WO2011029088A2 - Préparation de raloxifène et de ses sels - Google Patents

Préparation de raloxifène et de ses sels Download PDF

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Publication number
WO2011029088A2
WO2011029088A2 PCT/US2010/047966 US2010047966W WO2011029088A2 WO 2011029088 A2 WO2011029088 A2 WO 2011029088A2 US 2010047966 W US2010047966 W US 2010047966W WO 2011029088 A2 WO2011029088 A2 WO 2011029088A2
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WO
WIPO (PCT)
Prior art keywords
methylsulfonyloxy
ethoxy
piperidinyl
hydrochloride
raloxifene
Prior art date
Application number
PCT/US2010/047966
Other languages
English (en)
Other versions
WO2011029088A3 (fr
Inventor
Mohanty Sandeep
Prashanth Reddy Gaddameedhi
Gunti Murali Mohan
Kesava Reddy
Pavan Kumar Bathini
Venkateswara Reddy Kommareddy
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2011029088A2 publication Critical patent/WO2011029088A2/fr
Publication of WO2011029088A3 publication Critical patent/WO2011029088A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • aspects of the present application relate to processes for preparing raloxifene and its salts.
  • the drug compound having the adopted name "raloxifene hydrochloride” has a chemical name methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[i ]thien-3- yl]-[4-[2-(1 -piperidin l)ethoxy]phenyl]-, hydrochloride and has structural Formula I.
  • Raloxifene hydrochloride is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM), that belongs to the benzothiophene class of compounds and is the active ingredient in a product sold by Eli Lilly and Company as EVISTA® tablets, containing 60 mg of raloxifene hydrochloride, equivalent to 55.71 mg of raloxifene base.
  • SERM selective estrogen receptor modulator
  • U.S. Patent No. 4,418,068 describes the compound 6-hydroxy-2-(4- hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, and preparation of its pharmaceutically acceptable salts by various methods.
  • 6,723,739 and 6,756,388 disclose preparation of raloxifene free base, by hydrolysis of 6-methanesulfonyloxy-2-(4- methanesulfonyloxyphenyl)-3[4-(2-piperidinoethoxy)-benzoyl]benzo[b] thiophene using a base in the presence of a mixture of solvents.
  • the present application provides processes for preparing raloxifene or a pharmaceutically acceptable salt thereof, embodiments comprising hydrolyzing 6-methylsulfonyloxy-2-[(4-methylsulfonyloxy)phenyl]-3-[4(2- (piperidinyl)ethoxy]-benzoyl]benzothiophene hydrochloride of Formula III, in the presence of an aqueous base, to form raloxifene free base of Formula II.
  • the present application provides processes for preparing 6- methylsulfonyloxy-2-[(4-methylsulfonyloxy)phenyl]-3-[4(2-(piperidinyl)ethoxy]- benzoyl]benzothiophene hydrochloride, an intermediate for the preparation of raloxifene, embodiments comprising:
  • Fig. 1 is a schematic representation of a process for the preparation of raloxifene free base of Formula II. DETAILED DESCRIPTION
  • aspects of the present application provide processes for making raloxifene, which processes are simple, cost effective, ecologically friendly, reproducible, and afford high yields and purity of the final compound, therefore being well suited for production on an industrial scale.
  • embodiments of processes to prepare raloxifene and its salts can use only water as a solvent for hydrolysis, making the processes simple, non hazardous, and easily scalable for commercial production. Further the processes are free from the technical problems associated with the prior processes and are also cost effective, commercially viable, and well suited for scale-up.
  • the present application provides processes for preparing raloxifene or a pharmaceutically acceptable salt thereof, embodiments comprising hydrolyzing 6-methylsulfonyloxy-2-[(4-methylsulfonyloxy)phenyl]-3-[4(2- (piperidinyl)ethoxy]benzoyl]benzothiophene hydrochloride of Formula III, in the presence of an aqueous base, to form raloxifene free base of Formula II.
  • Suitable bases that can used for hydrolysis include, but are not limited to, inorganic bases including: alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonium
  • Suitable temperatures for conducting the reaction range from about 15°C to about 120°C, or from about 100°C to about 1 15°C.
  • the reaction can be conducted until its completion, typically, requiring from about 1 hour to about 10 hours, or longer.
  • the mixture is cooled and the reaction is quenched by adding additional water and an organic solvent, and the pH of the mass is adjusted to an acidic value.
  • the formed solid can be separated, such as by filtration, centrifugation, etc.
  • the obtained raloxifene can optionally be purified by crystallizing or any combination of acid and base treatments.
  • Suitable organic solvents used for reaction quenching and for purification include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and isopropanol; ketones, such as, for example, acetone, methyl isobutyl ketone, and the like; and any mixtures thereof in various proportions.
  • Raloxifene free base may be optionally converted into pharmaceutically acceptable salts, by reacting with a pharmaceutically acceptable acid.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable acids, including inorganic acids, such as, for example, hydrochloric acid and hydrobromic acid, and organic acids, such as, for example, acetic acid, tartaric acid, and methanesulfonic acid.
  • inorganic acids such as, for example, hydrochloric acid and hydrobromic acid
  • organic acids such as, for example, acetic acid, tartaric acid, and methanesulfonic acid.
  • the conversion of raloxifene free base to a hydrochloride salt may be achieved by treating the solution of raloxifene base with a source of hydrochloric acid.
  • Sources of hydrochloric acid that can be used include, but are not limited to, aqueous hydrochloric acid, hydrogen chloride gas purged into a suitable organic solvent, and ammonium chloride.
  • Suitable solvents used for salt formation include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and isopropanol; ketones, such as, for example, acetone, methyl isobutyl ketone, and the like; water; and any mixtures thereof in various proportions.
  • the methods by which a solid material is recovered from the final mixture, with or without cooling below the reaction temperature can be any of techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like.
  • a solid product may optionally be further dried. Drying can be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying can be carried out at temperatures about 40°C to about 50°C, or higher or lower temperatures can be used. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours, or longer, frequently being adequate.
  • the present application provides processes for preparing 6- methylsulfonyloxy-2-[(4-methylsulfonyloxy)phenyl]-3-[4(2-(piperidinyl)ethoxy]- benzoyl]benzothiophene hydrochloride, an intermediate for the preparation of raloxifene, embodiments comprising:
  • Step 1 involves reacting 4-[2-(piperidinyl)ethoxy]benzoic acid
  • Suitable organic solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; and any mixtures thereof in various proportions.
  • halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform
  • hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane
  • ethers such as 1 ,4-dioxane and tetrahydrofuran
  • Formula III to thionyl chloride may range from about 1 :5 to about 1 :2, or about 1 :3.
  • Suitable temperatures for conducting the reaction range from about 15°C to about 100°C, or from about 25°C to about 35°C.
  • the reaction can be conducted until its completion, typically requiring from about 1 hour to about 10 hours, or longer.
  • the 4-[2-(piperdinyl)ethoxy]benzoyl chloride obtained may be purified by converting it into an acid addition salt, using acids such as hydrochloric acid, hydrobromic acid, oxalic acid, acetic acid, formic acid, and the like, in a suitable solvent.
  • the obtained salt can be purified by recrystallization and converted back into the compound of Formula IV.
  • Step 2) involves acylating 6-methylsulfonyloxy-2-[4- methylsulfonyloxy)phenyl]benzothiophene of Formula III with 4-[2- (piperidinyl)ethoxy]benzoyl chloride hydrochloride of Formula IV, in the presence of a Lewis acid and suitable solvent, to form 6-methylsulfonyloxy-2-[(4- methylsulfonyloxy)phenyl]-3-[4(2-(piperidinyl)ethoxy]benzoyl]benzothioph hydrochloride of Formula III.
  • Suitable organic solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1 ,4-dioxane and tetrahydrofuran; and any mixtures thereof in various proportions.
  • halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform
  • hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane
  • ethers such as 1 ,4-dioxane and tetrahydrofuran
  • Suitable Lewis acids include, but are not limited to, aluminum trichloride, boron trifluoride, and the like;
  • Suitable temperatures for conducting the reaction range from about 10°C to about 50°C, or higher, or about 10°C to about 35°C.
  • the reaction can be conducted until its completion, typically requiring from about 1 hour to about 10 hours, or longer.
  • reaction After completion of the reaction, the reaction is quenched with water, pH of the mass is adjusted to an acidic value, and the product is extracted with a water immiscible organic solvent.
  • the organic layer can be distilled, or the solution can be progressed to the next stage without isolating a compound of Formula III.
  • the starting materials 4-[2-(piperidinyl)ethoxy]benzoic acid hydrochloride of Formula VI and 6-methylsulfonyloxy-2-[4-methylsulfonyloxy]phenyl]- benzothiophene of Formula IV can be prepared according to published processes, such as using a process of U.S. Patent No. 4,358,593.
  • EXAMPLE 1 PREPARATION OF 6-M ETHYLS U LFON YLOXY-2 [(4-M ETH YL- SULFONYLOXY)PHENYL]-3-[4(2-(PIPERIDINYL)ETHOXY]BENZOYL]- BENZOTHIOPHENE HYDROCHLORIDE.
  • the solid is charged into a round bottom flask containing isopropanol (150 mL), heated to reflux, maintained for 30 minutes, cooled to 25-30°C, and stirred for solid formation.
  • the solid is filtered and washed with isopropanol (50 mL).
  • the solid is dried under vacuum at 60-70°C for 5 hours, to afford 65 g of the title compound. Purity by HPLC: 96.27% .
  • 6-Methylsulfonyloxy-2[(4-methyl sulfonyloxy)phenyl]-3-[4(2- (piperidinyl)ethoxy]benzoyl]benzothiophene hydrochloride 50 g is charged into a round bottom flask. Potassium hydroxide (72 g) dissolved in water (250 mL) is added and the mixture is heated to 105-1 10°C and maintained for 30-45 minutes. Water (250 mL) is added and the mixture is cooled to 20-25°C. Acetone (50 mL) is added, the pH of the reaction solution is adjusted to 10, and the mixture is stirred for 45 minutes. The formed solid is filtered, washed with acetone (50 mL), and suction dried for 30 minutes.
  • the wet solid is charged into a round bottom flask containing acetone (172 mL) and water (86.2 mL) and heated to 60°C.
  • the pH is adjusted to 2 by addition of aqueous hydrochloric acid (5%, 10 mL) and the solution is cooled to 0-5°C and stirred for solid formation.
  • the solid is filtered, washed with acetone, and suction dried for 30 minutes, to afford 31 g of the title compound. Purity by HPLC:
  • EXAMPLE 3 PURIFICATION OF RALOXIFENE HYDROCHLORIDE.
  • Raloxifene hydrochloride (20 g) is charged into a round bottom flask containing methanol (200 mL) and maintained for 10-15 minutes under stirring. Water (40 mL) is added and the mass is heated to 60-70°C and maintained for 30- 45 minutes. Carbon is added and the mixture is maintained for 10-15 minutes at the same temperature, then the carbon is removed by filtration and the solid is washed with methanol (40 mL). The filtrate pH is adjusted to 2 by adding aqueous hydrochloric acid (5%, 2 mL), the mass is maintained at the same temperature 60- 70°C for 3-4 hours, then the mass is slowly cooled to 50 ⁇ 2.5°C over 30-90 minutes, and maintained for 45-75 minutes.
  • aqueous hydrochloric acid 5%, 2 mL
  • the reaction mass is slowly cooled to 40 ⁇ 2.5°C over 30-90 minutes and maintained at the same temperature for 45-75 minutes.
  • the reaction mass is slowly cooled to 22.5-27.5°C over 30-90 minutes and maintained for 45-75 minutes.
  • Water (200 mL) is added over 75-105 minutes and the mass is quickly cooled to 0-5°C and maintained for 75-105 minutes.
  • the solid is filtered and washed with methanol (20 mL) and petroleum ether (26 mL), is suction dried, and then is dried at 70°C.
  • Raloxifene free base (20 g) is charged into a round bottom flask containing methanol (201 mL) and water (40.5 mL) and stirred for about 10 minutes.
  • the pH is adjusted to 2 by adding aqueous hydrochloric acid (5%, 2 mL) and the mixture is heated to reflux.
  • Activated carbon (1 g) is added and the mixture is stirred for about 10 minutes, then the mixture is filtered through a Hyflow (flux-calcined diatomaceous earth) bed and the bed is washed with methanol (40.5 mL).
  • the filtrate is cooled to 0-5°C, water (201 mL) is added, and the mixture is stirred for solid formation.
  • EXAMPLE 5 PROCESS FOR THE PREPARATION OF 6- METHYLSULFONYLOXY-2[(4-METHYLSULFONYLOXY)PHENYL]-3-[4(2- (PIPERIDINYL)ETHOXY]BENZOYL]BENZOTHIOPHENE HYDROCHLORIDE.
  • the organic and aqueous layers are separated and the aqueous layer is extracted with methylene chloride (200 L*2).
  • the combined organic layer is washed with aqueous hydrochloric acid (250.5 L*2) and then water (213 L*2).
  • the organic layer is separated and cone, hydrochloric acid (20 L) is added, the mixture is heated to reflux and maintained for about 45-40 minutes, and the solvent is distilled completely under vaccum to afford a residue.
  • Methylene chloride (250 L) is mixed with the residue and the mixture is cooled to 5-10°C and stirred for solid formation.
  • the solid is filtered, washed with methylene chloride (50 L), and suction dried under vacuum to afford 98 kg of a wet solid.
  • the wet solid is combined with isopropyl alcohol (250 L) and acetone (100 L) and the mixture is stirred for about 30-45 minutes at 25-30°C.
  • the solid is filtered, washed with isopropyl alcohol (100 L, then 50 L) and petroleum ether (50 L), suction dried, then dried under vaccum for 8-10 hours at 70-80°C to afford 66.10 kg of the title compound. Purity by HPLC: 97.5%.
  • Potassium hydroxide (92.8 kg) and water (290 L) are mixed for about 10-15 minutes.
  • 6-Methylsulfonyloxy-2[(4-methyl sulfonyloxy)phenyl]-3-[4(2- (piperidinyl)ethoxy]-benzoyl]benzothiophene hydrochloride (58 Kg) is added, and the mixture is heated to 105-1 10°C and maintained for 30-45 minutes. The mass is cooled to ambient temperature, water (290 L) is added, and the mixture is stirred for 20-30 minutes.
  • Acetone (580 L) is added, the pH of the mixture is adjusted to 10 using aq. hydrochloric acid (120 L), and the mixture is stirred for about 45 minutes.
  • the formed solid is filtered, washed with acetone (58 L), and suction dried for 30 minutes.
  • Raloxifene free base 38.2 kg is combined with methanol (382 L) and water (76.4 L), and the mixture is heated to 60-70°C to form a solution.
  • Activated carbon is added, the mixture is stirred for 10-15 minutes at 60-70°C, the mixture is filtered through a leaf filter, and the filter is washed with methanol.
  • the filtrate is heated to 60-70°C, cone, hydrochloric acid (3 L) is added and the mixture is stirred for 2-3 hours.
  • the solution is cooled step-wise to 50-55°C, 40-45°C, 30- 35°C, and 20-25°C, with each cooling step requiring 45-60 minutes, and with stirring for about 60 minutes at each temperature.

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Abstract

Cette invention concerne des procédés de préparation de raloxifène pur ou de ses sels, comprenant l'hydrolyse de chlorhydrate de 6-méthylsulfonyloxy- 2-[(4-méthylsulfonyloxy)phényl]-3-[4(2-(pipéridinyl)éthoxy)benzoyl]- benzothiophène, à l'aide d'une base aqueuse.
PCT/US2010/047966 2009-09-07 2010-09-07 Préparation de raloxifène et de ses sels WO2011029088A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2163/CHE/2009 2009-09-07
IN2163CH2009 2009-09-07
US31098710P 2010-03-05 2010-03-05
US61/310,987 2010-03-05

Publications (2)

Publication Number Publication Date
WO2011029088A2 true WO2011029088A2 (fr) 2011-03-10
WO2011029088A3 WO2011029088A3 (fr) 2011-11-24

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6723739B1 (en) * 1994-05-20 2004-04-20 Eli Lilly And Company Glucopyranoside benzothiophenes
US6756388B1 (en) * 1993-10-12 2004-06-29 Pfizer Inc. Benzothiophenes and related compounds as estrogen agonists
WO2009008000A2 (fr) * 2007-04-12 2009-01-15 Sun Pharmaceutical Industries Ltd. Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6756388B1 (en) * 1993-10-12 2004-06-29 Pfizer Inc. Benzothiophenes and related compounds as estrogen agonists
US6723739B1 (en) * 1994-05-20 2004-04-20 Eli Lilly And Company Glucopyranoside benzothiophenes
WO2009008000A2 (fr) * 2007-04-12 2009-01-15 Sun Pharmaceutical Industries Ltd. Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène

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