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WO2017059040A1 - Procédés de préparation d'aprémilast, et ses intermédiaires - Google Patents

Procédés de préparation d'aprémilast, et ses intermédiaires Download PDF

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Publication number
WO2017059040A1
WO2017059040A1 PCT/US2016/054390 US2016054390W WO2017059040A1 WO 2017059040 A1 WO2017059040 A1 WO 2017059040A1 US 2016054390 W US2016054390 W US 2016054390W WO 2017059040 A1 WO2017059040 A1 WO 2017059040A1
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Prior art keywords
compound
formula
viii
process according
acid
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Inventor
Tivadar Tamas
Ferenc Korodi
Janos Hajko
Renata NAGY
Tihamer Paal
Miklos Toth
Csilla Nemethne Racz
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Pliva Hrvatska doo
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Pliva Hrvatska doo
Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Priority to EP16778644.1A priority Critical patent/EP3356327A1/fr
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to processes for the preparation of Apremilast and intermediates in the preparation thereof.
  • OTEZLA ® is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels which are thought to indirectly modulate the production of inflammatory mediators.
  • PDE4 phosphodiesterase 4
  • OTEZLA® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. OTEZLA is also indicated for the treatment of adult patients with active psoriatic arthritis.
  • US6020358 discloses a process using the reagents LiHMDS and n-butyllithium at -78 °C for the preparation of intermediate l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethan-l -amine. This process uses dangerous reagents and suffers from low yield, of about 36%, and is therefore not suitable for industrial scale application.
  • US 8242310 discloses a process for the preparation of the same racemic intermediate. According to this publication, the process has improved yield, however this process still uses a dangerous reagent of n-butyllithium.
  • the present disclosure relates to processes for preparing Apremilast and intermediates in the preparation thereof.
  • the present disclosure provides processes for preparing a compound of formula VIII or an acid addition salt thereof, from a compound of formula V according to the following scheme:
  • the compound V may be transformed to compound VIII by the route: V ⁇ VI ⁇ VIII or by the route: V ⁇ VII ⁇ VIII.
  • the compound V is converted to compound VI by a reductive animation reaction.
  • the compound VI may be subjected to a resolution procedure in order to obtain the compound VIII.
  • the compound V may be subjected to a stereoselective reductive animation reaction by reacting with a chiral auxiliary [preferably (R)-(+)-2-methyl-2-propylsulfinamide] to generate the intermediate compound VII, followed by reduction to form compound VIII.
  • a chiral auxiliary preferably (R)-(+)-2-methyl-2-propylsulfinamide
  • the reaction with (R)-(+)-2-methyl-2-propylsulfinamide and subsequent reduction can be carried out in one pot, i.e. without isolation of the intermediate compound VII.
  • the compound VIII can be converted to Apremilast in accordance with the processes disclosed herein.
  • the compound VIII may be converted to Apremilast by: (A) oxidation of compound VIII to form a compound of formula IX or an acid addition salt thereof:
  • the present disclosure comprises the compounds IV, V, VI and VIII, described hereinafter, processes for their preparation and their use as intermediates in the preparation of Apremilast, and intermediates of Apremilast, such as compound IX.
  • the disclosure further encompasses processes for preparing Apremilast comprising the preparation of any one or several of the above compounds according to the present disclosure and converting it to
  • the present disclosure relates to the compounds l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l-one (V) and enantiomeric (l S)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l -amine (VIII); processes for their preparation, and to the use of these compounds as intermediates in the preparation of apremilast.
  • the disclosure further encompasses processes for preparing Apremilast comprising preparing compound V and compound VIII according to the present disclosure and converting it to Apremilast, for example according to the processes described in Scheme 1 and Scheme 2 and/or Scheme 3 hereinafter.
  • the present disclosure comprises the preparation of 2-halo-l-(3-ethoxy-4- methoxyphenyl)ethan-l-one compounds (wherein halo can be fluoro, chloro, bromo or iodo, particularly chloro, bromo or iodo, more particularly chloro or bromo), and particularly 2-bromo- l-(3-ethoxy-4-methoxyphenyl)ethan-l-one (IV).
  • halo can be fluoro, chloro, bromo or iodo, particularly chloro, bromo or iodo, more particularly chloro or bromo
  • 2-bromo- l-(3-ethoxy-4-methoxyphenyl)ethan-l-one IV
  • the present disclosure comprises the preparation of compound l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan- 1 -one (V).
  • the present disclosure comprises the preparation of compound l-(3-ethoxy-4- methoxy pheny l)-2-(methy lthio)ethan- 1 -amine (VI).
  • the present disclosure comprises the preparation of compound (lS)-l-(3- ethoxy-4-methoxyphenyl)-2-(methylthio)ethan- 1 -amine (VIII).
  • Crystalline forms of Apremilast intermediates are also provided.
  • crystalline forms of compound (V), (VI) in the form of the hydrochloride salt, (VIII) in the form of the N-acetyl-L-leucine salt, and (IX) are provided.
  • An amorphous form of (XII) is also provided.
  • the present disclosure comprises the preparation of compound (S)-l-(3-ethoxy- 4-methoxyphenyl)-2-(methylsulfonyl)ethan-l -amine (IX), using the above mentioned intermediates IV, V, VI or VIII.
  • the present disclosure also comprises processes for preparing Apremilast (N-[2- [(lS)-l-(3ethoxy-4-methoxyphenyl))-2(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH- isoindol-4-yl]acetamide), using the above mentioned compounds as intermediates.
  • Figure 1 XRPD partem of a crystalline form of compound (V) (prepared according to Example 6).
  • Figure 2 XRPD partem of a crystalline form of compound (VI) hydrochloride salt (prepared according to Example 9).
  • Figure 3 XRPD partem of a crystalline form of compound (VIII) N-acetyl-L- leucine salt (prepared according to Example 13).
  • Figure 4 XRPD partem of a crystalline form of compound (IX) (prepared according to Example 17).
  • Figure 5 XRPD pattern of an amorphous form of compound (XII) (prepared according to Example 19).
  • the present disclosure relates to processes for the preparation of Apremilast and intermediates in the preparation thereof.
  • the disclosure relates to the novel compounds IV, V, VI and VIII, described hereinafter, processes for their preparation and their use as intermediates in the preparation of Apremilast, and Apremilast intermediates, such as compound IX.
  • the disclosure further encompasses processes for preparing Apremilast comprising preparing any one or several of the above compounds according to the present disclosure and converting it to Apremilast.
  • the disclosure provides improved processes for the preparation of (l S)-l -(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-l-amine (VIII), which uses inexpensive and commercially available starting materials.
  • the processes of the present disclosure consist of simple reaction steps and avoid the use of expensive reagents and extreme hazardous reaction conditions. Therefore they can be used on an industrial scale.
  • compound IV refers to 2-bromo-l -(3-ethoxy-4- methoxyphenyl)ethan-l-one having the following structure:
  • halo group can be chloro, bromo or iodo, and particularly chloro or bromo. However, preferably the halo group is bromo.
  • compound V refers to compound l -(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l-one (V) having the following structure:
  • compound VI refers to the compound l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l -amine (VI) having the following structure:
  • compound VIII refers to the compound (lS)-l-(3- ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-l -amine (VIII) having the following structure:
  • Compound VIII may be in the form of a salt, for example a salt with a chiral acid, such as a chiral amino acid.
  • compound VIII is in the form of the free base, or in the form of a salt with N-acetyl-L-leucine.
  • the salt of compound VIII may be derived from the optical resolution of compound V by crystallization with an optically active acid.
  • oxone refers to an oxidizing agent having the composition 2KHSO5.KHSO4.K2SO4 (CAS 70693-62-8) of which the active component is KHSO5 (CAS 10058-23-8), which is the potassium salt of peroxymonosulfuric acid (i.e.
  • the composition is a
  • isolated in reference to compounds described herein corresponds to a compound that is physically separated from the reaction mixture in which it is formed.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.
  • the present disclosure provides a process for the preparation of Apremilast comprising preparing a compound of formula (VIII) or an acid addition salt thereof, from a compound of formula (V) according to the following scheme:
  • the compound (V) may be transformed to compound (VIII) by the route: (V) ⁇ (VI) ⁇ (VIII) or by the route: (V) ⁇ (VII) ⁇ (VIII).
  • the compound (V) is converted to (VI) by a reductive animation reaction.
  • the compound (VI) is subjected to a resolution procedure in order to obtain the compound (VIII).
  • the compound (V) may be subjected to a stereoselective reductive amination by reacting with a chiral auxiliary [preferably (R)-(+)-2-methyl-2-propylsulfinamide] to generate the intermediate compound (VII), followed by reduction to form compound (VIII).
  • a chiral auxiliary preferably (R)-(+)-2-methyl-2-propylsulfinamide
  • the reaction with (R)-(+)-2-methyl-2-propylsulfinamide and subsequent reduction can be carried out in one pot, i.e. without isolation of the intermediate compound (VII).
  • the compound of formula (V) may be prepared by thioether formation of the corresponding brominated starting material of formula (IV).
  • the present disclosure encompasses a process according to the following scheme:
  • Thioether formation to form the compound V can be carried out by reaction of compound (IV) with an alkali metal salt of methanethiolate, particularly sodium methanethiolate.
  • the thioether formation can be done by reacting compound IV (preferably 2-bromo-l-(3-ethoxy- 4-methoxyphenyl)ethan-l-one) with sodium methane thiolate to yield compound V.
  • the compound of formula (IV) or other halo substituted derivatives of compound (IV) may be prepared in three steps starting from 3',4'-dimethoxyacetophenone [compound (I) below]:
  • the compound IV in the above reaction schemes may be a 2-halo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one, although compound IV is preferably 2- bromo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one as exemplified.
  • the compound VIII may be in the form of a salt, for example a salt with a chiral acid, such as a chiral amino acid.
  • compound VIII is in the form of the free base, or in the form of a salt with N-acetyl-L-leucine.
  • the present disclosure also provides a process for preparing Apremilast comprising preparing compound VIII or an acid addition salt thereof, according to the processes disclosed in any aspect or embodiment as disclosed herein, and converting the compound VIII or an acid addition salt thereof to Apremilast.
  • Compound III may be prepared by ethylation of compound II. Agents such as ethyl halides, diethyl sulfate or diethyl carbonate may be used as ethylating agents.
  • the present disclosure relates to 2-halo-l-(3-ethoxy-4- methoxyphenyl)ethan-l-one compounds (wherein halo can be chloro, bromo or iodo, particularly chloro or bromo), preferably wherein halo is bromo, i.e. 2-bromo-l-(3-ethoxy-4- methoxyphenyl)ethan-l-one, the preparation thereof and to their use as an intermediate in the process for preparing apremilast.
  • the 2-halo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one compounds particularly 2-bromo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one (compound IV) described herein may be isolated.
  • the 2-halo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one compounds, particularly 2-bromo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one are solids.
  • the 2-halo-l-(3-ethoxy-4-methoxyphenyl)ethan-l-one compounds can be prepared by halogenation of compound III.
  • Suitable halogenation agents include N- chlorosuccinimide, N-iodosuccinimide, phenyltrimethylammonium tribromide, Cu(II)Br, dichlorohydantoin, preferably N-bromosuccinimide or dichlorohydantoin.
  • the compound of formula IV is 2-bromo-l-(3-ethoxy-4- methoxyphenyl)ethan-l-one, which may be prepared by bromination of compound III. Any suitable brominating agent may be used.
  • phenyltrimethylammonium tribromide, Cu(II)Br, bromine, or N-bromosuccinimide can be used. More particularly, bromine or N- bromosuccinimide may be used as a bromination agent.
  • the present disclosure relates to l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l-one (V), to the preparation thereof and to its use as an intermediate in the process for preparing Apremilast.
  • Compound V may be isolated. In some embodiments, compound V is a solid.
  • Compound V may be prepared by a process comprising thioether formation of compound IV.
  • the thioether formation may be done by reacting compound IV with an alkali metal salt of methanethiolate, particularly sodium methanethiolate.
  • the thioether formation can be done by reacting compound IV (preferably 2-bromo-l-(3-ethoxy-4- methoxyphenyl)ethan-l-one) with sodium methane thiolate to yield compound V.
  • the present disclosure relates to l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l -amine (VI), to the preparation thereof and to its use as an intermediate in the process for preparing Apremilast.
  • Compound VI may be isolated. In some embodiments, compound VI is a solid.
  • Compound VI may be prepared by a process comprising reductive animation of compound V.
  • Reductive animation may be performed with in the presence of a reducing agent - preferably sodium borohydride - in the presence of titanium(IV) isopropoxide (or other titanium(IV) alkoxides, such as titanium (IV) ethoxide, titanium (IV) butoxide and titanium (IV) tert-butoxide).
  • Further reduction agents include borane complexes such as borane-THF, borane- triethylamine, borane-pyridine or borane-dimethylsulfide.
  • sodium reducing agent preferably sodium borohydride
  • titanium(IV) isopropoxide or other titanium(IV) alkoxides, such as titanium (IV) ethoxide, titanium (IV) butoxide and titanium (IV) tert-butoxide.
  • Further reduction agents include borane complexes such as borane-THF, borane- trieth
  • triacetoxyborohydride or sodium cyanoborohydride may be used for the reductive amination.
  • the reductive amination is performed with sodium borohydride in the presence of titanium(IV) isopropoxide.
  • the ammonia source for the reductive amination can be ammonia, ammonium formate, ammonium acetate or other ammonium salts.
  • the present disclosure relates to (lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l -amine (VIII), or an acid addition salt thereof, to the preparation thereof, and to its use as an intermediate in the process for preparing Apremilast.
  • the compound (VIII) may be in the form of an acid addition salt as discussed below.
  • Compound VIII may be prepared by a process comprising resolution of compound VI. Resolution of compound VI may be done by optical resolution using chiral acids, such as chiral amino acids. A particularly preferred chiral amino acid is N-acetyl-L-leucine.
  • compound VIII is reacted with a chiral amino acid in order to form a diastereomeric salt. The diastereomeric salt containing the desired isomer is isolated from the reaction mixture.
  • the chiral amino acid is N-acetyl-L-leucine.
  • Any suitable solvent may be used. A particularly preferred solvent is tetrahydrofuran.
  • the compound VIII obtained from the optical resolution is typically in the form of a salt, for example a salt with a chiral acid, such as a chiral amino acid.
  • compound VIII is either in the form of the free base (i.e. formed by basification of the salt of compound VIII), or in the form of a salt with N-acetyl-L- leucine.
  • the acid addition salt of compound VIII from the optical resolution process may be used directly in the next step (i.e. oxidation or condensation as discussed below), or may be converted to the free base form of compound VIII by basification prior to the next step.
  • compound VIII may be prepared by enzyme catalyzed kinetic resolution of compound VI, e.g. by enzymatic acylation of compound VI using lipases as catalysts. The reaction is preferably carried out in the presence of an acyl donor, with ethyl acetate being a preferred acyl donor.
  • the product from the stereoselective enzymatic acylation of compound VI is an N-acylated derivative of compound VIII (i.e. VHI-a), having the formula:
  • Compound VHI-a can be converted to compound VIII by deacylation, for example by reacting with an acid or base, preferably a base, and more preferably an alkali metal alkoxide (particularly sodium methoxide or sodium ethoxide) or alkali hydroxide (particularly sodium hydroxide or potassium hydroxide) in a suitable solvent (e.g. an aliphatic alcohol such as methanol or ethanol).
  • a suitable solvent e.g. an aliphatic alcohol such as methanol or ethanol.
  • the present disclosure relates to a process for preparing compound VIII by a stereoselective reductive amination of compound V.
  • the stereoselective reductive amination may for example be performed by reaction of compound V with (R)-(+)-2- methyl-(2)-propanesulfinamide in the presence of a titanium(IV) alkoxide such as titanium (IV) ethoxide, titanium (IV) butoxide, titanium (IV) tert-butoxide or titanium(IV) isopropoxide - preferably titanium(IV) isopropoxide and reduction with a reducing agent (preferably sodium borohydride).
  • a reducing agent preferably sodium borohydride
  • the stereoselective reductive amination is performed by reaction of compound V with (R)-(+)-2-methyl-(2)-propanesulfinamide in the presence of titanium(IV) isopropoxide and reduction with sodium borohydride.
  • the reaction of compound V with (R)-(+)-2-methyl-(2)-propanesulfinamide in the presence of a titanium(IV) alkoxide, preferably titanium(IV) isopropoxide generates an intermediate of formula (VII), which is preferably not isolated:
  • Reaction of compound VII with an acid results in the formation of compound VIII, which preferably can be isolated in its acid addition salt.
  • the resulting acid addition salt of compound VIII may be used directly in the next step (i.e. oxidation or condensation as discussed below), or may be converted to the free base form of compound VIII prior to the next step.
  • compound VIII may be isolated.
  • the isolated compound VIII may be in the form of an acid addition salt, for example with a mineral acid such as hydrochloric acid or with a chiral acid, such as a chiral amino acid, particularly N-acetyl-L- leucine, or as a free base.
  • the disclosure further encompasses a process for preparing Apremilast comprising the preparation of compound VIII or an acid addition salt of compound VIII, for example with a mineral acid such as hydrochloric acid or with a chiral acid, such as a chiral amino acid, particularly N-acetyl-L-leucine (preferably the acid addition salt is with a chiral amino acid, and more preferably N-acetyl-L-leucine), according to the present disclosure and converting it to Apremilast, for example according to the process described in Scheme 2:
  • the compound VIII may be in the form of a free base, or an acid addition salt (particularly a salt with a chiral acid, more particularly a chiral amino acid, and most preferably compound VIII is in the form of a salt with N-acetyl-L-leucine).
  • Oxidation of compound VIII either in free base form or an acid addition salt thereof may be done with the use of oxone, hydrogen peroxide, sodium persulfate, or per-carboxylic acids such as m- chloroperbenzoic acid or peracetic acid.
  • Condensation of compound IX and X may be performed as disclosed in WO 2003/080049. Any acid addition salt in the reaction can be removed by reaction with a base (e.g.
  • Apremilast may be prepared by first condensing compound VIII with compound X to compound XII (N-[2-[(l S)-l-(3ethoxy-4-methoxyphenyl))- (methylthio)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide), and then oxidizing the resulting condensation product.
  • the disclosure further encompasses a process for preparing Apremilast comprising the preparation of compound VIII in the form of a free base, or an acid addition salt (particularly a salt with a chiral acid, more particularly a chiral amino acid, and most preferably N-acetyl-L-leucine) according to the present disclosure and converting it to Apremilast, for example according to the process described in Scheme 3:
  • the compound VIII may be in the form of a free base, or an acid addition salt (particularly a salt with a chiral acid, more particularly a chiral amino acid, and most preferably N-acetyl-L-leucine).
  • Condensation of compound VIII (as a free base or as an acid addition salt) and compound X may be performed in refluxing acetonitrile in the presence of acetic acid.
  • Oxidation of the resulting compound XII may be done with the use of oxone, hydrogen peroxide, sodium persulfate, or per-carboxylic acids such as m-chloroperbenzoic acid or peracetic acid.
  • the oxidation reaction may be carried out in the presence of a catalyst, such as a titanium(IV) alkoxide (particularly titanium (IV) ethoxide, titanium (IV) butoxide, titanium (IV) tert-butoxide or titanium(IV) isopropoxide, preferably titanium(IV) isopropoxide) or an alkali metal tungstate, particularly sodium tungstate.
  • a catalyst such as a titanium(IV) alkoxide (particularly titanium (IV) ethoxide, titanium (IV) butoxide, titanium (IV) tert-butoxide or titanium(IV) isopropoxide, preferably titanium(IV) isopropoxide) or an alkali metal tungstate, particularly sodium tungstate.
  • the oxidation reaction is carried out using hydrogen peroxide as the oxidation agent and sodium tungstate as catalyst.
  • Apremilast can be carried out in one pot, i.e. without isolation of the intermediate compound XII.
  • compound VIII and compound X are condensed (preferably by refluxing with acetonitrile in the presence of acetic acid), and then adding the oxidation agent and catalyst as discussed above directly to the reaction mixture after the condensation reaction is complete.
  • the present disclosure further comprises the preparation of apremilast by first oxidizing compound VI, then performing resolution in order to obtain compound IX, which then may be converted to apremilast.
  • the present disclosure further encompasses a crystalline form of compound (V).
  • the crystalline form of compound (V) is preferably characterized by an X-ray powder diffraction partem having peaks at 8.2, 16.5, 19.5 and 27.3 ⁇ 0.2 degrees two-theta, and optionally further characterized by additional peaks at 10.8, 17.4, 18.6, 20.8, 21.8, 23.5, 24.2, 24.9, 25.0 and 28.0 ⁇ 0.2 degrees two-theta, or an X-ray powder diffraction pattern substantially as depicted in Figure 1.
  • a crystalline form of the compound of formula (VI) in the form a hydrochloride salt is characterized by an X-ray powder diffraction partem having peaks at 10.6, 15.5, 23.5, 25.2 and 26.4 ⁇ 0.2 degrees two-theta, and optionally further characterized by additional peaks at 1 1.8, 16.8, 18.7, 19.3, 20.2, 20.6, 21.3, 22.3, 23.3, 27.0, 27.6, 28.1 and 29.1 ⁇ 0.2 degrees two-theta, or an X-ray powder diffraction pattern substantially as depicted in Figure 2.
  • a crystalline form of the compound of formula (VIII) which is in the form of a salt with N-acetyl-L-leucine.
  • the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 6.4, 7.8, 8.4, 15.6 and 16.2 ⁇ 0.2 degrees two-theta, and optionally further characterized by peaks at 3.6, 4.8, 7.3, 9.6, 10.1, 11.3, 13.7, 14.2, 14.8, 17.4, 18.0, 19.8, 22.6, 23.7, 24.2 and 24.4 ⁇ 0.2 degrees two-theta, or an X-ray powder diffraction pattern substantially as depicted in Figure 3.
  • the present disclosure further provides a crystalline form of a compound of formula (IX) in free base form.
  • the crystalline form is preferably characterized by an X-ray powder diffraction pattern having peaks at 5.9, 1 1.8, 17.7 and 26.0 ⁇ 0.2 degrees two-theta, and optionally further characterized by additional peaks at 15.8, 16.7, 19.8, 20.6, 23.7, 26.6, 28.6, 29.8 and 31.6 ⁇ 0.2 degrees two-theta, or an X-ray powder diffraction pattern substantially as depicted in Figure 4.
  • the present disclosure comprises the use of the compounds disclosed herein, particularly compounds IV, V, VI, VII, VIII, XII, acid addition salts thereof, and their solid state forms as indicated above, as intermediates for the preparation of a compound of formula (IX) or for the preparation of Apremilast.
  • the Apremilast may further be combined with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation, or a
  • Scan range 2 - 40 degrees 2-theta
  • Step size 0.05 ⁇ 0.005 degrees
  • V20 The accuracy of peak positions is defined as ⁇ 0.2 degrees two theta due to experimental differences such as instrumentations, sample preparations etc.
  • Dimethoxyacetophenone derivative (I) (72.08 g; 0.4 mol) was dissolved in sulfuric acid (360 ml), and then the mixture was stirred at 62 - 64 °C for 48 h.
  • the reaction mixture was cooled to room temperature, poured into ice water (prepared from 2 kg of ice and 1.6 kg of water) and kept in a refrigerator overnight.
  • the product was collected by filtration, washed with water (5x100 ml) and dried in vacuum at 40 °C until constant weight to obtain the product (40.4 g; 60.2 %; HPLC purity: 96.4 %).
  • the crude product was dissolved in warm ethanol (80 ml) and precipitated by addition of n-heptane (80 ml).
  • the mixture was cooled to 0 - 10 °C, stirred at this temperature for 1 h, the product was collected, washed with n-heptane (40 ml) and dried in a vacuum at 40°C until constant weight to obtain the purified product (30.77 g; 46.2 %; HPLC purity: 99.5 %).
  • the mixture was concentrated in vacuum to about 100 g, diluted with ethyl acetate (300 ml) and about 100 ml of solvent was distilled out from the diluted mixture.
  • the resulting solution was diluted with water (100 ml), the obtained precipitate was removed by filtration and the filter cake was washed with ethyl acetate (100 ml).
  • the filtrate was diluted with n-heptane (100 ml) the resulting two phases were separated, the filter cake was washed once again with ethyl acetate (100 ml), which was used again for extraction of the water phase.
  • the organic phases were combined, evaporated to about 40 g in vacuum and the obtained solution is diluted with ethyl acetate.
  • the obtained solution was treated with concentrated hydrochloric acid (8 ml) to precipitate the hydrochloride salt of compound 6.
  • the precipitated material was collected, washed with ethyl acetate (2x30 ml) and dried in vacuum at 40 °C until constant weight to obtain the product (22.61 g; 81.0 %; HPLC purity: 96.4 %).
  • V l-(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan-l-one (V) (12.01 g; 50 mMol), abs. methanol (120 ml), titanium tetra-iso-propoxide (28.4 g; 29.5 ml; 100 mMol) and ammonia 7 Mol/1 in methanol (50 ml; 350 mMol) were charged into a reaction vessel under nitrogen. After charging, the reaction vessel was closed, and the mixture was stirred at 40 C° for 10 h.
  • the organic phase was evaporated to about 92 ml (about 86 g) in vacuum and the obtained solution was treated with cone hydrochloric acid (about 3.4 ml) to adjust the pH to about 4 - 5 while stirring and cooling at max. 40 C°.
  • the obtained slurry was cooled to 0 - 10 C°, and stirred at this temperature for 2 h.
  • the precipitated hydrochloride salt of l-(3-ethoxy-4- methoxyphenyl)-2-(methylthio)ethan-l -amine (VI) was collected, washed with ethyl acetate (2x30 ml) and dried in vacuum at 40 °C until constant weight to obtain the product.
  • optical purity is characterized by ee: 97.8 %.
  • NAL N-Acetyl-L-leucine
  • Substrate ( ⁇ )- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan- 1 -amine (VI) (320 mg, 1.326 mmol, 20 mg/ml concentration in reaction mixture) was dissolved in 16 ml toluene/ethyl acetate 3: 1 v/v mixture. Triethylamine (18.5 ⁇ , 0.1 equiv. to substrate) was dissolved in the obtained solution.
  • Enzymes available in immobilized form (adsorbed on sorption resins or macroporous resins or covalently immobilized on activated resins) were weighed into dry ampoules in 20-20 mg amount.
  • the solution prepared above was added to the enzymes in 1-1 ml volume, at room temperature.
  • the ampoules were closed with caps, and placed into an incubator shaker at 50 °C temperature, for 24 hours.
  • the shaking velocity of the incubator was 400 rpm.
  • the reaction mixtures were diluted quantitatively with acetonitrile and analyzed by HPLC.
  • Substrate ( ⁇ )- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan- 1 -amine (VI) (320 mg, 1.326 mmol, 20 mg/ml concentration in reaction mixture) was dissolved in toluene, ethyl methoxyacetate (396.8 mg, 3.359 mmol, 2.5 equiv. to substrate) was added and the mixture was completed to 16 ml.
  • Enzymes available in immobilized form were weighed into dry ampoules in 20-20 mg amount, together with molecular sieves (4 Angstrom pore size, 58.1 mg).
  • the solution prepared above was added to the enzymes in 1-1 ml volume, at room temperature.
  • the ampoules were closed with caps, and placed into an incubator shaker at 50 °C temperature, for 24 hours.
  • the shaking velocity of the incubator was 400 rpm. After 24 hours of shaking the reaction mixtures were diluted quantitatively with acetonitrile and analyzed by HPLC.
  • Diatomaceous earth (Hyflo Super Cel) was pretreated with 50% sulfuric acid at room temperature
  • the pretreated Hyflo Super Cel powder (in dried form) was weighed in 2-2 g amount into Petri dishes and the content of each Petri dish was mixed with the prepared enzyme solutions until an uniformly spread thick suspension was obtained. The Petri dishes were left to dry under a functioning fumehood for 48 hours. The obtained enzyme preparations were homogenized thereafter and tested in enzymatic reactions.
  • Reaction set A (with ethyl acetate as acyl donor):
  • Enzymes immobilized by deposition on diatomaceous earth were weighed into dry ampoules in 20-20 mg amount. The solution prepared above was added to the enzymes in 1-
  • Reaction set B (with ethyl methoxyacetate as acyl donor):
  • Substrate ( ⁇ )- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylthio)ethan- 1 -amine (280 mg, 1.160 mmol, 20 mg/ml concentration in reaction mixture) was dissolved in toluene, ethyl methoxyacetate (344 mg, 2.912 mmol, 2.5 equiv. to substrate) and triethylamine (16.24 ⁇ , 0.1 equiv. to substrate) was added and the mixture was completed to 14 ml.
  • Enzymes immobilized by deposition on diatomaceous earth were weighed into dry ampoules in 20-20 mg amount.
  • the solution prepared above was added to the enzymes in 1- 1 ml volume, at room temperature.
  • the ampoules were closed with caps, and placed into an incubator shaker at 50 °C for 48 hours.
  • the shaking velocity of the incubator was 400 rpm. After 48 hours of shaking, the reaction mixtures were diluted quantitatively with acetonitrile and analyzed by HPLC.
  • reaction mixture was cooled to 35°C and ethanol (2400 mL) was added to the solution in 2 hours. After ethanol addition the suspension was stirred for 10 hours. The suspension was cooled to 0-5°C and kept at this temperature for 2 hours. The suspension was filtered, washed with cooled (0-5°C) ethanol (1200 mL) and dried under vacuum at 50°C overnight.

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Abstract

L'invention concerne des procédés de préparation d'aprémilast, et des intermédiaires pour sa préparation.
PCT/US2016/054390 2015-09-29 2016-09-29 Procédés de préparation d'aprémilast, et ses intermédiaires Ceased WO2017059040A1 (fr)

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Cited By (4)

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CN108084066A (zh) * 2017-12-12 2018-05-29 中山大学 一种阿普斯特及对映异构体的合成方法
EP3619195A4 (fr) * 2017-05-04 2020-12-02 Unichem Laboratories Ltd Nouveau procédé de préparation de n-[2-[(1s)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthylsulfonyl)éthyl]-1,3-dioxo-2,3-dihydro-1h-isoindol-4-yl]acétamide
WO2022232037A1 (fr) * 2021-04-26 2022-11-03 Amgen Inc. Procédé de synthèse d'aprémilast
CN120554380A (zh) * 2025-05-30 2025-08-29 江西华邦药业有限公司 一种舒巴坦酸的制备方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3619195A4 (fr) * 2017-05-04 2020-12-02 Unichem Laboratories Ltd Nouveau procédé de préparation de n-[2-[(1s)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthylsulfonyl)éthyl]-1,3-dioxo-2,3-dihydro-1h-isoindol-4-yl]acétamide
CN108084066A (zh) * 2017-12-12 2018-05-29 中山大学 一种阿普斯特及对映异构体的合成方法
WO2022232037A1 (fr) * 2021-04-26 2022-11-03 Amgen Inc. Procédé de synthèse d'aprémilast
US12351555B2 (en) 2021-04-26 2025-07-08 Amgen Inc. Process for synthesizing apremilast
CN120554380A (zh) * 2025-05-30 2025-08-29 江西华邦药业有限公司 一种舒巴坦酸的制备方法

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