Compound-2 is loaded in 1,4-dioxane with BSA;
  • Compound-6 may be produced as a wet-cake, where in step C-10 the product is not dried rigorously. Compound-6 may be produced with a purity of greater than or equal to about 99%.
  • HMDS hexamethyldisilazane
  • the reaction in step (C-2) is stirred for up to 48 hours. In an embodiment, the reaction in step (C-2) is stirred for 2-8 hours. In an embodiment, the reaction in step (C-2) is stirred until the solution becomes clear.
  • the Compound-5 added in step (C-3) is used as a crude solution from the production of Compound-5.
  • di chloromethane is also added during step (C-3) before the addition of benzoic acid.
  • the reaction at step (C-3) is maintained at about 70 °C to about 75 °C.
  • the reaction at step (C-3) is first cooled to about 20 °C to about 30 °C before addition of Compound-5.
  • the reaction at step (C-3) is cooled to about 20 °C to about 25 °C before addition of benzoic acid.
  • the benzoic acid of step (C-3) is added in portions.
  • the temperature of step (C-3) is maintained at about 20 °C to about 25 °C during addition of the benzoic acid. In an embodiment, if the reaction mixture of (C-3) is cooled, it is returned to about 70 °C to about 75 °C after addition of the benzoic acid. In an embodiment, the reaction mixture of (C-3) is stirred at about 70 °C to about 75 °C for about 42 hours to about 75 hours. In an embodiment, the reaction mixture of (C-3) is stirred at about 70 °C to about 75 °C for about 48 hr. [OHl] In an embodiment, the sodium bicarbonate solution used in quenching and or washing is a 7% sodium bicarbonate solution.
  • reaction mixture of (C-4) is first cooled between about 20 °C to about 30 °C before quenching, and the temperature is maintained in this range during quenching.
  • sodium bicarbonate solution of (C- 4) is added until the mixture has a pH of about 7 to about 8.
  • the mixture of (C-5) can be filtered before separation of the aqueous and organic layers.
  • the organic layer of step (C-5) can be washed with sodium bicarbonate solution two or more times.
  • step (C-7) the addition and removal of EtOH of step (C-7) can be carried out two or more times.
  • distillation of EtOH in step (C-7) is carried out at temperature of about 65 °C or less under reduced pressure.
  • the EtOH mixture of step (C-8) is warmed to a temperature of about 80 °C to about 85 °C. In an embodiment, the EtOH mixture of step (C-8) is warmed for about 1 hour to about 5 hours until clear.
  • step (C-9) is cooled to a temperature of about 20 °C to about 25 °C. In an embodiment, step (C-9) is cooled gradually over 5 hours to 6 hours. In an embodiment, step (C-9) is stirred at the cooled temperature for about 5 hours to about 18 hours. In an embodiment, step (C-9) can be repeated to obtain the desired purity.
  • Step D Synthesis of Compound-7 (Clevudine)
  • Certain embodiments disclosed herein provide a process for the preparation of ATI- 2173 involving the preparation of Compound-7, where Compound-7 (Clevudine) is synthesized by reacting Compound-6 in the presence of sodium methoxide (NaOMe).
  • the preparation of Compound-7 is carried out where: [0118] (D-l) Compound-6 wet cake is added with methanol;
  • the resulting Compound-7 has a purity of about 99% or greater and about 80% to about 90% yield.
  • the reaction mixture of step (D-2) is cooled to about 10 °C to about 15 °C before addition of sodium methoxide.
  • the base is selected from sodium hydroxide, sodium methoxide, ammonia, pyridine, methylamine, potassium cyanide, or a combination thereof.
  • the base is selected from sodium hydroxide or sodium methoxide.
  • the base may be used in stoichiometric or catalytic amounts.
  • there reaction mixture of step (D-2) is not allowed to rise above 20 °C.
  • the reaction mixture of step (D-2) is warmed to a temperature of about 40 °C to about 45 °C. In an embodiment, the reaction mixture is stirred for about 12 hours to about 18 hours.
  • step (D-3) is maintained below about 30 °C.
  • step (D-4) is maintained below about 45 °C.
  • step (D-5) is stirred for about 5 hours to about 12 hours.
  • the wet cake of step (D-6) may be rinsed with additional IP Ac.
  • the wet cake of step (D-7) is crystallized.
  • crude Compound-7 can be crystallized from ethanol.
  • Step E triethylsilylating selective agent deprotection
  • Step E triethylsilylating selective agent deprotection
  • the new and improved synthesis includes a selective deprotection of Compound-8 to afford Compound-9.
  • Compound-7 (Clevudine) is first reacted in the presence of chlorotriethylsilane, imidazole, and methyl-tert butyl ether (MTBE) to yield the intermediate Compound-8, which is subsequently deprotected with a triethylsilylating agent to provide Compound-9.
  • the isolated yield for the two steps, protection (Step E) and selective deprotection (Step F) may be at least about 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, or even at least 95%.
  • Compound-9 may be recrystallized to afford a crystalline, white solid with a purity of >99%.
  • Certain embodiments disclosed herein provide a process for the preparation of ATI- 2173 involving the preparation of Compound-8, where:
  • (E-2) triethylsilylating agent is added at a rate to maintain the temperature at below about 5 °C;
  • the resulting Compound-9 has a purity of greater than 99% in a solution of greater than 40% assay.
  • Triethylsilylating agent refers to a reagent capable of converting an alcohol to a triethylsilyl ether.
  • the triethylsilylating agent is selected from triethylsilyl chloride (TES), A-methyl-A-triethylsilyltrifluoroacetamide, -tri ethyl silyl acetamide, allyl tri ethyl si lane, A-triethylsilylacetamide, 1-methoxy-l-triethylsiloxypropene, l-methoxy-2-m ethyl - 1-triethylsiloxypropene, triethylsilyl triflate, triethylsilyl trifluoromethane, triethylsilyl imidazole, triethylsilyl bromide, triethylsilyl iodide, triethy
  • a base is loaded along with Compound-7 to promote silylation.
  • the base is selected from imidazole, pyridine, triethylamine, diisopropyl ethylamine, 2,6-lutidine, 1 -methylimidazole, ammonia, pyrrolidine, pyrrole, pyrimidine, piperidine, l,8-diazabicyclo[5.4.0]undec-7-ene, 4-methylmorpholine, 1,4- diazabicyclo[2.2.2]octane (DABCO), tetramethylethylenediamine (TMEDA), trimethylamine, diisopropylamine, sodium hydride, n-butyllithium, lithium diisopropylamide (LDA), potassium tert-butoxide or a combination thereof.
  • a catalyst is loaded along with Compound-7 to promote silylation.
  • the catalyst is selected from an ammonium halide, sodium halide, potassium halide, dimethylaminopyridine, 2-hydroxypyridine, sodium cyanide, or a combination thereof.
  • the solvent is a solvent or solvent system in which selective silylation is carried out successfully.
  • the solvent is selected from methyl /-butyl ether (MTBE), tetrahydrofuran (THF), diethyl ether, 1,4-di oxane, hexanes, n-heptane, chloroform, dichloromethane (DCM), dimethylformamide (DMF), methanol, acetonitrile, ethyl acetate, isopropyl acetate, water, or a combination thereof.
  • the solvent is MTBE.
  • step (E-l) is adjusted to between about -5 °C and about 5 °C.
  • step (E-2) the temperature of step (E-2) is maintained at between about -5 °C and about 5 °C during addition of the tri ethyl silylating agent. In an embodiment, during step (E-2) additional solvent can be added.
  • the reaction in step (E-3) is stirred for about 5 hours to about 16 hours.
  • additional base can be added and the reaction stirred for additional time.
  • the amount of imidazole used may be regulated so as to prevent over de-protection in Step F.
  • the amount of residual imidazole present may be less than 0.1 weight % (“wt%”), less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.04 wt%, less than 0.03 wt%, less than 0.02 wt%, less than 0.01 wt%, or even less than 0.005 wt%.
  • the amount of residual imidazole present may be about 0.015 wt%. In some embodiments, there may be no measurable quantity of residual imidazole.
  • the ammonium acetate of step (E-4) is a 10% ammonium acetate solution.
  • quenching of step (E-4) is carried out at a temperature below about 5 °C.
  • the organic phase of (E-5) can be washed with ammonium acetate one or more time. In an embodiment, the organic phase of (E-5) can be washed with water one or more time. In an embodiment, the filtrate of (E-5) is concentrated to about 50% volume. In an embodiment, the filtrate of (E-5) is concentrated to provide MTBE solution of greater than about 70% assay.
  • Certain embodiments disclosed herein provide a process for the preparation of ATI- 2173 involving the preparation of Compound-9, where: [0154] (F-l) The MTBE solution containing Compound-8 is added with an additional solvent;
  • Compound-8 of step (F-l) is carried forward as a dried solid after concentration of the previous step, a paste after concentration of the previous step, or in concentrated solution from the previous step; and added to the additional solvent of step (F-l).
  • the additional solvent of step (F-l) is selected from methanol, ethanol, //-propanol, isopropanol, THF, water, dichloromethane or combinations thereof.
  • Compound-8 of step (F-l) may be added with additional MTBE.
  • the acidic reagent of step (F-2) is selected from pyridinium p- toluenesulfonate (PPTS); acetic acid; formic acid; proprionic acid; acidic resin such as AMBERLITE®, DOWEX®, AMBERLYST® or DUOLITE®; hydrochloric acid; trifluoroacetic acid; trichloroacetic acid; tetra-n-butyl ammonium fluoride (TBAF); tetrabutyl ammonium chloride; ceric ammonium nitrate immobilized on silica gel; ( ⁇ ) camphorsulfonic acid or combinations thereof.
  • PPTS pyridinium p- toluenesulfonate
  • acetic acid formic acid
  • proprionic acid acidic resin
  • acidic resin such as AMBERLITE®, DOWEX®, AMBERLYST® or DUOLITE®
  • hydrochloric acid trifluoroacetic acid
  • step (F-2) is cooled to abut -15 °C to about -5 °C and the temperature is maintained within this range during addition of the acidic reagent of step (F-2).
  • step (F-2) is stirred for 5-28 hr.
  • the reaction at step (F-4) can first be diluted with MTBE before quenching.
  • the ammonium acetate solution of (F-4) is 10% ammonium acetate.
  • the aqueous layer of step (F-4) can be further extracted with additional MTBE.
  • the organic layer of step (F-4) can be washed with additional ammonium acetate solution or water.
  • solvent is removed under pressure at a temperature of less than about 50 °C, such as less than about 45 °C.
  • Compound-9 is obtained in greater than about 75%. In another embodiment, Compound-9 is obtained in greater than about 85%. In yet another embodiment,
  • Compound-9 is obtained in greater than about 95%. In an embodiment, Compound-9 is obtained in greater than about 99%.
  • Step G & Step H Synthesis of ATI-2173:
  • Step H the crude reaction solution from Step G can be treated with 2% HC1 and stirred at ambient temperature to afford crude ATI-2173 (Step H).
  • the crude material may be recrystallized from isopropyl acetate/n-heptane or MTBE/n-heptane to afford purified ATI-2173.
  • ATI-2173 is produced in greater than about 70% yield with greater than about 90% purity.
  • the solvent of step (G-l) is selected from tetrahydrofuran, diethyl ether, isopropyl ether, diglyme, 1,4-di oxane, dibutyle ether, or combinations thereof.
  • the base of step (G-2) is selected from Zc/7-butylmagnesium chloride, Zc/7-butylmagnesium bromide, methylmagnesium chloride, methylmagnesium bromide, sodium hydride, or lithium aluminum hydride.
  • the base of step (G-2) is Zc/7- butylmagnesiumchloride, 1.7 M, in THF solution.
  • the reaction mixture of (G- 2) is cooled between about -10 °C and about -5 °C.
  • the base of step (G-2) is added dropwise.
  • the base of step (G-2) is added slowly enough such that the temperature is maintained below about -5 °C.
  • the reaction mixture of (G-3) is first stirred at about -10 to about -5 °C for about 0.5 hour to about 1.0 hr. In an embodiment, the reaction mixture of (G-3) is adjusted to between about 20 °C to about 50 °C and stirred for the prescribed time.
  • the acidic reagent of step (H-l) may be added neat or as a solution. In an embodiment, the acidic reagent of step (H-l) may be added as an aqueous solution. In an embodiment the acidic reagent of step (H-l) is selected from hydrochloric acid, pyridinium -toluenesulfonate; acetic acid; formic acid; proprionic acid; acidic resin such as AMBERLITE®, DOWEX®, AMBERLYST® or DUOLITE®; or combinations thereof. In an embodiment the acidic reagent of step (H-l) is a 2% solution of hydrochloric acid.
  • the reaction mixture is maintained below about 25 °C during addition of the acidic reagent of step (H-l).
  • the reaction mixture of (H-l) is stirred for about 12 hours to about 18 hours. In an embodiment, if there is not complete conversion during step (H-l), additional acidic reagent may be added and the reaction stirred for additional time.
  • the sodium bicarbonate solution of step (H-2) is a 7% sodium bicarbonate solution.
  • the work up of step (H-3) may also use THF in the organic layer.
  • the organic layer of (H-3) may be distilled to a smaller volume before or between washing.
  • the organic layer of (H-3) may also be washed using NaCl aqueous solution.
  • the concentrated solution of step (H-4) may be diluted with IP Ac and reconcentrated.
  • seed crystals are added to the mixture of step (H-5).
  • the mixture of step (H-5) is stirred for about 12 hours to about 16 hours.
  • the solid of step (H-6) is filtered by centrifuge.
  • crude ATI-2173 can be crystallized from an isopropyl acetate/heptane mixture. In an embodiment, crude ATI-2173 may be crystallized from MTBE/n-heptane to afford a crystalline, white solid with a purity of >99%. In an embodiment, ATI-2173 is produced in greater than about 75% yield. In another embodiment, ATI-2173 is produced in greater than about 85% yield. In yet another embodiment, ATI-2173 is produced in greater than about 95% yield. In an embodiment, ATI-2173 is produced with greater than about 95% purity. In another embodiment, ATI-2173 is produced with greater than about 99% purity.
  • a process for the preparation of ATI-2173 comprises silylating Compound-7 to form selectively silylated Compound-9; followed by coupling with Compound-3; and deprotection to provide ATI-2173.
  • ATI-2173 is substantively free of Impurity- 1.
  • a process for the formation of Compound-9 comprises reacting Compound-7 with a triethylsilylating agent to form intermediate Compound-8 then selectively deprotecting the primary alcohol to form Compound- 9.
  • the triethylsilylating agent is selected from triethylsilyl chloride, A-methyl-A-triethylsilyltrifluoroacetamide, N- tri ethyl silyl acetamide, allyl tri ethylsilane, A-tri ethyl silyl acetamide, 1 -methoxy- 1- triethylsiloxypropene, l-methoxy-2-methyl-l-triethylsiloxypropene, tri ethylsilyl triflate, triethylsilyl trifluoromethane, triethylsilyl imidazole, triethylsilyl bromide, triethylsilyl iodide, triethylsilyl cyanide, or a combination thereof.
  • the base selected from imidazole, pyridine, tri ethylamine, diisopropyl ethylamine, 2,6-lutidine, 1 -methylimidazole, ammonia, pyrrolidine, pyrrole, pyrimidine, piperidine, l,8-diazabicyclo[5.4.0]undec-7-ene, 4- methylmorpholine, l,4-diazabicyclo[2.2.2]octane (DABCO), tetramethylethylenediamine (TMEDA), trimethylamine, diisopropylamine, sodium hydride, n-butyllithium, lithium diisopropylamide (LDA), potassium tert-butoxide or a combination thereof.
  • the base selected from imidazole, pyridine, tri ethylamine, diisopropyl ethylamine, 2,6-lutidine, 1 -methylimidazole, ammonia, pyrrolidine
  • methyl /-butyl ether is used as a solvent.
  • the selective deprotection is carried out in the presence of a reagent selected from pyridinium /?-toluenesulfonate (PPTS); acetic acid; formic acid; proprionic acid; acidic resin such as AMBERLITE®, DOWEX®, AMBERLYST® or DUOLITE®; hydrochloric acid; trifluoroacetic acid; trichloroacetic acid; tetra-n-butylammonium fluoride (TBAF); tetrabutyl ammonium chloride; ceric ammonium nitrate immobilized on silica gel; ( ⁇ ) camphorsulfonic acid or combinations thereof.
  • a reagent selected from pyridinium /?-toluenesulfonate (PPTS); acetic acid; formic acid; proprionic acid; acidic resin such as AMBERLITE®, DOWEX®, AMBERLYST® or DUOLITE®; hydrochloric acid; tri
  • the triethylsilylating agent is triethylsilyl chloride, where the selective silylation is carried out in the presence of imidazole in methyl /-butyl ether, and the selective deprotection is carried out in the presence of pyridinium p- toluenesulfonate.
  • a process for the formation of ATI-2173 comprises reacting Compound-9 with Compound-3 forming the intermediate Compound- 10 where the silyl group is then removed to provide ATI-2173.
  • the basic reactant is /c/7-butylmagnesiumchloride.
  • the silyl group is removed in the presence of an acidic reagent, the acidic reagent selected from hydrogen chloride, acetic acid, acid resin, citric acid, sulfuric acid, sulfurous acid, phosphoric acid, methanoic acid, benzoic acid, formic acid, hydrogen bromide, or combinations thereof.
  • an acidic reagent selected from hydrogen chloride, acetic acid, acid resin, citric acid, sulfuric acid, sulfurous acid, phosphoric acid, methanoic acid, benzoic acid, formic acid, hydrogen bromide, or combinations thereof.
  • ATI-2173 is substantively free of Impurity- 1
  • ATI-2173 is crystallized in a mixture of IP Ac and //-heptane.
  • a process for the formation of Compound-4 comprises reacting Compound-1 in the presence of bis(2- methoxyethyl)aminosulfur trifluoride.
  • a process for the formation of Compound-6 comprises reacting Compound-4 with HBr/acetic acid to form Compound-5 then reacting Compound-2 with BSA, benzoic acid, and Compound-4 to form Compound-5.
  • Compound-4 may be purified before reaction with Compound-2.
  • Compound-4 may be used as a crude product in reaction with Compound-2.
  • Compound-6 is reacted with a base to form Compound-7, wherein the base is selected from sodium hydroxide, sodium methoxide, ammonia, pyridine, methylamine, potassium cyanide, or a combination thereof.
  • the base is selected from sodium hydroxide, sodium methoxide, ammonia, pyridine, methylamine, potassium cyanide, or a combination thereof.
  • Compound-4 was prepared from the reaction of Compound-1 and BAST in EtOAc. In order to avoid production of several unknown impurities caused by prolonging the reaction time, a modified purification process of Compound-4 was developed that utilized crystallization in EtOH. By crystallization in EtOH, the unknown impurities were purged and the purity of Compound-4 could be improved from 85-89% to >98%. The typical yield of this step in kilogram batches was in range of about 83-88%. [0218] Experimental Procedure 1
  • Compound-5 was prepared from the reaction of Compound-4 and HBr (33% AcOH sol.). In initial experiments, it was found that conversion of Compound-4 with HBr in EtOAc at 20 °C gave incomplete conversion of the starting material. In order to improve the conversion rate, the solvent was changed from EtOAc to DCM and the charging amount of HBr was increased. In addition, it was found that Compound-5 was unstable under the original HPLC conditions. At the beginning, the HPLC purity of isolated Compound-5 was -70%, but the 'H-NMR spectrum was clean and Q-NMR assay was high. After optimization of the analytical HPLC method, the HPLC purity of Compound-5 in typical kilo-lab scale-up batches was about 94%.
  • Compound-6 was prepared from the reaction of Compound-2 (5-methylpyrimidine-
  • N,O-bis(trimethylsilyl)acetamide could replace HMDS to prepare the Compound-2 intermediate and avoid generation of the nucleophilic compound TMS-NH2 and avoid degradation of Compound-5.
  • BZA N,O-bis(trimethylsilyl)acetamide
  • the addition of BzOH in the reaction of the Compound-2 intermediate and Compound-5 could help to increase the diastereoselectivity.
  • the typical IPC purity level of Compound-6 was 85-89%. After crystallization in EtOH, the diastereoisomer could be removed almost completely, and the purity of Compound-6 was >99%.
  • the yield of this step was >70%. Further experiments determined that a possible solvent is THF/DCM (5V:5V).
  • the impurity Compound- 11 was generated with 23.28%.
  • THF and ACN were used as solvents, and after stirring for total 22 hr at 63 °C, Compound-5 was consumed completely and >73% of Compound- 6 was generated.
  • the impurity Compound-11 was generated with 16.00%.
  • 1,4-dioxane was used as the solvent, and after stirring for a total of 41 hr at 65-70 °C, 87.83% of Compound-6 was generated, the residual amount of Compound-5 was 3% and the impurity Compound-11 was 2.86%.
  • 1,4- dioxane would be selected over the other solvents. However, it was found that upon scale up, 1,4- dioxane did not work well with an isolated yield of product Compound-6 of only -36%.
  • the compound Compound-7 (Clevudine) was prepared from the reaction of compound Compound-6 and NaOMe in MeOH. Losing a charging amount of NaOMe 0.4-0.5 eq and trifluoroacetic acid (TFA) quenching and an isopropyl acetate (IP Ac) crystallization process, Compound-7 (Clevudine) could be obtained as white solid with >99% purity and >85% yield.
  • TFA trifluoroacetic acid
  • IP Ac isopropyl acetate
  • IP Ac is charged to the mixtrure and concentrated under reduced pressure at ⁇ 35 °C (in-process check: residual THF (%, w/w) specification ⁇ 5%);
  • ATI-2173 The final compound, ATI-2173, is crystalline based on extensive XRPD and compared to a reference standard. It has also been subjected to DSC and shows a consistent, sharp melting point. ATI-2173 has been fully characterized by TGA, residual solvents by GC, heavy metals by ICP-MS and/or ICP-OES, residue on ignition and water content. Purity was established using HPLC and chiral HPLC; extensive NMR experiments ( 1 H, 13 C, 19 F and 31 P NMR as well as 2D experiments) were performed to determine/verify the structure. FIG. 1 shows the XRPD spectrum of the crystalline ATI-2173
  • Examples of methods to obtain optically active materials include at least the following, i) physical separation of crystals-a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization-a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions-a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis-a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical separation of crystals-a technique whereby mac
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations-a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions-this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors— a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography— a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography-a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents-a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes-a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
  • Chiral chromatography including simulated moving bed chromatography, is used in one embodiment.
  • a wide variety of chiral stationary phases are commercially available.
  • some of the nucleosides described herein may exist as tautomers, such as, keto-enol tautomers. The individual tautomers as well as mixtures thereof are intended to be encompassed within the compounds of the present subject matter.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the subject matter disclosed herein may be embodied in many different forms, there are described in detail herein specific embodiments. The present disclosure is an exemplification of the principles of the disclosed subject matter and is not intended to limit the subject matter to the particular embodiments illustrated.

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Abstract

La divulgation concerne la synthèse de promédicaments à base de phosphoramidate utiles dans le traitement d'infections virales. En particulier, la divulgation concerne une synthèse améliorée de nucléotides de phosphoramidate utile dans le traitement du virus de l'hépatite B.
PCT/US2022/031904 2021-06-03 2022-06-02 Synthèse améliorée de phosphoramidates pour le traitement du virus de l'hépatite b Ceased WO2022256490A2 (fr)

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