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WO2017005764A1 - Procédé de production d'intermédiaires tricyclocétones d'antagonistes de crth2 - Google Patents

Procédé de production d'intermédiaires tricyclocétones d'antagonistes de crth2 Download PDF

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Publication number
WO2017005764A1
WO2017005764A1 PCT/EP2016/065902 EP2016065902W WO2017005764A1 WO 2017005764 A1 WO2017005764 A1 WO 2017005764A1 EP 2016065902 W EP2016065902 W EP 2016065902W WO 2017005764 A1 WO2017005764 A1 WO 2017005764A1
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Prior art keywords
formula
compound
alkyl
ethyl
oxo
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PCT/EP2016/065902
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English (en)
Inventor
Christophe Pierre Alain Chassaing
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Intervet International BV
Intervet Inc
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Intervet International BV
Intervet Inc
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Publication of WO2017005764A1 publication Critical patent/WO2017005764A1/fr
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    • 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
    • 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

Definitions

  • WO2010/099039 published September 2, 2010, discloses indole derivatives as CRTH2 receptor antagonists and process for making the same.
  • WO2010/031183, published March 25, 2010, also discloses indole derivatives as CRTH2 receptor antagonists and process for making the same.
  • WO2014/060596 published April 24, 2014, discloses process for preparing indole derivatives.
  • the invention is a process for preparing intermediates of a compound of Formula (I)
  • the process further comprising reacting the compounds of Formula ( ⁇ ) with an acid preferably H 2 SO 4 or HCl to form the compound of Formula (X)
  • This invention is directed to an improved process for the preparation of tricyclic ketone compounds which are useful intermediates in the preparation of compounds of Formula (I)
  • Z is N or C
  • X 1 1 and X 2" are independently hydrogen, halogen or are not present;
  • R 1 , R 2 , R 3 are independently Ci-C 6 alkyl
  • R 4 is Ci-C 6 alkyl or forms a heterocyclic ring with Q; and Q is S0 2 , C(O) or forms a heterocyclic ring with R 4 ; and
  • Ci-C 6 alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C 6 alkyl.
  • the process comprises the use of magnesium ethoxide for the formation of the tricyclic ketone intermediate.
  • Compounds of Formula (I) are antagonists of the PGD2 receptor CRTH2 and are useful in the treatment and prevention of CRTH2 mediated diseases.
  • a subgenus of Formula (I) are the compounds of Formula (lb)
  • Scheme 1 demonstrates a synthetic access to intermediates (X) of compounds of Formula lb.
  • Scheme 2 demonstrates another synthetic access to intermediates (X) of compounds of Formula lb.
  • the invention is a process for preparing intermediates of Formula (IXa) and (r b) of a compound of Formula (I)
  • Z is N or C
  • X 1 and X 2 are independently hydrogen, halogen or are not present;
  • R , R R J are independently Ci-C 6 alkyl
  • R 4 is Ci-C 6 alkyl or forms a heterocyclic ring with Q
  • Q is S0 2 , C(O) or forms a heterocyclic ring with R 4 ;
  • Ci-C 6 alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C 6 alkyl.
  • the invention is a process for preparing intermediates of Formula (Bia) and (IXb) of a compound of Formula (I)
  • Z is N or C
  • X 1 and X 2 are independently hydrogen, halogen or are not present; 1 2 3
  • R , R R J are independently Ci-C 6 alkyl
  • R 4 is Ci-C 6 alkyl or forms a heterocyclic ring with Q
  • Q is S0 2 , C(O) or forms a heterocyclic ring with R 4 ;
  • Ci-C 6 alkyl is unsubstituted or substituted with one or more groups selected from halogen or Ci-C 6 alkyl.
  • the process further comprising reacting the compounds of Formula (Bia) and (IXb) with an acid, preferably H 2 SO 4 or HC1, to form the compound of Formula (X)
  • R 4 is methyl, Z is N, X 1 is not present, X 2 is F, Q is C(O) and J is CH(CH 3 ).
  • R 4 is methyl, Z is C, X 1 is hydrogen, X 2 is F, Q is S0 2 and J is a bond.
  • Z is C
  • X is F
  • X is F
  • J is CH2 and Q and R are taken together to form a 1 ,2,3-triazole as shown below
  • An embodiment of the invention is compound of Formula (IXa) wherein the compound is
  • An embodiment of the invention is compound of Formula (X) wherein the compound is
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. In one embodiment alkyl groups contain about 1 to about 12 carbon atoms in the chain. In another embodiment alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, or decyl.
  • Alkoxy means an -O-alkyl group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Trifiate means trifluoromethane sulfonate.
  • the term "independently”, in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Solidate means a physical association of a compound of this invention with one or more solvent molecules.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 0.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • Example 1 A - Synthesis of a mixture of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro- 6H-pyrido[3,2-b]indolizine-9-carboxylate and of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9- dihydro-6H-pyrido[3,2-b]indolizine-7-carboxylate
  • Ethyl 3-[l ,3-bis(2-ethoxy-2-oxo-ethyl)pyrrolo[2,3-b]pyridin-2-yl]propanoate (16.09 g; 41.2 mmol) is dissolved in dimethylformamide (70 mL) and magnesium ethoxide (9.43 g; 82 mmol) is added. The resulting mixture is stirred overnight at 45 °C. After 16 h reaction time, the mixture is cooled to room temperature and is diluted with ethyl acetate (125 mL). Aqueous IN hydrochloric acid is added to the reaction mixture until acidic pH is reached.
  • Protocol B Retention times: 1.34, 1.58 and 1.80 min (m z 345)
  • Example IB Synthesis of a mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro- 6H-pyrido[l,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9- dihydro-6H-pyrido [1,2-a] indole-8-carboxylate
  • Ethyl 3-[l ,3-bis(2-ethoxy-2-oxo-ethyl)indol-2-yl]propanoate (65 g; 167 mmol) (prepared according to the method described in J. Org. Chem. 2012, 77, 2299-2309) is dissolved in dimethylformamide (325 mL) and magnesium ethoxide (19.49 g, 167 mmol) is added. The resulting mixture is stirred for 18 h at 45 °C. The reaction mixture is cooled to room temperature and 1 M aqueous hydrochloric acid (500 mL) and tert-butylmethylether (500 mL) are added under stirring.
  • the aqueous layer is extracted with tert-butylmethylether (250 mL).
  • the combined organic layers are washed with half saturated aqueous sodium chloride (300 mL), are dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the isolated brown oil (56.5 g; 164 mmol) composed of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro-6H- pyrido[l ,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-7-oxo-8,9-dihydro- 6H-pyrido[l,2-a]indole-8-carboxylate is engaged in the next step without further purification.
  • Protocol A Retention times: 1.02 and 1.24 min (m/z 244)
  • Example 1C Synthesis of a mixture of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4-fluoro-7-oxo-8,9- dihydro-6H-pyrido[l,2-a]indole-6-carboxylate and of ethyl 10-(2-ethoxy-2-oxo-ethyl)-4- fluoro-7-oxo-8,9-dihydro-6H-pyrido[l,2-a]indole-8-carboxylate
  • the homogeneous reaction is inverse quenched into a stirring mixture of IN aqueous hydrochloric acid (250 mL) and toluene (200 mL). Cooling is applied such that the temperature does not exceed 20 °C.
  • the phases are separated and the aqueous phase is extracted with toluene (50 mL).
  • the combined organic phases are washed with 15% aqueous sodium chloride (50 mL) and the aqueous phase is discarded.
  • the organic phase is assayed by double dilution assay to show 19.96 g desired products (89% AY).
  • Protocol D Retention time: 1.31 min (m/z 244)
  • Aqueous 6 ⁇ sulfuric acid (132 mL; 395 mmol) is added and the resulting biphasic solution is heated to 80 °C while degassing is continued until the desired temperature is reached.
  • the reaction is aged at 80 °C for 24 h.
  • toluene (74 mL) is added and the organic phase is separated.
  • the aqueous phase is extracted with tert-butylmethylether (74 mL) and the combined organic phases are washed with 5 wt% aqueous sodium chloride (2 x 74 mL).
  • the organic phase was assayed via wt/wt% for 9.16 g keto-acid (88.8% AY).
  • the compound analysis was performed using UHPLC/MS 1290 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 4220A) including a degasser, a well plate sampler (G4226A), a column oven (G1316C), a diode array detector (G4212A), a mass detector (6130 Quadrupole LCMS) with ESI/APCI-source.
  • G 4220A binary pump
  • G4226A well plate sampler
  • G1316C column oven
  • G1316C diode array detector
  • G4212A diode array detector
  • mass detector (6130 Quadrupole LCMS) with ESI/APCI-source.
  • the compound analysis was performed using HPLC/MSD 1100 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 1312A) with a degasser (G1379A), a well plate sampler (G1367A), a column oven (G1316A), a diode array detector (G1315B), a mass detector (G1946D SL) with ESI source and a NQ AD 500.
  • HPLC/MSD 1100 series Alent, Santa Clara, CA, USA
  • a binary pump G 1312A
  • a degasser G1379A
  • G1367A well plate sampler
  • G1316A column oven
  • G1316A diode array detector
  • G1946D SL mass detector
  • Protocol B The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 35 °C. The injection volume was 1.2 ⁇ , the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:
  • the samples were diluted in a 1 : 1 mixture of solvents A and B before analysis.
  • the detection methods were UV at 210, 254 and 280 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.
  • the samples were diluted in a 1 : 1 mixture of solvents A and B before analysis.
  • the detection methods were UV at 210 and 254 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.
  • the samples were diluted in a 1 : 1 mixture of solvents A and B before analysis.
  • the detection methods were UV at 210 and 254 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation de composés cétoniques tricycliques qui sont des intermédiaires utiles dans la préparation de composés de formule (I) ou d'un solvate ou sel de ces composés.
PCT/EP2016/065902 2015-07-07 2016-07-06 Procédé de production d'intermédiaires tricyclocétones d'antagonistes de crth2 Ceased WO2017005764A1 (fr)

Applications Claiming Priority (2)

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EP15175755 2015-07-07
EP15175755.6 2015-07-07

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WO2017005764A1 true WO2017005764A1 (fr) 2017-01-12

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009049021A1 (fr) * 2007-10-10 2009-04-16 Chemietek, Llc Composés hétérocycliques sous forme d'antagonistes du récepteur crth2
WO2010099039A1 (fr) * 2009-02-24 2010-09-02 Merck Sharp & Dohme Corp. Dérivés d'indole en tant qu'antagonistes du récepteur crth2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009049021A1 (fr) * 2007-10-10 2009-04-16 Chemietek, Llc Composés hétérocycliques sous forme d'antagonistes du récepteur crth2
WO2010099039A1 (fr) * 2009-02-24 2010-09-02 Merck Sharp & Dohme Corp. Dérivés d'indole en tant qu'antagonistes du récepteur crth2

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CARMELA MOLINARO ET AL: "CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 5, 2012, pages 2299 - 2309, XP055088676, ISSN: 0022-3263, DOI: 10.1021/jo202620r *
DANIEL SIMARD ET AL: "Azaindoles as potent CRTH2 receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 2, 2011, pages 841 - 845, XP027593570, ISSN: 0960-894X, [retrieved on 20110107], DOI: 10.1016/J.BMCL.2010.11.084 *
MICHEL GALLANT ET AL: "Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 1, 2011, pages 288 - 293, XP027566645, ISSN: 0960-894X, [retrieved on 20101220] *

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