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WO2019021303A1 - Nouveau procédé de préparation d'apremilast sous une forme amorphe - Google Patents

Nouveau procédé de préparation d'apremilast sous une forme amorphe Download PDF

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Publication number
WO2019021303A1
WO2019021303A1 PCT/IN2018/050472 IN2018050472W WO2019021303A1 WO 2019021303 A1 WO2019021303 A1 WO 2019021303A1 IN 2018050472 W IN2018050472 W IN 2018050472W WO 2019021303 A1 WO2019021303 A1 WO 2019021303A1
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Prior art keywords
apremilast
water
solvent
amorphous form
amorphous
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Inventor
Emerich Eisenreich
Peter Leeming
Daniel Levin
Prashant Pandurang Pawar
Sandeep Shankar Sope
Birendrakumar YADAV
Rejoy Thomas
Santosh SHINDE
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Alkem Laboratories Ltd
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Alkem Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide

Definitions

  • the present invention relates to a novel process for the preparation of Apremilast in amorphous form.
  • U.S. Patent No. 6,030,358 discloses substituted phenethylsulfones, including Apremilast, and method of use thereof for reducing TNFa levels.
  • European Patent No. EP2420490B1 claims (+) Apremilast wherein it is synthesized from 3- acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l- (methylsulfonyl)-eth-2-ylamine in the presence of glacial acetic acid.
  • the present inventors have discovered a process for preparing Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent in the absence of glacial acetic acid by treating the crude Apremilast with a purification solvent comprising acetonitrile, DMF, DMSO or mixtures thereof , and isolating Apremilast in amorphous form by combining with water.
  • a purification solvent comprising acetonitrile, DMF, DMSO or mixtures thereof
  • WO200912067 teaches seven solid forms of the (+) enantiomer of Apremilast, designated as Forms A to G, including methods of preparation.
  • WO2009120167 also generally mentions an amorphous form of Apremilast, but does not teach a method of preparation of such an amorphous form or its characterization.
  • PCT publication WO2014072259 discloses Apremilast in amorphous form in a composition arrived at by a melting process. Though this PCT application discloses a composition containing Apremilast in amorphous form, it fails to disclose a process for preparing Apremilast in amorphous form as an active pharmaceutical ingredient itself.
  • U.S. Patent No. 9,351,957 discloses amorphous solid dispersion of Apremilast and a polymer, wherein the amorphous solid dispersion of Apremilast is prepared by a process comprising grinding a solid- solid mixture of Apremilast and a polymer under controlled humidity. It also teaches a general method of preparing Apremilast in amorphous form by spray drying. Though it discloses a composition consisting Apremilast in amorphous form, it fails to disclose a process for preparing Apremilast in amorphous form as an active pharmaceutical ingredient itself.
  • PCT publication WO2016135755 teaches a process for preparing Apremilast in amorphous form by dissolving Apremilast in solvents selected from methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-l- butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, chloroform, and mixtures thereof , followed by addition of a nonpolar antisolvent selected from a group consisting of an ethereal solvent, a non- polar hydrocarbon solvent, and mixtures thereof.
  • WO'792 teaches a method for converting specifically a Form I of Apremilast to amorphous form and would not be suitable for direct conversion of a crude Apremilast unlike the present invention.
  • the present invention provides a direct process for isolating Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy- 4-methoxyphenyl)-l-( methylsulfonyl)-eth-2-ylamine, isolated in amorphous form using a solvent- antisolvent mixture comprising acetonitrile-water , DMF-water, DMSO-water or mixtures thereof.
  • the process of the present invention which involves the use of a unique solvent combination comprising acetonitrile and water , DMF and water, DMSO and water or mixtures thereof, enables isolation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of glacial acetic acid, is not taught by any of the prior arts.
  • the advantageous property of better solubility, better availability, and purity of the present amorphous polymorph and also ease of removal of residual solvents achieved by the current process distinguishes the present invention from the rest.
  • the present invention provides an economical, ecofriendly, and simple industrial process for the preparation of Apremilast in a stable amorphous form with residual solvent content within the ICH prescribed limits.
  • a main aspect of the present invention is to provide a process for the preparation of Apremilast in amorphous form by treating a crude Apremilast obtained directly from the reaction mixture with a unique solvent - antisolvent combination comprising acetonitrile and water, DMF and water, DMSO and water or mixtures thereof.
  • a process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2- (3-ethoxy-4- methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent optionally in the absence of a condensing agent such as glacial acetic acid.
  • reaction solvent comprising a reaction solvent with a purification solvent comprising acetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof,
  • the present invention also provides a one pot process for the preparation of Apremilast in amorphous form by directly treating the crude Apremilast obtained from the crude reaction mixture comprising the final stage condensation of a 3- acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l- (methylsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of condensing agent such as glacial acetic acid.
  • a process for the preparation of amorphous form of Apremilast comprising the steps of:
  • reaction solvent comprises toluene, xylene, mesitylene, benzene, chlorobenzene and the like, or mixtures thereof.
  • reaction solvent comprises toluene, xylene, mesitylene, benzene, chlorobenzene and the like, or mixtures thereof.
  • FIGURE-1 IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST AS PER THE PRESENT INVENTION
  • FIGURE-2A IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
  • FIGURE-2B IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
  • FIGURE-2C IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
  • FIGURE-2D IS A SCHEMATIC REPRESENTATION OF A PROCESS FOR THE PREPARATION OF AMORPHOUS (S) (+) APREMILAST ACCORDING TO A SPECIFIC EMBODIMENT OF THE PRESENT INVENTION
  • FIGURE-3 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
  • FIGURE-4 IS A REPRESENTATIVE IR SPECTRUM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE ! OF THE PRESENT INVENTION
  • FIGURE S IS A REPRESENTATIVE DSC THERMOGRAM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
  • FIGURE-6 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST BY TREATING APREMILAST FORM B WITH ACN-WATER AS PER EXAMPLE-10
  • FIGURE-7 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST OBTAINED BY TREATING APREMILAST FORM M WITH ACN-WATER AS PER EXAMPLE-11
  • FIGURE-8 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS (S) (+) APREMILAST OBTAINED BY A ONE POT PROCESS AS PER EXAMPLE-12
  • FIGURE-9 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART ACETONE/n- HEPTANE COMBINATION AS PER REFERENCE EXPERIMENT-1
  • FIGURE- 10 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART ACETONE AVATER COMBINATION AS PER REFERENCE EXPERIMENT -2
  • FIGURE-11 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART MEK n- HEPTANE AS PER REFERENCE EXPERIMENT -3
  • FIGURE- 12 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE FORM OBTAINED BY TREATING APR-3 TOLUENE SOLVATE WITH PRIOR ART THF/n- HEPTANE AS PER REFERENCE EXPERIMENT -4
  • FIGURE-13 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING A PRIOR ART SOLVENT -MEK FOR AZEOTROPIC DISTILLATION FOR REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART SOLVENT- ANTISOLVENT MEK- WATER AS PER REFERENCE EXPERIMENT -5
  • FIGURE-14 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING A PRIOR ART SOLVENT -ACETONE FOR AZEOTROPIC DISTILLATION FOR THE REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART SOLVENT- ANTISOLVENT ACETONE-WATER AS PER REFERENCE EXPERIMENT -6
  • FIGURE-15 IS A REPRESENTATIVE XRPD PATTERN OF CRYSTALLINE APREMILAST OBTAINED BY USING PRIOR ART SOLVENT -THF FOR AZEOTROPIC DISTILLATION FOR THE REMOVAL OF RESIDUAL TOLUENE & EMPLOYING A PRIOR ART SOLVENT- ANTISOLVENT THF-WATER AS PER REFERENCE EXPERIMENT -7
  • FIGURE-16 IS A REPRESENTATIVE XRPD PATTERN OF APR-3-TOLUENE SOLVATE OF (S) (+) APREMILAST OBTAINED BY A PROCESS AS IN EXAMPLE-1 -WHICH IS SUBSEQUENTLY CONVERTED TO AMORPHOUS FORM BY ACN-WATER TREATMENT.
  • FIGURE-17 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH DMF- WATER AS PER EXAMPLE-13 OF THE PRESENT INVENTION.
  • FIGURE-18 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH A 1 :1 MIXTURE OF DMF-WATER AS PER EXAMPLE-15 OF THE PRESENT INVENTION.
  • a main aspect of the present invention is to provide a process for the preparation of Apremilast in amorphous form by treating a crude Apremilast obtained directly from the reaction mixture with a unique solvent - antisolvent combination comprising acetonitrile and water, DMF and water, DMSO and water or mixtures thereof.
  • a process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3-acetamidophthalic anhydride and a chiral amino acid salt of (S)-2- (3-ethoxy-4- methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine in a reaction solvent optionally in the absence of a condensing agent such as glacial acetic acid.
  • the present invention provides a one pot process for the preparation of Apremilast in amorphous form by directly treating the crude Apremilast obtained from the crude reaction mixture comprising the final stage condensation of a 3- acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-l- (methylsulfonyl)-eth-2-ylamine in a reaction solvent preferably toluene in the absence of a condensing agent such as glacial acetic acid.
  • a process for the preparation of amorphous form of Apremilast comprising the steps of: (a) reacting a compound of formula a reaction solvent, optionally in the absence of glacial acetic acid to afford a compound of
  • a process for the preparation of amorphous form of Apremilast comprising the steps of: (a) treating a compound of formula obtained from a feedstock comprising a reaction solvent with a purification solvent comprising acetonitrile, dimethylformamide, dimethylsulfoxide or mixtures thereof,
  • the condensation reaction may be carried out optionally in the presence of suitable condensing agents like glacial acetic acid as described in the prior art.
  • suitable condensing agents like glacial acetic acid as described in the prior art.
  • An embodiment of the present invention describes the reaction of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine with 3- acetamidopthalic anhydride, in the absence of glacial acetic acid in Toluene.
  • Suitable reaction solvents for condensation reaction are generally ketonic solvents, nitriles, alcohols, such as methanol, ethanol, isopropanol, hydrocarbons such as toluene, xylene, mesitylene, benzene, chlorobenzene , esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, polar solvents like DMF, DMSO, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably hydrocarbon or mixtures thereof, even more preferably toluene, xylene, mesitylene, benzene, chlorobenzene or mixtures thereof.
  • toluene is the preferred reaction solvent.
  • Suitable purifications solvents are generally ketonic solvents, nitriles such as acetonitrile, alcohols, such as methanol, ethanol, isopropanol, esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, polar solvents like DMF, DMSO, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably hydrocarbon or mixtures thereof, even more preferably acetonitrile, DMF, DMSO or mixtures thereof.
  • the removal of solvent may be achieved by any suitable method known to a person skilled in the art such as filtration, distillation.
  • the residual reaction solvent content in the reaction mixture or the feedstock is controlled to a range between zero and 1000 ppm, preferably between zero and 500 ppm and more preferably between zero and 100 ppm.
  • the reaction may generally be carried out at reflux temperature of the solvent for about 8 hours.
  • the completion of the reaction is monitored by any suitable technique known in the art such as by HPLC or TLC indicating the abse
  • the compound of formula is converted to amorphous form may be the crude obtained directly from the condensation step, or optionally obtained from a feedstock comprising a reaction solvent employed in the condensation step or a crystalline polymorph or a solvate thereof.
  • the compound of formula a crude toluene solvate obtained directly from the condensation step.
  • Figure-16 provides a representative XRPD pattern of APR-3 (toluene solvate of Apremilast) obtained by condensation of a 3-acetamidophthalic anhydride and a N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth- 2-ylamine in toluene in the absence of a condensing agent such as glacial acetic acid.
  • APR-3 toluene solvate of Apremilast
  • a preferred embodiment as in Example- 1 provides a process of the present invention for the preparation of amorphous (S) (+) Apremilast wherein N-acetyl Leucine salt of (S)-2- (3-ethoxy-4- methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine, 3- acetamidopthalic anhydride, and toluene were refluxed under N 2 atmosphere in a 4-necked RBF fitted with a Dean stark apparatus , condenser for about 8 hours until HPLC showed absence of starting material.
  • the purification solvents comprised Acetonitrile, DMF, DMSO or mixtures thereof.
  • the dissolution may be carried out at a suitable temperature ranging from room temperature to about reflux temperature of the solvent.
  • the amount of purification solvent employed may range to an amount sufficient to bring about dissolution and apparent to a person skilled in the art.
  • the amount of acetonitrile added initially for stripping ranged from about 36 - 40 volume with respect to the weight of the crude Apremilast.
  • the distillation carried out preferably at atmospheric pressure was done until about 4 volume solvent remained.
  • the distillation was carried to about dryness, followed by a fresh addition of purification solvent in a quantity ranging from about 4 volume to about 8 volume with respect to the weight of the crude Apremilast.
  • the in- process residual reaction solvent content was checked.
  • the in process residual reaction solvent content was controlled to a range between zero and 1000 ppm, preferably between zero and 500 ppm or even more preferably between zero and 100 ppm.
  • reaction solvent is toluene
  • the stripping was stopped, the reaction mass was fine filtered through Whatman® filter paper, cooled to around 50°C and then poured into water, and the precipitated solid filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S (+) Apremilast as an amorphous solid.
  • the amount of antisolvent-water employed was preferably in the range of about 20 to about 40 volume with respect to the final volume of the purification solvent used in the final recrystallization step.
  • an optimum RPM of about 180-200 resulted in amorphous form.
  • the rate of stirring was adjusted to an optimum level so as to ensure the formation of amorphous form of Apremilast.
  • the number of revolutions per minute (RPM) of the stirrer was adjusted to about 100-200, preferably to about 180-200 resulted in amorphous form, whereas at RPM's less than about 50 resulted in a sticky mass.
  • RPM's at about 300 and above resulted in a crystalline polymorph.
  • the amorphous solid obtained may initially be dried at a temperature ranging from about 30-35°C for about 3hours, the temperature gradually raised to about 40-45 °C for about 4 hours and finally at 50-60 °C for about 30-36 hours , all drying done under vacuum NLT 730 mm Hg.
  • the present inventors conducted experiments with a purification solvent-antisolvent combination of ACN-Water and studied the maximum amount of in- process residual toluene content that would afford Apremilast in a stable amorphous form and having a residual toluene content below the ICH prescribed limit of 890 ppm.
  • incorporated herein as in Examples 10 and 11 provide the use of ACN- Water for transforming other crystalline forms of Apremilast such as a polymorphic Form B or a polymorphic Form M to amorphous form.
  • a Form B of Apremilast was dissolved in acetonitrile, then combined with Water to afford amorphous form.
  • another embodiment provides a process wherein a Form M of Apremilast was dissolved in acetonitrile, and then combined with water to afford amorphous form.
  • the polymorph B employed herein may be obtained by a process as disclosed in a prior art such as in US7893101.
  • the polymorphic Form M employed herein may be obtained by a process as disclosed in WO2016189486
  • Example 12 provides a one pot process for the preparation of Apremilast in amorphous form, wherein N-acetyl Leucine salt of (S)-2- (3-ethoxy-4- methoxyphenyl)-l -(methylsulfonyl)-eth-2-ylamine, 3- acetamidopthalic anhydride, and toluene were refluxed under N 2 atmosphere in a 4-necked RBF fitted with a Dean stark apparatus, condenser for about 15 hours until HPLC showed absence of starting material.
  • Example 13 a crude Apremilast toluene solvate was added to DMF, and stirred at 25°C-30°C for 30 min until clear solution was obtained.
  • the reaction mixture was filtered through Hyflo®, washed with DMF and then heated to about 150 °C to 155°C.This was followed by distillation until about 3 volume DMF wrt weight of the crude remained. This was followed by addition of DMF and stripping by distillation until about 3 volume remained. The stripping with further DMF & distillation until 3 volume remained was done and each time, the in- process residual toluene content checked to ensure if it's content is less than about 100 ppm.
  • the reaction mass was cooled to about 50-55°C, & then poured into water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes.
  • the precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to 55°C to afford Apremilast as an amorphous solid.
  • Example 14 crude Apremilast toluene solvate was added to DMSO, and stirred at 25°C-30°C for 30 min until clear solution was obtained.
  • the reaction mixture was filtered through Hyflo®, washed with DMSO and then heated to about 185 °C to 192°C.This was followed by distillation until about 3 volume DMSO wrt weight of the crude remained. This was followed by addition of DMSO and stripping by distillation until about 3 volume remained. The stripping with further DMSO & distillation until 3 volume remained was done and each time, the in- process residual toluene content checked to ensure if it's content is less than about 100 ppm.
  • the reaction mass was cooled to about 50-55°C, & then poured into Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8-12°C for about 30 minutes.
  • the precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford amorphous solid.
  • Example 15 crude Apremilast toluene solvate was added to a 1 : 1 solvent mixture comprising ACN-DMF, and stirred at 25°C-30°C for 30 min until clear solution was obtained.
  • the reaction mixture was filtered through Hyflo®, washed with ACN:DMF mixture and then heated to about 70 °C to 110°C.This was followed by distillation until about 4 volume of ACN:DMF wrt weight of the crude remained.
  • the reaction mass was cooled to about 50-55°C, & then poured into Water at about 8 -12 °C in about 30-60 minutes and then stirred at 8- 12°C for about 30 minutes.
  • the precipitated solid was filtered, washed with about 100 ml water and then dried under vacuum NLT 730 mm Hg for about 30 hours at about 50°C to55°C to afford amorphous solid.
  • the present inventors discovered that the process of the present invention and the novel purification solvent-antisolvent combinations comprising Acetonitrile-Water, DMF-Water, DMSO-Water, ACN:DMF-Water or mixtures thereof was unique as they could convert a crude Apremilast or its solvates or polymorphs thereof, obtained directly from the reaction mixture or a feedstock comprising the final stage condensation of a 3-acetamidophthalic anhydride and a N-acetyl Leucine salt of (S)-2- (3-ethoxy-4-methoxyphenyl)-l-(methylsulfonyl)-eth-2-ylamine into stable amorphous form of Apremilast, whereas the prior art solvent-antisolvent combinations such as Acetone-n-Heptane, Acetone-Water, MEK-n-Heptane, THF-n-Heptane failed.
  • the present inventors discovered that the residual toluene content in the toluene solvate of Apremilast -APR-3 could not be restricted to a range between zero to 1000 ppm, preferably about zero to 500 ppm, or even more preferably about zero to 100 ppm by distillation using prior art solvents such as Acetone, MEK, or THF (which are known to not form an azeotrope with toluene). Consequently, since the reaction solvent toluene was not effectively removed by the solvent distillation, the polymorph after quenching in prior art anti-solvents - n-Heptane or Water resulted in a crystalline form and not the amorphous form as desired.
  • prior art solvents such as Acetone, MEK, or THF (which are known to not form an azeotrope with toluene).
  • the present inventors used a prior art solvent acetone as the stripping solvent for distillation to remove residual toluene at atmospheric pressure, the in-process initial toluene content was 2165.2 ppm, after 1 st stripping was 1248 ppm , after 2 nd stripping was 1097 ppm ,after 3 rd stripping was 894 ppm, after 4 th stripping was 782 ppm and after 5 th stripping was 588.2 ppm and after 6 th stripping was 458.3ppm.
  • the prior art solvent acetone was found to be incapable of removing residual toluene from a toluene solvate of Apremilast and , since the presence of residual toluene has been shown to provide crystalline Apremilast, consequently the prior art combinations of acetone-water or acetone-n-heptane could not transform a crude Apremilast or a solvate or a toluene solvate obtained directly from the reaction mixture into amorphous form as desired, but rather provided a crystalline form. Similar was the outcome with other prior art solvents- MEK, THF. In each case, the residual toluene remained and a crystalline form was obtained.
  • the wet cake was washed with sodium bicarbonate solution, water and filtered to afford 470 gm of crude APR-3 -Toluene solvate of (S) (+) Apremilast.
  • the crude solid was dissolved in 16920 ml acetonitrile(36 volume wrt crude wt of Apremilast) at RT, treated with 25 gm Activated Carbon, and filtered through Hyflo®, washed with 1880 ml acetonitrile(4 volume wrt crude wt of Apremilast) , followed by atmospheric distillation to about 4 volume.
  • the in process residual toluene content was checked for each stripping by atmospheric distillation .When the in process residual toluene content had reached to around 100 ppm, the stripping was stopped. The reaction mass was fine filtered through Whatman® filter paper , cooled to around 50 C and then poured into 37600 ml water(20 volume wrt 1880 ml ACN) , the precipitated solid was filtered, washed with water and then dried under vacuum-NLT 730 mm Hg to afford S(+) Apremilast as an amorphous solid.
  • FIGURE-3 IS A REPRESENTATIVE XRPD PATTERN OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
  • FIGURE-4 IS A REPRESENTATIVE IR SPECTRUM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION
  • FIGURE S IS A REPRESENTATIVE DSC THERMOGRAM OF AMORPHOUS S (+) APREMILAST OBTAINED BY TREATING A CRUDE TOLUENE SOLVATE WITH ACN - WATER AS PER EXAMPLE-1 OF THE PRESENT INVENTION.
  • REFERENCE EXPERIMENT-1 ACETONE-n-HEPTANE AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST.
  • REFERENCE EXPERIMENT-2 ACETONE-WATER AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST.
  • REFERENCE EXPERIMENT-3 MEK-n-HEPTANE AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST.
  • APR-3 toluene solvate of Apremilast
  • REFERENCE EXPERIMENT-4 THF-n-HEPTANE AS SOLVENT-ANTISOLVENT COMBINATION AFFORDED CRYSTALLINE APREMILAST. 10 gm (0.0217moles) of APR-3 (toluene solvate of Apremilast) was added to 80 ml THF and stirred at 25°C-30°C for 30 minutes. The reaction mixture was filtered through a Celite® bed and added into N-heptane (800ml) at 25°C-30°C. The reaction mixture stirred at 25°C-30°C for 6 hours, filtered and dried to afford crystalline solid.
  • APR-3 toluene solvate of Apremilast
  • the amorphous form of Apremilast described herein exhibits physical and chemical stability for a long term.
  • the table below presents stability data on amorphous form of Apremilast prepared by processes of the present invention.
  • the amorphous form of Apremilast described herein is stable since it shows no significant degradation or change in PXRD pattern when stored at 2-8°C and at 25 °C/60% relative humidity (RH).

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Abstract

La présente invention concerne un nouveau procédé de préparation d'apremilast sous une forme amorphe directement à partir du mélange réactionnel brut comprenant la condensation en stade final d'un anhydride de 3-acétamidophtalique et d'un sel d'acide aminé chiral de (S)-2-(3-éthoxy-4-méthoxyphényl)-1-(méthylsulfonyl)-éth-2-ylamine, isolés sous une forme amorphe en utilisant un mélange de solvant-antisolvant comprenant de l'acétonitrile-eau, du diméthylformamide-eau, du diméthylsulfoxyde-eau, de l'acétonitrile-diméthylformamide-eau ou leurs mélanges.
PCT/IN2018/050472 2017-07-23 2018-07-20 Nouveau procédé de préparation d'apremilast sous une forme amorphe Ceased WO2019021303A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12351555B2 (en) 2021-04-26 2025-07-08 Amgen Inc. Process for synthesizing apremilast

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016199031A1 (fr) * 2015-06-09 2016-12-15 Dr. Reddy’S Laboratories Limited Procédé de préparation de l'aprémilast et de ses intermédiaires
WO2017039537A1 (fr) * 2015-08-28 2017-03-09 Scinopharm Taiwan, Ltd. Nouvelles formes d'aprémilast et leur procédé de fabrication

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016199031A1 (fr) * 2015-06-09 2016-12-15 Dr. Reddy’S Laboratories Limited Procédé de préparation de l'aprémilast et de ses intermédiaires
WO2017039537A1 (fr) * 2015-08-28 2017-03-09 Scinopharm Taiwan, Ltd. Nouvelles formes d'aprémilast et leur procédé de fabrication

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12351555B2 (en) 2021-04-26 2025-07-08 Amgen Inc. Process for synthesizing apremilast

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