SAJJA ESWARAIAH (IN)
MATHAD VIJAYAVITTHAL T (IN)
PAVAN KUMAR REDDY BANDLA (IN)
CHITLA CHIRANJEEVI (IN)
SIDDIREDDYGARI MAHESHWAR REDDY (IN)
SALADI VENKATA NARASAYYA (IN)
KAMMARI BAL RAJU (IN)
SRINIVASAN THIRUMALAI RAJAN (IN)
| WO2016170451A1 | 2016-10-27 |
| IN201921029656A |
| We Claim: 1. 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 reducing agent to provide compound of general formula-9; Formula- 10 Formula-9 wherein “Pg” is selected from hydrogen or amino protecting group b) converting compound of general formula-9 to Glasdegib of formula- 1 or a salt thereof. 2. The process as claimed in claim 1 wherein, the 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. 3. 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 to provide compound of general formula-7; Formula-9 Formula-7 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. 4. The process as claimed in claim 3 wherein, the base used in step-a) is selected from inorganic base or organic base and the 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. A process for the preparation of Glasdegib maleate of formula- la, which comprises: a) treating compound of general formula-3 with acid in a solvent to provide its acid addition salt of compound of formula-2; Formula-3 Formula-2 wherein “Pg” is selected from hydrogen or amino protecting group and “n” = 0.5, 1, 1.5, 2, 3, 4, 5, 6. b) converting acid addition salt of compound of formula-2 to Glasdegib maleate of formula- la. Formula- la The process as claimed in claim 5 wherein, the 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. The process as claimed in claim 5 wherein, the solvent used in step-a) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof. The process as claimed in claim 5 wherein, in step-b) the process for the preparation of Glasdegib maleate compound of formula- la, comprises treating the acid addition salt of compound of formula-2 with a base to provide Glasdegib compound of formula- 1, which is further treating with maleic acid to provide Glasdegib maleate compound of formula- la. The process as claimed in claim 8 wherein, the base used is selected from inorganic base or organic base and the 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. An acid addition salt of compound of formula-2 or anhydrate or hydrate or solvate form. Formula-2 wherein acid is selected is selected from inorganic acid or organic acid and “n” = 0.5, 1, 1.5, 2, 3, 4, 5, 6. Dihydrochloride salt of formula-2a or anhydrate or hydrate or solvate form thereof. Formula-2 a . 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. . The crystalline Form-M of compound of formula- 2a as claimed in claim 12 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1. . A process for the preparation of crystalline Form-M of compound of formula-2a, which comprises: a) dissolving compound of formula-3 a in methanol; b) adding isopropanolic hydrochloric acid solution to the obtained solution in step-a); and c) isolating the crystalline Form-M of compound of formula-2a. . 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. . Glasdegib or its maleate salt obtained according to the preceding claims is having amino phenyl impurity, N-Boc impurity, desmethyl impurity, diastereomeric impurity and N-Oxide impurity less than 0.05% as measured by HPLC. . Glasdegib maleate obtained according to the preceding claims is having particle size distribution of D90 <300 pm. . Glasdegib maleate obtained according to the preceding claims is having purity of 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. 25 |
Related Application:
This application claims the benefit of priority of our Indian patent application numbers 202141036489 filed on 12 August 2021 and 202141042898 filed on 22 September 2021, which are incorporated herein by reference.
Field of the Invention:
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-cyanophe nyl)urea : maleic acid : oxalic acid and process for its preparation thereof.
Background of the Invention:
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.
Formula- 1 a
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. l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4- yl)-3-(4-cyanophenyl) urea was disclosed in US8148401 B2 (hereinafter described as US‘401).
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.
Crystalline form-1 of l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4- yl)- 3-(4-cyanophenyl)urea maleate and its process was disclosed in US 10414748 B2.
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.
Brief description of the Invention:
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.
Brief description of Drawings:
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.
Detailed description of the Invention:
As used herein the term “suitable solvent” used in the present invention 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, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethyl formamide (DMF), dimethylsulfoxide (DMSO), 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 isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2- ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.
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-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiiso propylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The term 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. The term 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. The term 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. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl. The term substituted or unsubstituted “arylalkyl" such as p-methoxy benzyl, p- nitrobenzyl, benzyl, p-bromo benzyl and the like.
The term “Pg”, N-protecting group, or amino-protecting group as used herein 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-nitro phenylsulfenyl; urea; urethane; nitroso; nitro and the like. A thorough discussion of amino-protecting groups disclosed in Protective Groups in Organic Synthesis, Fourth edition, Wiley, New York 2006 by T. W. Greene and P. G. M. Wuts.
In the first embodiment, 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.
In the process of the first embodiment, 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.
In the second embodiment, 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 Formula-7 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.
In the process of the second embodiment, 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.
In first aspect of the second embodiment, 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.
In the third embodiment, the present invention provides a process for the preparation of Glasdegib maleate of formula- la, which comprises: a) treating compound of general formula-3 with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of formula-2; and wherein “Pg” as defined above and “n” = 0.5, 1, 1.5, 2, 3, 4, 5, 6. b) converting acid addition salt of compound of formula-2 to Glasdegib maleate of formula- la.
Formula- la
In the process of the third embodiment, 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 solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
In the process of the third embodiment, treating the acid addition salt of compound of formula-2 with a suitable base to provide Glasdegib compound of formula- 1. Treating Glasdegib compound of formula- 1 with maleic acid to provide Glasdegib maleate compound of formula- 1 a.
In the fourth embodiment, the present invention provides an acid addition salt of compound of formula-2 or anhydrate or hydrate or solvate form thereof represented by the following structural formula. wherein “n” = 0.5, 1, 1.5, 2, 3, 4, 5, 6.
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.
In first aspect of the fourth embodiment, the present invention provides compound of formula-2a or anhydrate or hydrate or solvate form thereof.
Formula-2a
In the fifth embodiment, 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.
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.
In the sixth embodiment, 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.
In the process of the sixth embodiment, 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.
In the seventh embodiment, the present invention provides a crystalline Form comprising Glasdegib : maleic acid : oxalic acid.
In the eighth embodiment, 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.
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.
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.
In the ninth embodiment, 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.
In the process of the ninth embodiment, 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. In the process of the ninth embodiment, 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.
In the ninth embodiment, the present invention provides a pharmaceutical composition comprising 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.
Wherein the excipient can be selected from the ones described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
In an embodiment, 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.
In an embodiment, 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.
The process according to the embodiments of the present invention, conversion of compound of general formula-9 to Glasdegib as well as compound of general formula-7 to Glasdegib of formula- 1 or its salts are represented schematically by one or more steps as follows:
N 3 Reduction Pg OCH 3
Formula- 12 Formula- 11 Formula- 10 12a: Pg = Boc 1 la: Pg = Boc 10a: Pg = Boc
Formula- 13 Formula- 8 Formula-9
Formula-4 6a: Pg = Boc 7a: Pg = Boc 4a: Pg = Boc
3a: Pg = Boc wherein "R", "n" and "Pg" are defined above In the tenth embodiment, 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.
In the process of the tenth embodiment, 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.
In an embodiment, 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.
Aminophenyl impurity , N-Boc impurity Desmethyl impurity
Diastereomeric impurity N-Oxide impurity
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. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis:
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.
PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
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. Combined the total organic layers and washed with water. Distilled off the solvent completely from the organic layer and dried to get the title compound. Yield: 140.0 gm. Example-2: Preparation of (2R,4R)-l-tert-butyl 2-methyl 4-aminopiperidine-l,2- dicarboxylate of formual-9a.
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) was added to the mixture at 25-30°C and stirred for 20 minutes. 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.
A mixture of ethanol (750.0 ml) and water (250.0 ml) were added to the obtained compound at 25-30°C and stirred for 5 minutes. 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. Methyl tert-butyl ether (200.0 ml) and water (200.0 ml) were added to the obtained compound at 25-30°C and stirred for 20 minutes. The mixture pH was adjusted with aqueous hydrochloric acid solution. Layers were separated and aqueous layer extracted with methyl tert-butyl ether. Aqueous layer pH was adjusted with ammonia. Toluene was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and aqueous layer extracted with toluene and ethyl acetate. Combined the total organic layers. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 78.0 gm.
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) and lithium hydroxide (36.54 gm) were added to the mixture at 25-30°C and stirred for 1 hour. Distilled off the solvent completely from the mixture. Water and methyl tert-butyl ether were added to the obtained compound at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer washed with methyl tert-butyl ether. Aqueous layer pH was adjusted with Aqueous hydrochloric acid solution. Methyl tert-butyl ether (150.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer extracted with methyl tert-butyl ether. Aqueous layer pH was adjusted with aqueous hydrochloric acid solution. Ethyl acetate was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers. Distilled off the solvent completely from the organic layer and co-distilled with n-heptane. n-Heptane was added to the obtained compound and stirred for 30 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 97.0 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. Further, cooled the mixture to 25-30°C and stirred for 30 minutes. Cooled the mixture to 0-5°C and stirred for 90 minutes. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 51.6 gm.
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.
Methanol (440.0 ml) was added to compound of formula-3a (88.0 gm) at 25-30°C and stirred for 10 minutes. Isopropanol-HCl (308.0 ml) was slowly added to the mixture at 25-30°C and stirred for 6 hours. Isopropanolic hydrochloric acid solution (44.0 ml) was added to the mixture at 25-30°C and stirred for 2 hours. Cooled the mixture to 0-5°C and stirred for 90 minutes. Filtered the solid and washed with methanol. Isopropanol (440.0 ml) and methanol (440.0 ml) were added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with isopropanol and methanol and dried to get the title compound.
Yield: 68.6 gm; HC1 content: 16.83%; Purity by HPEC: 98.19%.
The PXRD pattern of the obtained compound is illustrated in Figure- 1.
Example-8: Preparation of Glasdegib of formula-1.
Methanol (200.0 ml) was added to crystalline Form-M of compound of formula-2a (20.0 gm) at 25-30°C and stirred for 10 minutes under nitrogen atmosphere. Formaldehyde (18.9 ml) was slowly added to the mixture at 25-30°C and stirred for 1 hour. Cooled the mixture to 0-5°C. Sodium cyanoborohydride (11.08 gm) was slowly added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Water (100.0 ml) was added to the mixture and pH was adjusted with aqueous sodium carbonate solution. 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.
Yield: 20.0 gm.
Example-9: Preparation of Glasdegib maleate of formula-la.
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-10: Preparation of Glasdegib maleate of formula-la.
Methanol (1420.0 ml) was added to crystalline Lorm-M of compound of formula-2a (142.0 gm) at 25-30°C and stirred for 10 minutes. Lormaldehyde (134.2 gm) was slowly added to the mixture at 25-30°C and stirred for 1 hour. Cooled the mixture to 0-5°C. Sodium cyanoborohydride (24.0 gm) was added to the mixture at 0-5°C and stirred for 30 minutes. Distilled off the solvent completely from the mixture. Water (725.0 ml) and ethyl acetate (725.0 ml) were added to the mixture at 25-30°C and pH was adjusted with aqueous sodium carbonate solution. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and washed with water and aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. Ethyl acetate (710.0 ml) and water (1420.0 ml) were added to the obtained compound at 25-30°C and stirred for 15 minutes. Layers were separated and organic layer washed with sodium sulfate. Distilled off the solvent completely from the organic layer and co-distilled with isopropanol. Isopropanol (994.0 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Heated the mixture to 60-65°C and stirred for 10 minutes. Maleic acid (45.63 gm) and isopropanol (426.0 ml) were added to the mixture at 60-65°C and stirred for 15 minutes. Cooled the mixture to 10-15°C. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 136.4 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. Filtered the mixture through hyflow bed and washed with isopropanol. Distilled off the solvent completely from the filtrate. The obtained compound was washed with isopropanol and dried to get the title compound. Yield: 121.6 gm.
Maleic acid content: 23.71%; Purity by HPLC: 99.85%; Aminophenyl impurity: Not detected; N-Boc impurity: Not detected; Desmethyl impurity: Not detected; Diastereomeric impurity: Not detected and N-Oxide impurity: 0.02%. Particle size distribution: D90: 75.27 pm.
Example-12: Preparation of Glasdegib of formula-1.
Ethyl acetate (25.0 ml) and water (25.0 ml) were added to Glasdegib maleate of formula- la (5.0 gm) at 25-30°C and stirred for 10 minutes. Aqueous sodium carbonate solution was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Organic layer was dried with sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound.
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.
The PXRD pattern of the obtained compound is illustrated in Figure-2.
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.
The PXRD pattern of the obtained compound is illustrated in Figure-3.
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.
Reference Example-1: Preparation of (2R,4R)-tert-butyl 2-(lH-benzo[d]imidazol-2-yl)-4-(3- (4-cyanophenyl)ureido)piperidine-l-carboxylate of formula-3a.
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.
Reference Example-2: Preparation of Glasdegib of formula-1.
Dichloromethane (42.5 ml) was added to compound of formula-3a (8.5 gm) at 25-30°C. Trifluoroacetic acid (42.5 ml) was added to the mixture at 25-30°C and stirred for 2 hour. Distilled off the solvent completely from the mixture. Methanol (102.0 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Sodium bicarbonate (9.0 gm) was added to the mixture at 25-30°C and stirred for 15 minutes. Filtered the mixture and washed with methanol. Formaldehyde (2.77 gm) and sodium cyanoborohydride (3.64 gm) were added to the filtrate at 25-30°C and stirred for 5 hours. Distilled off the solvent completely from the mixture. Sodium bicarbonate solution (265.0 ml), water (200.0 ml) and ethyl acetate (400.0 ml) were added to the obtained compound at 25-30°C and stirred for 10 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and distilled off the solvent completely from the organic layer to get the title compound. Yield: 5.6 gm.
Reference Example-3: Preparation of Glasdegib maleate of formula-la. Isopropanol (129.3 ml) was added to Glasdegib of formula- 1 (5.0 gm) at 25-30°C and stirred for 10 minutes. Heated the mixture to 60-65°C. Maleic acid (1.85 gm) and isopropanol (15.0 ml) were added to the mixture at 60-65°C and stirred for 2 hours. Cooled the mixture to 5- 10°C and stirred for 2 hours. Distilled off the solvent completely from the mixture. Methyl tertiary-butyl ether (50.0 ml) was added to the obtained compound at 35-40°C and stirred for 10 minutes. Decanted the methyl tertiary-butyl ether layer and isopropanol was added to the obtained compound at 25-30°C and stirred for 5 minutes. Cooled the mixture to 5-10°C and stirred for 1 hour. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 3.2 gm; Purity by HPLC: 97.64%.