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WO2018150327A1 - Procédé de production de crisaborole - Google Patents

Procédé de production de crisaborole Download PDF

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Publication number
WO2018150327A1
WO2018150327A1 PCT/IB2018/050883 IB2018050883W WO2018150327A1 WO 2018150327 A1 WO2018150327 A1 WO 2018150327A1 IB 2018050883 W IB2018050883 W IB 2018050883W WO 2018150327 A1 WO2018150327 A1 WO 2018150327A1
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Prior art keywords
acid
benzonitrile
compound
formula
crisaborole
Prior art date
Application number
PCT/IB2018/050883
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English (en)
Inventor
Li PEIJIE
Sun YUANCHAO
Zhang MUQUN
Du HENG
Gao SUWAN
Hu ZHENYU
Sonia Krivonos
Arkady KHASHPER
Vitaly Shteinman
Yana Sery
Revital Ben-Daniel
Original Assignee
Wavelength Enterprises Ltd
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Publication date
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Publication of WO2018150327A1 publication Critical patent/WO2018150327A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • A61K31/69—Boron compounds

Definitions

  • the present invention relates to novel process for production of crisaborole.
  • Crisaborole (code name AN2728) is a non-steroidal boron-containing drug (a phenoxybenzoxaborole) used for the topical treatment of psoriasis and atopic dermatitis (atopic eczema).
  • Crisaborole is a phosphodiesterase-4 inhibitor acting on the phosphodiesterase 4B gene, which is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family (PDE4B).
  • Crisaborole is 4-[(l-hydroxy-l,3-dihydro-2, l- benzoxaborol-5-yl)oxy]benzonitrile. It has a molecular formula of C14H10BNO3 and a molecular weight of 251.045. Crisaborole is soluble in organic solvents such as ethanol, DMF and ethyl acetate. Crisaborole is sparingly soluble in water. Crisaborole has the following structural formula:
  • Example 4 of the '451 patent describes a method for preparing a series of compounds, which include crisaborole (Compound No. 4.2.q).
  • the method described in Example 4 of the '451 patent involves metalation of an aryl halide using tert-butyllithim or ⁇ -butyllithim at -78 °C.
  • tert-butyllithim and n- butyllithim are extremely pyrogenic and hazardous to use on large scales as they can combust spontaneously on contact with air.
  • Using a temperature of -78 °C is also highly impractical and generally unsuitable for large scale syntheses. Accordingly, the method described in Example 4 of the '451 patent would not be commercially viable.
  • Step 1 the formyl group of Compound 1 is protected as ethylene acetal with excess ethylene glycol in the presence of 1-10% acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride, hydrogen bromide and using toluene, benzene or xylene as solvents.
  • acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride, hydrogen bromide and using toluene, benzene or xylene as solvents.
  • the reaction is carried out under azetropic condition with a Dean-Stark head at reflux and is complete within 1-24 hours.
  • Step 2 Compounds 2 and 3 are coupled in the presence of 1-5 equivalents of a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, potassium tert-butoxide in a solvent such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide and acetonitrile to afford compound 4.
  • a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, potassium tert-butoxide
  • a solvent such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide and acetonitrile.
  • Step 3 Compound 4 is treated with 1-50 equivalents of an acid such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid and acetic acid to hydrolyze the acetal.
  • the solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxy ethane and the reaction is complete within 1-24 hours.
  • Step 4 Compound 5 is subjected to Miyaura coupling to introduce boron atom.
  • a mixture of Compounds 5, 6, [l, l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane, and potassium carbonate is stirred at a temperature of 50°C to reflux in a solvent such as 1,4-dioxane, 1,2-dimethoxy ethane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide and toluene.
  • the palladium catalyst is used at 1-5 mol %, and the base is used at 2-5 equivalents. The reaction is complete within 1-24 hours.
  • Step 5 Compound 7 is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride in an inert solvent. 0.5-2 equivalents of reducing agent are used in a solvent such as methanol, ethanol, tetrahydrofuran and ether. The reaction is carried out at 0°C to room temperature, and is complete within 1 to 12 hours. The pinacol is removed by washing with aqueous boric acid during the extraction and the crude product is treated with water, or subjected to freeze drying after purification.
  • a reducing agent such as sodium borohydride or lithium aluminum hydride in an inert solvent. 0.5-2 equivalents of reducing agent are used in a solvent such as methanol, ethanol, tetrahydrofuran and ether.
  • the present invention provides a process for preparing crisaborole, which process comprises the following stages:
  • ammonium salts of AHBN (compounds of the formula IA) having the following structural formula:
  • the compound is a hydrochloride salt.
  • X " is selected from the group comprising CI “ , Br “ , ⁇ , BF 4 “ , PF 6 “ , H2BO3 “ , NO3 “ , HSO4- , CH3SO3-, CH3C6H4SO3- and CIO4-.
  • X " is CI " .
  • the present invention provides crisaborole obtainable by the process described herein, which employs the intermediate 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN) as starting material.
  • AHBN 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile
  • the present invention provides a process for preparing the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN), as depicted in Scheme 3, which process comprises the following stages:
  • the present invention provides pharmaceutical compositions comprising the crisaborole obtainable by a process depicted in Scheme 2 and at least one pharmaceutically acceptable excipient.
  • Figure 1 depicts the DSC curve of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN) showing peak maximum at 106.27°C.
  • Figure 2 depicts the IR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN).
  • Figure 4 depicts the proton NMR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN).
  • Figure 5 depicts the peak list of the proton NMR spectrum of the intermediate 4- (4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN).
  • Figure 6 depicts the 13 C NMR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN).
  • Figure 7 depicts the peak list of the C NMR spectrum of the intermediate 4-(4- amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN).
  • the present invention provides compounds, which are useful intermediates for the production of crisaborole, processes for producing such intermediates, and processes for producing crisaborole therewith.
  • Compounds of the present invention include the intermediate of formula I, 4-(4- amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN) and its ammonium salts (compounds of the formula IA), the compounds of formula II (the diazonium salts), the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)-benzonitrile and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)-benzonitrile.
  • AHBN 4-(4- amino-3-(hydroxymethyl)phenoxy)benzonitrile
  • AHBN amino-3-(hydroxymethyl)phenoxy)benzonitrile
  • ammonium salts compounds of the formula IA
  • the compounds of formula II the diazonium salts
  • the intermediate of formula III 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)-benzonitrile
  • the intermediate of formula IV 4-(4-nitro-3-formyl
  • the preparation of the intermediates (4- amino-3-(hydroxymethyl)-phenoxy)benzonitrile (AHBN) and its salts, the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile can be achieved in high yield and high purity.
  • the intermediates of the present invention are particularly useful for producing crisaborole.
  • the present invention provides a process for preparing crisaborole, which process comprises the following stages:
  • crisaborole may be obtained from 4-(4-amino-3- (hydroxymethy)phenoxy)benzonitrile (AHBN) in a one pot reaction, the process may optionally comprise isolating the diazonium salt of formula II.
  • the starting material 4-(4-amino-3-(hydroxymethy)-phenoxy)benzonitrile of formula I is mixed with an organic solvent selected from the group comprising methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran (THF), 2- methyltetrahydrofuran (methyl-THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), methyl isobutyl ketone (MIBK), acetonitrile and mixtures thereof, preferably methanol.
  • an organic solvent selected from the group comprising methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran (THF), 2- methyltetrahydrofuran (methyl-THF), 1,4-dioxane, dimethyl sulfoxide (DM
  • AHBN and the solvent is at least about 0.1 g per 8 mL, preferably 1 g per 8 mL.
  • the acid used for preparing the aqueous acidic solution employed in Stage 1 is selected from the group comprising hydrochloric acid (HCl), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid.
  • the acid is aqueous HCl solution.
  • the quantity of aqueous HCl solution is from about 1 equivalent to about 20 equivalents, preferably 4 equivalents.
  • the borylation agent, employed in Stage 3 is selected from the group comprising pinacoloborane, cathecholborane, bis(catecholo)diboron, bis(neopentyl glycolato) diboron, bis(hexylene glycolato)diboron, bis(pinacolo)diboron (B 2 Pin 2 ), tetrahydroxybiboron, 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane, 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane and 4,6,6-trimethyl-l,3,2-dioxaborinane.
  • the borylation agent can be used as is or in solution in a solvent such as methanol, THF, DMSO or 1,4-dioxane.
  • the borylation agent is bis(pinacolo)diboron (B 2 Pin 2 ) or tetrahydrobiboron.
  • working up the reaction mixture (Stage 4 in the process for preparing crisaborole) comprises the following steps:
  • the organic solvent used for the extractions in Steps 1-3 of the working up procedure is selected from the group comprising dichloromethane (DCM), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate, methyl-THF and mixtures thereof.
  • DCM dichloromethane
  • MEK methyl ethyl ketone
  • MIBK methyl isobutyl ketone
  • ethyl acetate methyl-THF and mixtures thereof.
  • the organic solvent used for the extractions is MIBK.
  • the base added to the aqueous phase in Step 2 is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium hydroxide and potassium hydroxide.
  • the base is potassium carbonate or sodium hydroxide.
  • the acid used to acidify the aqueous phase in Step 3 of the work up is selected from the group comprising hydrochloric acid (HQ), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid.
  • the acid is acetic acid.
  • working up the reaction mixture comprises the following steps:
  • the base added to the aqueous phase in Step I is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium hydroxide and potassium hydroxide.
  • the base is 10% solution of potassium carbonate.
  • the organic solvent used for the extraction in Step II is selected from the group comprising dichloromethane (DCM), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate, methyl-THF and mixtures thereof.
  • DCM dichloromethane
  • MEK methyl ethyl ketone
  • MIBK methyl isobutyl ketone
  • ethyl acetate methyl-THF and mixtures thereof.
  • methyl-THF methyl-THF
  • the organic solvent used for the extraction is MIBK.
  • the acid used to acidify the aqueous phase in Step III is selected from the group comprising hydrochloric acid (HQ), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid.
  • the acid is acetic acid.
  • the solvent used to wash the crude crisaborole in Step IV is selected form the group comprising n-pentane, n-hexane, n-heptane, toluene, methyl tert-butyl ether (MTBE), water and mixtures thereof.
  • the solvent is water.
  • a process for preparing crisaborole comprises the steps of mixing the starting material of formula I, 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile (AHBN) with methanol and adding aqueous hydrochloric acid solution while cooling to about 0°C and stirring; adding an aqueous solution of sodium nitrite (NaNCh) while maintaining stirring and cooling; adding bis(pinacolo)diboron and methanol and mixing for about one hour; evaporating the methanol and adding MIBK to form a two-phase system, extracting and separating the phases; adding saturated solution of potassium carbonate to the aqueous phase, extracting with MIBK, and separating the phases; acidifying the aqueous phase with acetic acid, extracting with MIBK and separating the phases; washing the organic phase with water, drying and evaporating the solvent.
  • AHBN 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile
  • a process for preparing crisaborole comprises the steps of mixing the starting material of formula I 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile (AHBN) with methanol and adding aqueous hydrochloric acid solution while cooling to about 0°C and stirring; adding an aqueous solution of sodium nitrite (NaNCh) while maintaining stirring and cooling; adding tetrahydrodiboron and methanol and mixing for about one hour; adding a basic solution and filtering off the thus formed solid; extracting the obtained aqueous solution with MIBK and discarding the organic phase; adding an acid to the aqueous phase and filtering off the thus precipitated solid; washing with water and drying.
  • AHBN 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile
  • the present invention provides a process for preparing the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN), which process comprises the following stages:
  • the base used in the coupling reaction to afford the compound 4-(4-nitro-3-(l,3-dioxolane-2- yl)phenoxy)benzonitrile is selected from sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate and combinations thereof.
  • the base is potassium carbonate.
  • the organic solvent used in Stage 1 (the coupling reaction) to afford the compound of formula III, 4-(4-nitro-3- (l,3-dioxolane-2-yl)phenoxy)benzonitrile is selected from acetonitrile, N-methyl-2- pyrrolidone (NMP), THF, methyl-THF, 1,4-dioxane, DMSO, N,N-dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA) and mixtures thereof.
  • the solvent is DMF.
  • deprotecting the compound of formula III to afford the compound of formula IV is carried out using an acid selected from HCl, HBr, TFA, p-toluenesulfonic acid, methanesulfonic acid and sulfuric acid.
  • the acid is p-toluenesulfonic acid.
  • the solvent used in the deprotection of the compound of formula III to afford the compound of formula IV is selected form methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, THF, toluene, diethylene glycol, water and mixtures thereof.
  • the solvent is methanol.
  • reduction of the compound 4-(4-nitro-3-formylphenoxy)benzonitrile in Stage 3 is carried out using sodium borohydride in an organic solvent such as ethanol followed by homogenous catalytic hydrogenation with hydrogen using metal catalyst selected from palladium, platinum, ruthenium and Raney nickel, preferably the metal catalyst is palladium on carbon in an organic solvent such as methanol.
  • reduction of the compound 4-(4-nitro-3-formylphenoxy)benzonitrile in Stage 3 is carried out using the catalyst aluminum sec-butylae and/or aluminum isopropoxide in an organic solvent such as isopropanol followed by using a metal catalyst such as iron or zinc in an organic solvent such as methanol.
  • zinc dust in methanol and hydrazine are used at ambient temperature, under which conditions nitrile and ether groups are tolerated.
  • the present invention relates to methods of purifying crisaborole, e.g., by crystallization or by using liquid chromatography comprising reducing the level of impurities such as the isolated impurity 4-(3-(hydroxymethyl)phenoxy)benzonitrile (the Des-amine) of formula V, which is a byproduct formed in the process.
  • the Des-amine impurity has the formula C14H11NO2, a molecular weight of 225.246 and the following structural formula:
  • the present invention provides crisaborole obtainable by the process described herein, employing the compound 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN) as starting material.
  • crisaborole having purity greater than about 99.5%, preferably greater than about 99.8%, containing less than about 0.1% of the Des-amine impurity by weight, according to HPLC.
  • the present invention provides a method of isolating the Des-amine impurity that comprises providing a solution containing, inter alia, crisaborole, the Des-amine impurity and a solvent; precipitating the Des-amino impurity from the solution; and isolating the Des- amine impurity and/or subjecting said mixture to preparative HPLC or column chromatography.
  • Suitable solvents include, but are not limited to, at least one of an alcohol, preferably methanol, a halogenated hydrocarbon such as dichloromethane, a ketone such as MIBK, a C5-C8 hydrocarbon such as n-hexane or n-heptane, or an ester such as ethyl acetate and mixtures thereof.
  • the solvent is MIBK.
  • the method may include a step of concentrating a solution containing the Des-amine impurity.
  • Isolating the crystals by a method selected from evaporation or removal of a solvent or solvents optionally under reduced pressure, freeze drying or spray drying and filtration, preferably, isolating the crystals by filtration, washing and, optionally, drying.
  • a process for purifying crisaborole comprises the steps of dissolving crisaborole in acetone (1 g per about 4 mL), adding activated carbon and mixing for about 30 minutes at ambient temperature followed by filtering off the activated carbon and obtaining a filtrate; adding water drop-wise to the filtrate (4 mL per about 1 g) and filtering the thus formed crystals, washing and drying.
  • a process for purifying crisaborole comprises the steps of dissolving crisaborole in isopropanol (1 g per about 4 mL), adding activated carbon and mixing for about 30 minutes at ambient temperature followed by filtering off the activated carbon and obtaining a filtrate; adding water drop-wise to the filtrate (4 mL per about 1 g) and filtering the thus formed crystals, washing and drying.
  • a process for purifying crisaborole comprises the steps of dissolving crisaborole in ethyl acetate (4 mL per about 1 g) and stirring at ambient temperature to complete dissolution; adding n-heptane while mixing (10 mL per about 1 g); collecting the precipitated crystals washing with n-heptane and drying under reduced pressure.
  • the process of the present invention for the preparation of crisaborole provides substantially pure crisaborole having purity greater than or equal to about 99.5% and preferably greater than or equal to about 99.8% by weight, as determined by using HPLC. Furthermore, the present invention also provides crisaborole containing less than about 0.1% of the Des-amine impurity.
  • the impurities in crisaborole may be analyzed using various methods such as liquid chromatography methods, e.g., an HPLC method.
  • ammonium salts of AHBN (compounds of the formula IA) having the following structural formula:
  • the compound is a hydrochloride salt.
  • X " is selected from the group comprising CI “ , Br “ , ⁇ , BF 4 “ , PF 6 “ , H2BO3 “ , NO3 “ , HS04 “ , CH3SO3 “ , CH3C6H4SO3 “ and CIO4-.
  • X " is CI " .
  • the present invention provides pharmaceutical compositions comprising the crisaborole obtainable by a process depicted in Scheme 2 and at least one pharmaceutically acceptable excipient.
  • Tetrahydroxydiboron (4.48 g, 50 mmol, 3.0 equiv.) was added to the reaction mixture followed by addition of methanol (60 mL); [tetrahydroxydiboron may be added also as a solution in DMSO, 22 mL]. The reaction mixture was stirred for 1 hour.
  • Crisaborole (1.5 g) was dissolved in acetone (10 mL), activated carbon (0.15 g) was added and the mixture was stirred for about 30 minutes at ambient temperature. The activated carbon was discarded by filtration and water (10 mL) was added drop-wise to the filtrate. The precipitated crystals were collected by filtration, washed with water (9 mL), and dried at 45°C under reduced pressure to afford purified crisaborole (1.2 g) having purity of 99.86%) and containing about 0.03% of the Des-amine impurity (according to HPLC).
  • Example 4- Purification of crisaborole by crystallization from ethyl acetate and hexane
  • Crisaborole (7.4 g) was dissolved in isopropanol (10 mL), activated carbon ( 20 g) was added and the mixture was stirred for about 30 minutes at a temperature of 25-40°C. The activated carbon was discarded by filtration and water (70 mL) was added drop-wise to the filtrate. The precipitated crystals were collected by filtration, washed with isopropanol (9 mL) and dried at 45°C under reduced pressure to afford purified crisaborole having purity of 99.6% containing about 0.09% of the Des-amine impurity (according to HPLC).
  • the combined extracts are evaporated to dryness and the obtained product is treated with 100 mL 1 N HC1 at room temperature for 1 hr.
  • the pH is adjusted to neutral with NaOH (10N), extracted three times with methylene chloride, and the combined extracts are dried over magnesium sulfate, filtered, and evaporated to dryness.
  • the obtained product is dissolved in 200 mL tetrahydrofurane and 10 g of sodium borohydride is added. The reaction mixture is stirred overnight, filtered, and evaporated to dryness. The residue is recrystallized from acetonitrile to afford approximately 52 g of the desired product.

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Abstract

La présente invention concerne des procédés pour produire du crisaborole et des procédés pour isoler et purifier du crisaborole. La présente invention concerne également des intermédiaires, qui peuvent être utilisés dans la production de crisaborole et des procédés de production de tels intermédiaires. La présente invention concerne en outre des compositions pharmaceutiques contenant du crisaborole produit conformément à la présente invention.
PCT/IB2018/050883 2017-02-14 2018-02-13 Procédé de production de crisaborole WO2018150327A1 (fr)

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CN113087733A (zh) * 2021-04-06 2021-07-09 南京科默生物医药有限公司 克立硼罗的晶型a、晶型b、晶型c、晶型d、晶型e及其制备方法
CN114702408A (zh) * 2022-02-22 2022-07-05 南京康川济医药科技有限公司 一种克立硼罗杂质的制备方法和应用
CN115215765A (zh) * 2022-07-20 2022-10-21 湖北丽益医药科技有限公司 一种克立硼罗聚合物杂质的制备方法
CN115716846A (zh) * 2022-11-16 2023-02-28 南通常佑药业科技有限公司 一种制备克立硼罗的新方法
CN116253756A (zh) * 2023-05-11 2023-06-13 北京元延医药科技股份有限公司 克立硼罗的制备方法
CN116715687A (zh) * 2023-05-25 2023-09-08 福建南方制药股份有限公司 一种工业化制备克立硼罗晶型i的方法
CN117003694A (zh) * 2023-10-07 2023-11-07 南京科思化学股份有限公司 一种高品质去屑剂吡罗克酮乙醇胺盐的制备方法

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Publication number Priority date Publication date Assignee Title
CN109456347A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种克立硼罗的制备方法
CN109456347B (zh) * 2018-10-29 2021-02-05 安徽省庆云医药股份有限公司 一种克立硼罗的制备方法
CN113087733A (zh) * 2021-04-06 2021-07-09 南京科默生物医药有限公司 克立硼罗的晶型a、晶型b、晶型c、晶型d、晶型e及其制备方法
CN114702408A (zh) * 2022-02-22 2022-07-05 南京康川济医药科技有限公司 一种克立硼罗杂质的制备方法和应用
CN114702408B (zh) * 2022-02-22 2024-01-16 南京康川济医药科技有限公司 一种克立硼罗杂质的制备方法和应用
CN115215765A (zh) * 2022-07-20 2022-10-21 湖北丽益医药科技有限公司 一种克立硼罗聚合物杂质的制备方法
CN115716846A (zh) * 2022-11-16 2023-02-28 南通常佑药业科技有限公司 一种制备克立硼罗的新方法
CN116253756A (zh) * 2023-05-11 2023-06-13 北京元延医药科技股份有限公司 克立硼罗的制备方法
CN116715687A (zh) * 2023-05-25 2023-09-08 福建南方制药股份有限公司 一种工业化制备克立硼罗晶型i的方法
CN117003694A (zh) * 2023-10-07 2023-11-07 南京科思化学股份有限公司 一种高品质去屑剂吡罗克酮乙醇胺盐的制备方法
CN117003694B (zh) * 2023-10-07 2023-12-26 南京科思化学股份有限公司 一种去屑剂吡罗克酮乙醇胺盐的制备方法

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