WO2024023845A1 - Amorphous solid dispersions of evocalcet and procesess therof - Google Patents

Amorphous solid dispersions of evocalcet and procesess therof Download PDF

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Publication number
WO2024023845A1
WO2024023845A1 PCT/IN2023/050720 IN2023050720W WO2024023845A1 WO 2024023845 A1 WO2024023845 A1 WO 2024023845A1 IN 2023050720 W IN2023050720 W IN 2023050720W WO 2024023845 A1 WO2024023845 A1 WO 2024023845A1
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WIPO (PCT)
Prior art keywords
compound
evocalcet
formula
hpmc
amorphous solid
Prior art date
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PCT/IN2023/050720
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French (fr)
Inventor
SIRAZODDIN, Md
Ashok Arige
Srinivas ORUGANTI
Saikat Sen
Vishnu Vardhana Vema Reddy EDA
Saravanan Mohanarangam
Srinivas Achanta
Rakeshwar Bandichhor
Rajeev REHANI BUDHDEV
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Dr. Reddy's Laboratories Limited
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Publication of WO2024023845A1 publication Critical patent/WO2024023845A1/en

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    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 no 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • aspects of the present application relates to amorphous solid dispersions of evocalcet with polymer matrix, formic acid salt of evocalcet and process for the preparation of evocalcet.
  • Evocalcet is useful for the prevention or treatment of diseases such as hyperparathyroidism.
  • the chemical name of Evocalcet is 2- ⁇ 4-[(3 S ) -3- ⁇ [(1 R ) -1- (Naphthalen-l-yl) ethyl] amino ⁇ pyrrolidin-l-yl] phenyl ⁇ acetic acid, the structural formula is shown below.
  • US9643920B2 describes two crystalline forms of Evocalcet (Form A and Form B) and processes thereof.
  • W02017061621A1 describes evocalcet or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising excipients.
  • aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application provides a formic acid salt of evocalcet.
  • the present application provides a formic acid salt of evocalcet (DRL1), characterized by a PXRD pattern comprising the peaks at about 7.2, 13.1, 23.4 ⁇ 0.2° 29.
  • DRL1 formic acid salt of evocalcet
  • the present application provides a formic acid salt of evocalcet (DRL2), characterized by a PXRD pattern comprising the peaks at about 7.6, 11.4, 13.1 and 16.9 ⁇ 0.2° 29.
  • DRL2 formic acid salt of evocalcet
  • the present application provides a process for the preparation of formic acid salt of evocalcet comprising the steps of: a) dissolving evocalcet in formic acid; b) adding the solution obtained in step a) to anti solvent; c) isolating the formic acid salt of evocalcet; d) optionally drying the solid material obtained in step c)
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising formic acid salt of evocalcet with at least one pharmaceutically acceptable excipient.
  • the present application provides process for the preparation of compound of formula (III), a") wherein P is 4-Nitrobenzenesulfonyl, 4-methylbenzenesulfonyl, methyl sulfonyl, which comprises reacting a compound of formula (II) with suitable sulfonyl halide to provide the compound of formula (III).
  • the present application provides a process for the preparation of compound of formula (IV), which comprises reacting a compound of formula (III) wherein P is 4-Nitrobenzenesulfonyl, 4-methylbenzenesulfonyl, methyl sulfonyl, with a compound of formula (IVA) to provide the compound of formula (IV).
  • the present application provides a process for the preparation of compound of formula (IV), which comprises reacting a compound of formula (F) with a compound of formula (IB) to provide the compound of formula (IV).
  • the present application provides a process for the preparation of compound of formula (E), wherein PG is Boc, Cbz and Fmoc. which comprises reacting a compound of formula (C) with a compound of formula (IVA) to provide the compound of formula (E)
  • the present application provides a process for the preparation of compound of formula (C), wherein PG is Boc, Cbz and Fmoc. which comprises reacting a compound of formula (A) with 4-Nitrobenzenesulfonyl chloride (compound of formula (B)) to provide the compound of formula (C)
  • the present application provides a process for the preparation of evocalcet comprising the steps of:
  • the present application provides a process for the preparation of evocalcet comprising the steps of:
  • Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion (ASD) of Evocalcet with HPMC E5 prepared by the method of Example No 1.
  • ASD amorphous solid dispersion
  • Figure 2 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC AS prepared by the method of Example No 2.
  • Figure 3 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Eudragit L-100 prepared by the method of Example No 3.
  • Figure 4 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC E5 prepared by the method of Example No 4.
  • Figure 5 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC AS prepared by the method of Example No 5.
  • Figure 6 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 6.
  • Figure 7 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 7.
  • Figure 8 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Co-povidone prepared by the method of Example No 8.
  • Figure 9 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 9.
  • Figure 10 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Copovidone prepared by the method of Example No 10.
  • Figure 11 is an illustrative powder X-ray diffraction pattern of formic acid salt of evocalcet (DRL1) prepared by the method of Example No 11.
  • Figure 12 is an illustrative powder X-ray diffraction pattern of formic acid salt of evocalcet (DRL2) prepared by the method of Example No 12
  • aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
  • polymer matrix may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC; also referred to as hypromellose) such as HPMC E3; hydroxypropyl methylcellulose acetate succinate (HPMC AS; also referred to as hypromellose acetate succinate) such as L, M, and H grades of HPMC AS; eudragit L-100; hydroxypropyl cellulose (HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose acetate phthalate; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinyl pyrrolidone (PVP); polymethacrylate-based copolymers; polyvinylcaprolactam- based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPMC AS also referred
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • solvent may be selected from the group consisting of methanol, di chloromethane, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3- pentanol, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, water or mixtures thereof.
  • the solvent is mixture of methanol and dichloromethane.
  • a solution of Evocalcet and polymer matrix may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
  • a solution of Evocalcet and polymer matrix may be filtered to make it clear and free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application.
  • removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
  • amorphous solid dispersion of Evocalcet with polymer comprising the ratio of Evocalcet and polymer is 1 : 1 to 1 :20 w/w.
  • the present application relates to amorphous solid dispersion of Evocalcet with HPMC E3.
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E3, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application relates to amorphous solid dispersion of Evocalcet with HPMC AS.
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application relates to amorphous solid dispersion of Evocalcet and Eudragit L-100.
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application relates to amorphous solid dispersion of Evocalcet and Co-povidone.
  • the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone, comprising
  • step (b) optionally heating the reaction mixture obtained in step (a);
  • the present application provides a process for the preparation of evocalcet comprising the steps of
  • the step a) can be performed in presence of suitable base.
  • the base can be any organic or inorganic base.
  • Bases that are useful in the reaction include but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, carboxylates e.g., potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, lithium carbonate, lithium acetate, or the like; and organic bases such as, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine.
  • the preparation of compound of formula (C) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; C2-6 ethers; polar aprotic solvents; or any mixtures thereof.
  • suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; C2-6 ethers; polar aprotic solvents; or any mixtures thereof.
  • the step a) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent.
  • the reaction can be performed from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • the compound of formula (C) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
  • the step b) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent.
  • the reaction can be performed from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • the compound of formula E) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
  • step c) can be performed in presence of suitable deprotecting reagent that is not limited to acid, base or Pd-C/H2
  • the step c) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
  • suitable solvent such as aliphatic or aromatic or halogenated hydrocarbon
  • the step c) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent.
  • the reaction can be performed from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • the compound of formula F) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
  • solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
  • compound of formula F) can be converted into its free base.
  • Free base formation of compound of formula F) can be performed in presence of a suitable base.
  • the base can be any organic or inorganic base.
  • Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, magnesium oxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, N-
  • free base formation of compound of formula F) can be carried out in a suitable solvent that is not limited to: halogenated hydrocarbon, Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
  • the step d) can be performed in presence of suitable reagents that are known in the art.
  • suitable reagents refer to palladium (II) acetate [Pd(OAc)2], Cesium carbonate (CS2CO3) and XPhos.
  • the step d) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
  • suitable solvent such as aliphatic or aromatic or halogenated hydrocarbon
  • the step d) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent.
  • the reaction can be performed from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • the compound of formula (IV) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
  • solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
  • the step e) can be performed in presence of suitable acid that is not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
  • suitable acid that is not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
  • the step e) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
  • suitable solvent such as aliphatic or aromatic or halogenated hydrocarbon
  • Ci-6 alcohols such as aliphatic or aromatic or halogenated hydrocarbon
  • C3-6 ketones such as C2-6 ethers
  • polar aprotic solvents such as water or any mixtures thereof.
  • the step e) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • the purification of the evocalcet can be carried out in a suitable solvent to produce purified compound.
  • Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent.
  • Solvents that are useful in the reaction include, but are not limited to: Ci-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.
  • the purification of product can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent.
  • the reaction can be carried out from about room temperature to about boiling point of the solvent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
  • evocalcet in another embodiment, can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
  • the present application provides chemical purity of evocalcet may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
  • the present application provides particle size (D90) of evocalcet may be less than 100 microns or less than 50 microns or less than 20 microns.
  • the number of carbon atoms present in a given group is designated “C x -C y ”, where x and y are the lower and upper limits, respectively.
  • a group designated as “Ci-Ce” contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • reacting is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place.
  • aliphatic or aromatic hydrocarbon is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution.
  • Cs-Cs aliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3 -methylpentane, 2, 3 -dimethylbutane, neohexane, n-heptane, isoheptane, 3- methylhexane, neoheptane, 2, 3 -dimethylpentane, 2,4-dimethylpentane, 3, 3 -dimethylpentane, 3 -ethylpentane, 2,2, 3 -trimethylbutane, n-octane, isooctane, 3 -methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, tol
  • Alcohols are organic solvents containing a carbon bound to a hydroxyl group.
  • Ci-Ce Alcohols include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, di ethylene glycol, 1-, 2-, or 3 -pentanol, neo-pentyl alcohol, t-pentyl alcohol, di ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
  • C3-6 Ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
  • An “ether” is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms.
  • C2-6 Ether solvents include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
  • a “halogenated hydrocarbon” is an organic solvent containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, di chloromethane, 1,2-di chloroethane, trichloroethylene, perchloroethylene, 1,1,1 -tri chloroethane, 1, 1,2-tri chloroethane, chloroform, carbon tetrachloride, or the like.
  • Example-1 Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
  • Evocalcet 250 mg
  • HPMC AS 1 g
  • methanol 25 mL
  • dichloromethane 25 mL
  • the solution was filtered to make it particle free.
  • the obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with HPMC-AS.
  • Example-3 Process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100
  • Evocalcet 250 mg
  • Eudragit L-100 (1 g) were dissolved in methanol (25 mL) and di chloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with Eudragit L-100.
  • Example-4 Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
  • Evocalcet (2 g) and HPMC E5 (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC E5.
  • Example-5 Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS
  • Evocalcet (2 g) and HPMC AS (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC AS.
  • Example-6 Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
  • Evocalcet (1 g) and PVP K-30 (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
  • Example-7 Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
  • Evocalcet (1 g) and PVP K-30 (10 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
  • Example-8 Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
  • Evocalcet (1 g) and Co-povidone (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.
  • Example-9 Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
  • Evocalcet (2 g) and PVP K-30 (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
  • Example-10 Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
  • Evocalcet (2 g) and Co-povidone (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.
  • Evocalcet 500 mg was dissolved in formic acid (2 ml) at 25°C. The obtained clear solution was added to water (30 ml) at 25°C. The reaction mixture was stirred for 45 hrs at 25°C. The resulted slurry was filtered under vacuum to obtain the title compound.
  • Evocalcet 500 mg was dissolved in formic acid (2 ml) at 25°C.
  • the obtained clear solution was added to MTBE (30 ml) at 25°C.
  • the reaction mixture was stirred for 1 hr 15 minutes at 25°C.
  • the resulted slurry was filtered under vacuum and washed with MTBE (20 ml).
  • the obtained solid material was dried for 24 hrs at 60°C to obtain the title compound.
  • Example-13 Preparation of tert-butyl (5)-3-(((l?)-l-(naphthalen-l- yl)ethyl)amino)pyrrolidine-l-carboxylate (Compound of Formula E).
  • Example-14 Preparation of (S)- ⁇ -((/?)-l-(naphthalen-l-yl)ethyl)pyrrolidin-3- amine*dihydrochloride*mono isopropyl alcohol solvate (Compound of Formula F).
  • Example-15 Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l-yl)ethyl) amino)pyrrolidin-l-yl)phenyl)acetate (Compound of Formula IV).
  • Example-17 Preparation of tert-butyl (l?)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-l- carboxylate
  • Example-19 Preparation of tert-butyl (l?)-2-(4-(3-((tert- butyldimethylsilyl)oxy)pyrrolidin-l-yl)phenyl)acetate.
  • Example-20 Preparation of tert-butyl (l?)-2-(4-(3-hydroxypyrrolidin-l-yl)phenyl) acetate.
  • Example-21 Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l-yl)ethyl) amino)pyrrolidin-l-yl)phenyl)acetate.
  • Example-23 Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l- yl)ethyl)amino)pyrrolidin-l-yl)phenyl)acetate.

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Abstract

Aspects of the present application relates to amorphous solid dispersions of evocalcet with polymer matrix, formic acid salt of evocalcet and process for the preparation of evocalcet.

Description

AMORPHOUS SOLID DISPERSIONS OF EVOCALCET AND PROCESESS THEROF
This application claims the benefit of priority from the Indian patent application numbers IN202241043603 filed on 29 Jul 2022; IN202241056753 filed on 3 Oct 2022 and IN202341007742 filed on 7 Feb 2023 which are incorporated herein by reference.
INTRODUCTION
Aspects of the present application relates to amorphous solid dispersions of evocalcet with polymer matrix, formic acid salt of evocalcet and process for the preparation of evocalcet.
Evocalcet is useful for the prevention or treatment of diseases such as hyperparathyroidism. The chemical name of Evocalcet is 2- {4-[(3 S ) -3- {[(1 R ) -1- (Naphthalen-l-yl) ethyl] amino} pyrrolidin-l-yl] phenyl} acetic acid, the structural formula is shown below.
Figure imgf000002_0001
US8362274B2 describes Evocalcet and its pharmaceutical composition.
US9643920B2 describes two crystalline forms of Evocalcet (Form A and Form B) and processes thereof.
W02017061621A1 describes evocalcet or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising excipients.
However, there remains a need for alternate solid forms of Evocalcet and processes thereof, exhibiting desired properties such as bioavailability and stability.
The prior art process for the preparation of evocalcet have major drawbacks such as slow reaction rate for the 2-nitrobenzenesulfonate ester formation step; the need to employ toxic, extremely hygroscopic and difficult to store trimethylamine hydrochloride, late stage palladium mediated buchwald coupling, and difficulties with respect to removal of process related metal impurities. Therefore, there remains a need for additional processes for the preparation of evocalcet in an environmentally-friendly, cost-effective, and industrially applicable manner.
SUMMARY
Aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.
In an aspect, the present application provides a formic acid salt of evocalcet.
In an aspect, the present application provides a formic acid salt of evocalcet (DRL1), characterized by a PXRD pattern comprising the peaks at about 7.2, 13.1, 23.4 ± 0.2° 29.
In an aspect, the present application provides a formic acid salt of evocalcet (DRL2), characterized by a PXRD pattern comprising the peaks at about 7.6, 11.4, 13.1 and 16.9 ± 0.2° 29.
In another aspect, the present application provides a process for the preparation of formic acid salt of evocalcet comprising the steps of: a) dissolving evocalcet in formic acid; b) adding the solution obtained in step a) to anti solvent; c) isolating the formic acid salt of evocalcet; d) optionally drying the solid material obtained in step c)
In another aspect, the present application provides a pharmaceutical composition comprising formic acid salt of evocalcet with at least one pharmaceutically acceptable excipient.
In an aspect, the present application provides process for the preparation of compound of formula (III),
Figure imgf000003_0001
a") wherein P is 4-Nitrobenzenesulfonyl, 4-methylbenzenesulfonyl, methyl sulfonyl, which comprises reacting a compound of formula (II)
Figure imgf000003_0002
with suitable sulfonyl halide to provide the compound of formula (III).
In an aspect, the present application provides a process for the preparation of compound of formula (IV),
Figure imgf000004_0001
which comprises reacting a compound of formula (III)
Figure imgf000004_0002
wherein P is 4-Nitrobenzenesulfonyl, 4-methylbenzenesulfonyl, methyl sulfonyl, with a compound of formula (IVA)
Figure imgf000004_0003
to provide the compound of formula (IV).
In an aspect, the present application provides a process for the preparation of compound of formula (IV),
Figure imgf000004_0004
which comprises reacting a compound of formula (F) with a compound of formula (IB)
Figure imgf000004_0005
to provide the compound of formula (IV).
In an aspect, the present application provides a process for the preparation of compound of formula (E),
Figure imgf000004_0006
wherein PG is Boc, Cbz and Fmoc. which comprises reacting a compound of formula (C)
Figure imgf000005_0001
with a compound of formula (IVA)
Figure imgf000005_0002
to provide the compound of formula (E)
In an aspect, the present application provides a process for the preparation of compound of formula (C),
Figure imgf000005_0003
wherein PG is Boc, Cbz and Fmoc. which comprises reacting a compound of formula (A)
Figure imgf000005_0004
with 4-Nitrobenzenesulfonyl chloride (compound of formula (B)) to provide the compound of formula (C)
In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A)
Figure imgf000005_0005
wherein PG is Boc, Cbz and Fmoc. with 4-Nitrobenzenesulfonyl chloride (compound of formula (B)) to provide the compound of formula (C)
Figure imgf000006_0001
(b) reacting a compound of formula (C) with a compound of formula (IVA)
Figure imgf000006_0002
to provide the compound of formula (E);
Figure imgf000006_0003
(c) reacting a compound of formula (E) with deprotecting reagent to provide the compound of formula (F);
Figure imgf000006_0004
(d) reacting a compound of formula (F) with a compound of formula (IB)
Figure imgf000006_0005
to provide the compound of formula
Figure imgf000006_0006
(e) reacting a compound of formula (IV) with acid to provide evocalcet.
In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A) with suitable silyl chloride in the presence of imidazole;
Figure imgf000006_0007
wherein PG is Boc Cbz and Fmoc. to provide the compound of formula (AAG);
Figure imgf000007_0001
wherein Rl, R2 and R3 is alkyl, aryl or arylalkyl group.
(b) reacting a compound of formula (AAG) with a trifluoroacetic acid (TFA) to provide the compound of formula (IAG);
Figure imgf000007_0002
wherein Rl, R2 and R3 is alkyl, aryl or arylalkyl group.
(c) reacting a compound of formula (IAG) with a compound of formula (IB)
Figure imgf000007_0003
to provide the compound of formula (IG);
Figure imgf000007_0004
wherein Rl, R2 and R3 is alkyl, aryl or arylalkyl group.
(d) reacting a compound of formula (IG) with appropriate fluoride reagent, such as a tetra- n-butylammonium fluoride (TBAF) to provide the compound of formula (II);
Figure imgf000007_0005
(e) reacting a compound of formula (II) with 4-Nitrobenzenesulfonyl chloride to provide the compound of formula (Ills);
Figure imgf000008_0001
(f) reacting a compound of formula (III) with a compound of formula (IVA)
\ . NH2
00
(IVA) to provide the compound of formula (IV);
Figure imgf000008_0002
(g) reacting a compound of formula (IV) with acid to provide evocal cet.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion (ASD) of Evocalcet with HPMC E5 prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC AS prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Eudragit L-100 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC E5 prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with HPMC AS prepared by the method of Example No 5.
Figure 6 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 6.
Figure 7 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 7.
Figure 8 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Co-povidone prepared by the method of Example No 8.
Figure 9 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with PVP K-30 prepared by the method of Example No 9.
Figure 10 is an illustrative X-ray powder diffraction pattern of ASD of Evocalcet with Copovidone prepared by the method of Example No 10.
Figure 11 is an illustrative powder X-ray diffraction pattern of formic acid salt of evocalcet (DRL1) prepared by the method of Example No 11.
Figure 12 is an illustrative powder X-ray diffraction pattern of formic acid salt of evocalcet (DRL2) prepared by the method of Example No 12
DETAILED DESCRIPTION
Aspects of the present application relates to amorphous solid dispersions of Evocalcet with polymer matrix.
In embodiments, polymer matrix may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC; also referred to as hypromellose) such as HPMC E3; hydroxypropyl methylcellulose acetate succinate (HPMC AS; also referred to as hypromellose acetate succinate) such as L, M, and H grades of HPMC AS; eudragit L-100; hydroxypropyl cellulose (HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose acetate phthalate; vinylpyrrolidone-vinyl acetate copolymer (copovidone); polyvinyl pyrrolidone (PVP); polymethacrylate-based copolymers; polyvinylcaprolactam- based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof. Preferably, the polymer chosen to form the polymer matrix is HPMC E3, HPMCAS, Eudragit L-100, PVP K-30, Co-povidone (or) mixture thereof.
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.
In embodiments, solvent may be selected from the group consisting of methanol, di chloromethane, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3- pentanol, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, water or mixtures thereof. Preferably, the solvent is mixture of methanol and dichloromethane.
In embodiments, a solution of Evocalcet and polymer matrix may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Evocalcet and polymer matrix may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
In embodiments, amorphous solid dispersion of Evocalcet with polymer, comprising the ratio of Evocalcet and polymer is 1 : 1 to 1 :20 w/w.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet with HPMC E3.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E3, comprising
(a) providing a solution or suspension of Evocalcet and HPMC E3 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with HPMC E3.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet with HPMC AS.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS, comprising
(a) providing a solution or suspension of Evocalcet and HPMC AS in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with HPMC AS.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet and Eudragit L-100.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100, comprising
(a) providing a solution or suspension of Evocalcet and Eudragit L-100 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with Eudragit L-100. In specific aspect, the present application relates to amorphous solid dispersion of Evocal cet and PVP K-30.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30, comprising
(a) providing a solution or suspension of Evocalcet and PVP K-30 in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with PVP K-30.
In specific aspect, the present application relates to amorphous solid dispersion of Evocalcet and Co-povidone.
In specific aspect, the present application provides a process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone, comprising
(a) providing a solution or suspension of Evocalcet and Co-povidone in mixture of methanol and dichloromethane;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet with Co-povidone.
In an aspect the amorphous solid dispersion of Evocalcet is stable at various conditions and the details are tabulated below
Figure imgf000011_0001
In an aspect, the present application provides a process for the preparation of evocalcet comprising the steps of
(a) reacting a compound of formula (A)
Figure imgf000012_0001
wherein PG is Boc Cbz and Fmoc. with 4-Nitrobenzenesulfonyl chloride (compound of formula (B)) to provide the compound of formula (C) to provide the compound of formula (C);
Figure imgf000012_0002
(b) reacting a compound of formula (C) with a compound of formula (IVA)
Figure imgf000012_0003
to provide the compound of formula
Figure imgf000012_0004
(c) reacting a compound of formula (E) with deprotecting reagent to provide the compound of formula (F);
Figure imgf000012_0005
(d) reacting a compound of formula (F) with a compound of formula (IB)
Figure imgf000012_0006
to provide the compound of formula
Figure imgf000012_0007
(e) reacting a compound of formula (IV) with acid to provide evocalcet.
In one embodiment, the step a) can be performed in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, carboxylates e.g., potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, lithium carbonate, lithium acetate, or the like; and organic bases such as, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, the preparation of compound of formula (C) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; C2-6 ethers; polar aprotic solvents; or any mixtures thereof.
In another embodiment, the step a) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (C) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the step b) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula E) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the step c) can be performed in presence of suitable deprotecting reagent that is not limited to acid, base or Pd-C/H2
In another embodiment, the step c) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step c) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula F) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
In another embodiment, compound of formula F) can be converted into its free base. Free base formation of compound of formula F) can be performed in presence of a suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, magnesium oxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, N-methylmorpholine.
In another embodiment, free base formation of compound of formula F) can be carried out in a suitable solvent that is not limited to: halogenated hydrocarbon, Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step d) can be performed in presence of suitable reagents that are known in the art. Specifically, the suitable reagents refer to palladium (II) acetate [Pd(OAc)2], Cesium carbonate (CS2CO3) and XPhos.
In another embodiment, the step d) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step d) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment, the compound of formula (IV) can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.
In another embodiment, the step e) can be performed in presence of suitable acid that is not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
In another embodiment, the step e) can be performed in presence of suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; Ci-6 alcohols; C3-6 ketones; C2-6 ethers; polar aprotic solvents; water or any mixtures thereof.
In another embodiment, the step e) can be performed at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be performed from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment of step e), the purification of the evocalcet can be carried out in a suitable solvent to produce purified compound. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Solvents that are useful in the reaction include, but are not limited to: Ci-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.
In another embodiment of step e), the purification of product can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.
In another embodiment of step e), evocalcet can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.
In another embodiment, the present application provides chemical purity of evocalcet may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another embodiment, the present application provides particle size (D90) of evocalcet may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “Ci-Ce” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place. An “aliphatic or aromatic hydrocarbon” is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of “Cs-Cs aliphatic or aromatic hydrocarbons”, include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3 -methylpentane, 2, 3 -dimethylbutane, neohexane, n-heptane, isoheptane, 3- methylhexane, neoheptane, 2, 3 -dimethylpentane, 2,4-dimethylpentane, 3, 3 -dimethylpentane, 3 -ethylpentane, 2,2, 3 -trimethylbutane, n-octane, isooctane, 3 -methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof. “Alcohols” are organic solvents containing a carbon bound to a hydroxyl group. “Ci-Ce Alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, di ethylene glycol, 1-, 2-, or 3 -pentanol, neo-pentyl alcohol, t-pentyl alcohol, di ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like. A “ketone” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-6 Ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like. An “ether” is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. “C2-6 Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like. A “halogenated hydrocarbon” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbons” include, but are not limited to, di chloromethane, 1,2-di chloroethane, trichloroethylene, perchloroethylene, 1,1,1 -tri chloroethane, 1, 1,2-tri chloroethane, chloroform, carbon tetrachloride, or the like.
Examples
Example-1: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
Evocalcet (250 mg) and HPMC E5 (1 g) were dissolved in methanol (25 mL) and di chloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with HPMC E5. Example-2: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS
Evocalcet (250 mg) and HPMC AS (1 g) were dissolved in methanol (25 mL) and dichloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with HPMC-AS.
Example-3: Process for the preparation of amorphous solid dispersion of Evocalcet with Eudragit L-100
Evocalcet (250 mg) and Eudragit L-100 (1 g) were dissolved in methanol (25 mL) and di chloromethane (25 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was evaporated under reduced pressure at 55°C to obtain amorphous solid dispersion of Evocalcet with Eudragit L-100.
Example-4: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC E5
Evocalcet (2 g) and HPMC E5 (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC E5.
Example-5: Process for the preparation of amorphous solid dispersion of Evocalcet with HPMC AS
Evocalcet (2 g) and HPMC AS (8 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with HPMC AS.
Example-6: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (1 g) and PVP K-30 (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
Example-7: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (1 g) and PVP K-30 (10 g) were dissolved in methanol (100 mL) and dichloromethane (100 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
Example-8: Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
Evocalcet (1 g) and Co-povidone (20 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.
Example-9: Process for the preparation of amorphous solid dispersion of Evocalcet with PVP K-30.
Evocalcet (2 g) and PVP K-30 (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with PVP K-30.
Example-10: Process for the preparation of amorphous solid dispersion of Evocalcet with Co-povidone.
Evocalcet (2 g) and Co-povidone (10 g) were dissolved in methanol (150 mL) and dichloromethane (150 mL) at 30°C. The solution was filtered to make it particle free. The obtained clear solution was spray dried to obtain amorphous solid dispersion of Evocalcet with Co-povidone.
Example 11: Preparation of formic acid salt of evocalcet (DRL1)
Evocalcet (500 mg) was dissolved in formic acid (2 ml) at 25°C. The obtained clear solution was added to water (30 ml) at 25°C. The reaction mixture was stirred for 45 hrs at 25°C. The resulted slurry was filtered under vacuum to obtain the title compound.
Example 12: Preparation of formic acid salt of evocalcet (DRL2)
Evocalcet (500 mg) was dissolved in formic acid (2 ml) at 25°C. The obtained clear solution was added to MTBE (30 ml) at 25°C. The reaction mixture was stirred for 1 hr 15 minutes at 25°C. The resulted slurry was filtered under vacuum and washed with MTBE (20 ml). The obtained solid material was dried for 24 hrs at 60°C to obtain the title compound.
Example-13: Preparation of tert-butyl (5)-3-(((l?)-l-(naphthalen-l- yl)ethyl)amino)pyrrolidine-l-carboxylate (Compound of Formula E).
Compound of Formula A (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25°C. Triethylamine (0.81 g) was added to the reaction mixture at 25°C. 4- nitrobenzenesulfonyl chloride (Compound of Formula B, 0.71 mg) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 2 hours. The reaction mixture was added to ice-cold aq. NaHCOs solution (10 mL) and extracted with MTBE (15 mL X 4). The MTBE extracts was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound of Formula C.
Compound of Formula C (1 g) and (A)-l-(naphthalen-l-yl)ethan-l-amine (Compound of Formula Iva, 1.6 g) were charged into a reactor at 25 °C. The reaction mixture was heated to 90°C and stirred for 16 hrs. After completion of the reaction, the obtained product was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the desired product, were concentrated under reduced pressure to obtain the title compound as colorless gummy liquid. Yield: 68.9%; Purity by chiral HPLC: 98.1%
Example-14: Preparation of (S)-\-((/?)-l-(naphthalen-l-yl)ethyl)pyrrolidin-3- amine*dihydrochloride*mono isopropyl alcohol solvate (Compound of Formula F).
Isopropyl alcohol (1.7 L) was charged into a reactor at 25°C. Acetyl chloride (319.1 g) was added to isopropyl alcohol at 5°C and stirred for 30 minutes. A solution of compound of Formula E (213 g), dissolved in isopropyl alcohol (1 L), was added to the reaction mixture at 5°C. The reaction mixture was heated to 60 °C and stirred for 2 hrs. The reaction mixture was cooled to 10°C and stirred for 30 minutes. The reaction mixture was filtered and washed with isopropyl alcohol (639 mL). The resultant solid was dried under reduced pressure at 45°C for 30 minutes to obtain the title compound. Yield: 87.19%; HPLC purity: 99.77%
Example-15: Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l-yl)ethyl) amino)pyrrolidin-l-yl)phenyl)acetate (Compound of Formula IV).
Compound of Formula F (203 g) and water (609 mL) were charged into a reactor at 25 °C. 10% aqueous sodium hydroxide solution (1.21 L) was slowly added to the reaction mixture at 10 °C. The reaction mixture was stirred at 10 °C for 10 minutes, and then extracted with toluene (1 L X 3). The toluene extracts were combined, washed with water and brine, and finally dried over anhydrous sodium sulfate. The organic layer was concentrated at 45°C under reduced pressure to obtain the free base of compound of Formula F. The free base and toluene (2.03 L) were charged into a reactor at 25°C under nitrogen atmosphere. Cesium carbonate (531.4 g), Compound of Formula IB (162.17 g) and water (0.87 mL) were added to the reaction mixture at 25°C. The reaction mixture was de-gassed with nitrogen under stirring for 30 minutes at 25°C. Xphos (5.18 g) and palladium(II) acetate (2.43 g) were added to the reaction mixture at 25°C under nitrogen atmosphere. The reaction mixture was heated to 95°C and stirred for 22 hrs under nitrogen atmosphere. Water (2.03 L) was added to the reaction mixture at 25 °C and stirred for 10 minutes. The organic layer was separated from the aqueous layer which was then extracted with toluene (1 L X 2). The separated organic layers were combined, washed sequentially with 10% thiourea solution (1 L X 2), water (1 L X 2) and brine (1 L), and finally dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure at 45°C to obtain a brown colored syrup (HPLC purity: 90.86%).
The crude material was purified by column chromatography using 15% EtOAc-hexane. The fractions, containing the desired product, were concentrated at 40 °C under reduced pressure to obtain the title compound as a light brown colored syrup. Yield: 83.5%; HPLC purity: 95.39%
Example-16: Preparation of evocalcet
Compound of Formula IV (195 g) and di chloromethane (975 mL) were charged into a reactor at 25 °C. A 4M solution of HC1 in dioxane (975 mL) was slowly added to the reaction mixture at 10°C. The reaction mixture was warmed to 25°C and stirred for 24 hrs. The reaction mixture was concentrated under reduced pressure at 45°C. Water (975 mL) and 10% aq. NaOH solution (585 mL) were added to the residue at 25°C. The resultant mixture was washed with ethyl acetate (975 mL X 2). The aqueous layer was charged into a reactor at 25°C. 10% citric acid solution (195 mL) was slowly added to the reaction mixture at 15°C and stirred for 1 hr. The reaction mixture was filtered and washed with water (975 mL) and ethanol (975 mL). The obtained crude solid was dried in a hot-air oven at 45°C for 22 hrs. Yield: 79.6%; HPLC purity: 96.40%; Purity by chiral HPLC: 98.4%
The crude solid (135 g) and dimethylacetamide (675 mL) were charged into a reactor at 25°C. The reaction mixture was heated to 65°C and stirred for 45 minutes. Ethanol (2 L) was slowly added to the reaction mixture at 65°C over 2 hrs. The reaction mixture was cooled to 10°C and stirred for 45 minutes. The resultant suspension was filtered and washed with ethanol (675 mL). The obtained solid was dried at 48°C under vacuum for 3 hrs. to obtain the title compound as an off-white solid. Yield: 69.0%; HPLC purity: 99.40%; Purity by chiral HPLC: 99.7%
Example-17: Preparation of tert-butyl (l?)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine-l- carboxylate
Compound of Formula A (20 g), imidazole (18.17 g) and dichloromethane (150 mL) were charged into a reactor at 25°C under nitrogen atmosphere. A solution of tertbutyldimethylsilyl chloride (TB SCI, 16.1 g), dissolved in 50 mL of dichloromethane, was added to the reaction mixture at 0 °C over 30 minutes. The reaction mixture was heated to 25 °C and stirred for 16 hrs. Water (200 mL) was added to the reaction mixture at 25 °C. The organic layer was separated from aqueous layer, which was then extracted with DCM (40 mL X 4). The separated organic layers were combined, washed sequentially with water (150 mL) and brine (150 mL), and finally dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography using 10-15% EtOAc-hexane. The fractions, containing the product, were concentrated under reduced pressure to obtain the title compound as a pale yellow oil. Yield: 90%
Example-18: Preparation of (l?)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine
Compound of Formula AA (10 g) and dichloromethane (60 mL) were charged into a reactor at 25 °C under nitrogen atmosphere. Trifluoroacetic acid (TFA) (28.5 mL) was added to the reaction mixture at 0°C over 30 minutes. The reaction mixture was stirred at 0 °C for 2 hrs. The pH of the reaction mixture was adjusted to ~8 using aq. NaHCO, at 0 °C. The volatiles were removed from the reaction mixture by concentration under reduced pressure. The remaining mixture was extracted with ethyl acetate (200 mL X 3). The ethyl acetate extracts were combined, washed with and brine (100 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain the title compound as a light brown oil, which was taken forward to the next step without any further purification. Yield: 6.70 g.
Example-19: Preparation of tert-butyl (l?)-2-(4-(3-((tert- butyldimethylsilyl)oxy)pyrrolidin-l-yl)phenyl)acetate.
Compound of Formula IA (6.7 g), tert-butyl 2-(4-bromophenyl)acetate (Compound of Formula IB, 9.02 g), cesium carbonate (43.3 g) and toluene (70 mL) were charged into a reactor at 25°C and under nitrogen atmosphere. The reaction mixture was de-gassed at 25°C with argon for 10 minutes. Pd(OAc)2 (0.372 g) and Xphos (0.762 g) were added to the reaction mixture at 25°C. The reaction mixture was de-gassed again with argon for 10 minutes and then heated to 95 °C and stirred for 20 hrs. The reaction mixture was cooled to 25°C and filtered through a pad of celite. The celite pad was washed with MTBE (200 mL). The filtrate and washings were concentrated under reduced pressure to obtain the title compound as a brown oil, which was taken forward to the next step without any further purification. Yield: 13.0 g
Example-20: Preparation of tert-butyl (l?)-2-(4-(3-hydroxypyrrolidin-l-yl)phenyl) acetate.
Compound of Formula I (13.0 g) and THF (100 mL) were charged into a reactor at 25°C under nitrogen atmosphere. Tetrabutylammonium fluoride (TBAF, 50 mL) was added to the reaction mixture at 0°C over 20 minutes under nitrogen atmosphere. The reaction mixture was warmed to 25 °C and stirred for 2 hrs. Aqueous NH4CI solution (100 mL) was added to the reaction mixture at 0°C. The organic layer was separated from the aqueous layer, which was then extracted with ethyl acetate (75 mL X 3). The separated organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain a brown residue. The obtained residue was dissolved in 1 : 1 hexane-MTBE (500 mL). The obtained solution was washed with water (300 mL X 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a brown residue. The obtained crude product was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the product, was concentrated under reduced pressure to obtain the title compound as a pale brown solid. Yield: 5.3 g (57.6% over 3 steps, i.e. from Compound of Formula AA)
Example-21: Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l-yl)ethyl) amino)pyrrolidin-l-yl)phenyl)acetate.
Compound of Formula II (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25°C under nitrogen atmosphere. Triethylamine (0.92 mL) was added to the reaction mixture at 25°C. 4-nitrobenzenesulfonyl chloride (Compound of Formula B, 600 mg) added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 2 hrs. The reaction mixture was added to ice-cold 1.0% aqueous NaHCOs solution (50 mL) and the resulting mixture was extracted with MTBE (20 mL X 2). The MTBE extracts were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain a brown oil.
Compound III (850 mg) and (R)- 1 -(naphthal en-l-yl)ethanamine (1.0 mL) were charged into a reactor at 25 °C under nitrogen atmosphere. The reaction mixture was heated to 95 °C and stirred for 16 hrs. The reaction mixture was purified by column chromatography using 15- 20% EtOAc-hexane. The fractions, containing the product, were concentrated under reduced pressure to obtain the title compound as a pale brown oil. Yield: 470 mg.
Example-22: Preparation of evocalcet
Compound of Formula IV (100 mg), obtained in Example-9, and dichloromethane (0.5 mL) were charged into a reactor at 25°C under nitrogen atmosphere. A 4M HC1 solution in 1,4- dioxane (0.5 mL) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure. Toluene (2 mL) was added to the obtained residue and the mixture concentrated under reduced pressure. The preceding operation was repeated twice. The obtained solid was washed twice with 1 : 1 hexane-MTBE (2 mL), and dissolved in water (2.0 mL) and 10% aqueous NaOH (3.0 mL). The solution obtained was washed with ethyl acetate (2 mL X 2). 10% aqueous citric acid solution (1.0 mL) was added to the reaction mixture at 0°C. The resultant suspension was filtered and the solid obtained dried under reduced pressure to obtain the title compound. Yield: 65 mg; HPLC purity: 97.82%; Purity by chiral HPLC: 96.5%
Example-23: Preparation of tert-butyl 2-(4-((5)-3-(((l?)-l-(naphthalen-l- yl)ethyl)amino)pyrrolidin-l-yl)phenyl)acetate.
Compound of Formula II (500 mg) and dichloromethane (5 mL) were charged into a reactor at 25 °C under nitrogen atmosphere. Triethylamine (0.76 mL) was added to the reaction mixture at 0 °C. A solution of methanesulfonyl chloride (310 mg) in dichloromethane (2.5 mL) was added to the reaction mixture at 0 °C over 5 minutes. The reaction mixture was warmed to 25 °C and stirred for 2 hrs. The reaction mixture was added to ice-cold 1.0% aqueous NaHCO, solution (50 mL) and the resulting mixture was extracted with MTBE (20 mL X 2). The MTBE extracts were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to obtain the compound of formula III as a brown oil.
Compound of Formula III (680 mg) and (R)- 1 -(naphthal en-l-yl)ethanamine (1.0 mL) were charged into a reactor at 25 °C under nitrogen atmosphere. The reaction mixture was heated to 95 °C and stirred for 16 hrs. The reaction mixture was purified by column chromatography using 15-20% EtOAc-hexane. The fractions, containing the product, was concentrated under reduced pressure to obtain the title compound as a pale yellow oil. Yield: 527 mg Example-24: Preparation of evocalcet.
Compound of Formula IV (100 mg), obtained by Example-11, and dichloromethane (0.5 mL) were charged into a reactor at 25°C under nitrogen atmosphere. 4M HC1 solution in 1,4- dioxane (0.5 mL) was added the reaction mixture at 0 °C. The reaction mixture was warmed to 25°C and stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure. Toluene (2 mL) was added to the obtained residue and the mixture concentrated under reduced pressure. The preceding operation was repeated twice. The obtained solid was washed twice with 1 : 1 hexane-MTBE (2 mL) and then dissolved in water (2.0 mL) and 10% aqueous NaOH (2.0 mL The solution obtained was washed with ethyl acetate (2 mL X 2). 10% aqueous citric acid solution (1.0 mL) was added to the mixture at 0°C. The resultant suspension was filtered and the solid obtained dried under reduced pressure for 16 hrs. to obtain the title compound. Yield: 68 mg; Purity by chiral HPLC: 94.5%.

Claims

1. Amorphous solid dispersion of Evocalcet comprising an amorphous Evocalcet and polymer matrix.
2. The amorphous solid dispersion of claim 1, wherein the polymer matrix is selected from of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), eudragit, vinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), hypromellose phthalate (HPMC-P), cellulose acetate phthalate, polymethacrylate-based copolymers; polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof.
3. The amorphous solid dispersion of claim 1, wherein the polymer selected from HPMC E3, HPMC AS, eudragit L-100, PVP K-30, Co-povidone (or) mixture thereof.
4. A process for the preparation of amorphous solid dispersion of Evocalcet and polymer matrix, comprising
(a) providing a solution or suspension of Evocalcet and polymer matrix in a solvent;
(b) optionally heating the reaction mixture obtained in step (a); and
(c) isolating amorphous solid dispersion of Evocalcet.
5. The process of claim 4, where in the polymer matrix is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), eudragit, vinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), hypromellose phthalate (HPMC-P), cellulose acetate phthalate, polymethacrylate-based copolymers; polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl alcohol, alginic acid or mixture thereof.
6. The process of claim 4, wherein the solvent is selected from methanol, di chloromethane, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3- pentanol, tetrahydrofuran, 1,4-di oxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.
7. The process of claim 4, wherein the solvent is selected from methanol, dichloromethane or mixtures thereof.
8. Formic acid salt of evocalcet.
9. A process for the preparation of evocalcet comprising the steps of:
(a) reacting a compound of formula (A)
Figure imgf000026_0001
wherein PG is Boc Cbz and Fmoc. with a compound of formula (B)
Figure imgf000026_0002
to provide the compound of formula (C);
Figure imgf000026_0003
(b) reacting a compound of formula (C) with a compound of formula (IVA)
Figure imgf000026_0004
to provide the compound of formula (E);
Figure imgf000026_0005
(c) reacting a compound of formula (E) with deprotecting reagent to provide the compound of formula (F);
Figure imgf000026_0006
(d) reacting a compound of formula (F) with a compound of formula (IB)
Figure imgf000026_0007
to provide the compound of formula
Figure imgf000026_0008
(e) reacting a compound of formula (IV) with acid to provide evocalcet.
10. The process of claim 9, wherein the deprotecting reagent is selected from acid, base or Pd-C/EE
PCT/IN2023/050720 2022-07-29 2023-07-27 Amorphous solid dispersions of evocalcet and procesess therof WO2024023845A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090258949A1 (en) * 2006-06-27 2009-10-15 Johannes Ludescher Amorphous form of cinacalcet

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090258949A1 (en) * 2006-06-27 2009-10-15 Johannes Ludescher Amorphous form of cinacalcet

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MIYAZAKI HIROSHI; IKEDA YOUSUKE; SAKURAI OSAMU; MIYAKE TSUTOMU; TSUBOTA RIE; OKABE JYUNKO; KURODA MASATAKA; HISADA YUTAKA; YANAGID: "Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 28, no. 11, 24 April 2018 (2018-04-24), Amsterdam NL , pages 2055 - 2060, XP085402241, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.04.055 *

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