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WO2011141928A1 - Procédé de préparation de bexarotène hautement purifié - Google Patents

Procédé de préparation de bexarotène hautement purifié Download PDF

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Publication number
WO2011141928A1
WO2011141928A1 PCT/IN2011/000322 IN2011000322W WO2011141928A1 WO 2011141928 A1 WO2011141928 A1 WO 2011141928A1 IN 2011000322 W IN2011000322 W IN 2011000322W WO 2011141928 A1 WO2011141928 A1 WO 2011141928A1
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Prior art keywords
bexarotene
impurity
formula
impurities
mixture
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PCT/IN2011/000322
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English (en)
Inventor
Shekhar Bhaskar Bhirud
Gurdeep Singh Sarin
Bimal Kumar Sharma
Pardeep Gera
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Ind-Swift Laboratories Limited
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Publication of WO2011141928A1 publication Critical patent/WO2011141928A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
    • C07C49/792—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • C07C49/798—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention provides an improved process for the preparation of highly pure bexarotene of formula I.
  • the present invention also provides isolated impurities of bexarotene, process for their removal and use of impurities as reference standard as well as reference marker.
  • Bexarotene of formula I is a retinoid specifically selective for retinoid X receptors, as opposed to the retinoic acid receptors and is chemically known as 4-[l-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl] benzoic acid.
  • RXRs retinoid X receptors
  • RXRs retinoid X receptors
  • Activated RXRs form homodimers or heterodimers with RAR (retinoic acid receptors), vitamin D receptors, thyroid receptors or peroxisome proliferator activator receptors.
  • Retinoid agonists can activate the expression of retinoid regulated genes by removing negative transcription control or by facilitating positive transcriptional activity. They exert anticancer action by interfering with the growth of cells of the tumor.
  • the olefinic ester intermediate thus obtained is hydrolyzed using aqueous potassium hydroxide in methanol to give bexarotene, which is recrystallized from a mixture of ethyl acetate and hexane.
  • the main disadvantage of the process is use of silica gel chromatography for the purification of the intermediate which is time consuming and cumbersome technique.
  • the patent is also silent about the purity of the intermediate as well as of bexarotene.
  • US patent 5,466,861 describes a process for the preparation of bexarotene by reaction of 1,2,3,4,- tetrahydro-l-l,4,4,6-pentamethylnaphthalene with 4-carbomethoxybenzoyl chloride in presence of aluminium chloride in dichloromethane to form keto ester intermediate which was purified by flash chromatography.
  • the keto ester intermediate is then reacted with methyl triphenylphosphonium bromide in the presence of potassium hexamethyldisilazide to form olefinic ester intermediate which is purified using flash chromatography.
  • the olefinic ester intermediate is then hydrolyzed using potassium hydroxide in methanol to form bexarotene.
  • the main disadvantage is use of flash chromatography for the purification of intermediate which suffers from disadvantages in convenience, safety and reliability.
  • a publication namely, Journal of Medicinal Chemistry 1994, 37, 2930-2941 discloses a process for preparation of bexarotene by reaction of l,2,3,4,-tetrahydro-l-l,4,4,6-pentamethylnaphthalene with 4- carbomethoxybenzoyl chloride in presence of aluminium chloride to form keto ester intermediate which is crystallized from ethyl acetate followed by the addition of methanol. Keto ester intermediate is then reacted with methyl triphenylphosphonium bromide in the presence of sodium amide to form olefinic ester intermediate which is crystallized from a mixture of ethyl acetate and methanol.
  • Olefinic ester intermediate is then hydrolyzed using potassium hydroxide in methanol to form bexarotene, which is then crystallized from a mixture of ethyl acetate and hexane.
  • the process involve the use of sodium amide as a base for the Wittig reaction which is highly flammable, reacts violently with water producing very toxic fumes.
  • process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction, in the manufacturing process.
  • these limits are less than about 0.15 % by weight of each identified impurity.
  • Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.1 % by weight. Therefore, in the manufacture of a drug substance, the purity of the products, such as bexarotene is required before commercialization. Therefore, pharmaceutical active compounds must be either free from these impurities or contain impurities in acceptable limits.
  • regulatory authorities worldwide require that drug manufacturers should isolate, identify and characterize the impurities in their products.
  • present invention fulfills the need in the art and provides an improved, simple and commercially viable process for the preparation of highly pure bexarotene having impurities in acceptable amounts or free from impurities.
  • the present invention also provides novel impurities, their preparation, isolation and use as reference standard as well as reference marker.
  • the present invention provides a process for the removal of these impurities along with other unidentified from bexarotene.
  • Another objective of the invention is to provide a process for the preparation of bexarotene free from process related impurities.
  • Yet another objective of the present invention is to provide a method for determining identification and quantification of impurities in a sample of bexarotene.
  • the present invention provides an efficient and industrially advantageous process for the preparation of highly pure bexarotene containing any individual identified impurity less than 0.15% and unidentified impurity less than 0.10 % by HPLC.
  • present invention provides a process for the preparation of highly pure bexarotene, comprising the steps of:
  • a) activating the mono alkyl ester of terphthalic acid using a suitable activating agent to form reactive derivative of formula II;
  • Formula II wherein X is selected from halo such as chloro, bromo and the like; and R is alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like
  • present invention provides a process for the removal of impurities from bexarotene, comprising the steps of:
  • the present invention provides a process for the identification of an impurity in a sample of bexarotene, selected from one or more of the following compounds:
  • step (b) carrying out a chromatographic analysis on the sample of bexarotene to determine the relative retention time of impurities present in the sample compared to bexarotene; and comparing the relative retention- times determined in step (a) and (b); where if the relative retention times determined are substantially same, the impurity of bexarotene in the sample is identified as being the same as reference marker.
  • the present invention provides a method of determining the amount of an impurity, selected from one or more of impurity among A, B, C, D, E and F, the method comprising performing steps (a) and (b) in either order:
  • step (a) and calculating the amount of one or more of impurity among A, B, C, D, E and F in bexarotene, by reference to area of the HPLC peak in the sample against the area of HPLC peak associates with the same impurity in step (a).
  • present invention provides novel impurity A, B, C, D, E and F. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 is an X-ray powder diffraction pattern of bexarotene
  • Figure 2 is an infrared spectrum of bexarotene
  • Figure 3 is DSC thermogram of bexarotene
  • Figure 4 is HPLC chromatogram of a highly pure bexarotene sample
  • Figure 5 is HPLC chromatogram of a bexarotene sample containing impurities
  • highly pure bexarotene refers to bexarotene containing any individual identified impurity less than 0.15% and unidentified impurity less than 0.10 % by HPLC.
  • RRT relative retention time
  • the present invention provides an improved and industrially advantageous process for the preparation of highly pure bexarotene.
  • process involves the synthesis of highly pure bexarotene starting from mono alkyl ester of terphthalic acid.
  • process involves conversion of mono alkyl ester of terphthalic acid into reactive derivative by reaction with a suitable activating agent at a temperature -20 to 150 °C for few minutes to several hours, preferably till the completion of the reaction.
  • Suitable activating agent employed for the reaction includes phosphorus halides such as phosphorus pentachloride; phosphorus tribromide, phosphorus oxy halide such as phosphorus oxy chloride; oxalyl halide such as oxalyl chloride, oxalyl bromide; thionyl halide such as thionyl chloride and the like.
  • the reaction can be carried out in the presence of aprotic solvent selected from halogenated solvent such as dichloromethane, 1,2-dichloroethane, chloroform and the like.
  • reaction can be monitored by suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), thin layer chromatography (TLC), ultra pressure liquid chromatography (UPLC), gas chromatography (GC) and the like.
  • HPLC high-pressure liquid chromatography
  • TLC thin layer chromatography
  • UPLC ultra pressure liquid chromatography
  • GC gas chromatography
  • the compound of formula II is then in situ made to react with 1,2,3,4,-tetrahydro- 1,1, 4,4,6- pentamethylnaphthalene of formula III in presence of suitable catalyst in suitable solvent to form keto ester intermediate of formula IV.
  • reaction is carried out at temperature of -50 to 100 °C for few minutes to several hours, preferably for 5 minutes to 24 hours, more preferably till completion of the reaction.
  • Catalyst employed for the reaction can be Lewis acids that include aluminum chloride, titanium tetrachloride, boron trifluoride and the like.
  • Suitable solvent can be selected from halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, 1 ,2-diethoxyethane and the like.
  • keto ester intermediate of formula IV can be isolated from reaction mixture using suitable techniques.
  • reaction mixture is quenched with suitable quenching agent such as water, hydrochloric acid, dilute sulfuric acid and the like. Thereafter layers are separated.
  • quenching agent such as water, hydrochloric acid, dilute sulfuric acid and the like.
  • organic layer can be charcoalized and/or washed with water.
  • Keto ester intermediate of formula IV can be recovered from the resulting organic layer after removal of solvent.
  • Keto ester intermediate of formula IV when isolated, may contain certain identified and unidentified impurities. It is found that samples of keto ester intermediate of formula IV may contain certain impurities out of which two major impurities, which have been identified as impurity A and impurity B. The percentage of impurity A found to be directly proportional to amount of terphthalic acid present as an impurity in starting material i.e. mono alkyl ester of terphthalic acid. Keto ester intermediate of formula IV, if desired, can be purified to enhance the purity of the intermediate and/or to minimize the presence of identified and unidentified impurities or to make the intermediate free from these impurities.
  • keto ester intermediate of formula IV in a suitable solvent may be stirred at a temperature -25 to 50°C for few minutes to several hours.
  • the reaction mixture is stirred at a temperature of 5 to 25 °C for 5 minutes to 3 hours.
  • Suitable solvents include aliphatic hydrocarbons such as n- pentane, n-heptane, n-hexane, cyclohexane, pentane, hexane, heptane; aliphatic ethers such as isopropyl ether, methyl tert-butyl ether, diethyl ether; C ]-4 alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixture thereof.
  • Purified keto ester intermediate of formula IV can be isolated from the reaction mixture using a suitable techniques such as filtration, centrifugation and the like.
  • Keto ester intermediate of formula IV thus purified, may have purity more than 95.0 %, preferably more than 99.0% by HPLC, more preferably 99.5% by HPLC and may have impurities (identified and unidentified) less than 0.5 %, preferably less than 0.1 % by HPLC.
  • Specific purification method as described by the present invention is highly efficient in removing non-polar impurities along with some identified impurities such as impurity A and keto acid impurity B from the product.
  • X is halo selected from chloro, bromo, iodo and the like
  • Terphthalic acid if present in mono alkyl ester of terphthalic acid, even in traces will undergo reaction with activating agent to form a reactive derivative of the terphthalic acid, wherein both carboxylic groups are activated.
  • the activated diacid derivative then may reacts with 1, 2,3, 4,-tetrahydro- 1,1, 4,4,6- pentamethylnaphthalene of formula III under usual reaction conditions to give an halo impurity and/or impurity A as described above, depending upon the molar ratio of the compound of formula III present in the reaction medium.
  • keto ester intermediate of formula IV may be contaminated with the process related impurities such as impurities A and B along with some other unidentified impurities.
  • impurities As the main source of the above impurities is presence of terphthalic acid in starting material. So, higher contamination of teiphthalic acid in mono alkyl ester of terphthalic acid, will result in formation of said impurities during reaction in higher amounts. Therefore, formation of above impurities in keto ester intermediate of formula IV can be controlled by reducing the amount of terphthalic acid in the starting material. Further, impurities can be removed by purifying keto ester intermediate of formula IV using suitable solvents as described above.
  • Keto ester intermediate of formula IV is then made to react with methyl triphenylphosphonium halide in the presence of a suitable base to form olefinic ester intermediate of formula V.
  • the process involves the reaction of compound of formula IV with a methyl triphenylphosphonium halide in the presence of suitable base in an inert solvent at a temperature of -15 to 60 °C for few minutes to few hours, preferably till the completion of the reaction.
  • suitable bases employed for the reaction include alkali or alkaline metal hexamethyldisilazanes, C1-4 alkoxide, hydrides thereof such as potassium hexamethyldisilazane, sodium hydride (in paraffin oil), potassium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and the like.
  • Solvents used for the reaction include aliphatic or aromatic hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like or mixture thereof.
  • aliphatic or aromatic hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene
  • ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like or mixture thereof.
  • reaction completes in approximately in 2-3 hours.
  • olefinic ester intermediate of formula V can be isolated from the reaction mixture using suitable techniques.
  • reaction mixture can be quenched with suitable quenching agent that includes organic acid such as carboxylic acid like acetic acid, formic acid, tartaric acid; or inorganic acid such as hydrochloric acid, dilute sulfuric acid and the like.
  • suitable quenching agent that includes organic acid such as carboxylic acid like acetic acid, formic acid, tartaric acid; or inorganic acid such as hydrochloric acid, dilute sulfuric acid and the like.
  • Layers are separated by the addition of aqueous acid.
  • the organic layer can be charcoalized and/or washed with water and olefinic ester intermediate of formula V can be recovered from the resulting organic layer by removal of solvent by distillation or evaporation and the like.
  • Olefinic ester intermediate of formula V thus obtained can be optionally purified to enhance the purity as well to minimize the presence of impurities. Specifically, olefinic ester intermediate of formula V in a suitable solvent can be stirred at a temperature of -25 to 100 °C for few minutes to several hours, preferably at a temperature of 10 to 60 °C for 30 minutes to 12 hours.
  • Suitable solvents include C 1-4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; alkyl nitriles such as acetonitrile, propionitrile; C 5- aliphatic alkanes such as n-pentane, n-heptane, n-octane, cyclohexane, cyloheptane, pentane, hexane, heptane; aliphatic ethers such as diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1 ,2-diethoxyethane; cyclic ethers such as tetrahydrofuran and the like or mixture thereof or in mixture with water.
  • alkyl nitriles such as acetonitrile, propionitrile
  • Olefinic ester intermediate of formula V may be isolated from the reaction mixture using suitable techniques such as filtration, centrifugation and the like. Above described process for the purification of olefinic ester intermediate of formula V is highly efficient in removing triphenylphosphine oxide, which is formed as by product in the reaction, along with some other impurities.
  • impurities E and F are also potential impurities that may be present in the intermediate of formula V.
  • impurity A which may be carried forward from keto ester intermediate of formula IV.
  • the presence of impurity A in a sample of keto ester intermediate of formula IV results in the formation of impurities E and F by the sequence of reaction sequence as shown below:
  • impurities can be controlled by employing optimum amount of methyl triphenylphosphonium halide and base.
  • reaction is carried out using 1.5 to 2.0 mol equivalent of methyl triphenylphosphonium halide and 1.6 to 1.8 mol equivalent of base which will result in olefinic ester intermediate of formula V having fewer amounts of impurities C, D, E and F.
  • non-polar impurities if present, remain intact with compound of formula V and are carried forward due to similar non-polar nature of olefinic ester intermediate of formula V.
  • purification of intermediate of formula V to minimize the amount of impurities result in extensive loss of yield, which makes the process commercially unviable.
  • Removal of such non-polar impurities from intermediate of formula V require tedious purification method such as column chromatography or flash chromatography which is not amenable for the industrial synthesis. Therefore, the present invention avoids extensive purification as well as chromatographic purification at this stage and result in the development of a method for the removal of such impurities at final stage.
  • Olefinic ester intermediate of formula V is then hydrolysed to form bexarotene of formula I.
  • the reaction involves reaction of compound of formula V in the presence of suitable hydrolyzing agent at a temperature of 10 to 90 °C for few minutes to several hours, preferably till the completion of the reaction.
  • suitable hydrolyzing agent at a temperature of 10 to 90 °C for few minutes to several hours, preferably till the completion of the reaction.
  • hydrolysis reaction can be carried out using basic conditions.
  • Base employed for hydrolysis includes alkali or alkaline earth metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • reaction can be carried out in the presence of a suitable solvent that includes C 1-4 alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol; aliphatic ketone such as acetone; ethers such as diethyl ether, ethyl methyl ether, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like or mixture thereof.
  • a suitable solvent that includes C 1-4 alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, iso-butanol; aliphatic ketone such as acetone; ethers such as diethyl ether, ethyl methyl ether, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane and the like or mixture thereof.
  • reaction can
  • the suitable solvents for washing include aliphatic esters such as ethyl acetate, n-propyl acetate, n-butyl acetate; C 5- 9 aliphatic alkanes such as n-pentane, n-hexane, n-heptane, n-octane, pentane, hexane, heptane, octane, cyclopentane, cyclohexane; aromatic hydrocarbons such as benzene, toluene, 1,2-xylene, 1,4-xylene; halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, C 5-8 alkyl ethers such as diethyl ether, diisopropyl
  • mixture of aliphatic ester and aliphatic alkane for washing of reaction mixture as salt of bexarotene formed during reaction has very less or no solubility in the solvent mixture and most of impurities have high solubility in solvent mixture.
  • aqueous reaction mixture is acidified to precipitate the desired product from the reaction mixture.
  • the product, thus precipitated may be isolated from the reaction mixture by suitable techniques such as filtration, centrifugation and the like.
  • the present inventors have developed a selective purification method for the removal of polar and non- polar impurities from the reaction mixture containing bexarotene or salts thereof that are carried forward from olefinic intermediate of formula V along with other impurities to obtain highly pure bexarotene which complies with all the regulatory needs of process development and ICH guidelines.
  • Process of removal of impurities involves washing of the reaction mixture containing bexarotene or salts thereof with a suitable solvent as specified above.
  • the process of present invention is highly advantageous to remove non-polar impurities from the reaction mixture.
  • Bexarotene of formula I, thus prepared can be optionally further purified using a suitable solvent to enhance the purity by crystallization.
  • process involves dissolution of bexarotene in a suitable solvent; which can be accomplished by optionally heating to a temperature of 25 to 100 °C for 5 minutes to 6 hours, preferably till clear solution is obtained.
  • suitable solvents include Ci -4 alcohols such as methanol, ethanol, propanol, isopropanol; aliphatic C 3-5 ketones such as acetone, ethyl methyl ketone, diethyl ketone; C 4-8 aliphatic esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate; C 5- 8 aliphatic ethers such as diethyl ether, ethyl methyl ether, isopropyl ether, methyl tert-butyl ether; cyclic ether such as tetrahydrofuran; halogenated solvent such as dichloromethane, dichloroethane, chloroform and the
  • the resulting mixture can be optionally charcoalized to improve colour of product.
  • Crystallization of bexarotene can be induced by cooling reaction mixture or by adding suitable anti solvent to reaction mixture.
  • Anti-solvents employed include solvents in which bexarotene has less solubility or no solubility, preferably selected from water, aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, pentane, hexane, heptane, octane, and the like or mixture thereof.
  • Purified bexarotene can be isolated from the mixture using a suitable technique such as filtration, centrifugation and the like.
  • bexarotene of formula I can be dissolved in a suitable solvent as described above followed by removal of solvent to give a residue. Purified bexarotene can be isolated from the residue by addition of suitable anti solvent. The reaction mixture can be stirred for few minutes to few hours, preferably for 2 to 4 hours and filtered or centrifuged to give pure bexarotene.
  • bexarotene can be purified by washing with a suitable solvent.
  • bexarotene is slurried in a suitable solvent at temperature of -20 to 25 °C for few minutes to few hours.
  • suitable solvent employed include water, C 1-4 alcohols such as methanol, ethanol; C 3- 5 aliphatic ketones such as acetone, ethyl methyl ketone, diethyl ketone; C 4-8 aliphatic ester such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate; C 5-8 ethers such as diethyl ether, ethyl methyl ether, isopropyl ether, methyl tert-butyl ether and the like or mixture thereof.
  • Purified bexarotene can be isolated from the mixture using a suitable technique such as filtration, centrifugation and the like.
  • Purification process as described by the present invention has several advantageous effects; mainly it improves the purity of compound and increases assay of bexarotene by reducing inorganic impurities present in bexarotene. Purification processes described are also efficient in removing non-polar as well as polar impurities present in crude bexarotene. Crystallization process can be repeated or can be used along with other purification processes till the product of desired purity is obtained. It is advantageous to involve purification of bexarotene with water miscible organic solvent followed by crystallization from water immiscible organic solvent to get rid of impurities and to yield highly pure bexarotene.
  • Bexarotene thus prepared have displays purity of more than 99.0% by HPLC, preferably 99.5% by HPLC, more preferably 99.9%.
  • Bexarotene prepared by the present invention contain identified and unidentified impurities less than 0.15%, preferably less than 0.10 %, respectively more preferably free from impurities.
  • Bexarotene thus synthesized can be characterized by X-Ray diffraction (XRD), Infrared spectroscopy (IR) or differential scanning calorimetry (DSC). Crystalline nature of bexarotene is characterized by X- ray diffractogram, which shows the unique characteristic peaks as shown in Figure 1. X-ray diffraction patterns of bexarotene is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • XRD X-Ray diffraction
  • IR Infrared spectroscopy
  • DSC differential scanning calorimetry
  • Bexarotene is also characterized by Infrared spectrum (IR) and differential scanning calorimetry (DSC) as shown in Figures 2 and 3 respectively.
  • IR Infrared spectrum
  • DSC differential scanning calorimetry
  • thermogram shows an endothermic peak at around 224 °C.
  • Highly pure bexarotene obtained by the process of present invention is also characterized by chromatographic analysis, preferably by HPLC as shown by Figure 4.
  • present invention provides novel impurities such as A, B, C, D, E and F.
  • the impurities as described in the present invention can be either isolated from reaction mixture or can be synthesized so that they can be used as reference standard as well as reference marker.
  • the isolation as well as synthesis of each of impurities is described herein below.
  • Isolation of impurities A and/or B is accomplished by concentrating the filtrate, obtained during purification of keto ester intermediate of formula IV, followed by separation of impurities using various purification techniques such as column chromatography, preparative column chromatography, preparative thin layer chromatography and the like.
  • impurity A and/or B can be prepared by following same reaction sequence as described earlier for the preparation of keto ester intermediate of formula IV using terphthalic acid in place of mono alkyl ester of terphthalic acid.
  • Keto acid impurity B can also be prepared by the hydrolysis of the keto ester intermediate of formula IV. The hydrolysis can be carried out under acidic or basic condition.
  • keto ester intermediate of formula IV if present, unreacted in olefinic ester intermediate of formula V then keto ester intermediate present as an impurity gets hydrolyzed in the last stage of base assisted hydrolysis and result in the formation of impurity B in the final product i.e. bexarotene.
  • Isolation of impurities C, D, E and F is accomplished from residue obtained by concentrating the organic layer obtained after washing of aqueous reaction mixture containing bexarotene salt.
  • these impurities may be eluted from the column using mixture of solvents such as ethyl acetate: hexane or ethyl acetate: heptane.
  • the impurities are eluted in different fractions based upon the polarity of the solvent used for elution.
  • Impurity F is eluted first followed by impurities E, D and C.
  • impurities C and D can be synthesized by reacting olefinic ester intermediate of formula V with methyl triphenylphosphonium halide using the reaction sequence as described in the present invention.
  • impurities E and F can be synthesized by reacting impurity A with methyl triphenylphosphonium halide using the reaction sequence as described in the present invention.
  • the presence or absence of an impurity in a product s ou d be identified in any quality control process in order to ensure that process complies with the required standards set down in the regulatory approval of that product prior to it being released for commercial sale. Therefore, presence of the above impurities present at intermediate stage or bexarotene may be identified by chromatographic techniques like thin layer chromatography (TLC) or high-pressure liquid chromatography (HPLC) and preferably using HPLC.
  • TLC thin layer chromatography
  • HPLC high-pressure liquid chromatography
  • present invention provides a HPLC method for identification as well as quantification of the impurities present in a sample of bexarotene.
  • a reference sample of bexarotene containing all the six impurities along with the intermediate of formula V, as an impurity is prepared by dissolving bexarotene (containing impurities) in diluent as specified above and then analyzed chromatographic HPLC method of the present invention to identify the impurities by calculating their RRT. Specifically, 1 mg sample of bexarotene is dissolved in 1 ml of diluent (mixture of mobile phase A and B in ration of 30: 70). Bexarotene containing impurities displays HPLC chromatogram as shown in Figure 5.
  • the present invention provides a process for identification of an impurity in a sample of bexarotene, selected from one or more of impurities amongst A, B, C, D, E or F.
  • the process for identification of impurities involves the chromatographic analysis of reference sample containing one or more of impurities amongst A, B, C, D, E or F (reference marker) and bexarotene. The same analysis is also carried out on the sample of bexarotene. Thereafter, relative retention times of the impurities present in reference sample and sample of bexarotene is carried out. Then by comparing the relative retention times calculated in the two samples, presence of impurity can be determined.
  • the reference sample can be prepared by adding any one or more of the identified impurities of present invention to bexarotene sample. If the relative retention times thus determined in the two samples are substantially same, the impurity of bexarotene in the sample is identified as being the same as reference marker.
  • the chromatographic analysis can be carried out by HPLC or TLC. Preferably, HPLC analysis is carried out by the method as described above.
  • the present invention provides a method of determining the amount of an impurity, selected from one or more of impurity among A, B, C, D, E and F.
  • the process for quantification of impurities involves the chromatographic analysis of the reference sample containing known amount of one or more of impurities amongst A, B, C, D, E or F (reference marker) and bexarotene. Same analysis is also carried out on sample of bexarotene. Thereafter, relative retention times of the impurities present in reference sample and sample of bexarotene is calculated and also area under the peak with the specific impurity or impurities of present invention are calculated. Then by comparing the area under the peaks (referring to RRT of the specific impurity) amount of one or more of impurity among A, B, C, D, E and F in bexarotene can be calculated.
  • the reference sample can be prepared by adding known concentration of one or more of the identified impurities of present invention to bexarotene sample.
  • the chromatographic analysis can be carried out by HPLC. Preferably, HPLC analysis is carried out by the method as described above.
  • Major advantages realized in the present invention are that process can be easily and conveniently scaled-up for industrial large-scale production and that the process is simple, economical, high throughput and provides highly pure bexarotene.
  • the other advantage of the present invention is that it circumvents the need for chromatographic purification and use of hazardous reagent such as sodium amide.
  • the present invention provides method for the selective removal of the impurities.
  • the present invention also provides novel impurities that may be present in bexarotene and their isolation, characterization so that their presence in final product can be easily identified and quantified.
  • reaction mass was cooled to 15-20 °C and poured into 5N hydrochloric acid (1L). Layers were separated and aqueous layer was extracted with dichloromethane (600 ml). The combined organic layer was washed successively with demineralized water (2 L) and sodium bicarbonate solution (8 % solution, 1600 ml)) The resulting organic layer was distilled off at atmospheric pressure to give residue which was dried to give title compound having purity 98.58 %, impurity A: 0.52 % and keto acid impurity B: 0.22 % by HPLC. Purification:
  • n-Heptane 400 ml was added to the resulting product and stirred for 30 minutes. The mixture is then cooled to 5-10 °C, stirred for 1 hour and filtered. The solid, thus obtained, is slurry washed with cold n- heptane (200 ml) and dried at 65°C to give 173 g of title compound as white to off white crystalline powder having purity 99.75%, impurity A: 0.14 % and keto acid impurity B: 0.02% by HPLC.
  • reaction mixture was poured into 2N hydrochloric acid (1 L). Layers were separated and aqueous layer was extracted with toluene (300 ml). The combined organic layer was washed with water (2 L). Activated carbon (0.05 g) was added to the resulting organic layer and stirred for 15 minutes at 25-30 °C. Resulting reaction mass was filtered through hyflo. The filtrate was distilled off under vacuum at 50-55°C to give title compound which was stirred in methanol (1 L) to remove triphenylphosphine oxide.
  • Method A Bexarotene (lOOg) was dissolved in tetrahydrofuran (400 ml) and activated carbon (0.04 g) was added to the solution. The reaction mixture was stirred for 30 minutes, filtered through hyflow and bed was washed with tetrahydrofuran (50 ml). Demineralized water (500 ml) was added to resulting filtrate at 15-20°C and stirred for 60 minutes. The precipitated solid was filtered, slurry washed with demineralized water (2 x 250 ml) and dried under vacuum at 55-60°C to give 75.6 g of title compound having purity 99.87% by HPLC.
  • Method B Bexarotene (100 g) in ethyl acetate (1500 ml) was heated to 60-65°C to dissolve the solid and filtered hot to remove the suspended particles. n-Heptane (1500 ml) was added to the resulting mixture and stirred for 30 minutes. Thereafter, the reaction mixture was cooled to 5-10 °C and stirred for 1 hour. The precipitated solid was filtered, slurry washed with n-heptane (500 ml), dried under vacuum at 60-65°C to give 69.8 g of the title compound having purity 99.95 % by HPLC.
  • Method C Bexarotene (100 g) in ethyl acetate (1500 ml) was heated to dissolve the solid and filtered hot to remove the suspended particles. The resulting solution is distilled off under vacuum at 40-45 °C to give white to off white powder.
  • n-Heptane (500 ml) was added to the resulting product at 25-30 °C and stirred. The reaction mixture was heated to 60-65°C and stirred for 30 minutes. Thereafter, reaction mixture was cooled to 5-10°C and stirred for 1 hour. The precipitated solid was filtered, slurry washed with n-heptane (100 ml) and then dried under vacuum at 60-65°C to give 90.2 g of the title compound having purity 99.99 % by HPLC.
  • Method D Bexarotene (10 g) in methanol (500 ml) was stirred at room temperature and heated to 65- 68°C to obtain a clear solution. The reaction mixture was stirred for 25 minute at 65-68°C, followed by addition of activated carbon (0.5g) at 65-68°C. Thereafter, the reaction mixture was filtered hot through hyflo at 60-65°C and the bed was washed with methanol (150 ml). The resulting solution was cooled to 10-15°C, stirred for 1 hour and filtered. The solid thus obtained was washed with cooled methanol (30 ml) and dried under vacuum at 55-60°C to give 5.82 g of title compound having purity 99.81 % by HPLC.
  • Method E Bexarotene (10 g) in ethyl acetate (150 ml) was stirred at room temperature and heated to 65-68°C to obtain a clear solution. The reaction mixture was stirred for 25 minute at 65-68°C, followed by addition of activated carbon (0.5g) at 65-68°C. Reaction mixture was then filtered hot through hyflo bed, cooled to 10-15°C, stirred for 1 hour and filtered. The solid thus obtained was washed with cold ethyl acetate (20 ml) and dried under vacuum at 55-60°C to give 5.01 g of title compound having purity 99.81 % by HPLC.
  • Method F Bexarotene (10 g) in acetone (400 ml) was stirred at room temperature and heated to 55- 58°C to obtain a clear solution. The reaction mixture was stirred for 25 minute at 55-58°C, followed by addition of activated carbon (0.5g) at 55-58°C. Thereafter, reaction mixture was filtered through hyflo bed at 50-55°C, cooled to 0-5°C, stirred for 1 hour and filtered. The solid thus obtained was washed with cold acetone (20 ml) and dried under vacuum at 55-60°C. to give 4.82 g of title compound having purity 99.81 % by HPLC.
  • Method G Bexarotene (50 g) was dissolved in tetrahydrofuran (200 ml) and activated carbon (5.0 g) was added to the solution. The reaction mixture was stirred for 30 minutes, filtered through hyflow and bed was washed with tetrahydrofuran (50- ml). Demineralized water (200ml) was slowly added to resulting filtrate at 15-20°C and stirred for 60 minutes. Solid thus precipitated was filtered and dissolved in ethyl acetate 600 ml) at 60-65°C and was filtered to remove the suspended particles, n- Heptane (720 ml) was added to the resulting mixture and stirred for 30 minutes.
  • reaction mixture was cooled to 5-10 °C stirred for 1 hour, slurry washed with n-heptane (100 ml). The resulting solid was dried under vacuum at 60-65°C to give 28 g of the title compound having purity 99.72 % by HPLC.
  • Method H Bexarotene (10 g) in dichloromethane (400 ml) was stirred at room temperature and heated to 35°C to obtain a clear solution. n-Hexane (600 ml) was added to the resulting mixture and stirred for 1 hour at 15-20 °C. The precipitated solid was filtered and washed with a mixture of dichloromethane and n-hextane The resulting solid was dried under vacuum at 65°C to give 6.35 g of the title compound having purity 99.91 % by HPLC.
  • Method I Bexarotene (10 g) in ethyl acetate (150 ml) was stirred at room temperature and heated to 65-70°C to obtain a clear solution. n-Hexane (400 ml) was added to the resulting mixture and stirred for 1 hour at 15-20 °C. The precipitated solid was filtered and washed with ethyl acetate and n-hexane (1 :2, 100 ml). The resulting solid was dried under vacuum at 65°C to give 5.21 g of the title compound having purity 99.51 % by HPLC.
  • Method J Bexarotene (10 g) in dichloromethane (400 ml) was stirred at room temperature and heated to 35-38°C to obtain a clear solution. The reaction mixture was stirred for 25 minute at 35-38°C, followed by addition of activated carbon (0.5g) at 35-38°C. Thereafter, reaction mixture was filtered through hyflpbed at 35-38°C and the bed was washed with dichloromethane (50 ml). The resulting solution was cooled to 0-5°C, stirred for 1 hour and filtered. The solid thus obtained was washed with cold dichloromethane (20 ml) and dried under vacuum at 55-60°C to give 4.25 g of title compound having purity 99.85 % by HPLC.
  • phosphorous pentachloride 60g was added at 25-30 °C and reaction mixture was heated to 38-44°C. After completion of reaction (monitored by TLC), the reaction mass was cooled to -5 to -10 °C. Thereafter, aluminum chloride (113 g) and l,2,3,4,-tetrahydro-l-l,4,4,6-pentamethylnaphthalene (40 g) were successively added to the reaction mixture and refluxed for 2 hours at 35 to 40 °C.
  • the first fraction eluted with mixture of ethyl acetate and heptane was collected and the solvent was distilled to give 1.08 g of impurity F.
  • the second fraction eluted with mixture of ethyl acetate and heptane was collected and concentrated to give 1.8 g of impurity E.

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Abstract

L'invention concerne un procédé amélioré de préparation de bexarotène hautement purifié de formule (I). L'invention concerne également des impuretés de bexarotène, un procédé d'isolement et d'identification de ces impuretés, et l'utilisation de ces impuretés en tant que marqueurs de référence et que normes de référence.
PCT/IN2011/000322 2010-05-11 2011-05-09 Procédé de préparation de bexarotène hautement purifié WO2011141928A1 (fr)

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CN106146313A (zh) * 2015-04-15 2016-11-23 天津药物研究院有限公司 贝沙罗汀关键中间体的制备方法
CN110455974A (zh) * 2018-05-07 2019-11-15 人福普克药业（武汉）有限公司 采用高效液相色谱法检测贝莎罗汀软胶囊杂质的方法
CN115057776A (zh) * 2022-06-15 2022-09-16 必维申瓯质量技术服务温州有限公司 2-萘甲酸乙酯衍生物的合成方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146313A (zh) * 2015-04-15 2016-11-23 天津药物研究院有限公司 贝沙罗汀关键中间体的制备方法
CN110455974A (zh) * 2018-05-07 2019-11-15 人福普克药业（武汉）有限公司 采用高效液相色谱法检测贝莎罗汀软胶囊杂质的方法
CN110455974B (zh) * 2018-05-07 2021-09-14 人福普克药业（武汉）有限公司 采用高效液相色谱法检测贝莎罗汀软胶囊杂质的方法
CN115057776A (zh) * 2022-06-15 2022-09-16 必维申瓯质量技术服务温州有限公司 2-萘甲酸乙酯衍生物的合成方法
CN115057776B (zh) * 2022-06-15 2023-08-22 必维申瓯质量技术服务温州有限公司 2-萘甲酸乙酯衍生物的合成方法

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