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WO2014184754A1 - Procédé de préparation d'anastrozole à des fins pharmaceutiques - Google Patents

Procédé de préparation d'anastrozole à des fins pharmaceutiques Download PDF

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Publication number
WO2014184754A1
WO2014184754A1 PCT/IB2014/061435 IB2014061435W WO2014184754A1 WO 2014184754 A1 WO2014184754 A1 WO 2014184754A1 IB 2014061435 W IB2014061435 W IB 2014061435W WO 2014184754 A1 WO2014184754 A1 WO 2014184754A1
Authority
WO
WIPO (PCT)
Prior art keywords
anastrozole
methyl
solution
water
preparing
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/IB2014/061435
Other languages
English (en)
Inventor
Alberto ANTONINI
Lauso OLIVIERI
Doralinda SACCHITELLI
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.)
Corden Pharma Latina SpA
Original Assignee
Corden Pharma Latina SpA
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 Corden Pharma Latina SpA filed Critical Corden Pharma Latina SpA
Publication of WO2014184754A1 publication Critical patent/WO2014184754A1/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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention concerns a simple direct process for preparing pure anastrozole, with IUPAC name 2 , 2 ' - [5 - ( lH-1 , 2 , 4 - triazol-l-yl-methyl) -1, 3-phenylene] is (2- methylpropanenitrile) .
  • Anastrozole is an active ingredient in the category of hormone drugs, able to inhibit the action of a specific enzyme for the regulation and control of female sex hormones.
  • anastrozole In medicine anastrozole is usually used in the treatment of advanced or recurrent breast cancer in post-menopausal women.
  • the typical dosage for administration of the drug is 1 mg/day orally.
  • Said intermediate after being isolated and purified, in general by means of crystallization or chromatography, is reacted with 1' 1-2-4-triazole or with its sodium salt to form anastrozole.
  • US2010/0099887 claims purification conditions of the intermediate [COMPOUND 2] which, after being isolated with a high purity level, is treated with 1 , 2 , 4 -triazole , a base and a phase transfer catalyst.
  • the product obtained is isolated by crystallization from ethyl acetate/diethyl ether.
  • the main characteristic common to all the methods of preparation of anastrozole described above is the different approach aimed at removing from the product the unreacted substrates, the by-products and the isomers formed in the general sequence of the two reaction steps.
  • [IMPURITY 2] regioisomer of anastrozole (isoanastrozole)
  • the procedures described above which entail either the use of chromatographic techniques or isolation and purification of the [compound 2] , or isolation and purification of an anastrozole salt or the use of multiple crystallization/recrystallization sequences, although they are able to guarantee a degree of pharmaceutical purity of the end product, necessarily also involve drawbacks both in terms of applicability in the industrial field and productivity with the inevitable loss of overall yield and lengthening of the process times due to the isolation of an intermediate reaction product.
  • the subject of the present invention is a method for the preparation of anastrozole, the essential characteristics of which are described in claim 1, and the preferred and/or auxiliary characteristics of which are described in claims 2- 10.
  • the reaction is quenched by the addition of 100 ml toluene and 125 ml distilled water. After separation of the phases, the rich organic phase is treated with a water solution HC1 0.1M. After separation of the phases, 1 g of carbon is added to the resulting organic phase and it is kept under stirring at ambient temperature .
  • the clarified organic phase is extracted twice with 100 ml of HC1 2 .
  • the rich water phase, containing high purity dissolved anastrozole, is lastly back-washed with toluene .
  • a solution of NaOH at 30% by weight is added to the rich acid solution in 60-90 minutes until pH 1 is reached.
  • the mixture is then left in crystallization break at 0°-5°C for 2 hours.
  • a solution of NaOH 0.5 M is then added until a pH of between 2.5 and 3.5 is obtained.
  • the resulting suspension is then left in break at 0°-5°C for a further 2 hours.
  • a last quantity of NaOH 0.5 M solution is then added until a final pH of between 5 and 7 is reached, followed by a last break at 0°-5°C.
  • the product is lastly filtered, washed with distilled water and then dried in a vacuum at a temperature of 50°C.
  • the method subject of the present invention offers the important advantages of not requiring the use of purification by column chromatography, which is costly and difficult to apply on an industrial scale, of not requiring the step of isolation and purification of the bromoderivative intermediate or other intermediates, therefore facilitating operation and productivity of the process, of using ester solvents readily available on the market, with low toxicity and environmental impact, and lastly of not requiring multiple processes of crystallization/isolation/recrystallization but of allowing anastrozole to be obtained for pharmaceutical purposes by means of one single crystallization from purely water solvent by control of the pH.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'anastrozole caractérisé en ce qu'il comprend : une étape de bromuration, dans laquelle du 2-2' (5-méthyl-1, 3- phénylène) bis (2-méthylpropanenitrile) est soumis à une réaction de bromuration en présence d'un solvant à base d'ester de façon à obtenir du 2- [3 -bromométhyl-5 - (cyano-diméthyl-méthyl) -phényl]- 2-méthyl-propanenitrile; - une étape de substitution nucléophile, dans laquelle un mélange organique comprenant du 2-2' ( 5-méthyl-l, 3 -phénylène) bis (2-méthylpropanenitrile) n'ayant pas réagi, le 2- [3 -bromométhyl-5- (cyano-diméthyl- méthyl)-phényl]-2-méthyl-propanenitrile formé et, si nécessaire, d'autres sous-produits réactionnels est mis à réagir dans du diméthylformamide avec du 1-2-4-triazole ou son sel sodique à une température allant de 0 à 25 °C pour la formation d'anastrozole; - une étape de purification de l'anastrozole.
PCT/IB2014/061435 2013-05-14 2014-05-14 Procédé de préparation d'anastrozole à des fins pharmaceutiques Ceased WO2014184754A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000285A ITRM20130285A1 (it) 2013-05-14 2013-05-14 Metodo per la preparazione di anastrozolo di grado farmaceutico
ITRM2013A000285 2013-05-14

Publications (1)

Publication Number Publication Date
WO2014184754A1 true WO2014184754A1 (fr) 2014-11-20

Family

ID=48672716

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/061435 Ceased WO2014184754A1 (fr) 2013-05-14 2014-05-14 Procédé de préparation d'anastrozole à des fins pharmaceutiques

Country Status (2)

Country Link
IT (1) ITRM20130285A1 (fr)
WO (1) WO2014184754A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296749A1 (fr) 1987-06-16 1988-12-28 Zeneca Limited Composés hétérocycliques renfermant un groupe aralkyle substitué
US20060035950A1 (en) 2004-08-09 2006-02-16 Mohammed Alnabari Novel processes for preparing substantially pure anastrozole
US20070010048A1 (en) 2005-03-23 2007-01-11 Taiwan Semiconductor Manufacturing Co., Ltd. Semiconductor-on-insulator (SOI) strained active areas
US20070028192A1 (en) 2005-08-01 2007-02-01 Williams Frank J Method for providing serialized technical support
WO2007054963A2 (fr) * 2005-09-30 2007-05-18 Cadila Healthcare Limited Procede de preparation d’anastrozole pur
WO2007105231A1 (fr) * 2006-03-10 2007-09-20 Shilpa Medicare Ltd. Procédé amélioré permettant de préparer un anastrozole a haut degré de pureté
WO2009010991A2 (fr) * 2007-07-17 2009-01-22 Ind-Swift Laboratories Limited Procédé de purification pour préparer de l'anastrozole de haute pureté
US20100099887A1 (en) 2006-10-17 2010-04-22 Cipla Limited Process for the Preparation of Pure Anastrozole

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0296749A1 (fr) 1987-06-16 1988-12-28 Zeneca Limited Composés hétérocycliques renfermant un groupe aralkyle substitué
US20060035950A1 (en) 2004-08-09 2006-02-16 Mohammed Alnabari Novel processes for preparing substantially pure anastrozole
US20070010048A1 (en) 2005-03-23 2007-01-11 Taiwan Semiconductor Manufacturing Co., Ltd. Semiconductor-on-insulator (SOI) strained active areas
US20070028192A1 (en) 2005-08-01 2007-02-01 Williams Frank J Method for providing serialized technical support
WO2007054963A2 (fr) * 2005-09-30 2007-05-18 Cadila Healthcare Limited Procede de preparation d’anastrozole pur
WO2007105231A1 (fr) * 2006-03-10 2007-09-20 Shilpa Medicare Ltd. Procédé amélioré permettant de préparer un anastrozole a haut degré de pureté
US20090286989A1 (en) 2006-03-10 2009-11-19 Vishnukant B Process for High Purity Anastrozole
US20100099887A1 (en) 2006-10-17 2010-04-22 Cipla Limited Process for the Preparation of Pure Anastrozole
WO2009010991A2 (fr) * 2007-07-17 2009-01-22 Ind-Swift Laboratories Limited Procédé de purification pour préparer de l'anastrozole de haute pureté

Also Published As

Publication number Publication date
ITRM20130285A1 (it) 2014-11-15

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