EP2714711A1 - Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques - Google Patents

Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques

Info

Publication number
EP2714711A1
EP2714711A1 EP12727392.8A EP12727392A EP2714711A1 EP 2714711 A1 EP2714711 A1 EP 2714711A1 EP 12727392 A EP12727392 A EP 12727392A EP 2714711 A1 EP2714711 A1 EP 2714711A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
iii
fluticasone
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.)
Withdrawn
Application number
EP12727392.8A
Other languages
German (de)
English (en)
Inventor
Emilia Perpetua Tavares Leitao
Maria Rita VENTURA
Christopher Maycock
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.)
Hovione Inter AG
Original Assignee
Hovione Inter AG
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 Hovione Inter AG filed Critical Hovione Inter AG
Priority claimed from PCT/GB2012/000469 external-priority patent/WO2012160338A1/fr
Publication of EP2714711A1 publication Critical patent/EP2714711A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003

Definitions

  • the present invention describes processes for the preparation of monofluoromethylated organic biologically active compounds, starting from protected intermediates and/or reagents to obtain compounds such as Fluticasone Propionate and Fluticasone Furoate, in presence of decarboxylating reagents XeF 2 and BrF 3 , or using FCH 2 SH as a reagent.
  • the carbon-fluorine bond is commonly found in pharmaceutical and agrochemical products, because it is generally metabolically stable and the fluorine atom acts as a bio.isostere of the hydrogen atom (Ann M. Thayer "Fabulous Fluorine” Chemical and Engineering News, June 5, 2006 , Volume 84, pp. 15-24) .
  • Fluorination and fluoroalkylation are the two major synthetic methods to prepare selectively fluorinated organic compounds.
  • Monofluoromethylatiori selective introduction of a CH 2 F group into the organic molecule is less studied than fluorination.
  • hydrohalofluorocarbons or freons which is a subclass of chlorofluorocarbons (CFCs) . Every permutation of fluorine, chlorine, and hydrogen on the methane and ethane template has been examined and most have been commercialized. Furthermore, many examples containing bromine are known for higher numbers of carbon as well as related compounds.
  • the use of this class of compounds include refrigerants, blowing agents, propellants in medicinal applications, and degreasing solvents (M. Rossberg et al. "Chlorinated Hydrocarbons" in Ullmann's. Encyclopedia of Industrial Chemistry, ⁇ 006, Wiley-VCH, einheim) .
  • the literature describes a method for replacing a carboxylic group with a fluorine group in a halogenated aliphatic carboxylic compound having the general formula, R-COOH, to prepare a fluorinated product having the general formula, R-F.
  • the fluorodecarboxylation is carried out in the presence of XeF 2 (Timothy B. Patrick, Kamalesh . Johri, David H. White, William S. Bertrand, Rodziah Mokhtar, Michael R. Kilbourn,and Michael J. Welch, Can. J. Che . , Vol. 64, 1986, 138) or BrF 3 (U.S. Patent 4, 996,371) .
  • XeF 2 Timothy B. Patrick, Kamalesh . Johri, David H. White, William S. Bertrand, Rodziah Mokhtar, Michael R. Kilbourn,and Michael J. Welch, Can. J. Che . , Vol.
  • Copending patent application PT105138 describes the application of these reagents, for example, in the synthesis of Fluticasone Propionate and Fluticasone Furoate, as depicted in Scheme 1 below, hence avoiding the use of bromofluoromethane or any other related substance that deplete the ozone layer.
  • Scheme 2 illustrates the reaction of steroid (II) / with a carboxymethyl ester to afford intermediate (III) .
  • intermediate (III) The hydroxyl group in the ⁇ C-ll position is . protected to yield a Intermediate (IV), which is hydrolyzed to obtain the corresponding . free carboxylic acid (V) , which is then fluorodecarboxylated to obtain compound of formula (VI) and deprotected to obtain compound of formula (I) ' .
  • the order and number of steps is not limited to the scheme presented above.
  • Scheme 3 illustrates the reaction of steroid (VII) , with X- acetic acid or X-acetic ester (VIII) to afford intermediate (IX) .
  • Intermediate (IX-) is converted to the free carboxylic acid (X) which, is then fluorodecarboxylated to obtain compound of formula (XI) and deprotected to obtain compound of formula (XII) : Fluticasone, Fluticasone Propionate or Fluticasone Furoate.
  • the order and numbe of steps is not limited to the scheme presented above.
  • Ri is selected from group consisting of hydroxyl, ester and carbonate
  • R 2 is selected from a group consisting of H and alkyl
  • Xi and X 2 are selected from the group consisting of H and halogen;
  • X3 is selected from a group consisting oxygen and sulphur; which method comprises one or more of the following steps:
  • R' 3 is an alkyl group
  • R 3 is an (alkylcarboxy)methyl group
  • X is a leaving group selected from halogen triflate, mesylate, fluorosulfonate and phosphonate;
  • Ri, Xi; 3 ⁇ 4 and X 3 are as defined with reference to formula (I) ; and/or
  • R 4 is a suitable protecting group
  • Ri » X-i, 3 ⁇ 4 and 3 are as defined with reference t formulae (I) and (III); and/o
  • R lr R 2 , R 3 , R 4 , Xi, X 2 and X 3 are as defined with reference to formulae (I), (III) and (IV); and/or reacting a compound of formula (V) with a suitable fluorodecarboxylating agent to yield a compound of formula (VI).
  • Ri, R 2 , R4, Xi, X 2 and X 3 are as defined with reference to formulae (I), (III) and (IV); and/or
  • Ri represents hydroxyl or an este ' group of formula -OC(0)R r , wherein R' represents an alkyl of aryl group.
  • R' represents a linear or branched ⁇ chain Cj-a alkyl group, more preferably a linear or., branched chain Cj_g alkyl group, and most preferably a linear or branched chain C 1 -4 alkyl group, such as methyl, ethyl n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert- butyl, preferably ethyl.
  • R' represents an aryl group, it is preferably a C 3 - 6 aryl group, optionally containing one or more heteroatoms, such as phenyl, furan or thiophene.
  • R' represents ethyl or thiophene; i.e. Ri represents propionate or furoate.
  • R 2 represents an alkyl group, it is preferably a linear or branched chain Ci- 8 alkyl group, more preferably a linear or branched chain Ci- 6 ' alkyl group, and most preferably a linear or branched chain C 1 -4 alkyl group.
  • Preferred examples of R 2 include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl and tert-butyl. More preferred examples of .R 2 include methyl and ethyl, especially methyl. In an alternative preferred embodiment, R 2 is H.
  • the alkyl group of the (alkylcarboxy) methyl substituent R 3 is preferably a linear or branched chain Ci-g alkyl group, more preferably a linear or branched chain Ci- S alkyl group, and most preferably a linear or branched chain C 1 - alkyl group.
  • Preferred examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
  • a particularly preferred example is tert-butyl.
  • organic biologically active compound means an organic compound which is of medicinal or therapeutic use ' in the broadest sense.
  • the organic biologically active compound is a pharmaceutically active compound.
  • halogen means F, CI, Br or I.
  • Xi and X 2 represent F.
  • X 3 represents 0. In an alternative " embodiment of the invention, X 3 represents S.
  • Particularly preferred examples of a compound of formula (I) include, but are not limited to, Fluticasone, Fluticasone Propionate and Fluticasone Furoate.
  • a method of preparing a biologically active organic compound of formula (I) comprises performing reaction step (a) as hereinbefore defined and optionally one or more of steps (b) , (c), (d) and (e) .
  • method comprises performing reaction step (b) as hereinbefore defined and optionally one or more of steps (a), (c), (d) and (e) .
  • a method of preparing a biologically active organic compound of formula (I) comprises performing reaction step (c) as hereinbefore defined optionally one or more of steps (a), (b) , (d) and (e) .
  • a method of preparing a biologically active organic compound of formula (I)- comprises performing reaction step (d) as hereinbefore defined and optionally one or more of steps (a), (b), (c) ' and (e) .
  • a method of preparing a biologically active organic compound of formula (I) comprises performing reaction step (e) as hereinbefore defined and optionally one or more steps (a), (b), (c) and (d) .
  • Suitable protecting groups for use in the present invention are commercially available and/or may be prepared by methods known in the art. Preferred examples include, but are not limited to, trifluoroacetate, acetate and trichloroacetate .
  • Suitable deprotection reagents for use in the present invention are commercially available . and/or may be prepared by methods known in the art. Preferred examples include, but are not limited to, trifluroacetic anhydride (TFA) , triethylamine, pyridine and Hunig's base.
  • TFA trifluroacetic anhydride
  • Suitable, fluorodecarboxylating agents for use in the present invention are commercially available and/or may be prepared by methods known in the art. Preferred examples include, but are not limited to, XeF2 and BrF 3 .
  • Intermediate (III) can be prepared by the reaction of steroid (II) with a carboxyl methyl ester in an organic solvent and in presence of organic or inorganic base at a temperatures range within -70 °C and 70 °C.
  • the product can be isolated by precipitation in water or water with acid or water with base, by extraction with organic solvent and/or concentration, by recrystallization in organic solvent, and/or by column chromatography. Resin and activated charcoal can also be used during the work-up to purify the product.
  • the intermediate (IV) can be prepared in the same conditions as intermediate (III), protecting the C-ll position with a protecting group.
  • Intermediate ⁇ V) can be prepared in the same conditions as intermediate (III) , deprotecting the ester in C- 21 position of formula (IV) to yield a compound of formula (V) .
  • Intermediate (VI) can be prepared in : the. same conditions as intermediate (III), in the presence of XeF 2 or BrF3 by fluorodecarboxylation. Intermediate (VI) is then hydrolyzed to give compound of formula (I) ⁇ .
  • Scheme 4 illustrates a preferred example of a three step reaction according to the present invention, where fluoromethanethiol is prepared in situ, starting from 2- mercaptoacetic acid, and reacts then with an intermediate toafford Fluticasone, Fluticasone Propionate or. Fluticasone Furoate.
  • reaction is not limited to the number of steps presented above . .
  • a compound of formulae (III), (IV), (V) and/or (VI) for the - preparation of a biologically active organic compound containing a monofluoromethylated CH 2 F" moiety, in particular a compound of formula (I) as described herein, , preferably Fluticasone, Fluticasone Propionate and/or Fluticasone Furoate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un composé organique biologiquement actif de formule (I), (Formule (I)), dans laquelle R1, R2, R3, R4, X1, X2 et X3 sont tels que définis dans la description, certains intermédiaires nouveaux pouvant être obtenus par un tel procédé et leur utilisation.
EP12727392.8A 2011-05-26 2012-05-25 Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques Withdrawn EP2714711A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT2011105723 2011-05-26
PCT/GB2012/000469 WO2012160338A1 (fr) 2011-05-26 2012-05-25 Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques

Publications (1)

Publication Number Publication Date
EP2714711A1 true EP2714711A1 (fr) 2014-04-09

Family

ID=50185350

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12727392.8A Withdrawn EP2714711A1 (fr) 2011-05-26 2012-05-25 Procédé de production d'esters fluorométhyliques d'acides androstane-17-bêta-carboxyliques

Country Status (1)

Country Link
EP (1) EP2714711A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012160338A1 *

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