WO2023205779A1 - Procédé de fabrication d'intermédiaires d'inhibiteurs de cystéine protéase - Google Patents

Procédé de fabrication d'intermédiaires d'inhibiteurs de cystéine protéase Download PDF

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WO2023205779A1
WO2023205779A1 PCT/US2023/066066 US2023066066W WO2023205779A1 WO 2023205779 A1 WO2023205779 A1 WO 2023205779A1 US 2023066066 W US2023066066 W US 2023066066W WO 2023205779 A1 WO2023205779 A1 WO 2023205779A1
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formula
mono
alcohol
mixture
hydrochloride
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PCT/US2023/066066
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Erika BUTLER
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Pardes Biosciences, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

Definitions

  • Coronaviridae family of viruses are enveloped, single-stranded, positive-sense RNA viruses and include 141 species classified into four genera according to their phylogenetic relationships: a-, P-, y-, and 3-coronavirus.
  • Coronaviruses are zoonotic viruses that infect a variety of animals from whales to birds, bats, cats, and humans. Typically, CoV infection results in mild to moderate respiratory tract infections; however, some CoV species are extremely virulent and can result in widespread fatality.
  • Severe acute respiratory syndrome coronavirus (SARS-CoV) is a human CoV responsible for the first pandemic of the 21 st century, infecting over 8,000 people with a 10% mortality rate.
  • Middle East respiratory syndrome coronavirus (MERS-CoV) was identified in November 2012 and had since infected over 1,600 people in 26 countries with a 36% mortality rate. More recently, COVID- 19 (SARS CoV2) coronaviruses have raised a global pandemic since first identified in late 2019. Therefore, it is important to identify coronavirus drug targets that can be utilized for the development of broad-spectrum anti-coronaviral therapeutics to combat infections of existing and emerging coronaviruses.
  • SARS CoV2 COVID- 19 coronavirus
  • All Co Vs express a >800 kDa replicase polyprotein that contains either two or three cysteine proteases, the papain-like protease(s) (PLPpro, nsp3, or PLP1 and PLP2) and the 3C-like protease (3CLpro, nsp5, or Mpro). These proteases process the CoV replicase polyprotein by cleaving it into 16 non-structural proteins, which are responsible for a variety of aspects of CoV replication.
  • the CoV 3CLpro is responsible for processing 11 cleavage sites of within the replicase polyprotein and is essential for CoV replication, making it a highly valuable target for therapeutic development.
  • the overall active site architecture and substrate recognition pockets are structurally conserved across CoV 3CLpros, increasing its attractiveness as a target for the development of broad-spectrum anti-CoV therapeutics.
  • high sequence conservation in the vicinity of active site among CoV 3CLpros from different coronavirus subclasses make them an excellent target for the development of broadspectrum therapeutics for coronavirus infections.
  • the development of CoV 3CLpro inhibitors is a promising path for the treatment of respiratory tract infections and related diseases.
  • R 1 and R 2 are each independently selected from C1-3 alkyl and H; alternatively, R 1 and R 2 , along with the atom to which they are attached, form a 3 to 4 membered cycloalkyl ring; and “n” represents an integer selected from 0 and 1 ; to a mono-hydrochloride salt of Formula I:
  • Formula I said process comprising mixing the dihydrochloride compound of Formula D with an aqueous mixture of an alcohol to form a mixture- 1 , followed by stirring said mixture- 1 to yield a mixture-2 comprising the mono-hydrochloride compound of Formula I.
  • the compound of Formula I is, for example, methyl 2-amino-3-(2- oxopiperidin-3-yl)propanoate mono-hydrochloride.
  • a crystalline form of methyl 2-amino-3-(2-oxopiperidin-3- yl)propanoate mono-hydrochloride as characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 12.0; for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 12.0, 16.3, and 18.3; for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 12.0, 16.3, 18.0, 18.3, 19.4, and 30.0; for example, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 12.0, 16.3, 18.0, 18.3, 18.7, 19.4, 19.9,
  • composition comprising a disclosed crystalline form of 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride and a pharmaceutically acceptable excipient.
  • FIG. 1 depicts the X-ray powder diffraction (XRPD) pattern of methyl 2-amino-3-(2- oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a kilogram scale. Overlays of small scale experiment samples are shown.
  • XRPD X-ray powder diffraction
  • FIG. 2 depicts the high performance liquid chromatography (HPLC) profile of methyl 2- amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride as prepared on a kilogram scale.
  • FIG. 3 depicts the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a kilogram scale.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • FIG. 4 depicts the X-ray powder diffraction (XRPD) pattern of methyl 2-amino-3-(2- oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a gram scale.
  • XRPD X-ray powder diffraction
  • FIG. 5 depicts the differential scanning calorimetry (DSC) profile of methyl 2-amino-3-(2- oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a gram scale.
  • FIG. 6 depicts the thermogravimetric analysis (TGA) profile of methyl 2-amino-3-(2- oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a gram scale.
  • FIG. 7 depicts the high performance liquid chromatography (HPLC) profile of methyl 2- amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride (Form C) as prepared on a gram scale
  • FIG. 8 depicts the high performance liquid chromatography (HPLC) profile of methyl 2- amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride as prepared on a kilogram scale.
  • R 1 and R 2 are each independently selected from C1-3 alkyl, and H; alternatively, R 1 and R 2 , along with the atom to which they are attached, form a 3 to 4 membered cycloalkyl ring; and “n” represents an integer selected from 0 and 1 ; to a mono-hydrochloride salt of Formula I:
  • Formula I said process comprising mixing the dihydrochloride compound of Formula D with an aqueous mixture of an alcohol to form a mixture- 1 , followed by stirring said mixture- 1 to yield a mixture-2 comprising the mono-hydrochloride compound of Formula I.
  • R 1 and R 2 each independently represent C1-3 alkyl (e.g., methyl, ethyl, and propyl).
  • R 1 represents C1-3 alkyl (e.g., methyl, ethyl, and propyl) and R 2 represent H.
  • R 1 represent H and R 2 represents C1-3 alkyl (e.g., methyl, ethyl, and propyl).
  • R 1 and R 2 along with the atom to which they are attached, form a cycloalkyl ring (e.g., cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl).
  • n is 0. In some embodiments, n is 1.
  • R 1 and R 2 each independently represent -CH3.
  • Another embodiment provides a process wherein R 1 and R 2 , along with the atom to which they are attached, form a cyclopropyl ring.
  • R 1 and R 2 each independently represent H; and n represents the integer 1.
  • Another embodiment provides a process wherein the ratio of the alcohol to water in mixture - 1 ranges from about 80% alcohol : about 20% water to about 99.9% alcohol : about 0.1% water, wherein the alcohol is selected from the group consisting of a primary alcohol, secondary alcohol, tertiary alcohol, and mixtures thereof.
  • a further embodiment of this aspect of the disclosure provides a process wherein the ratio of the alcohol to water in the aqueous mixture ranges from about 90% alcohol : about 10% water to about 98% alcohol : about 2% water.
  • Yet another embodiment provides a process wherein the alcohol is selected from the group consisting of IPA, n-propanol, methanol, ethanol, t-butanol, benzyl alcohol, and i-butyl alcohol.
  • Yet another embodiment provides a process wherein, the mixture- 1 is stirred from about 1 hour to about 48 hours.
  • a further embodiment provides a process wherein the mixture- 1 is stirred from about 1 hour to about 24 hours.
  • the mixture- 1 is stirred for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.
  • the mixture- 1 is stirred for about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours.
  • the mixture- 1 is stirred at a temperature of from about -25 °C to about +25 °C. In some embodiments, the mixture- 1 is stirred at a temperature of about -25 °C, about -20 °C, about -15 °C, about -10 °C, about -5 °C, about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C.
  • Another further embodiment provides a process wherein the mixture- 1 is stirred at a temperature of from about 0 °C to about 25 °C. In some embodiments, the mixture- 1 is stirred at a temperature of about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C.
  • a further embodiment provides a process wherein the mono-hydrochloride compound of Formula I is isolated by filtering the mixture-2 to yield the compound of Formula I as a solid, wherein said solid is washed with the aqueous alcohol mixture followed by drying said solid.
  • a further embodiment provides a process wherein the mono-hydrochloride compound of Formula I is isolated by filtering the mixture-2 to yield the compound of Formula I as a solid, wherein said solid is sequentially washed with the aqueous alcohol mixture and an inert nonpolar organic solvent, followed by drying said solid.
  • a process wherein the mono-hydrochloride compound of Formula I is isolated by filtering the mixture-2 to yield the compound of Formula I as a solid, wherein said solid is washed with an inert nonpolar organic solvent, followed by drying said solid.
  • inert nonpolar organic solvents include, but not limited to, benzene, toluene, xylene, ethylbenzene, propylbenzene, chlorobenzene, dichlorobenzenes , trichlorobenzenes, biphenyl, terphenyl, diphenylether, diphenyl sulfide, acetophenone, chlorinated biphenyl, chlorinated diphenylethers, dichloroethane, tetrachloroethane, trichloroethylene, tetrachloroethylene, methylcyclohexane, octane, isooctane, decane, and the like.
  • the inert nonpolar organic solvent is methylcyclohexane.
  • a further embodiment provides a process wherein the mono-hydrochloride compound of Formula I is isolated by filtering the mixture-2 to yield the compound of Formula I as a solid, wherein said solid is sequentially washed with the aqueous alcohol mixture and methylcyclohexane, followed by drying said solid.
  • a process wherein the mono-hydrochloride compound of Formula I is isolated by filtering the mixture-2 to yield the compound of Formula I as a solid, wherein said solid is washed with methylcyclohexane, followed by drying said solid.
  • a process wherein the mono-hydrochloride compound of Formula I is dried at an elevated temperature of from about 25 °C to about 60 °C (e.g., about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, and about 60 °C).
  • Another embodiment provides a process wherein the mono-hydrochloride salt of Formula I has a purity of from about 90% to about 99.8%.
  • Another embodiment provides a process wherein the monohydrochloride salt of Formula I has a purity of from about 93% to about 99.8%.
  • Yet another embodiment provides a process wherein the mono-hydrochloride salt of Formula I has a purity of from about 95% to about 99.8%.
  • a further embodiment provides a process wherein the mono-hydrochloride salt of Formula I has a purity of from about 99% to about 99.8%.
  • Form C methyl 2-amino-3-(2-oxopiperidin-3- yl)propanoate mono-hydrochloride characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 12.0 (referred to herein as “Form C”).
  • the crystalline Form C of methyl 2-amino-3-(2-oxopiperidin-3- yl)propanoate mono-hydrochloride is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 12.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 14.6, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 16.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 18.0, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 18.3, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 19.4, is characterized by a powder X-ray diffraction pattern that has a characteristic peak in degrees 20 at about 19.9, is characterized by
  • crystalline Form C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 20 at about 12.0, 16.3, and 18.3.
  • crystalline Form C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 20 at about 12.0, 16.3, 18.0, 18.3, 19.4, and 30.0.
  • crystalline Form C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 20 at about 12.0, 16.3, 18.0, 18.3, 18.7, 19.4, 19.9, 25.5, and 30.0.
  • crystalline Form C is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks in degrees 20 at about 12.0, 14.6, 16.3, 18.0, 18.3, 18.7, 19.4, 19.9, 25.5, 26.1, 27.6, and 30.0.
  • a contemplated crystalline form has a powder X-ray diffraction pattern shown in FIG. 4.
  • the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Koi radiation.
  • the contemplated crystalline Form C of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride may be characterized by a differential scanning calorimetry (DSC) profile showing a characteristic endotherm with an onset of about 158 °C and a peak of about 160 °C.
  • DSC differential scanning calorimetry
  • Form C for example, may be characterized by the differential scanning calorimetry profile shown in FIG. 5.
  • the contemplated crystalline C of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride may be characterized by a thermogravimetric analysis (TGA) profile showing a first-step mass loss of about 1.5 wt. % between about 30 °C to about 175 °C; and a second-step mass loss of about 15.2% between about 180 °C to about 260 °C.
  • TGA thermogravimetric analysis
  • Form C may be characterized by the TGA profile shown in FIG. 6.
  • crystalline Form C may be characterized by a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 26.6 wt.% between about 5 to about 80% relative humidity (RH) at 25 °C.
  • crystalline Form C may be characterized by Karl Fischer (KF) analysis showing 0.43% water by weight.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-4, carbon atoms, referred to herein as C1-3 alkyl.
  • Exemplary alkyl groups include methyl, ethyl, and propyl.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cs-Ciocycloalkyl, C3- ecycloalkyl or C4-6cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl and cyclopropyl.
  • IP A iso-propyl alcohol
  • alcohol as used herein is intended to include primary alcohols, secondary alcohols, and tertiary alcohols.
  • primary alcohol refers to an alcohol in which the hydroxy group is bonded to a primary carbon atom. It can also be defined as a molecule containing a “-CH2OH” group. Illustrative examples of a primary alcohol are methanol/methyl alcohol, ethanol/ethyl alcohol, propanol/propyl alcohol, benzylalcohol, and 1 -butanol.
  • second alcohol refers to an alcohol having a formula CHROH”, where “R” indicates a carbon-containing group.
  • R indicates a carbon-containing group.
  • Illustrative examples include 2-propanol, iso-propanol/iso propyl alcohol, and 2-butanol.
  • tertiary alcohol refers to a tertiary alcohol has a formula CR2OH”, where “R” indicates a carbon-containing group.
  • tert-amyl alcohol 2-methylbutan-2-ol
  • 2-methyl-2-butanol 2-methyl-2-butanol
  • an inert nonpolar organic solvent refers to nonpolar organic solvents that have no chemical reaction with the dissolved compound.
  • inert nonpolar organic solvents include, but not limited to, benzene, toluene, xylene, ethylbenzene, propylbenzene, chlorobenzene, dichlorobenzenes , trichlorobenzenes, biphenyl, terphenyl, diphenylether, diphenyl sulfide, acetophenone, chlorinated biphenyl, chlorinated diphenylethers, dichloroethane, tetrachloroethane, trichloroethylene, tetrachloroethylene, methylcyclohexane, octane, isooctane, decane, and the like.
  • the term “about” as used herein is intended to mean a variance of no more than 5% of a particular value. For example, from about 95% to about 99.9% means there can be a variance of 5% from the lower value of 95% and higher value of 99.9%.
  • the term “about” in the context of peaks at degrees 20 means that there is an uncertainty in the measurements of the 20 of ⁇ 0.1 (expressed in 20).
  • a DSC thermogram may have a variation in the range of ⁇ 2 °C. Therefore, the temperature values should be understood as including values in the range of about ⁇ 2 °C.
  • crystalline forms of methyl 2-amino-3-(2-oxopiperidin-3- yl)propanoate mono-hydrochloride that are substantially free of any other crystalline forms, unless indicated otherwise.
  • “substantially pure”, “substantially free” or “substantially free of any other crystalline forms” means that the disclosed crystalline form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less, of any other materials, e.g., other crystalline forms of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride as measured, for example, by XRPD, or less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1%, of any other materials, such as other crystalline forms of methyl 2-amino-3-(2-oxopiperidin
  • a disclosed crystalline form of methyl 2- amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride described herein as “substantially pure” or as “substantially free of any other crystalline forms” would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the said crystalline forms of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate monohydrochloride.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • a crystalline compound disclosed herein has 90%, 93%, 95%, 98% or 99% purity based on HPLC and/or NMR. In some embodiments, the compound has 90% purity. In some embodiments, the compound has 93% purity. In some embodiments, the compound has 95% purity. In some embodiments, the compound has 98% purity. In some embodiments, the compound has 99% purity.
  • the purity is enantiomeric purity. In other embodiments, the purity is diastereomeric purity. In other embodiments, the purity is optical purity.
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analyses
  • Thermogravimetric analyses were carried out using a Mettler Toledo TGA/DSC3L Protective and purge gas was nitrogen at a flowrate of 20-30 mL/min and 50-100 mL/min, respectively.
  • the desired amount of sample (5-10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed using a ramp method with a heating range of 10.0 °C/min and a temperature range of 30 °C to 300 °C.
  • High performance liquid chromatography was conducted using an Agilent 1220 Infinity LC with a glow rate range of 0.2-5.0 mL/min, operating pressure range of 0-600 bar, temperature range of 5 °C above ambient to 60 °C, and a wavelength range of 190-600 nm.
  • the mobile phase A was 0.1 % MSA in distilled water
  • the mobile phase B was MeOH
  • the diluent was DMSO
  • the injection volume was 2 pL
  • the monitoring wavelength was 210 nm
  • the column was an Atlantis T3, 4.6 x 150 mm, 3.0 m
  • the column temperature was 40 °C.
  • Example 1 Preparation of Form C of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono hydrochloride (kilogram scale)
  • the suspended solids were collected by filtration.
  • the residual solids in the vessel were rinsed with pre-chilled (4-6 °C) 98:2 v:v isopropyl alcohol: water (1.5L, 1.5L/kg), and the filter cake washed with the vessel rinse.
  • the remaining and residual solids in the vessel were again rinsed with pre-chilled (4-6 °C) 98:2 v:v isopropyl alcohokwater (1.5 L, 1.5L/kg), and the filter cake washed with the vessel rinse.
  • the filtered solids were dried under vacuum at 48-52 °C until no further weight loss was observed.
  • Example 2 Preparation of Form C of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono hydrochloride (kilogram scale) [00056] Under a nitrogen atmosphere and an initial temperature of about 15-25 °C, pre-chilled and pre-mixed 98:2 v:v isopropyl alcohohwater (101.5 L, 5.8 L/kg) was charged to a vessel fitted with a mechanical stirrer, a condenser, and a temperature probe.
  • the temperature of the premix was adjusted to about 0-10°C, methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate di-hydrochloride (17.5 kg) was then added to the vessel at 0-10 °C, and the resulting mixture was stirred using a mechanical stirring device.
  • the reaction mixture ranged from a clear to milky solution.
  • the reaction mixture was cooled to 0-10 °C and mechanically stirred at this temperature for 10-20 hours (17 hours). The reaction mixture became a thick slurry.
  • the suspended solids were collected by filtration.
  • the filter cake solids in the vessel were rinsed with methylcyclohexane (35 L, 2L/kg), and the filter cake washed with the vessel rinse.
  • the remaining and residual solids in the vessel were again rinsed with methylcyclohexane (35 L, 2L/kg).
  • the filtered solids were dried under vacuum at 15-25 °C for 4-1 Oh, and then was dried under vacuum at 40-50 °C until KF value of not more than 2% was tested.
  • Methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate mono-hydrochloride was obtained with a purity of about 98.1% as observed by HPLC (FIG. 8). As shown in FIG. 8, the HPLC retention time was 8.709 min, the peak area was 2365.286 pA*sec.
  • Methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate di -hydrochloride (2 g) was weighed into a 20 mL vial inside of a glove bag purged with nitrogen ( ⁇ 12 % RH). To the vial was added IPA:water (98:2 vol.) in an amount about eight times that of the di-HCl salt forming a heterogenous mixture. The vial was capped and brought out of the glove bag into the ambient atmosphere. The heterogenous mixture was agitated at ambient temperature for about 6 minutes leading to the dissolution of the solids (the di-HCl salt) and resulting in a hazy mixture. This hazy mixture was further agitated an additional 10 minutes resulting in the formation of a flowable slurry.
  • FIG. 5 depicts the differential scanning calorimetry (DSC) profile of crystalline Form C. As shown in FIG. 5, crystalline Form C shows a characteristic broad endotherm with an onset of about 158 °C and a peak of about 160 °C.
  • Crystalline Form C of methyl 2-amino-3-(2-oxopiperidin-3-yl)propanoate monohydrochloride displayed a thermogravimetric analysis (TGA) profile s showing a first-step mass loss of about 1.5 wt. % between about 30 °C to about 175 °C; and a second-step mass loss of about 15.2% between about 180 °C to about 260 °C (FIG. 6).
  • Crystalline Form C was obtained in 99.8% purity as observed by HPLC (FIG. 7).
  • Crystalline Form C displayed a dynamic vapor sorption (DVS) profile showing a reversable total mass change of about 26.6 wt.% between about 5 to about 80% relative humidity (RH) at 25 °C. Karl Fischer (KF) analysis showed 0.43% water by weight.
  • TGA thermogravimetric analysis
  • articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La divulgation concerne un procédé de préparation d'un composé de formule I à partir du sel de di-chlorhydrate correspondant de formule D, qui sert d'intermédiaire dans la synthèse de composés biologiquement actifs ayant des applications antivirales. La divulgation concerne également un polymorphe particulier de mono-chlorhydrate de 2-amino-3-(2-oxopipéridin-3-yl) propanoate de méthyle, monochlorhydrate de 2-amino-3-(2-oxopipéridin-3-yl) propanoate d'éthyle méthyle, monochlorhydrate de 2-amino-3-(2-oxopipéridin-3-yl) propanoate de méthyle.
PCT/US2023/066066 2022-04-22 2023-04-21 Procédé de fabrication d'intermédiaires d'inhibiteurs de cystéine protéase WO2023205779A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
KR20210158591A (ko) * 2020-06-24 2021-12-31 이연제약주식회사 신규한 카르바메이트 화합물
WO2023044509A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Procédé de production d'inhibiteurs de cystéine protéase et composés obtenus selon ce procédé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
KR20210158591A (ko) * 2020-06-24 2021-12-31 이연제약주식회사 신규한 카르바메이트 화합물
WO2023044509A1 (fr) * 2021-09-20 2023-03-23 Pardes Biosciences, Inc. Procédé de production d'inhibiteurs de cystéine protéase et composés obtenus selon ce procédé

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