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WO2007110734A1 - Procede de preparation de tadalafil - Google Patents

Procede de preparation de tadalafil Download PDF

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Publication number
WO2007110734A1
WO2007110734A1 PCT/IB2007/000737 IB2007000737W WO2007110734A1 WO 2007110734 A1 WO2007110734 A1 WO 2007110734A1 IB 2007000737 W IB2007000737 W IB 2007000737W WO 2007110734 A1 WO2007110734 A1 WO 2007110734A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solvent
tadalafil
mixtures
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2007/000737
Other languages
English (en)
Inventor
Anthony Melvin Crasto
Narendra Shriram Joshi
Nitin Sharad Chandra Pradhan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Pharmaceuticals Ltd
Original Assignee
Glenmark Pharmaceuticals Ltd
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.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals Ltd filed Critical Glenmark Pharmaceuticals Ltd
Priority to EP07734067A priority Critical patent/EP2004644A1/fr
Publication of WO2007110734A1 publication Critical patent/WO2007110734A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates generally to a process for preparing tadalafil or a pharmaceutically acceptable salt or derivative thereof.
  • Tadalafil also known as (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-
  • Tadalafil is an orally administered phosphodiesterase type 5 (PDE5) inhibitor and has been developed as a treatment for male erectile dysfunction and the treatment of female sexual dysfunction. [0004] Tadalafil can be prepared via a series of intermediates. One synthesis for preparing tadalafil is illustrated below in Scheme I:
  • U.S. Patent No. 5,859,006 discloses the synthesis of a tadalafil intermediate
  • WO 2004/011463 discloses a process of preparing tadalafil intermediates from D-tryptophan methyl ester HCl salt and piperonal by refluxing the reagents in isopropyl alcohol, reacting the intermediate thus obtained with chloroacetyl chloride and tetrahydrofuran (THF) to provide another intermediate of tadalafil.
  • WO 2006/110893 discloses a process for the preparation of methyl ester intermediate (Compound III), and tadalafil using the methyl ester intermediate (Compound III).
  • Compound II and piperonal (Compound I) using a dehydrating agent selected from Na 2 SO 4 , K 2 SO 4 , MgSO 4 , CaSO 4 , CaCl 2, molecular sieve or mixtures thereof and a high boiling solvent such as N,N-Dimethyl acetamide.
  • Compound III is then reacted with chloroacetyl chloride (Compound IV) in the presence of a base such as NaHCO 3 and an organic solvent such as dichloromethane, providing another intermediate of tadalafil (Compound V), which is further reacted with aqueous methyl amine solution to provide tadalafil.
  • a dehydrating agent selected from Na 2 SO 4 , K 2 SO 4 , MgSO 4 , CaSO 4 , CaCl 2, molecular sieve or mixtures thereof and a high boiling solvent such as N,N-Dimethyl acetamide.
  • Compound III is then reacted with chloroacetyl chloride (
  • a process for preparing tadalafil or a pharmaceutically acceptable salt or derivative thereof comprising cyclizing a cis-isomer of a compound of Formula II in the presence of a base:
  • a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt or derivative thereof prepared by the processes of the present invention.
  • a pharmaceutical composition comprising a therapeutically effective amount of substantially pure tadalafil or a pharmaceutically acceptable salt or derivative thereof.
  • One embodiment of the present invention provides an intermediate of tadalafil of Formula II and a process for its preparation
  • X may be any suitable leaving group known in the art, which facilitates cyclization of compound of Formula II to provide the compound of formula I.
  • a leaving group include halogen, preferably chlorine; mesylate, tosylate and the like.
  • the process for preparing intermediate compound of Formula II includes the step of reacting a compound of Formula III or a salt thereof (e.g., a hydrochloride salt):
  • Y is a halogen, e.g., chlorine, bromine, iodide, etc.
  • X has the aforestated meaning in the presence of an organic reaction solvent and a base.
  • Suitable organic reaction solvents include halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof; aromatic hydrocarbons such as benzene, toluene, xylene and the like and mixtures thereof; non-cyclic ethers such as 1,2-dimethoxy ethane, di- or Methylene glycol dimethyl ether and the like and mixtures thereof.
  • the solvent is used in an amount of about 2 volumes to about 25 volumes.
  • Suitable bases include, but are not limited to, Ci-C 6 mono-, di- or tri-alkyl amines wherein the alkyl groups may be the same or different, e.g., triethylamine (TEA), C 3 -C 25 cyclic amines, e.g., pyridine; alkali metal carbonate and bicarbonates, e.g., sodium, potassium or lithium carbonates or bicarbonates, and the like and mixtures thereof.
  • TAA triethylamine
  • C 3 -C 25 cyclic amines e.g., pyridine
  • alkali metal carbonate and bicarbonates e.g., sodium, potassium or lithium carbonates or bicarbonates, and the like and mixtures thereof.
  • the base is present in an amount of about 1 equivalent to about 5 equivalents per equivalent of the compound of Formula III.
  • Formula IV is carried out at a temperature ranging from about -10 0 C to about 25 0 C and maintaining the reaction mixture at a temperature less than about 10 0 C for a time period of about 1 to about 5 hours, where the temperature and time may be suitably based on the base and solvent selected, to obtain a compound of Formula II.
  • the compound of Formula III can be reacted with the compound of Formula IV in an amount sufficient to form the compound of Formula II, e.g., an amount of compound of Formula III ranging from about 1 equivalent to about 3 equivalents and preferably from about 1 equivalent to about 1.8 equivalents per equivalent of the compound of Formula IV.
  • the compound of Formula II may be present in any form, for example, a mixture of cis and trans isomers.
  • the compound of Formula II is advantageously a mixture of cis:trans isomers in the ratio of from about 90:10 to about 10:90 and preferably from about 60:40 to about 40:60.
  • the desired cis-isomer of the compound of Formula II may be isolated by any known techniques in the art, for example, by crystallizing the cis isomer out from an organic solvent such as a halogenating solvent, for example, methylene chloride, ethylene chloride, chloroform and the like.
  • Another embodiment of the present invention provides a process for the preparation of intermediate compound of Formula III:
  • the process involves reacting D-tryptophan methyl amide of Formula VI or a salt thereof (e.g., the hydrochloride salt)
  • organic reaction solvent selected from the group consisting of halogenated solvents, alkyl esters of lower carboxylic acids, aromatic hydrocarbons and mixtures thereof.
  • Suitable halogenated solvents include dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof.
  • Suitable alkyl esters of lower carboxylic acids include those having the general formula R'-COOR 2 wherein R 1 and R 2 are each independently is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Representative examples of alkyl esters of lower carboxylic acids for use herein include ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate and the like and mixtures thereof.
  • Suitable aromatic hydrocarbons include, but are not limited to, benzene, toluene, xylene and the like and mixtures thereof.
  • the organic reaction solvent is ordinarily present in the reaction in an amount ranging from about 5 volumes to about 40 volumes.
  • Formula VII can be carried out at a temperature ranging from about 0 0 C to about 50 0 C for a time period of about 1 to about 20 hours where the temperature and time may be suitably based on the base and solvent employed, to obtain compound of Formula III.
  • the compound of Formula VI can be reacted with the compound of Formula VII in an amount sufficient to form the compound of Formula III, e.g., an amount of compound of Formula VI ranging from about 1 equivalent to about 2 equivalents and preferably from about 1 equivalents to about 1.5 equivalents per equivalent of the compound of Formula VII.
  • the compound of Formula III is a mixture of cis:trans isomers in the ratio of from about 90:10 to about 10:90 and preferably from about 60:40 to about 40:60.
  • the invention provides a process for the preparation of intermediate compound of Formula III involves reacting mono methyl amine (MMA) with a compound of Formula V:
  • R is selected from the group consisting of -OH, -halogen and -OCi-C 8 alkyl; in the presence of an organic reaction solvent selected from the group consisting of alcoholic solvents such as Ci-C 8 cyclic or aromatic alcohols; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and carbon tetrachloride; aromatic hydrocarbon; non-cyclic ethers and mixtures thereof with preferred solvents being the alcoholic solvents such as methanol and ethanol.
  • the reaction can be carried out at temperature ranging from about 0 0 C to about 9O 0 C for a period of about 1 to about 20 hours where the temperature and time may be suitably based on the base and solvent employed, to obtain compound of Formula III.
  • a process for preparing tadalaf ⁇ l is provided involving cyclization of a cis-isomer of a compound of Formula II:
  • X is a leaving group in the presence of a base.
  • Any suitable leaving group can be used such as a halogen leaving group, e.g., chlorine, bromine and the like with chlorine being most preferred.
  • a suitable base includes, but is not limited to, inorganic bases such as alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates; organic bases such as amine derivatives, alkyl lithium and the like and mixtures thereof.
  • inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • Suitable organic bases includes such as isopropyl amine, diisopropyl amine, n-butyl lithium, lithium diisopropyl amide and the like and mixtures thereof.
  • the base will be present in an amount of about 1 equivalent to about 5 equivalents per equivalent of the compound of Formula II.
  • Suitable solvents include, but are not limited to, alcoholic solvents having from about Ci to about Ci 2 carbon atom such as methanol, ethanol, isopropanol and the like, aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like, non- aromatic hydrocarbon solvents such as hexane and the like and mixtures thereof.
  • the solvent can be present in an amount of about 5 to about 50 volumes.
  • the cyclization can be carried out at a temperature ranging from about -90 0 C to about 20 0 C, for a time period ranging from about 1 to about 8 hours. As one skilled in the art will readily appreciate the temperature and time for the reaction may be suitably based on the base and solvent employed in the reaction.
  • the base used is lithium diisopropyl amide, preferably generated in situ by the reaction of n-butyl lithium and diisopropyl amine.
  • Preferred embodiments of the process of the present invention can be generally set forth below in Scheme II and III.
  • the tadalafil or a pharmaceutically acceptable salt or derivative thereof thus obtained can then be purified using a suitable solvent.
  • suitable solvents include, but are not limited to, alcoholic solvents having from 1 to about 6 carbon atoms, aromatic hydrocarbon solvents, non-aromatic hydrocarbon solvents and the like and mixtures thereof.
  • the process of the present invention advantageously provides tadalafil in relatively high purity, e.g., greater than or equal to about 98%, preferably greater than or equal to about 99% and more preferably greater than or equal to about 99.5%.
  • the tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention may then be formulated into a pharmaceutical composition or dosage form.
  • Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.
  • Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • the tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
  • the dosage forms may contain the tadalafil or pharmaceutically acceptable salt or derivative thereof of the present invention as is or, alternatively, as part of a composition.
  • B Acetonitrile
  • reaction mixture was concentrated under vacuum to about 1/3 its original volume, cooled to 5 to 1O 0 C and stirred for 1 hour at this temperature.
  • the solids were filtered and washed with chilled ethanol (50 ml). The wet solids were dried under vacuum for 6 hours.
  • the lower organic layer was separated and washed twice with water (75 ml).
  • the chloroform extract was dried over anhydrous sodium sulfate.
  • the organic layer was concentrated under vacuum until a thick yellow slurry was obtained.
  • the slurry was cooled to 0 to5°C.
  • the solids obtained were filtered and washed with 50 ml chilled chloroform.
  • the wet product was dried at 75 0 C under vacuum for 6 hours.
  • reaction was monitored by TLC, workup was done as follows, the pH of the reaction mixture was adjusted to 8-9 using sodium carbonate solution under stirring, the two layers were settled, separated and the lower MDC layer was washed with water. The MDC layer was then dried over anhydrous sodium sulfate. The reaction mass was concentrated under vacuum at 40 to 5O 0 C to remove the solvent. The compound was precipitated using ethyl acetate, the solids were filtered, washed with ethyl acetate and dried.
  • MDC layer was concentrated to distill out MDC until a stirrable mass was left behind.
  • the mass was cooled to 25-3O 0 C and filtered, washed, to yield off-white to light yellow colored solids.
  • the resulted product was the cis isomer, the trans isomer left behind in the mother liquor.
  • a solution of Compound of formula II (125 g) obtained in Example 7 in THF (625 ml) was prepared and slowly added to the reaction mixture while maintaining the temperature between -40 to -5O 0 C. After the addition was complete, the reaction mixture was stirred at -35 to -40 0 C for 2-6 hours. Saturated aqueous ammonium chloride solution (250 ml) and ethyl acetate (125 ml) was added to the reaction mixture at -35 to -40 0 C. The temperature was raised to 25 to 30 0 C and the two layers formed were separated. The upper organic layer was collected. The lower aqueous layer was extracted with ethyl acetate (65 ml). The organic layers were combined together and distilled.
  • Example 8 The crude tadalafil obtained in Example 8 was suspended in methanol (600 ml) and stirred for 1 hour at reflux. The mixture was cooled and the solids obtained were filtered and washed with chilled methanol (60 ml). The wet product was dried at under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des intermédiaires innovants du tadalafil et leurs procédés de préparation. L'invention concerne également la préparation du tadalafil ou d'un de ses sels ou solvates pharmaceutiquement acceptable en utilisant les intermédiaires.
PCT/IB2007/000737 2006-03-24 2007-03-23 Procede de preparation de tadalafil Ceased WO2007110734A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07734067A EP2004644A1 (fr) 2006-03-24 2007-03-23 Procede de preparation de tadalafil

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
IN438/MUM/2006 2006-03-24
IN438MU2006 2006-03-24
IN1135/MUM/2006 2006-07-17
IN1135MU2006 2006-07-17
IN1918MU2006 2006-11-20
IN1918/MUM/2006 2006-11-20
US87264806P 2006-12-04 2006-12-04
US60/872,648 2006-12-04

Publications (1)

Publication Number Publication Date
WO2007110734A1 true WO2007110734A1 (fr) 2007-10-04

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PCT/IB2007/000737 Ceased WO2007110734A1 (fr) 2006-03-24 2007-03-23 Procede de preparation de tadalafil

Country Status (2)

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EP (1) EP2004644A1 (fr)
WO (1) WO2007110734A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2181997A1 (fr) 2008-10-30 2010-05-05 Chemo Ibérica, S.A. Procédé de préparation de tadalafil
CN114213414A (zh) * 2022-01-24 2022-03-22 山东安信制药有限公司 一种他达拉非制备方法
CN115184531A (zh) * 2021-04-07 2022-10-14 浙江康恩贝制药股份有限公司 一种同时测定他达拉非中3种杂质含量的方法
WO2023235719A3 (fr) * 2022-05-31 2024-04-04 The Scripps Research Institute Inhibiteurs allostériques stéréosélectifs de sarm1

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859006A (en) * 1994-01-21 1999-01-12 Icos Corporation Tetracyclic derivatives; process of preparation and use
WO2002088123A1 (fr) * 2001-04-25 2002-11-07 Lilly Icos Llc Composes chimiques
WO2004011463A1 (fr) * 2002-07-31 2004-02-05 Lilly Icos, Llc. Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859006A (en) * 1994-01-21 1999-01-12 Icos Corporation Tetracyclic derivatives; process of preparation and use
WO2002088123A1 (fr) * 2001-04-25 2002-11-07 Lilly Icos Llc Composes chimiques
WO2004011463A1 (fr) * 2002-07-31 2004-02-05 Lilly Icos, Llc. Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAUGAN A ET AL: "THE DISCOVERY OF TADALAFIL: A NOVEL AND HIGHLY SELECTIVE PDE5 INHIBITOR. 2: 2,3,6,7,12,12a-HEXAHYDROPYRAZINO- [1',2':1,6]PYRIDO[3,4-b]INDOLE-1,4-DIONE ANALOGUES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 46, no. 21, 2003, pages 4533 - 4542, XP008052656, ISSN: 0022-2623 *
I. M. MCDONALD ET AL: "2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H- benzo[h][1,4]diazonine as a New Template for the Design of CCK2 Receptor Antagonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, no. 19, 2000, pages 3518 - 3529, XP002444680 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2181997A1 (fr) 2008-10-30 2010-05-05 Chemo Ibérica, S.A. Procédé de préparation de tadalafil
CN115184531A (zh) * 2021-04-07 2022-10-14 浙江康恩贝制药股份有限公司 一种同时测定他达拉非中3种杂质含量的方法
CN115184531B (zh) * 2021-04-07 2024-06-11 浙江康恩贝制药股份有限公司 一种同时测定他达拉非中3种杂质含量的方法
CN114213414A (zh) * 2022-01-24 2022-03-22 山东安信制药有限公司 一种他达拉非制备方法
WO2023235719A3 (fr) * 2022-05-31 2024-04-04 The Scripps Research Institute Inhibiteurs allostériques stéréosélectifs de sarm1

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Publication number Publication date
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