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WO2025104624A1 - Synthèse de 1,5-anhydro-3-(5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1h-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-didésoxy-d-thréo-pentitol - Google Patents

Synthèse de 1,5-anhydro-3-(5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1h-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-didésoxy-d-thréo-pentitol Download PDF

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Publication number
WO2025104624A1
WO2025104624A1 PCT/IB2024/061303 IB2024061303W WO2025104624A1 WO 2025104624 A1 WO2025104624 A1 WO 2025104624A1 IB 2024061303 W IB2024061303 W IB 2024061303W WO 2025104624 A1 WO2025104624 A1 WO 2025104624A1
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formula
compound
viii
potassium
peaks
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Inventor
Katy Louise ALEXANDER
Zarrin Fazal Khadija ANSARI
David Sydney Bernard Daniels
Luke Harry HASSEL
Stephen Philip Keen
Jeremy Peter Scott
Reuben John SCOTT
Johathan Andrew SIMMONS
Emma Louise STOLL
Alexandre Fonseca TRINDADE
Anna Chiara VICINI
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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 disclosure provides processes to prepare 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-0 hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3- dideoxy-D-threo-pentitol monohydrate Form 2.
  • the disclosure also provides intermediates used for the preparation of such compounds.
  • Cyclin-dependent kinases are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be useful for the treatment of proliferative disorders, including cancer.
  • Compound A refers to 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan- 2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-threo- pentitol, which has the following chemical structure, including hydrates (such as, monohydrate), salts and polymorphs thereof: Compound A.
  • Compound A can be prepared from amino alcohols of Formula (V), and the compound of Formula (VIII), 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol.
  • the amino alcohols of Formula (IV) can be prepared from the potassium sulfonate of Formula (I), and alternately can be prepared from the compound of Formula (II), 3-(benzyloxy)tetrahydro-4H-pyran-4-one.
  • the compound of Formula (VII) can be prepared from compound of Formula (VI), 2-(6-bromo-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol.
  • a retrosynthetic scheme of the improved routes is provided in Scheme 1 below.
  • Scheme 1 A comprising: (a) providing a compound Formula (VIII) ; (b) (VIII) with a compound of Formula (V) wherein X ⁇ in the presence of a base and a suitable solvent to produce Compound A.
  • the disclosure provides a process for preparing a compound of Formula (V) ), wherein X ⁇ is OTs ⁇ or H2PO4 ⁇ , comprising: (a) providing a co pou o Formula (II) O O HO S O K ; (b) Formula (II) to a compound of Formula (III) ; (c) of Formula (III) with an acid selected from p- toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) , wherein X ⁇ is OTs ⁇ or H2PO4 ⁇ ; and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V) .
  • the disclosure provides a process for preparing 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) ; comprising: (a) a (VI) with bis(neopentyl glycolato)diboron in the presence of a potassium salt of an organic acid, a suitable organic solvent and an organopalladium catalyst to produce a compound of Formula (VII)
  • the disclosure provides a crystalline form of a compound of Formula (VII) having the structure: .
  • FIG.1. PXRD pattern of crystalline tosylate salt Formula (IVa) (Form 1).
  • FIG.2. PXRD pattern of crystalline tosylate salt Formula (IVa) (Form 2).
  • FIG.3. PXRD pattern of crystalline phosphate salt Formula (IVb) (Form 1).
  • FIG.4. PXRD pattern of crystalline tosylate salt Formula (Va) (Form 1).
  • FIG.5. PXRD pattern of crystalline phosphate salt Formula (Vb) (Form 1).
  • FIG.6 PXRD pattern of crystalline Formula (VII) (Form 1).
  • FIG.7 PXRD pattern of crystalline Formula (VIII) (Form 3).
  • FIG.8 PXRD pattern of crystalline Formula (VIII) (Form 1).
  • DETAILED DESCRIPTION OF THE INVENTION The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.
  • a suitable solvent may include one or more suitable solvents (i.e., a suitable solvent mixture).
  • suitable solvents i.e., a suitable solvent mixture.
  • alkyl refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons (C 1 -C 6 alkyl), sometimes from one to five carbons (C1-C5 alkyl), and preferably from one to four carbons (C1-C4 alkyl).
  • alkyl groups are methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, and the like.
  • OTs refers to p-toluenesulfonate or tosylate (i.e., 4- CH3C6H4SO3) moiety.
  • protecting group refers to selectively introducible and removable groups which protect functional groups against undesirable side reactions during synthetic procedures. Examples of suitable protecting groups for various functional groups and relevant reaction conditions are provided in Wuts, Peter G.M. Greene’s Protective Groups in Organic Synthesis (5 th ed.).
  • Compound A refers to the compound 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3- dideoxy-D-threo-pentitol, and all of the existing crystalline forms, which includes the monohydrate form 2.
  • Compound A include deuterium substitutes where they may be formed.
  • “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance.
  • An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • water activity refers to the measure of the free water in a system that can participate in chemical reactions and support microbial growth. It is expressed as a ratio of the vapor pressure of water in a substance to the vapor pressure of pure water under the same conditions. For reference, water has a water activity of 1.0.
  • the present disclosure provides more efficient process to synthesize Compound A as demonstrated in Scheme 2.
  • the compound of Formula (V) is (4R)-3-hydroxytetrahydro-2H-pyran-4-aminium dihydrogen phosphate salt, Formula (Vb), wherein X is H 2 PO 4 .
  • the inventors of this disclosure discovered that the formation and isolation of the salt Formula (IV) and thus salt Formula (V) are significant in enhancing efficiency in the synthesis of Compound A. Scale-up synthesis of Compound A via salts Formula (IV) and (V) provide more options for isolation and confer greater stability on the isolated intermediates.
  • the process of coupling 2-[6-(2,5- dichloropyrimidin-4-yl)- 4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII), with a compound of Formula (V) is conducted in the presence of a base and a suitable solvent to produce Compound A.
  • the process of coupling 2-[6-(2,5- dichloropyrimidin-4-yl)- 4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with a compound of Formula (V) is conducted at a temperature of from about 80 to about 110°C, from about 80 to about 100°C, or from about 80 to about 95°C.
  • Preferred solvents suitable for such coupling reaction includes a polar solvent, such as, 1-propanol, 2-propanol, 2-butanol, t-amyl alcohol, acetonitrile, sulfolane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide (DMF), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and mixtures thereof.
  • the polar solvent is acetonitrile.
  • the polar solvent is sulfolane.
  • Suitable bases for such coupling reaction includes trialkylamines (such as, N,N- diisopropylethylamine (DIPEA), triethylamine, tri-n-butyl, tri-n-octyl, etc.); alkaline earth carbonate or bicarbonates (such as, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.); alkaline earth carboxylates (such as, potassium propionate etc.); alkaline earth phosphate bases (such as, mono-, di-, tri-potassium phosphate, etc.); and other inorganic bases (such as, barium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, etc.); and mixtures thereof.
  • DIPEA N,N- diisopropylethylamine
  • DIPEA diisopropylethylamine
  • triethylamine tri-n-butyl, tri-n-octyl, etc.
  • the base is a buffered carbonate mixture, such as, a mixture of potassium carbonate and sodium bicarbonate.
  • the base includes an organic and an inorganic bases, such as, a mixture of a trialkylamine and an alkaline earth phosphate base (e.g., mixture of DIPEA and K 3 PO 4 ).
  • the stoichiometry of the base to 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1- (propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) ranges from about 1.0 to about 4.5 molar equivalents, from about 1.5 to about 4.0 molar equivalents, or from about 1.5 to about 3.5 molar equivalents.
  • the coupling reaction comprises about 2.0 or about 3.0 molar equivalent base and about 1.0 of 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII).
  • Scheme 3 illustrates the preparation of the compounds of Formulae (Va) and (Vb) from the benzyl protected compounds of Formula (I) or (II).
  • Scheme 3 In one aspect, the disclosure provides a process for preparing a compound of Formula (V) , wherein X ⁇ is or X ⁇ is H2PO4 ⁇ (Formula Vb).
  • the process for preparing the compound of Formula (V) comprising (a) providing a compound of Formula (II); (b) converting the compound of Formula (II) to a compound of Formula (III); (c) contacting the compound of Formula (III) with an acid selected from p- toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) ), wherein X ⁇ is X ⁇ is H2PO4 ⁇ (Formula IVb); and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V).
  • the compound of Formula (V) can be prepared from a compound of Formula (I).
  • the process for preparing the compound of Formula (V) comprising (a) providing a compound of Formula (I); (b) converting the compound of Formula (I) to a compound of Formula (III); (c) contacting the compound of Formula (III) with an acid selected from p-toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) described above; and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V).
  • the step (b) of converting the compound of Formula (II) to a compound of Formula (III) or the step (b) of converting the compound of Formula (I) to a compound of Formula (III) is conducted at a pH ranging from about 8 to about 12, from about 9 to about 12, or from about 10 to about 12. In some embodiments, the step (b) is conducted at a temperature ranging from about 35 to about 55°C, from about 35 to about 50°C, or from about 40 to about 50°C. In some embodiments, the step (b) is conducted in the presence of an enzyme, such as an engineered transaminase enzyme, for example ATA-303 enzyme sold by Codexis, Inc., described in U.S.
  • an enzyme such as an engineered transaminase enzyme, for example ATA-303 enzyme sold by Codexis, Inc., described in U.S.
  • the step (b) is conducted in the presence of a donor amine, such as, isopropylamine, and ⁇ -methylbenzylamine.
  • a donor amine such as, isopropylamine, and ⁇ -methylbenzylamine.
  • the disclosure provides a process for preparing 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII).
  • the process comprising (a) contacting a compound of Formula (VI) with bis(neopentyl glycolato)diboron in the presence of a potassium salt of an organic acid, a suitable organic solvent and an organopalladium catalyst to provide a compound of Formula (VII); and (b) contacting the compound of Formula (VII) with 2,4,5- trichloropyrimidine in the presence of a base to produce the compound of Formula (VIII).
  • the potassium salt of an organic acid in step (a) is selected from the group consisting of potassium pivalate, potassium 2-ethylhexanoate, potassium acetate, and mixtures thereof.
  • the organic solvent used in step (a) comprises a tertiary alcohol, or a tertiary ether, or an optionally substituted tetrahydrofuran or tetrahydropyran.
  • Preferred organic solvents used in step (a) include tert-butanol, tert- amyl alcohol, methyl tert-butyl ether, cyclopentyl methyl ether (CPME), tert-amyl-methyl ether (TAME), tetrahydropyran, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF), 3- methyltetrahydrofuran (3-MeTHF), or mixture thereof.
  • the organopalladium catalyst used in step (a) is selected from the group consisting of bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl]2), tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), bis(triphenylphosphine)palladium(II) diacetate (Pd(OAc)2(PPh3)2), 1,4- bis(diphenylphosphino)butane-palladium(II) chloride (PdCl 2 (dppb)), 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (PdCl2(dppf)), and [9,9- dimethyl-4,5-bis(diphenylphosphino)xant
  • the organopalladium catalyst is bis(triphenylphosphine)palladium(II) dichloride (PdCl 2 (PPh 3 ) 2 ).
  • the base used in step (b) is an alkali metal hydroxide or carbonate base, or an alkaline earth hydroxide or carbonate base.
  • the base is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, cesium carbonate, and mixture thereof.
  • the disclosure provides intermediates and their crystalline forms useful in the synthesis of Compound A.
  • the disclosure provides a compound and a crystalline form of Formula (IVa) (Form 1) having the structure:
  • the crystalline form of Formula (IVa) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (IVa) has a PXRD pattern comprising peaks at 2 ⁇ values of: 5.1, 12.4, 16.8, and 22.5 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (IVa) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 1 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.1.
  • the crystalline form of Formula (IVa) is anhydrous (Form 1).
  • the disclosure provides a compound and a crystalline form of Formula (IVa) (Form 2) having the structure: (IVa).
  • the crystalline form of Formula (IVa) (Form 2) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (IVa) has a PXRD pattern comprising peaks at 2 ⁇ values of: 5.5, 8.5, 21.2, and 23.4 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (IVa) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 2 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.2.
  • the crystalline form of Formula (IVa) is hemi-hydrate (Form 2).
  • the disclosure provides a compound and a crystalline form of Formula (IVb) having the structure: .
  • the crystalline form of Formula (IVb) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (IVb) has a PXRD pattern comprising peaks at 2 ⁇ values of: 5.0, 18.3, 21.5, 22.7 and 23.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (IVb) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 3 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.3.
  • the crystalline form of Formula (IVb) is anhydrous (Form 1).
  • the disclosure provides a compound and a crystalline form of Formula (Va) (Form 1) having the structure: .
  • crystalline form of Formula (Va) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • PXRD powder X-ray diffraction
  • the crystalline form of Formula (Va) has a PXRD pattern comprising peaks at 2 ⁇ values of: 6.5, 17.0, 19.5, 21.4, and 22.6 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (Va) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 4 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.4.
  • the crystalline form of Formula (Va) is anhydrous (Form 1).
  • the disclosure provides a compound and a crystalline form of Formula (Vb) (Form 1) having the structure: .
  • the crystalline form of Formula (Vb) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (Vb) has a PXRD pattern comprising peaks at 2 ⁇ values of: 10.7, 15.9,17.3, 21.0, and 21.4 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (Vb) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 5 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.5.
  • the crystalline form of Formula (Vb) is anhydrous (Form 1).
  • the disclosure provides a crystalline form of Formula (VII) (Form 1) having the structure: . form of Formula (VII) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (VII) has a PXRD pattern comprising peaks at 2 ⁇ values of: 10.0, 12.4, 14.6, 18.6, and 23.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (VII) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 6 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.6.
  • the crystalline form of Formula (VII) is anhydrous (Form 1).
  • the disclosure provides a crystalline form of Formula (VIII) (Form 3) having the structure: .
  • the crystalline form of Formula (VIII) (Form 3) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (VIII) has a PXRD pattern comprising peaks at 2 ⁇ values of: 5.1, 10.7, 14.1, and 17.3 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (VIII) (Form 3) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 7 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.7.
  • the crystalline form of Formula (VIII) is anhydrous (Form 3).
  • the disclosure provides a crystalline form of Formula (VIII) (Form 1) having the structure: . form of Formula (VIII) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern.
  • the crystalline form of Formula (VIII) has a PXRD pattern comprising peaks at 2 ⁇ values of: 9.4, 12.8, 14.5, and 16.4 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Formula (VIII) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 8 in °2 ⁇ ⁇ 0.2 °2 ⁇ ; or (b) peaks at 2 ⁇ values essentially the same as in FIG.8.
  • the crystalline form of Formula (VIII) is monohydrate (Form 1). Examples All reactions were performed under a nitrogen atmosphere. All reagents purchased from vendors were used as received unless specified otherwise. 1H Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker XWIN- NMR (400 or 700 MHz) spectrometer.
  • 1 H resonances are reported in parts per million (ppm) downfield from tetramethylsilane.
  • 1 H NMR data are reported as multiplicity (e.g., s, singlet; d, doublet; t, triplet; q, quartet; quint, quintuplet; dd, doublet of doublets; dt, doublet of triplets; br s, broad singlet; m, multiplet).
  • the residual protons 7.27, 2.50, and 3.31 ppm, respectively
  • All observed coupling constants, J are reported in Hertz (Hz). “ ⁇ ” means chemical shift.
  • the PXRD patterns were collected with a PANalytical X’Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using a long, fine-focus source.
  • the tube voltage and amperage were set to 45 kV to 40 mA, respectively.
  • An elliptically graded multilayer mirror was used to focus Cu K ⁇ X-rays through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640f
  • a specimen of the sample was sandwiched between 3- ⁇ m-thick films and analyzed in transmission geometry and rotated at 1 revolution per second.
  • Diffracted radiation was detected using an X’Celerator Scientific RTMS X-ray detector.
  • a beam- stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Colelctor sofrware v. 5.5. Data were collected from 1 to 40 degrees 2-theta (°2 ⁇ ) using a step size of 0.0167 °2 ⁇ and a counting time of 36.83 s.
  • Peaks with a relative intensity greater than or equal to 2 were chosen for inclusion in the table.
  • General PXRD method 2 The powder X-ray diffraction pattern was generated using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The motorized divergence slits were set at constant illumination of 11 mm. Diffracted radiation was detected using a LYNXEYE XE-T energy dispersive X-ray detector, with the position sensitive detector (PSD) opening set at 4.00°.
  • PSD position sensitive detector
  • the minor error associated with this measurement can occur because of a variety of factors including: (a) sample preparation (e.g., sample height), (b) instrument characteristics, (c) instrument calibration, (d) operator input (e.g. in determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency effects).
  • Ambient temperature is generally between 20 and 25 °C.
  • ACN is acetonitrile.
  • aq is aqueous.
  • CDCl 3 is deuterochloroform.
  • DMSO-d6 is fully deuterated dimethyl sulfoxide.
  • DIPEA is N,N-diisopropylethyl amine. ca. is circa. psiq is pounds per square inch gauge EtOH is ethanol.
  • Et 3 N is triethylamine. eq. is molar equivalent.
  • IPA is isopropyl alcohol.
  • KOAc is potassium acetate.
  • Me is methyl (-CH 3 ).
  • MeOH is methanol.
  • mL is milliliter.
  • mmol is millimole.
  • PXRD powder X-ray diffraction
  • THF is tetrahydrofuran.
  • the solution of iodine was added to the reaction over 3 hours maintaining temperature ⁇ 5°C and excluding light. Following addition, the reaction was heated to 20°C and stirred for 30 minutes. The mixture was concentrated under reduced pressure at 40°C to leave a slurry. Dichloromethane (410 mL, 6.6 mL/g) was added to the residue and the slurry was filtered. The filtrate was concentrated under reduced pressure at 40°C to leave an oil. n-Heptane (104 mL, 1.7 mL/g) was added and the mixture concentrated under reduced pressure at 40°C to leave an oil.
  • Step 2 Compound 3: 3-(benzyloxy)-4,4-dimethoxytetrahydro-2H-pyran
  • Compound 2 (73.6 g, 454 mmol, 1 eq.) was combined with toluene (390 mL, 5.3 mL/g) and the mixture was concentrated under vacuum to leave an oil to which tetrahydrofuran (390 mL, 5.3 mL/g) was added.
  • the resultant mixture was heated to 35°C and stirred for 24 hours then was cooled to 20°C.
  • Water (780 mL, 10.6 mL/g) was added and the phases separated.
  • the aqueous phase was extracted three time with methyl tert-butyl ether (3 x 780 mL, 3 x 10.6 mL/g).
  • the combined organic phases were concentrated under reduced pressure to leave an oil.
  • the oil was purified by flash chromatography on silica gel (10 to 100% iso-propyl acetate in n-heptane) to leave Compound 3 (82.75 g, 328 mmol, 72% yield) as a yellow oil.
  • Step 3 Compound 4: 3-(benzyloxy)tetrahydro-4H-pyran-4-one mmol, 1 eq.) was with water (450 mL, 6 mL/g) and toluene (900 mL, 12 mL/g) and the mixture was stirred at 20°C.
  • Formic acid 450 mL, 6 mL/g was added over 11 minutes and the reaction stirred for 20 hours at 20°C.
  • the reaction was cooled to 5°C and a solution of sodium hydroxide in water (10 M, 1.21 L, 16 mL/g) was added over 3 hours maintaining temperature ⁇ 12°C.
  • Step 4 Formula (II): potassium 3-(benzyloxy)-4-hydroxytetrahydro-2H-pyran-4- sulfonate A soluti , , 250 mL, 10 mL/g) was cooled to 10°C and a solution of potassium metabisulfite (17 g, 73 mmol, 0.6 eq.) in water (25 mL, 1 mL/g) was added over ⁇ 30 minutes. The reaction was stirred at 10°C for 2 hours then filtered and the filter cake rinsed with toluene (75 mL, 3 mL/g). The filter cake was combined with ethanol (300 mL, 12 mL/g) and the slurry stirred at 25-30°C for 30 minutes.
  • Example 2 Preparation of salts Formula V : A buffer was prepared from boric acid (0.50 g, 8.1 mmol), isopropylamine (6.8 mL, 79 mmol) and water (25 mL), and adjusted to pH 11.5 using concentrated HCl. Further water was added to give a total volume of 40 mL. To a vessel was charged pyridoxal phosphate (22.5 mg, 0.75% w/w), ATA-303 (105 mg, 3.5% w/w; obtained from Codexis, Inc.) and the prepared buffer (19.5 mL, 6.5 mL/g).
  • the mixture was stirred at 40°C for 15 minutes and a slurry of the compound of Formula (II) (3.0 g, 9.2 mmol, 1.0 eq.) in the prepared buffer (6.0 mL, 2 mL/g) was added.
  • the reaction was stirred for 22 hours, and methyl ethyl ketone (30 mL, 10 mL/g) was added.
  • the biphasic mixture was filtered to remove insoluble matter and the filtrate separated into two phases. The aqueous phase was extracted with methyl ethyl ketone (15 mL, 5 mL/g) and the organics combined.
  • n- Heptane (2.5 mL, 0.83 mL/g) was added to the organic phase and any aqueous phase was separated. The organics were washed with saturated brine (15 mL, 5 mL/g) and concentrated to dryness to leave a yellow oil. The oil was taken up in 2- methyltetrahydrofuran (7.5 mL, 2.5 mL/g) and concentrated to dryness to leave the compound of Formula (III) (1.80 g, 8.7 mmol, >99%ee, >90:10 dr, 95% yield) as a pale yellow oil.
  • Step 1 (Alternate): (3S,4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine, Formula (III):
  • the compound of Formula (III) can be prepared from 3- (benzyloxy)tetrahydro-4H-pyran-4-one, Formula (I).
  • a buffer was prepared from boric acid (9.9 g), isopropylamine (68 mL) and water (500 mL), and adjusted to pH 11.5 using 4M HCl. Further, water was added to give a total volume of 800 mL (final borate concentration of 0.2M and isopropylamine concentration of 1M).
  • pyridoxal phosphate 401 mg, 2% w/w
  • borate buffer solution 320 mL, 18 mL/g
  • a fluorescent yellow solution formed on stirring.
  • ATA- 303 (4 g, 20% w/w) was added and the mixture heated to 40°C and stirred for 45 minutes to give a thin slurry.
  • the reaction mixture was filtered to remove any solids, then the filtrate extracted three time with MeTHF/heptane (4:1 v:v, 1.0 L, 50 mL/g).
  • the combined organic phase was washed with 10%wt. aq. Na2SO4 (200 mL, 10 mL/g) then clarified by filtration through a pad of Celite (30 g, 150%wt.).
  • the filter cake was washed with MeTHF (60 mL, 3 mL/g).
  • the combined filtrate and wash were concentrated under reduced pressure to leave a clear yellow oil (19.3 g, 93.1 mmol, 96%) as a 95.3:4.7 trans:cis mixture of diastereomers.
  • the assay yield of the compound of Formula (III) was 87% (17.6 g).
  • the oil was dissolved in MeTHF (200 mL, 10.4 mL/g) and the resultant solution is stored at ⁇ 20°C.
  • Step 2a (3S, 4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-aminium tosylate salt
  • Formula (IVa) A solution of (3S,4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine, Formula (III) (26.63 g, 129 mmol, 1 eq.) in 2-MeTHF (270 mL, 10 mL/g) was charged to a vessel.
  • Tosylate salt Formula (IVa) was isolated as a low density white solid (42.49 g, 112 mmol, 87%) after drying for 6 hours at 50°C.
  • Step 2b (3S, 4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-aminium dihydrogen phosphate salt, Formula (IVb):
  • a - pyran- Formula (III) (32.4 g, 156 mmol, 1 eq.) in IPA (500 mL, 15.4 mL/g) was treated with a solution of 85% H3PO4 (18 g, 156 mmol, 1 eq.) in IPA (130 mL, 4 mL/g). The resulting slurry was aged at 20°C for 1 hour, then collected by filtration.
  • Dihydrogen phosphate salt Formula (IVb) was isolated as a white solid (42.4 g, 139 mmol, 89%) after drying overnight at 50°C.
  • Step 3a (3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-aminium tosylate salt, Formula Tosylate salt Formula (IVa) obtained from step 2a (30.4 g, 80.1 mmol) and 10% Pd/C (7.52 g, 25 wt%, obtained from Johnson Matthey) were charged to an autoclave. MeOH (600 mL, 20 mL/g) was charged and the vessel placed under a hydrogen atmosphere (2.8 bar). The resulting reaction mixture was stirred at room temperature for 16 hours. Following reaction completion, the vessel was vented to atmospheric pressure and purged with nitrogen.
  • the reaction mixture was filtered through celite (ensuring the filter pad remained wet) and the cake washed with MeOH (300 mL, 10 mL/g).
  • the combined filtrate and the wash was concentrated under partial vacuum to 5 mL/g, diluted with 2-MeTHF (450 mL, 15 mL/g) and concentrated under partial vacuum to 10 mL/g.
  • a further portion of 2-MeTHF (300 mL, 10 mL/g) was added and the mixture concentrated to 10 mL/g giving a slurry.
  • a further portion of 2-MeTHF (300 mL, 10 mL/g) was charged and the slurry was concentrated under partial vacuum to 10 mL/g.
  • the dihydrogen phosphate salt Formula (IVb) obtained from step 2b (4.0 g, 13.1 mmol, 1 eq.), water (8.0 mL, 2 mL/g), 85% H3PO4 (0.4 g, 10%w/w) and activated charcoal (0.4 g, 10%w/w).
  • the resulting slurry was stirred at 40°C for 1 hour.10% Pd/C (80 mg, 2%w/w) was charged and the reactor purged with hydrogen to 50 psig.
  • the reaction was stirred and heated to 60°C for 22 hours.
  • the reaction was cooled to 20°C and vented.
  • the organic phase was combined with toluene (300 mL, 10 mL/g) and the mixture was concentrated at atmospheric pressure to ca.120 mL (ca.4 mL/g).
  • the mixture was cooled to 70°C and n-heptane (720 mL, 24 mL/g) was added over ca.20 minutes.
  • the resultant slurry was stirred at 70°C for 30 minutes, then cooled to 10°C.
  • the slurry was collected by filtration, washed with cold n-heptane (2 x 60 mL, 2 x 2 mL/g), and dried at 40°C to leave compound 7 as a white solid (35.71 g, 121.4 mmol, 84.2% yield).
  • Step 4 Formula (VI): 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- 2-ol (250 mL, 5 mL/g) at 21°C, and methanesulfonic acid (9.75 mL, 150.1 mmol, 1 eq.) was added over ca.1 hour.
  • the reaction was heated to 100°C for 18 hours then cooled to 22°C.
  • Water (100 mL, 2 vol) was added over 30 minutes, then a solution of NaOH (6.5 g, 162.5 mmol, 1.08 eq.) in water (275 mL, 5.5 mL/g) was added over 2 hours.
  • the resultant slurry was stirred at 23°C for 16 hours.
  • Step 5 2-(6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol, Formula (VII):
  • the compound of Formula (VI) (5.00 g, 15.86 mmol, 1 eq.) was combined with bis(neopentyl glycolato)diboron (4.12 g, 18.25, 1.15 eq.), potassium pivalate (2.50 g, 17.45 mmol, 1.10 eq.), potassium 2-ethylhexanoate (1.18 g, 6.34 mmol, 0.4 eq.) and bis(triphenylphosphine)palladium(II) dichloride (0.114 g, 0.159 mmol, 0.01 eq.).
  • the cake was washed with methyl tert-butyl ether (45 mL, 5 mL/g) and water (23 mL, 2.5 mL/g) and dried to give a pale colored solid (2.03 g).
  • the methyl tert-butyl ether filtrate was concentrated to dryness, dissolved in ethyl acetate (90 mL, 10 mL/g) and washed twice with water (45 mL, 5 mL/g). The organics were dried over MgSO 4 , filtered and concentrated and dried to give a brown solid.
  • the brown solid was redissolved in ethyl acetate (90 mL) and treated with activated charcoal (1 g) at 50°C for 1 hr.
  • Step 6 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]propan-2-ol, Formula (VIII):
  • the slurry of the compound of Formula (VII) from step 5 was stirred at 50°C and to it was charged a degassed solution of sodium hydroxide in water (2M, 11.9 mL, 1.5 eq.).
  • the biphasic mixture was stirred for 1 hr at 50°C and a pH probe was added.
  • the pH of the mixture was adjusted to ca.10 using additional degassed sodium hydroxide in water (2M, ca. 8 mL, ca. 1 eq.).
  • the organics were combined are washed at 40-45°C with sodium hydroxide in water (1M, 30 mL, 6 mL/g) then with sodium chloride in water (23.5%w/w, 35 mL, 7 mL/g).
  • the organic phase was treated with silica thiol (2.5 g, 0.5 g/g) at 40-45°C for 18 hours, then the slurry filtered on a pad of Arbocel.
  • the filter cake was washed with methyl tert-butyl ether at 40-45°C (3 x 15 mL, 9 mL/g total).
  • the filtrate was concentrated to ca.15 mL (ca.3 mL/g) and n-heptane (50 mL, 10 mL/g) was added at 40-45°C to give a mobile slurry.
  • the slurry was cooled to 0°C and the solids isolated by filtration.
  • the cake was washed with cold n-heptane (10 mL, 2 mL/g) and dried to leave the compound of Formula (VIII) in 86-98% uncorrected yield (5.2-6.0 g).
  • the compound of Formula (VIII) was recrystallized from ethanol/water as follows.
  • Example 4a Preparation of 1,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-threo- pentitol monohydrate (Form 2), Compound A 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]propan-2-ol, Formula (VIII) (7.05 g, 18.4 mmol, 1 eq.) and tosylate salt Formula (Va) (7.59 g, 25.7 mmol, 1.4 eq.) were charged to a vessel and purged with nitrogen.
  • Example 4b Alternately, Compound A was prepared using hydrogen phosphate salt Formula (Vb) 2- - - 2- yl]propan-2-ol, Formula (VIII) (40.0 g, 104 mmol, 1 eq.), dihydrogen phosphate salt Formula (Vb) (24.7 g, 115 mmol, 1.1 eq.) and dipotassium hydrogen phosphate (54.4 g, 312 mmol, 3 eq.) were charged to a vessel and purged with nitrogen. Sulfolane (3% wet, 124 mL, 3.1 mL/g) and water (40 mL, 1 mL/g) were added and the reaction mixture was heated to 92-98°C for 41 hrs.
  • the mixture was cooled to 90°C and water (76 mL, 1.9 mL/g) is added.
  • the mixture was aged at 90°C for 20 minutes then 2-propanol (40 mL, 1 mL/g) was added).
  • the mixture was aged for 20 minutes, then cooled to ca.65°C over 1 hour and seeded with Compound A.
  • the resultant slurry was cooled to 0°C over 30 minutes and stirred at 0°C for 1.5 hours.
  • the slurry was collected by filtration and the cake was further washed with water (2 x 240 mL, 2 x 6 mL/g) and dried to leave Compound A as a white solid (43.24 g, 89.7 mmol, 86% yield).
  • Example 5a Evaluation of reaction conditions for the formation of Compound A step described in Example 4a Several combinations of base and solvent were explored for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan- 2-ol, Formula (VIII) with the tosylate salt Formula (Va).
  • Compound A was synthesized according to the procedure described in Example 4a above except that the reaction conditions (i.e., base, solvent, water) were altered. Tables 1 and 2 summarize the reaction yields of Compound A obtained from different combinations of base and solvent with or without the presence of water respectively.
  • Table 1 Base/solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the tosylate salt Formula (Va) with the presence of water
  • ACN anisole sulfolane 2-
  • DIPEA 49.40 43.90 67.53 60.76 67.13 10.78 84.93 19.34 K 2 HPO 4 56.51 44.89 58.64 57.04 61.31 5.86 79.19 26.70 Et 2 N 62.25 51.60 62.81 65.13 60.86 6.19 68.64 29.01 Calcium 21.42 21.48 26.06 24.18 n.d.
  • Table 3 Base/solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the dihydrogen phosphate salt Formula (Vb) with the presence of water
  • FIG.1 shows PXRD data for the tosylate salt Formula (IVa) (Form 1), collected according to general PXRD method 1.
  • a list of PXRD peaks at diffraction angles 2-theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 5.
  • Table 5 PXRD Peak list for the tosylate salt Formula (IVa) (Form 1) (2 ⁇ °) Angle (2-theta °) Relative Intensity Angle (2-theta °) ⁇ Relative Intensity ⁇ 0.2 °2 ⁇ (%) 0.2 °2 ⁇ (%) 5.1 10 25.5 8 12.4 61 25.8 5 15.2 2 26.3 4 16.0 9 26.9 6 16.8 31 27.3 8 17.5 14 27.7 4 17.6 12 27.9 7 19.0 2 29.3 3 19.6 11 30.2 3 19.7 36 34.3 3 22.5 100 35.4 2 23.1 48 37.9 4 24.8 5 38.3 6 25.0 2 Characterization of the tosylate salt Formula (IVa) (Form 2): Form 2 (hemi-hydrate) was prepared by exposing Form 1 to water and was characterized as follows: FIG.2 shows PXRD data for the tosylate salt Formula (IVa) (Form 2), collected according to General PXRD method 1.
  • FIG.3 shows PXRD data for the phosphate salt Formula (IVb) (Form 1), collected according to General PXRD method 1.
  • a list of PXRD peaks at diffraction angles 2-Theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 7.
  • FIG.4 shows PXRD data for the tosylate salt Formula (Va) (Form 1), collected according to General PXRD method 1.
  • a list of PXRD peaks at diffraction angles 2-Theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 8.
  • FIG.5 shows PXRD data for the phosphate salt Formula (Vb) (Form 1), collected according to General PXRD method 1.
  • a list of PXRD peaks at diffraction angles 2-Theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 9.
  • FIG.6 shows PXRD data for the compound of Formula (VII) (Form 1), collected according to General PXRD method 2.
  • a list of PXRD peaks at diffraction angles 2-theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 10.
  • Form 1 (monohydrate) and Form 3 (anhydrous) were observed along with several solvates.
  • the solvates have shown to be unstable at ambient conditions, drying to either an anhydrous or monohydrate form.
  • Both Form 1 and Form 3 have been isolated during synthesis dependent on the water activity of the isolation solvents and the extent of drying, and both forms have been successfully used in the next step (i.e., Example 4a or 4b).
  • Form 3 was physically stable under ambient and 40°C/75% RH conditions. Characterization of the Compound of Formula (VIII) (Form 3): The Compound of Formula (VIII) (Form 3) was characterized as follows: PXRD data: FIG.7 shows PXRD data for the compound of Formula (VIII) (Form 3), collected according to General PXRD method. A list of PXRD peaks at diffraction angles 2-Theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 11.
  • form 1 was prepared from evaporation of acetone/water (90:10 v/v) and dioxane/water (82:18 v/v).
  • Form 1 is a stable physical form at a water activity (a.w) greater than 0.543.
  • the sample analyzed in this experiment was prepared on a ⁇ 700 mg scale by slurring Form 3 in acetone/water 1:5 v/v for 88 hours.
  • Form 1 was physically stable under ambient and 40°C/75% RH conditions.
  • FIG.8 shows PXRD data for the compound of Formula (VIII) (Form 1), collected according to General PXRD method. A list of PXRD peaks at diffraction angles 2-theta ° (°2 ⁇ ) ⁇ 0.2 °2 ⁇ and their relative intensities is provided in Table 12.
  • Table 12 PXRD Peak list for the compound of Formula (VIII) (Form 1) (2 ⁇ °) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ⁇ 0.2 °2 ⁇ (%) ⁇ 0.2 °2 ⁇ (%) 9.4 44.3 22.3 11.9 10.4 50.0 22.8 16.6 12.8 28.8 23.4 100.0 14.5 77.8 25.4 21.3 15.3 14.0 25.6 24.1 16.1 56.0 26.7 10.6 16.4 35.9 27.9 12.8 18.9 16.2 28.3 89.9 19.1 18.0 28.4 41.0 19.8 21.9 29.3 13.0 21.5 25.6 32.1 16.6
  • Example 12 The compounds shown in Table 13 are prophetic deuterated analogs (PDA) of Compound A.
  • BioTransformer 3.0 biotransformer.ca/new
  • MetaSite molecular Identities
  • MetaSite molecular Identities
  • Meteor Nexus Lhasa Meteor Nexus (lhasalimited.org/products/meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules.

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Abstract

La présente divulgation concerne de nouveaux procédés destinés à préparer du 1,5-anhydro-3-(5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-didésoxy-D-thréo-pentitol et ses hydrates et stéréo-isomères, ainsi que des intermédiaires, y compris des formes solides des intermédiaires, utiles pour la préparation de tels composés et la synthèse desdits intermédiaires.
PCT/IB2024/061303 2023-11-14 2024-11-14 Synthèse de 1,5-anhydro-3-(5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1h-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-didésoxy-d-thréo-pentitol Pending WO2025104624A1 (fr)

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