WO2023199345A1 - Novel solid state forms of voxelotor and their preparation methods thereof - Google Patents

Novel solid state forms of voxelotor and their preparation methods thereof Download PDF

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Publication number
WO2023199345A1
WO2023199345A1 PCT/IN2023/050337 IN2023050337W WO2023199345A1 WO 2023199345 A1 WO2023199345 A1 WO 2023199345A1 IN 2023050337 W IN2023050337 W IN 2023050337W WO 2023199345 A1 WO2023199345 A1 WO 2023199345A1
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Prior art keywords
voxelotor
formula
crystalline form
solvent
mixture
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PCT/IN2023/050337
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French (fr)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Rajeshwar Reddy Sagyam
Mohammad Rafee Shaik
Venkata Narasayya SALADI
Balraju KAMMARI
Srinivas Reddy GIDDALAPATI
Beerappa DODLE
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2023199345A1 publication Critical patent/WO2023199345A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • 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

  • cocrystals can also contain solvent molecules or water to form cocrystal solvates or hydrates. It is further understood that, in common with all other types of crystalline system, cocrystals are capable of existing as different packing arrangements of the same molecular components to give polymorphic forms of a particular cocrystal.
  • the fourth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein designated as crystalline form-S2 and its process.
  • the fifth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein after designated as crystalline form-N and its process.
  • solvent used in the present invention refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents” such as dichloro solvents
  • the first aspect of the first embodiment provides cocrystal of Voxelotor and Polyethylene glycol-6000 (PEG-6000).
  • cocrystal of Voxelotor and polyethylene glycol-6000 is characterized by PXRD pattern as illustrated in Figure 1.
  • the second embodiment of the present invention provides a process for preparation of cocrystal of Voxelotor of Formula- 1 and co-crystal former, comprising: a) providing a solution of Voxelotor of Formula- 1 in methanol; b) adding co-crystal former to the solution obtained in step-a); and c) isolating the cocrystal of Voxelotor of Formula- 1 and co-crystal former.
  • the present invention provides a process for preparation of crystalline form-Sl of Voxelotor, comprising: a) grinding Voxelotor of formula- 1 and oxalic acid or its hydrates, b) adding methanol to the compound obtained in step-a), c) isolating the crystalline form-S 1 of the Voxelotor of Formula- 1.
  • isolation of Crystalline form-Sl of Voxelotor of Formula- 1 in step-c) can be obtained by removing solvent by distillation, concentration.
  • the Crystalline form-Sl of Voxelotor may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze-drying, air-drying, or agitated thin film drying.
  • the amount of oxalic acid or its hydrates is about 0.1 mole equivalents to about 5 mole equivalents with respect to Voxelotor.
  • the fourth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein designated as crystalline form-S2, which is characterized by PXRD pattern as illustrated in Figure 3.
  • the crystalline form-S2 of Voxelotor is characterized by its DSC thermogram having endotherm peak at about 123 °C ⁇ 3 °C and illustrated in Figure 4.
  • the solvent used in step-a) is selected from acetone, n-heptane, diisopropyl ether, methanol, methyl tertiary butyl ether or mixtures thereof; isolation of crystalline form-S2 of Voxelotor in step-b) can be done by cooling the obtained solution to the temperature ranging about 25 °C to -5 °C followed by filtering the precipitated solid or can be done by the removal of solvent by concentrating the solution obtained in step-a).
  • the Crystalline form-S2 of Voxelotor may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze-drying, air-drying, or agitated thin film drying.
  • the crystalline form-S2 of Voxelotor containing Voxelotor and oxalic acid.
  • the amount of oxalic acid or its hydrates is about 0.5 mole equivalents to about 5 mole equivalents with respect to Voxelotor.
  • the crystalline form-S2 of Voxelotor is “co-crystal of Voxelotor and Oxalic acid”.
  • co-crystal consisting of Voxelotor and oxalic acid in a mole ratio of 1:0.1 to 2; preferably 1:0.5 to 1.
  • step-c) can be carried out at temperature ranging between about 25° C to reflux temperature of the solvent used; isolation of the crystalline form-N of Voxelotor of formula- 1 in step-d) can be done by the removal of solvent by concentrating the mixture obtained in step-c).
  • the said crystalline form-N of Voxelotor of formula- 1 containing Voxelotor and L- Arginine.
  • the amount of L-Arginine is about 0.5 mole equivalents to about 5 mole equivalents with respect to Voxelotor.
  • the sixth embodiment of the present invention provides a process for the preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5, comprising of
  • the base in steps-a) and b) is selected from an organic base and inorganic base; solvent in steps a) to b) are as defined above; solvent in step-c) is hydrocarbon solvents, ether solvent, non-polar solvents, polar aprotic solvents and/or mixtures thereof; deprotection followed by reduction in step-c) is carried out in presence of a reducing agent selected but not limited to LiAIH 4 , NaAlH 4 , NaBH 4 , KBH4, mixture of NaBH 4 & acetic acid, mixture of NaBH 4 & trifluoroacetic acid, mixture of NaBH 4 & iodine, mixture of NaBH 4 & trimethylchlorosilane, mixture of NaBH 4 & magnesium chloride, mixture of NaBH 4 & calcium chloride, mixture of NaBH 4 & one of transition metal chlorides, mixture of sodium borohydride BF 3 .
  • a reducing agent selected but not limited to LiAIH 4 , NaAlH 4 , Na
  • the compound of formula-5 is further converted into Voxelotor of formula- 1 by the known processes described in the available literature or the process described in the present application.
  • Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor according to the present application can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC ⁇ High Performance Liquid Chromatography ⁇ .
  • a liquid chromatographic system is to be equipped with variable wavelength UV/V is Detector or PDA Detector and integrator Software; Column: Zorbax SB-Phenyl 3.5 ⁇ m, 4.6 x 100 mm
  • Wavelength 215 nm; Column temperature: 20°C; Injection volume: 5 pF; Elution: Gradient;
  • Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor of formula- 1 produced by the process of the present invention can be further micronized or milled by any known process in the art, to get desired particle size and particle size distribution to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
  • Crystalline form-S2 of Voxelotor obtained according to the present invention has particle size distribution as characterized by 90% particles having particle size (D90) less than about 600 ⁇ m, 50% particles having particle size (D50) less than about 400 ⁇ m and 10% particles having particle size (D10) less than about 100 ⁇ m.
  • Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor of formula- 1 of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
  • the ninth embodiment of the present invention provides a pharmaceutical composition comprising the Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor and at least one pharmaceutically acceptable excipient.
  • compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • suitable pharmaceutically acceptable excipients selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants.
  • Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatin, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glyceryl dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic
  • Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta- cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.
  • Example 3 Preparation of crystalline form-S2 of Voxelotor.
  • Example 4 Preparation of crystalline form-S2 of Voxelotor.
  • Di isopropyl ethylamine (251.66 ml) was added to the solution of 2-ethyl-5-hydroxy-2- methyl-4H-benzo[d][1,3]dioxin-4-one (100 g) in acetone at 25-30°C.
  • Chloro (methoxy) methane (251.66 ml) slowly added to the above reaction mixture and stirred at 25-30°C. Cooled the reaction mixture to 5-10°C.
  • Water (1000 ml) was added to the reaction mixture at 5-10°C and stirred at the same temperature. Filtered the precipitated solid washed with water and dried to get the title compound.
  • Aqueous layer extracted with dichloro methane Distilled of the solvent completely from the organic layer under reduced pressure and co-distilled with toluene.
  • 500 ml of Mixture of toluene and n-heptane was added to the obtained compound and stirred the mixture at 50-60°C. Cooled to the mixture 0-10°C and stirred at same temperature. Filtered the solid, washed with mixture of n-heptane and toluene, dried to get the title compound.
  • Potassium carbonate (384.48) was added to above solution at 5- 15 °C and followed by added the solution of 2-hydroxy-6- (methoxymethoxy) benzaldehyde (107.85 g) in dimethyl formamide (300 ml) at the same temperature. Heated the reaction mixture temperature to 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C and water was added to the above mixture at 25-30°C and stirred. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water, then filtered the solid, washed with water and dried to get the title compound.
  • Aqueous sodium carbonate solution was added to the above mixture and stirred. Separated the both layers. Aqueous layer extracted with dichloro methane, combined the organic layers and followed by treated with activated carbon. Filtered the mixture through hyflow bed washed with dichloro methane. Distilled of the solvent under reduced pressure and co-distilled with methanol. The obtained compound was recrystallized from methanol. Further recrystallized in the mixture of tetrahydrofuran and methyltertiary butyl ether and dried to get pure title compound.
  • Example 13 Preparation of 2-hydroxy-6-((2-(l-isopropyl-l-H-pyrazol-5-yl) pyridine-3- yl)methoxy)benzaldehyde hemi oxalic acid ⁇ Crystalline form-S2 of Voxelotor ⁇ 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridine-3-yl)methoxy)-6-(methoxymethoxy) benzaldehyde (50.0 g) was added to pre-cooled mixture of methanol (125 ml) and water (125 ml) at 18-22°C.
  • Methyltertiary butyl ether was added to the obtained compound, heated to 45-55°C and stirred at the same temperature. The mixture was cooled to 25-35°C, further cooled to 0-10°C and stirred at the same temperature. Filtered the solid, washed with methyltertiary butyl ether. Repeated the same purification process and dried to get the title compound.

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Abstract

The present invention relates to novel solid-state forms of Voxelotor of formula-1 and their preparation methods thereof. The Voxelotor of formula-1 is represented by the following structural formula. The present invention also related to an improved process for the preparation of the 2- hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5 which is a key intermediate of Voxelotor of formula-1.

Description

Novel solid state forms of Voxelotor and their preparation methods thereof
Related Application:
This application claims the benefit of priority to our Indian patent application number 202241022403 filed on Apr 14, 2022 the disclosures of all that are incorporated by reference in their entirety.
Field of the invention:
The present invention relates to novel crystalline forms of 2-hydroxy-6-((2-(l- isopropyl-lH-pyrazol-5-yl) pyridine-3-yl)methoxy)benzaldehyde of formula- 1 is represented by the following structural formula.
Figure imgf000002_0001
Formula- 1
The present invention also related to an improved process for the preparation of the 2- hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5 which is a key intermediate of Voxelotor of formula- 1.
Background of the invention:
2-Hydroxy-6-((2-( 1 -isopropyl- 1 H-pyrazol-5-yl )pyridin-3-yl )methoxy)benzaldehyde of formula (I) is commonly known as “Voxelotor” and it is a hemoglobin S polymerization inhibitor, indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older. Voxelotor is approved by United States Federal Drug Administration (USFDA) on Nov 25, 2019 to Global Blood Therapeutics Inc under the brand name OXBRYTA™. USFDA approved Voxelotor on December 2021 for the treatment of sickle cell disease for those aged between four to eleven years. It is available in 500mg oral tablet and 300mg oral tablet and tablet for suspension. Recommended dosage for sickle cell disease is 1500 mg and for hepatic impairment patients with severe hepatic impairment (Child Pugh C) is 1000 mg taken orally once daily with or without food.
US 9018210 B2 patent describes the Voxelotor and process for the preparation. Further it discloses the purification of Voxelotor by silicagel column chromatography eluting with using ethyl acetate and hexane.
US 9447071 B2 patent describes the crystalline ansolvate Form-I, Form- II, Material N of Voxelotor, crystalline solvate forms such as Material E, Material F, Material G, Material H, Material J, Material K, Material L, Material M, Material O and Material P of Voxelotor of formula- 1 and process for its preparation thereof.
US 10077249 B2, WO 2020/127924, WO/2020/128945, and Metcalf, B. et al. ACS Med. Chem. Lett. 2017, 8, 321-326 describe the certain process for the preparation of Voxelotor and intermediates for making it.
It is described in USFDA chemical reviews that Voxelotor belongs to BCS class-II drug which means low solubility drug.
The physicochemical properties endowed by the solid-state structure is a critical parameter in the development of solid dosage forms of pharmaceuticals as these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient.
Crystalline solid forms of a drug is a necessary stage for many orally available drugs. Suitable solid forms possess the desired properties of a particular drug. Such suitable forms often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself or may be used as a drug product intermediate during the preparation of the drug. For example, new drug formulations comprising crystalline forms of a given drug may have superior properties, such as solubility, dissolution and storage stability over existing formulations of the drug.
It is known that a solid active pharmaceutical ingredient can potentially exist in both amorphous and crystalline forms. It is further known that for a crystalline solid, various polymorphs and solvates are possible. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, solubilities, stabilities, hygroscopicity and different mechanical properties such as filterability and flowability. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties.
On the other hand, the formation of pharmaceutically acceptable cocrystals of active pharmaceutical ingredients provides an alternative approach to the generation of new solid forms of the active substance. In this context a cocrystal, or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state.
A pharmaceutical co-crystal is a crystalline single-phase material containing a stoichiometric ratio of two or more molecules, where at least one of the co-formers is drug molecule.
In this case, the terms "cocrystal" and "co-crystal" are generally understood to be synonymous terms referring to such a system.
The second component in the cocrystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a "cocrystal former or co-former". Pharmaceutically acceptable cocrystal formers include any molecule considered acceptable as a counter ion for a pharmaceutical salt or known as a pharmaceutical excipient.
A widely accepted definition of a pharmaceutical cocrystal is a crystalline system containing an active pharmaceutical molecule and a cocrystal former that is a solid at ambient temperature and pressure in a defined stoichiometric ratio, although a cocrystal is not limited to containing only two components. The components of the cocrystal are linked by hydrogen bonding and other non-covalent and non-ionic interactions. This definition differentiates co crystals from crystalline solvates, in which case one of the components is a liquid at ambient temperature and pressure.
It is also understood that, in general, with single -component crystalline systems and salts, cocrystals can also contain solvent molecules or water to form cocrystal solvates or hydrates. It is further understood that, in common with all other types of crystalline system, cocrystals are capable of existing as different packing arrangements of the same molecular components to give polymorphic forms of a particular cocrystal.
The inventors of the present application have surprisingly found the cocrystal of Voxelotor after significant efforts and novel crystalline forms. The cocrystal of Voxelotor of formula- 1 and novel crystalline forms obtained according to the present invention are useful for the preparation of various pharmaceutical compositions.
Brief description of the invention:
The first embodiment of the present invention provides the cocrystal of Voxelotor of formula- 1 and co-crystal former.
The second embodiment of the present invention provides a process for the preparation of cocrystal of Voxelotor and co-crystal former.
The third embodiment of the present invention provides the novel crystalline form of Voxelotor, herein designated as crystalline form-Sl and its process.
The fourth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein designated as crystalline form-S2 and its process.
The fifth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein after designated as crystalline form-N and its process.
The sixth embodiment of the present invention provides an improved process for the preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5.
Brief description of the drawings:
Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of co-crystal of Voxelotor and PEG-6000.
Figure 2: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-Sl of Voxelotor.
Figure 3: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-S2 of Voxelotor. Figure 4: Illustrates the DSC thermogram of crystalline form-S2 of Voxelotor.
Figure 5: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-N of Voxelotor.
Detailed description of the invention:
The various embodiments in the present invention will be described in detail with reference to the accompanying drawings. References made to particular examples and implementations are for illustrative purpose and are not intended to limit the scope of the invention or the claims.
The term "solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert- butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-l-ol, 2- butanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
The term “base” used in the present invention refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and like and “organic bases” selected from but not limited to methyl amine, ethyl amine, diisopropylamine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n-methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5 -diazabicycle [4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal amides”such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; or mixtures thereof.
The “room temperature” used in the present invention is the temperature about 25 °C- 35°C.
The first embodiment of the present invention provides cocrystal of Voxelotor of formula- 1 and co-crystal former.
The first aspect of the first embodiment provides cocrystal of Voxelotor and Polyethylene glycol-6000 (PEG-6000).
Further the cocrystal of Voxelotor and polyethylene glycol-6000 is characterized by PXRD pattern as illustrated in Figure 1.
The second embodiment of the present invention provides a process for preparation of cocrystal of Voxelotor of Formula- 1 and co-crystal former, comprising: a) providing a solution of Voxelotor of Formula- 1 in methanol; b) adding co-crystal former to the solution obtained in step-a); and c) isolating the cocrystal of Voxelotor of Formula- 1 and co-crystal former.
Wherein the co-crystal former used in step-b) is polyethylene glycol-6000 (PEG-6000); a solution of Voxelotor of formula- 1 in step-a) can be prepared by dissolving Voxelotor in a solvent at any suitable temperature such as about 25° C to about reflux temperature of the solvent used; the co-crystal former in step-b) can be added to the solution obtained in step-a) at a temperature ranging about 25° C to about reflux temperature; isolation of cocrystal of Voxelotor of Formula- 1 and co-crystal in step-c) can be obtained by removing solvent by any techniques, such as decantation, filtration by gravity or suction, distillation, chromatography, concentration, crystallization, recrystallization, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, to reduce the amount of entrained impurities or can be isolated by filtration of the slurry containing precipitated product. The Co-Crystal of Voxelotor and a co-crystal former may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze-drying, air-drying, or agitated thin film drying.
The first aspect of second embodiment provides the amount of co-crystal former and Voxelotor of formula- 1 is about 0.5 to 5: 1.
The third embodiment of the present invention provides novel crystalline form of Voxelotor of formula- 1, herein designated as crystalline form-Sl, which is characterized by PXRD pattern as illustrated in Figure 2.
In the first aspect of the third embodiment, the present invention provides a process for preparation of crystalline form-Sl of Voxelotor, comprising: a) grinding Voxelotor of formula- 1 and oxalic acid or its hydrates, b) adding methanol to the compound obtained in step-a), c) isolating the crystalline form-S 1 of the Voxelotor of Formula- 1.
Wherein, isolation of Crystalline form-Sl of Voxelotor of Formula- 1 in step-c) can be obtained by removing solvent by distillation, concentration. The Crystalline form-Sl of Voxelotor may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze-drying, air-drying, or agitated thin film drying.
In the second aspect of the third embodiment the crystalline form-S 1 of Voxelotor of formula- 1 containing Voxelotor and oxalic acid.
The third aspect of third embodiment, the amount of oxalic acid or its hydrates is about 0.1 mole equivalents to about 5 mole equivalents with respect to Voxelotor. The fourth embodiment of the present invention provides the novel crystalline form of Voxelotor, herein designated as crystalline form-S2, which is characterized by PXRD pattern as illustrated in Figure 3.
In the first aspect of the fourth embodiment, the crystalline form-S2 of Voxelotor is characterized by PXRD {Powder X-Ray Diffraction} pattern having peaks at about 9.1°, 17.6° and 18.3° ± 0.2° 2θ.
In the second aspect of the fourth embodiment, the crystalline form-S2 of Voxelotor is characterized by its DSC thermogram having endotherm peak at about 123 °C ± 3 °C and illustrated in Figure 4.
In the third aspect of the fourth embodiment, the present invention provides a process for preparation of crystalline form-S2 of Voxelotor, comprising: a) providing a solution of Voxelotor and oxalic acid or its hydrates in a solvent or mixture of solvents, b) isolating crystalline form-S2 of the Voxelotor.
Wherein providing the solution in step-a) can be done by dissolving Voxelotor and oxalic acid or its hydrates in a solvent at temperature ranging from about 25° C to reflux temperature of the solvent used {or} by dissolving Voxelotor and oxalic acid or its hydrates separately in a solvent at a temperature ranging from about 25° C to reflux temperature of the solvent used followed by combining both {or} the solution which is obtained by adding oxalic acid or its hydrates to a solution of Voxelotor in a solvent or a mixture of solvents, which is obtained during the course of its synthesis.
In the fourth aspect of the fourth embodiment, the solvent used in step-a) is selected from acetone, n-heptane, diisopropyl ether, methanol, methyl tertiary butyl ether or mixtures thereof; isolation of crystalline form-S2 of Voxelotor in step-b) can be done by cooling the obtained solution to the temperature ranging about 25 °C to -5 °C followed by filtering the precipitated solid or can be done by the removal of solvent by concentrating the solution obtained in step-a).
In the fifth aspect of the fourth embodiment, the Crystalline form-S2 of Voxelotor may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze-drying, air-drying, or agitated thin film drying.
In the sixth aspect of the fourth embodiment the crystalline form-S2 of Voxelotor containing Voxelotor and oxalic acid.
In the seventh aspect of fourth embodiment, the amount of oxalic acid or its hydrates is about 0.5 mole equivalents to about 5 mole equivalents with respect to Voxelotor.
In the eighth aspect of fourth embodiment, the crystalline form-S2 of Voxelotor is “co-crystal of Voxelotor and Oxalic acid”. In the above said co-crystal consisting of Voxelotor and oxalic acid in a mole ratio of 1:0.1 to 2; preferably 1:0.5 to 1.
In the ninth aspect of the fourth embodiment, oxalic acid or its hydrates can be optionally purified in solvent or a solvent mixture.
In a preferred aspect, the structural formula of crystalline form-S2 of Voxelotor is as shown below:
Figure imgf000010_0001
Formula- la
Tenth aspect of fourth embodiment, Crystalline form-S2 of Voxelotor is stable which is suitable for pharmaceutical preparations with having greater stability.
The term “stable” includes Crystalline form-S2 of Voxelotor that does not convert to any other solid form when stored at a temperature of up to about 40° C and at a relative humidity of about 25% to about 75% for about six months or more and also stable in chemical purity having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC{High Performance Liquid Chromatography}. Eleventh aspect of the fourth embodiment, the accelerated and long-term stability data of Crystalline form-S2 of Voxelotor is outlined in below Table as follows:
Figure imgf000011_0001
The fifth embodiment of the present invention provides novel crystalline form of Voxelotor of formula- 1, herein designated as crystalline form-N, which is characterized by PXRD pattern as illustrated in Figure 5.
In the first aspect of the fifth embodiment, the present invention provides a process for preparation of crystalline form-N of Voxelotor, comprising: a) grinding Voxelotor of formula- 1 and L- Arginine, b) adding methanol to the obtained mixture followed by grinding, c) dissolving the obtained compound in the mixture methanol and water, d) isolating the crystalline form-N of Voxelotor of formula- 1.
Wherein dissolution in step-c) can be carried out at temperature ranging between about 25° C to reflux temperature of the solvent used; isolation of the crystalline form-N of Voxelotor of formula- 1 in step-d) can be done by the removal of solvent by concentrating the mixture obtained in step-c). In the second aspect of the fifth embodiment the said crystalline form-N of Voxelotor of formula- 1 containing Voxelotor and L- Arginine.
The third aspect of fifth embodiment, the amount of L-Arginine is about 0.5 mole equivalents to about 5 mole equivalents with respect to Voxelotor.
Voxelotor used in the preparation of polymorphic forms of the present invention is prepared by any of the processes disclosed in literature such as US 9018210 B2, US 9447071 B2 or any other relevant references or of the process described in the present invention.
The sixth embodiment of the present invention provides a process for the preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5, comprising of
Figure imgf000012_0001
Formula-5 a) reacting the 2,6-dihydroxybenzoic acid of formula-2 with methyl ethyl ketone in presence of a base in a solvent to provide 2-ethyl-5-hydroxy-2-methyl-4H-benzo[d][ 1 ,3]diox in-d- one of formula-3,
Figure imgf000012_0002
Formula-2 Formula-3 b) reacting the compound of formula-3 with Methoxymethyl chloride {MOM-CI} in presence of a base in a solvent to provide 2-ethyl-5-(methoxymethoxy)-2-methyl-4H- benzo[<7][l,3]dioxin-4-one of formula-4,
Figure imgf000012_0003
Formula-4 c) deprotection followed by reduction of the compound of formula-4 to provide the compound of formula-5.
In the first aspect of the sixth embodiment, wherein the base in steps-a) and b) is selected from an organic base and inorganic base; solvent in steps a) to b) are as defined above; solvent in step-c) is hydrocarbon solvents, ether solvent, non-polar solvents, polar aprotic solvents and/or mixtures thereof; deprotection followed by reduction in step-c) is carried out in presence of a reducing agent selected but not limited to LiAIH4, NaAlH4, NaBH4, KBH4, mixture of NaBH4 & acetic acid, mixture of NaBH4 & trifluoroacetic acid, mixture of NaBH4 & iodine, mixture of NaBH4 & trimethylchlorosilane, mixture of NaBH4 & magnesium chloride, mixture of NaBH4 & calcium chloride, mixture of NaBH4 & one of transition metal chlorides, mixture of sodium borohydride BF3. etherate, sodium cyanoborohydride, sodium triacetoxy borohydride, Aluminium hydride (AIH3), diisobutylaluminium hydride (DIBAL), Vitride {=Sodium bis(2-methoxyethoxy) aluminum hydride}, Lithium Tri-tert-butoxyaluminum Hydride, Tributyltin Hydride; boranes such as not limited to BH3-tetrahydrofuran, BH3-dimethyl sulfide.
In the second aspect of the sixth embodiment of the present invention, the compound of formula-5 is further converted into Voxelotor of formula- 1 by the known processes described in the available literature or the process described in the present application.
The seventh embodiment of the present invention provides novel intermediate compounds of formula-3 and formula-4.
Figure imgf000013_0001
Formula-3 Formula-4
In an aspect of the seventh embodiment, the compound of formula-3 and formula-4 used in the preparation of Voxelotor of formula- 1. Schematic representation for the synthesis of Voxelotor:
Figure imgf000014_0001
Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor of formula- 1 produced according to the present invention is having purity of greater than about 99%, preferably greater than about 99.5%, more preferably greater than about 99.7%, most preferably greater than about 99.8% by HPLC {High Performance Liquid Chromatography } .
Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor according to the present application can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC {High Performance Liquid Chromatography}.
The following impurities are observed during the synthesis of the compound of formula- 1 or formula- la as per the present invention. Along with these impurities, the starting materials are well controlled as per ICH guidelines in the compound of formula- 1 or formula- 1 a.
Figure imgf000015_0001
HPLC Method of Analysis:
Voxelotor and its related substances were analyzed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV/V is Detector or PDA Detector and integrator Software; Column: Zorbax SB-Phenyl 3.5μm, 4.6 x 100 mm
Wavelength: 215 nm; Column temperature: 20°C; Injection volume: 5 pF; Elution: Gradient;
Diluent: Acetonitrile: Buffer; Needle wash: Methanol.
Buffer preparation:
(i) Accurately transfer 2000 ml of milli-Q-water into a suitable cleaned and dry beaker,
(ii) Weigh accurately about 5.52g of Sodium dihydrogen phosphate monohydrate and transfer it into above beaker and mix well,
(iii) Adjust pH of the above solution to 4.2±0.05 with 1 % Orthophosphoric acid solution,
(iv) Filter the above solution through 0.22 μm PVDF filter paper. Mobile phase-A:- Buffer: Methanol; Mobile phase-B:- Acetonitrile:Buffer:Methanol
Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor of formula- 1 produced by the process of the present invention can be further micronized or milled by any known process in the art, to get desired particle size and particle size distribution to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
In general, Crystalline form-S2 of Voxelotor obtained according to the present invention has particle size distribution as characterized by 90% particles having particle size (D90) less than about 600 μm, 50% particles having particle size (D50) less than about 400 μm and 10% particles having particle size (D10) less than about 100 μm.
Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor of formula- 1 of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition in particular polymorphic form mentioned.
The eighth embodiment of the present invention provides the use of Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor for the preparation of various pharmaceutical formulations.
The ninth embodiment of the present invention provides a pharmaceutical composition comprising the Cocrystal of Voxelotor and PEG-6000, Crystalline form-Sl, form-S2 and form-N of Voxelotor and at least one pharmaceutically acceptable excipient.
As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Wherein, suitable pharmaceutically acceptable excipients selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatin, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glyceryl dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta- cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.
P-XRD Method of Analysis:
The PXRD analysis of compound of formula- 1 of the present invention was carried out by using BRUKER/D8 ADVANCE or BRUKER/D2 PHASER diffractometer using CuKα radiation of wavelength 1.5406Aº. The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be considered as limitation of the scope of the invention.
Examples:
Example 1: Preparation of Cocrystal of Voxelotor and PEG-6000.
Dissolved Voxelotor (500 mg) in methanol (10 ml) at 60°C. PEG-6000 (500 mg) was added to the obtained solution at 60°C and concentrated the solution to get the title compound. Yield: 920 mg. PXRD of the obtained compound is illustrated in figure- 1.
Example 2: Preparation of Crystalline form-Sl of Voxelotor.
In a mortar, Voxelotor (200 mg) and oxalic acid dihydrate (74 mg) ground together. To the obtained mixture, methanol (0.1 ml) was added dropwise and continued grind. Collected the obtained solid and dried to get the title compound.
Yield: 180 mg. PXRD of the obtained compound is illustrated in figure-2.
Example 3: Preparation of crystalline form-S2 of Voxelotor.
Dissolved Voxelotor (2 g) in diisopropyl ether (70 ml) at 30°C. Dissolved oxalic acid dihydrate (747 mg) in diisopropyl ether (30 ml) at 60°C. The obtained oxalic acid solution was added into the solution of Voxelotor in diisopropyl ether at 30°C and cooled to 3 °C. Stirred the mixture, filtered the precipitated solid and dried to get the title compound.
Yield: 1.8 g. PXRD of the obtained compound is illustrated in figure-3.
Example 4: Preparation of crystalline form-S2 of Voxelotor.
Dissolved Voxelotor (1 g) and oxalic acid dihydrate (373 mg) in acetone (5 ml) at 30°C. The obtained solution was cooled to 0°C and stirred. Filtered the precipitated solid and dried to get the title compound.
Yield: 900 mg. PXRD of the obtained compound is similar to the figure-3. Example 5: Preparation of crystalline form-N of Voxelotor.
In a mortar, Voxelotor (200 mg) and L- Arginine (206 mg) ground together. Methanol (0.2 ml) was added dropwise to the obtained mixture and ground for 5 min. Dissolved 300 mg of the compound from the obtained compound in 1: 1 mixture of methanol and water at 60°C. Concentrated the resulted solution, collected the solid and dried the obtained solid to get the title compound.
PXRD of the obtained compound is illustrated in figure-5.
Example 6: Preparation of 2-ethyl-5-hydroxy-2-methyl-4H-benzo[d][l,3]dioxin-4-one of formula-4
Trifloro acetic anhydride (272 g) was added to the mixture of 2,6-dihydroxybenzoic acid (100 g) and trifluoro acetic acid (500 ml) at 25-30°C. Methyl ethyl ketone (581 ml) was slowly added to the mixture at 25-30°C. Heated the reaction mixture to 70-80°C and stirred. The reaction mixture cooled to 45±5°C. Distilled off the reaction mixture under reduced pressure. Cyclohexane was added to the obtained compound at 25-30°C. Aqueous sodium carbonate solution was added to the mixture at 25-30°C and stirred. Organic and aqueous layers were separated. Aqueous layer extracted with cyclohexene. Combined the organic layers and distilled of the solvent under reduced pressure. (600 ml) Mixture of isopropyl alcohol and water was added to the obtained compound at 40-45°C. Further heated the mixture to 55±5°C and stirred. The mixture was cooled to 25-30°C, further cooled to 10±5°C and stirred at the same temperature. Filtered the precipitated solid washed with water and dried to get the title compound.
Yield: 107 g.
Example 7: Preparation of 2-ethyl-5-(methoxymethoxy)-2-methyl-4H-benzo[d][l,3] dioxin-4-one of formula-4
Di isopropyl ethylamine (251.66 ml) was added to the solution of 2-ethyl-5-hydroxy-2- methyl-4H-benzo[d][1,3]dioxin-4-one (100 g) in acetone at 25-30°C. Chloro (methoxy) methane (251.66 ml) slowly added to the above reaction mixture and stirred at 25-30°C. Cooled the reaction mixture to 5-10°C. Water (1000 ml) was added to the reaction mixture at 5-10°C and stirred at the same temperature. Filtered the precipitated solid washed with water and dried to get the title compound.
Yield: 97.0 g.
Example 8: Preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde
DiBAL-H (450 ml (25% in toluene)) was slowly added to the pre cooled solution of 2-ethyl- 5-(methoxymethoxy)-2-methyl-4H-benzo[d][l,3]dioxin-4-one (100 g) in Toluene (500 ml) at -65±5°C and stirred at the same temperature. The reaction mixture was quenched into pre- cooled aqueous tartaric acid solution at 5±5°C. The pH of the reaction mixture was adjusted with aqueous hydrochloric acid solution at 5±5°C. Raised the temperature of the mixture 25- 30°C. Filtered the mixture through hyflow bed and washed the hyflow bed with toluene. Organic and aqueous layers were separated from the filtrate. Aqueous layer extracted with toluene at 25-30°C. Combined the organic layers and washed with aqueous sodium bicarbonate solution. Distilled off the solvent completely under reduced pressure and co- distilled with isopropyl alcohol. The obtained compound isolated and recrystallized from the mixture of isopropanol and water to get the pure title compound.
Yield: 55 g.
Example 9: Preparation of (2-chloropyridin-3-yl) methanol of formula-8
Thionyl chloride (115.84 ml) was slowly added to the mixture of 2-chloronicotinic acid (100 g), toluene (500 ml) and dimethyl formamide (5 ml) at 25-35°C under nitrogen atmosphere. Heated the reaction mixture to 65 -75 °C and stirred at the same temperature. Reaction mixture cooled to 25-30°C. Methanol (150 ml) was added to the reaction mixture at 25-35°C and stirred same temperature at 25-35°C. The mixture was cooled to 5-15°C and pH of the mixture was adjusted with aqueous sodium carbonate solution. Organic and aqueous layers were separated and aqueous layer extracted with toluene. Combined the organic layers. Distilled of the solvent under reduced pressure. 400 ml of mixture of methanol and water was added to the obtained compound at 25-30°C. The mixture was cooled to 0 to 10°C. Sodium borohydrate (47 g) was added in lot-wise to reaction mixture at 0 to 10°C and stirred at same temperature. The reaction mixture was quenched with an aqueous hydrochloric acid solution at 0-10°C and stirred. Basified the mixture using aqueous sodium carbonate solution. Water was added to the mixture at 25-30°C and stirred at same temperature. Filtered the mixture through hyflow bed and washed the hyflow bed with dichloro methane. Dichloro methane was added to the filtrate at 25-30°C. Layers were separated. Aqueous layer extracted with dichloro methane. Distilled of the solvent completely from the organic layer under reduced pressure and co-distilled with toluene. 500 ml of Mixture of toluene and n-heptane was added to the obtained compound and stirred the mixture at 50-60°C. Cooled to the mixture 0-10°C and stirred at same temperature. Filtered the solid, washed with mixture of n-heptane and toluene, dried to get the title compound.
Yield: 70 g.
Example 10: Preparation of 2-((2-chloropyridin-3-yl)methoxy)-6-(methoxymethoxy) benzaldehyde
Thionyl chloride (76.26 ml) was slowly added to the mixture of (2-chloropyridin-3-yl) methanol (100 g), toluene (500 ml) and dimethyl formamide (5 ml) at 25-35°C. Reaction mixture was heated to 65-75°C and stirred at the same temperature. After completion of the reaction, reaction mixture was cooled to 55±5°C and distilled of the solvent under reduced pressure and then co-distilled with toluene. Dimethyl formamide (300 ml) was slowly added to obtained compound at 25-30°C, further cooled to 5-15°C. Potassium carbonate (384.48) was added to above solution at 5- 15 °C and followed by added the solution of 2-hydroxy-6- (methoxymethoxy) benzaldehyde (107.85 g) in dimethyl formamide (300 ml) at the same temperature. Heated the reaction mixture temperature to 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C and water was added to the above mixture at 25-30°C and stirred. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water, then filtered the solid, washed with water and dried to get the title compound.
Yield: 180 g.
Example 11: Preparation of 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridine-3-yl)methoxy)- 6-(methoxymethoxy)benzoldehyde
Carbon treatment was given to the solution of 2-((2-chloropyridin-3-yl)methoxy)-6-(methoxy methoxy)benzaldehyde (25 g) in dimethylacetamide (175 ml) at 25-30°C. l-isopropyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (23.0 g) and dimethylamino pyridine (1.0 g) was added to the obtained filtrate at 25-30°C. Degassing the reaction mixture at 25-35°C, heated the mixture to 45-55°C under nitrogen atmosphere and stirred. Followed by degassing the aqueous potassium carbonate solution at 45-55 °C. The reaction mixture was cooled to 40°C under nitrogen atmosphere. This solution was added to the above reaction mixture under nitrogen degassing condition. Pd(PPh3)4 (5 g) was added to the mixture at 25- 35°C, further heated the mixture to 45-55°C and removed degassing condition. Further heated the mixture to 80-90°C and stirred. Cooled the reaction mixture 25-35°C and water was added. Further cooled to the mixture to 5- 15 °C and stirred. Filtered the precipitated solid washed with water. The obtained compound was dissolved in dichloromethane, added an aqueous N-acetyl-L-cysteine solution and stirred. Aqueous sodium carbonate solution was added to the above mixture and stirred. Separated the both layers. Aqueous layer extracted with dichloro methane, combined the organic layers and followed by treated with activated carbon. Filtered the mixture through hyflow bed washed with dichloro methane. Distilled of the solvent under reduced pressure and co-distilled with methanol. The obtained compound was recrystallized from methanol. Further recrystallized in the mixture of tetrahydrofuran and methyltertiary butyl ether and dried to get pure title compound.
Yield: 21.0 g.
Example 12: Purification of Oxalic acid
Dissolved Oxalic acid (100 g) in methyltertiary butyl ether (1100 ml) at 50-60°C. Cooled the solution to 0-10°C and stirred at same temperature. Filtered the precipitated solid washed with methyltertiary butyl ether and dried to get pure title compound.
Yield: 71 g.
Example 13: Preparation of 2-hydroxy-6-((2-(l-isopropyl-l-H-pyrazol-5-yl) pyridine-3- yl)methoxy)benzaldehyde hemi oxalic acid {Crystalline form-S2 of Voxelotor} 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridine-3-yl)methoxy)-6-(methoxymethoxy) benzaldehyde (50.0 g) was added to pre-cooled mixture of methanol (125 ml) and water (125 ml) at 18-22°C. Slowly added hydrochloric acid (46.52 ml) to the above mixture at 18-22°C and stirred at same temperature. Methyltertiary butyl ether was added to the above reaction mixture. Reaction mixture pH adjusted with aqueous sodium carbonate solution at 5-15°C. Raised the temperature of the mixture to 25-30°C, organic layer and aqueous layers were separated. Aqueous layer extracted with methyltertiary butyl ether. Combined the organic layers, Oxalic acid (16.5 g) was added to it at 25-30°C. Heated the mixture to 40-50°C and stirred at same temperature. Filtered the solution, washed with methyltertiary butyl ether and distilled off the solvent under reduced pressure. Methyltertiary butyl ether was added to the obtained compound, heated to 45-55°C and stirred at the same temperature. The mixture was cooled to 25-35°C, further cooled to 0-10°C and stirred at the same temperature. Filtered the solid, washed with methyltertiary butyl ether. Repeated the same purification process and dried to get the title compound.
Yield: 42.0 g. PXRD of the obtained compound is similar to the figure-3. DSC thermogram of the obtained compound is illustrated in figure-4.
Example 14: Preparation of Crystalline form-I of Voxelotor
Water (150 ml) was added to the mixture of Voxelotor (30.0 g) and ethyl acetate (300 ml) and at 25-30°C. Organic layer and aqueous layers were separated. Aqueous layer extracted with ethyl acetate. Combined the organic layers and washed with water. Total organic layer filtered the hyflow bed and washed with ethyl acetate. Distilled off the solvent under reduced pressure and co-distilled with n-heptane. n-Heptane was added to the obtained compound at 20-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n- heptane and dried to get pure title compound.
Yield: 27.0 g.
Example 15: Preparation of Crystalline form-II of Voxelotor
Water (125 ml) was added to the mixture of Voxelotor (25.0 g) and ethyl acetate (125 ml) 2and at 25-30°C. Organic layer and aqueous layers were separated. Aqueous layer extracted with Ethyl acetate. Combined the organic layers and washed with water. Treated the organic layer with activated carbon. Filtered the mixture through hyflow bed washed with ethyl acetate. Distilled off the solvent under reduced pressure and co-distilled with n-heptane. n- Heptane was added to the obtained compound at 20-30°C and stirred for 35 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get pure title compound. Yield: 22.0 g.
Example-16: Preparation of Voxelotor
Hydrochloric acid (135 ml) was slowly added to the mixture of 2-((2-( 1 -isopropyl- 1H- pyrazol-5-yl)pyridine-3-yl)methoxy)-6-(methoxymethoxy)benzoldehyde (130.0 g) and water (675 ml) at 25-30°C and stirred the reaction mixture. Reaction mixture was cooled to 5-10°C. Ethyl acetate was added to the mixture and reaction pH adjusted with aqueous sodium carbonate solution at 5-10°C. Raised the reaction mixture temperature to 20-30°C, organic layer and aqueous layers were separated. Aqueous layer extracted with ethyl acetate. Combined the organic layers and treated with activated carbon. Filtered the mixture through hyflow bed washed with ethyl acetate. Distilled off the solvent under reduced pressure and co-distilled with ethanol. Ethanol was added to the obtained compound at 45-50°C. Mixture was cooled to 5-15°C and stirred same temperature. Filtered the solid, washed with ethanol and dried to get pure title compound.
Yield: 118.4 g.

Claims

Claims:
1. A crystalline form of Voxelotor which having the following structural formula with oxalic acid
Figure imgf000025_0001
is characterized by its Powder X-Ray diffractogram having peaks at about 9.1°, 17.6° and 18.3° ± 0.2° 2θ.
2. The crystalline form of claim 1 is further characterized by its PXRD pattern is illustrated in figure-3.
3. The crystalline form of claim 1 is further characterized by its DSC thermogram is illustrated in figure-4.
4. The crystalline form of claim 1 consisting of Voxelotor and oxalic acid in a mole ratio about 1 :0.1 to 1.
5. The process for preparation of crystalline form of claim 1, comprising: a) providing a solution of Voxelotor and oxalic acid or its hydrates in a solvent or mixture of solvents, b) isolating the crystalline form of claim 1.
6. The process according to claim 5, wherein the solvent used in step-a) is selected from acetone, n-heptane, diisopropyl ether, methanol, methyl tertiary butyl ether or mixtures thereof.
7. The process according to claim 5, wherein isolation of crystalline form in step-b) is done by the removal of solvent from the solution obtained in step-a). The process according to claim 5, wherein isolation of crystalline form in step-b) is done by cooling the obtained solution to a temperature ranging from about 25°C to -5°C followed by filtering the precipitated solid. A process for the preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5, comprising:
Figure imgf000026_0001
a) reacting the 2,6-dihydroxybenzoic acid of formula-2 with methyl ethyl ketone in presence of a base in a solvent to provide 2-ethyl-5-hydroxy-2-methyl-4H - benzo[d][l,3]dioxin-4-one of formula-3,
Figure imgf000026_0002
b) reacting the compound of formula-3 with Methoxymethyl chloride {M0M-C1} in presence of a base in a solvent to provide 2-ethyl-5-(methoxymethoxy)-2-methyl-4H - benzo[ ][l,3]dioxin-4-one of formula-4,
Figure imgf000026_0003
c) deprotection followed by reduction of the compound of formula-4 with a reducing agent in a solvent to provide the compound of formula-5. The process according to claim 10, 2-hydroxy-6-(methoxymethoxy)benzaldehyde of formula-5 is further converted into Voxelotor and its solvates or co-crystals. A pharmaceutical composition comprising Crystalline form of claim 1 and one or more pharmaceutically acceptable excipients. A method of treating a mammal by administering a therapeutically effective amount of Crystalline form of claim 1 for the treating sickle cell disease in adults and pediatric patients 12 years of age and older.
Figure imgf000027_0001
PCT/IN2023/050337 2022-04-14 2023-04-06 Novel solid state forms of voxelotor and their preparation methods thereof WO2023199345A1 (en)

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WO2015031285A1 (en) * 2013-08-27 2015-03-05 Global Blood Therapeutics, Inc. Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts
WO2015120133A1 (en) * 2014-02-07 2015-08-13 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2020127945A1 (en) * 2018-12-21 2020-06-25 Bionice, S.L.U. Process and intermediates for the synthesis of voxelotor
WO2020127924A1 (en) * 2018-12-21 2020-06-25 Bionice, S.L.U. Process and intermediates for the preparation of voxelotor
EP3693364A1 (en) * 2019-02-11 2020-08-12 Sandoz Ag Crystalline salts of a hemoglobin s allosteric modulator
WO2021170977A1 (en) * 2020-02-24 2021-09-02 Johnson Matthey Public Limited Company Crystalline forms of voxelotor, and processes for the preparation thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015031285A1 (en) * 2013-08-27 2015-03-05 Global Blood Therapeutics, Inc. Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts
WO2015120133A1 (en) * 2014-02-07 2015-08-13 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2020127945A1 (en) * 2018-12-21 2020-06-25 Bionice, S.L.U. Process and intermediates for the synthesis of voxelotor
WO2020127924A1 (en) * 2018-12-21 2020-06-25 Bionice, S.L.U. Process and intermediates for the preparation of voxelotor
EP3693364A1 (en) * 2019-02-11 2020-08-12 Sandoz Ag Crystalline salts of a hemoglobin s allosteric modulator
WO2021170977A1 (en) * 2020-02-24 2021-09-02 Johnson Matthey Public Limited Company Crystalline forms of voxelotor, and processes for the preparation thereof

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