WO2023017541A1 - Processus amélioré pour la préparation de maléate de 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée - Google Patents

Processus amélioré pour la préparation de maléate de 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée Download PDF

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WO2023017541A1
WO2023017541A1 PCT/IN2022/050722 IN2022050722W WO2023017541A1 WO 2023017541 A1 WO2023017541 A1 WO 2023017541A1 IN 2022050722 W IN2022050722 W IN 2022050722W WO 2023017541 A1 WO2023017541 A1 WO 2023017541A1
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formula
acid
compound
solvents
glasdegib
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PCT/IN2022/050722
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English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Bandla PAVAN KUMAR REDDY
Chiranjeevi CHITLA
Maheshwar Reddy SIDDIREDDYGARI
Venkata Narasayya SALADI
Bal Raju Kammari
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2023017541A1 publication Critical patent/WO2023017541A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Definitions

  • the present invention relates to an improved process for the preparation of l-((2R,4R)-2- ( lH-benzo[d]imidazol-2-yl)- 1 -methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate.
  • the present invention also relates to a crystalline form comprising l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea : maleic acid : oxalic acid and process for its preparation thereof.
  • Glasdegib maleate is chemically known as l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate represented by the following structural formula.
  • Glasdegib is an inhibitor of Smoothened (SMO), a key protein in the hedgehog (Hh) pathway. Aberrant Hh signalling has been identified in many solid tumour types and in haematological malignancies. As an inhibitor of the Hh signalling pathway, Glasdegib may act as an anti-leukaemic stem cell agent. Glasdegib is approved in the USFDA and Europe in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are > 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. Pfizer is marketing Glasdegib under the brand name Daurismo.
  • US‘401 discloses process for the preparation of l-((2R,4R)-2-(lH-benzo[d]imidazol-2- yl)- 1 -methylpiperidin-4-yl)-3-(4-cyanophenyl)urea hydrochloride.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
  • the present invention relates to an improved process for the preparation of Glasdegib maleate of formula- la.
  • the present invention relates to acid addition salts of l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(4-cyanophenyl)urea of formula-2 or anhydrate or hydrate or solvate forms thereof.
  • the present invention also relates to a crystalline Form of l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(4-cyanophenyl)urea dihydrochloride of formula-2a, hereinafter designated as Form-M.
  • the present invention also relates to a process for the preparation of crystalline Form-M of l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(4-cyanophenyl)urea dihydrochloride of formula-2a.
  • the present invention also relates to a crystalline form comprising Glasdegib: maleic acid : oxalic acid, hereinafter designated as Form-S.
  • the present invention also relates to a process for the preparation of crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid.
  • Figure 1 Illustrates the PXRD pattern of crystalline Form-M of l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)piperidin-4-yl)-3-(4-cyanophenyl)urea dihydrochloride of formula-2a.
  • Figure 2 Illustrates the PXRD pattern of amorphous form of Glasdegib of formula- 1.
  • Figure 3 Illustrates the PXRD pattern of crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid.
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, is
  • the “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-di
  • substituted or unsubstituted alkyl group refers to straight or branched chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylthiono, sulfonyl, nitro, cyano, alkoxycarbonyl, aryl, aralkoxy, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
  • substituted or unsubstituted “alkenyl group” refers to straight or branched chain hydrocarbon groups ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
  • substituted or unsubstituted “aryl” refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatom independently selected from nitrogen, oxygen and sulfur.
  • Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like.
  • the aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above.
  • multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl.
  • substituted or unsubstituted “arylalkyl” such as p-methoxy benzyl, p- nitrobenzyl, benzyl, p-bromo benzyl and the like.
  • N-protecting group refers to those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures.
  • N-protecting group includes, aryloxycarbonyl such as benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc); alkoxycarbonyl such as methyloxycarbonyl, acetoxy carbonyl, propoxycarbonyl, tert-butyl oxycarbonyl (Boc); acyl such as acetyl, propanoyl, isobutyryl, tert-butyryl, t-butylacetyl, pivaloyl; aroyl groups such as benzoyl; silyl such as trimethylsilyl, ter-butyldimethylsilyl; sulphonyl such as methanesulphonyl, p-tolylsulphonyl; sulphenyl such as 2-
  • the present invention provides a process for the preparation of Glasdegib of formula- 1 or a salt thereof, which comprises: a) reduction of compound of general formula- 10 with suitable reducing agent to provide compound of general formula-9; and
  • Formula- 10 Formula-9 wherein “Pg” is selected from hydrogen or amino protecting group b) converting compound of formula-9 to Glasdegib of formula- 1 or a salt thereof.
  • the suitable reducing agent used in step-a) is selected from Zn dust, Fe, Raney Nickel, Pt, Rh, Sn, Ru, Re, Cu, Platinum oxide, (NF S and NaSH and the like.
  • the present invention provides a process for the preparation of Glasdegib of formula- 1 or a salt thereof, which comprises: a) reacting compound of general formula-9 with compound of general formula-8 in the presence of suitable base in a suitable solvent to provide compound of general formula-7; and
  • Formula-9 wherein “R” is selected from substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl and “Pg” is selected from hydrogen or amino protecting group. b) converting compound of formula-7 to Glasdegib of formula- 1 or a salt thereof.
  • the suitable base used in step-a) is selected from inorganic base or organic base and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • the present invention provides a process for the preparation of Glasdegib of formula- 1 or a salt thereof, which comprises: a) reacting compound of formula-9a with compound of formula-8a in the presence of trimethyl amine in tetrahydrofuran to provide compound of formula-7a; and
  • Formula-9a Formula-7a b) converting compound of formula-7a to Glasdegib of formula- 1 or a salt thereof.
  • the suitable acid used in step-a) is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, para toluene sulfonic acid, ethane- 1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvent
  • the suitable acid is selected from inorganic acid or organic acid same as defined above.
  • Acid addition salts of compound of formula-2 are useful in the preparation of Glasdegib of formula- 1 or a salt thereof.
  • the present invention provides compound of formula-2a or anhydrate or hydrate or solvate form thereof.
  • the present invention provides a crystalline Form-M of compound of formula-2a characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 6.0, 16.2 and 21.7 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M of compound of formula-2a is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
  • XRD X-ray powder diffraction
  • the present invention provides a process for the preparation of crystalline Form-M of compound of formula-2a, which comprises: a) dissolving compound of formula-3a in methanol; b) adding isopropanolic hydrochloric acid to the obtained solution in step-a); and c) isolating the crystalline Form-M of compound of formula-2a.
  • isolation of crystalline Form-M of compound of formula-2a can be carried out by any methods known in the art or crystalline Form-M of compound of formula-2a can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the starting materials compound of formula- 13, formula-5 and formula- 12a used in the preparation of Glasdegib or its salt thereof can be prepared from the any of the prior known processes.
  • the present invention provides a crystalline Form comprising Glasdegib : maleic acid : oxalic acid.
  • the present invention provides a crystalline Form-S comprising Glasdegib: maleic acid: oxalic acid, characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 13.7, 15.0 and 20.4 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-S comprising Glasdegib: maleic acid: oxalic acid is further characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.6, 21.0, 22.7 and 32.4 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-3.
  • the present invention provides a process for the preparation of crystalline Form-S comprising Glasdegib: maleic acid : oxalic acid, which comprises: a) contacting Glasdegib maleate and oxalic acid in a mixture of methyl t-butyl ether and n- heptane; and b) isolating the crystalline Form-S comprising Glasdegib: maleic acid : oxalic acid.
  • isolation of crystalline Form-S comprising Glasdegib: maleic acid: oxalic acid can be carried out by any methods known in the art or crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid can be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • Crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid according to the present invention may be used as intermediates in preparation of other polymorphic forms of Glasdegib maleate of formula- 1 a.
  • the present invention provides a pharmaceutical composition
  • crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid and one or more pharmaceutically acceptable excipients, which is formulated in a manner suitable for the route of administration to be used.
  • excipient can be selected from the ones described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
  • the present invention provides Glasdegib maleate having purity at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC.
  • Glasdegib maleate produced according to the present invention is having particle size distribution of D90 ⁇ 300 pm.
  • Glasdegib of formula- 1 or its salt e.g., maleate salt obtained according to the present invention can be purified using a suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • a suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
  • the present invention provides a process for the preparation of amorphous form of Glasdegib compound of formula- 1, which comprises: a) suspending or dissolving Glasdegib in n-heptane, b) isolating to provide amorphous Glasdegib compound of formula- 1.
  • isolation of amorphous form of Glasdegib can be carried out by any methods known in the art or amorphous form of Glasdegib can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • Glasdegib or its maleate salt obtained according to the present invention is having Aminophenyl impurity, N-Boc impurity, Desmethyl impurity, Diastereomeric impurity and N-Oxide impurity less than 0.05% as measured by HPLC.
  • Glasdegib of formula- 1 or its salt e.g., maleate salt produced by the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that can be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling, and jet mills. Milling or micronization can be performed before drying, or after the completion of drying of the product.
  • the invention also encompasses pharmaceutical compositions comprising Glasdegib or salts thereof of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • PXRD analysis of compounds obtained according to the present invention can be carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.
  • Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • Example-1 Preparation of (2R,4S)-l-tert-butyl 2-methyl 4-((methylsulfonyl)oxy) piperidine-l,2-dicarboxylate of formula-lla.
  • Toluene (1000.0 ml) was added to (2R,4S)-1 -tert-butyl 2-methyl 4-hydroxypiperidine- 1 ,2-dicarboxylate of formula-12a (100.0 gm) at 25-30°C and stirred for 15 minutes.
  • Triethylamine (97.56 gm) was added to the mixture at 25-30°C and stirred for 15 minutes.
  • Methanesulfonyl chloride (66.25 gm) was slowly added to the mixture at 25-30°C and stirred for 2 hours.
  • Water 500.0 ml was slowly added to the mixture at 25-30°C and stirred for 2 hours. Layers were separated and aqueous layer extracted with toluene.
  • Dimethylformamide (250.0 ml) was added to compound of formula-1 la (125.0 gm) at 25- 30°C and stirred for 10 minutes.
  • Sodium azide (75.28 gm) was added to the mixture at 25-30°C and stirred for 5 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 25 hours. Cooled the mixture to 25-30°C and stirred for 25 minutes.
  • Water 500.0 ml
  • Ethyl acetate (300.0 ml) was added to mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer.
  • Zinc dust (32.12 gm) were added to the mixture at 25-30°C and stirred for 5 minutes.
  • Ammonium chloride (46.40 gm) was added lot to the mixture at 25-30°C and stirred for 3 hours.
  • Ammonia (500.0 ml) was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Filtered the mixture and washed with ethanol. Distilled off the solvent completely from the filtrate.
  • Example-3 Preparation of phenyl(4-cyanophenyl) carbamate of formula-8a.
  • Dimethylformamide (1875.0 ml) was added to 4- aminobenzonitrile of formula-13 (250.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to -20 to -15°C and stirred for 15 minutes. Pyridine (334.77 gm) and sodium bicarbonate (177.7 gm) were added to the mixture at -20 to -15°C and stirred for 15 minutes. Phenyl chloroformate (397.58 gm) was slowly added to the mixture at -20 to -15°C and stirred for 4 hours. Water (5.0 Lt) was slowly added to the mixture at 0-5°C and stirred for 90 minutes. Filtered the solid, washed with water and dried to get the title compound. Yield: 496.0 gm.
  • Example-4 Preparation of (2R,4R)-l-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido) piperidine-2-carboxylic acid of formula-6a.
  • Tetrahydrofuran (750.0 ml) was added to compound of formula-9a (75.0 gm) at 25-30°C and stirred for 10 minutes.
  • Triethylamine (141.64 ml) was added to the mixture at 25-30°C and stirred for 10 minutes.
  • Compound of formula-8a (69.17 gm) was added to the mixture at 25-30°C and stirred for 17 hours.
  • Methanol 500.0 ml
  • water 250.0 ml
  • lithium hydroxide 36.54 gm
  • Example-5 Preparation of (2R,4R)-tert-butyl 2-((2-aminophenyl)carbamoyl)-4-(3-(4- cyanophenyl)ureido)piperidine-l-carboxylate of formula-4a.
  • Dimethylformamide (250.0 ml) was added to 1,2-Diaminobenzene of formula-5 at 25- 30°C and stirred for 10 minutes.
  • N,N’ -Diisopropylethylamine (33.27 gm) was added to the mixture at 25-30°C stirred for 10 minutes. Cooled the mixture to 0-5°C and stirred for 15 minutes.
  • Compound of formula-6a (50.0 gm) and N-hydroxybenzotriazole (17.39 gm) were added to the mixture at 0-5°C and stirred for 25 minutes.
  • N-Ethyl-N'-(3-dimethyl aminopropyl)carbodiimide hydrochloride (49.35 gm) was added to the mixture at 0-5°C and stirred for 26 hours.
  • Aqueous potassium carbonate solution was slowly added to the mixture at 0- 5°C and stirred for 1 hour. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Filtered the solid and washed with water. Water (500.0 ml) was added to the obtained compound and stirred for 90 minutes. Filtered the solid, washed with water and dried.
  • Ethyl acetate (300.0 ml) was added to the obtained compound at 25-30°C. Raised the temperature of the mixture to 70-75°C and stirred for 50 minutes.
  • Example-6 Preparation of (2R,4R)-tert-butyl 2-(lH-benzo[d]imidazol-2-yl)-4-(3-(4-cyano phenyl)ureido)piperidine-l-carboxylate of formula-3a.
  • Acetic acid (480.0 ml) was added to compound of formula-4a (96.0 gm) at 25-30°C and stirred for 15 minutes. Heated the mixture to 65-70°C and stirred for 1 hour. Distilled off the solvent completely from the mixture. Water (960.0 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours. Filtered the solid and washed with water. Water (960.0 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with water and dried to get the title compound. Yield: 88.2 gm.
  • Example-7 Preparation of crystalline Form-M of l-((2R,4R)-2-(lH-benzo[d]imidazol-2- yl)piperidin-4-yl)-3-(4-cyanophenyl)urea dihydrochloride of formula-2a.
  • Example-8 Preparation of Glasdegib of formula-1.
  • Ethyl acetate (100.0 ml) and sodium chloride (10.0 gm) were added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and washed with sodium chloride solution. Layers were separated and aqueous layer extracted with ethyl acetate. Distilled off the solvent completely from the organic layer. Ethyl acetate (150.0 ml) and water (100.0 ml) were added to the obtained compound at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water and aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with isopropanol to get the title compound.
  • Isopropanol 132.0 ml was added to Glasdegib of formula-1 (20.0 gm) at 25-30°C and stirred for 10 minutes. Raised the temperature of mixture to 60-65°C and stirred for 1 hour. Maleic acid (6.99 gm) and isopropanol (56.0 ml) were added to the mixture at 60-65°C and stirred for 50 minutes. Cooled the mixture to 0-5°C and stirred for 2 hours. Eiltered the solid, washed with isopropanol and dried to get the title compound. Yield: 18.8 gm.
  • Example-11 Purification of Glasdegib maleate of formula-la.
  • Isopropanol (3400.0 ml) was added to Glasdegib maleate of formula- la (136.0 gm) at 25- 30°C and stirred for 15 minutes. Heated the mixture to 70-75°C. Water (170.0 ml) was added to the mixture at 70-75°C and stirred for 20 minutes. Filtered the mixture through hyflow bed and washed with isopropanol. Distilled off the solvent completely from the filtrate. Isopropanol (3060.0 ml) was added to the obtained compound at 25-30°C and stirred for 5 minutes. Heated the mixture to 70-75°C. Water (153.0 ml) was added to the mixture at 70-75°C and stirred for 15 minutes.
  • Example-12 Preparation of Glasdegib of formula-1.
  • Example-13 Preparation of amorphous form of Glasdegib of formula-1. n-Heptane (25.0 ml) was added to the obtained compound in example- 12 at 25-30°C and stirred for 30 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 3.77 gm.
  • Example-14 Preparation of crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid.
  • Oxalic acid (154.1 mg) and mixture of methyl t-butyl ether (18.0 ml) and n-heptane (18.0 ml) were added to Glasdegib maleate (0.6 gm) at 25-30°C. Cooled the mixture to 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and dried to get the title compound. Yield: 650.1 mg.
  • Example-15 Preparation of crystalline Form-S comprising Glasdegib : maleic acid : oxalic acid.
  • Oxalic acid (27.5 mg) and mixture of methyl t-butyl ether (3.0 ml) and n-heptane (3.0 ml) were added to Glasdegib maleate (0.1 gm) at 25-30°C. Cooled the mixture to 0-5°C and stirred for 3 hours. Raised the temperature of the mixture to 25-30°C and stirred for 3 hours. Filtered the solid and dried to get the title compound. Yield: 112.0 mg.
  • Acetic acid (68.75 ml) was added to compound of formula-4a (11.0 gm) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 60-65°C and stirred for 1 hour. Distilled off the solvent completely from the mixture. The obtained compound was purified by silica gel column chromatography using ethyl acetate and cyclohexane as eluents to get the title compound. Yield: 8.8 gm.

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Abstract

L'invention concerne un processus amélioré pour la préparation de maléate de 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée. La présente invention concerne un processus amélioré pour la préparation de maléate de 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée représenté par la formule structurale suivante. La présente invention concerne également des sels d'addition d'acide de 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)pipéridin-4-yl)-3-(4-cyanophényl)urée de formule 2 ou de ses formes anhydre, hydrate ou solvate.
PCT/IN2022/050722 2021-08-12 2022-08-11 Processus amélioré pour la préparation de maléate de 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée WO2023017541A1 (fr)

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IN202141036489 2021-08-12
IN202141036489 2021-08-12
IN202141042898 2021-09-22
IN202141042898 2021-09-22

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016170451A1 (fr) * 2015-04-24 2016-10-27 Pfizer Inc. Formes cristallines du maléate de 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016170451A1 (fr) * 2015-04-24 2016-10-27 Pfizer Inc. Formes cristallines du maléate de 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-méthylpipéridin-4-yl)-3-(4-cyanophényl)urée

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