WO2010007408A2 - Intermédiaires ester tert-butylique d’acide 2-(2-chloro-5-hydroxy-4-méthylcarbamoylphénoxy)-2-méthylpropionique et glycidylbenzène­sulfonates ou sels de ceux-ci et procédé pour la préparation desdits intermédiaires - Google Patents

Intermédiaires ester tert-butylique d’acide 2-(2-chloro-5-hydroxy-4-méthylcarbamoylphénoxy)-2-méthylpropionique et glycidylbenzène­sulfonates ou sels de ceux-ci et procédé pour la préparation desdits intermédiaires Download PDF

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Publication number
WO2010007408A2
WO2010007408A2 PCT/GB2009/050833 GB2009050833W WO2010007408A2 WO 2010007408 A2 WO2010007408 A2 WO 2010007408A2 GB 2009050833 W GB2009050833 W GB 2009050833W WO 2010007408 A2 WO2010007408 A2 WO 2010007408A2
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WO
WIPO (PCT)
Prior art keywords
oxiran
ylmethyl
chloro
compounds
salts
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PCT/GB2009/050833
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English (en)
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WO2010007408A3 (fr
Inventor
Kirsty Chilvers
Phillip Hopes
Thomas Langer
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2010007408A2 publication Critical patent/WO2010007408A2/fr
Publication of WO2010007408A3 publication Critical patent/WO2010007408A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/34—Compounds containing oxirane rings with hydrocarbon radicals, substituted by sulphur, selenium or tellurium atoms

Definitions

  • the present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic drugs.
  • the invention relates to the intermediates 2-(2-Chloro-5-hydroxy-4- methylcarbamoylphenoxy)-2-methylpropionic acid tert-butyl ester and glycidyl benzene sulfonates or salts thereof.
  • the present invention relates to the intermediates 2-(2-Chloro-5- hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert-butyl ester and novel glycidyl benzene sulfonates of formula IV as defined below, useful in the preparation of 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5-chloro-l > H,3H-spiro[l-benzofuran-2,4 > -piperidin]-r-yl)-2- hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, atherosclerosis and respiratory diseases such as Chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD Chronic obstructive pulmonary disease
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 - C family.
  • These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
  • WO2008/010765 discloses a series of compounds having a structure (I) shown below, wherein:
  • R 1 is halogen
  • R 3 is hydrogen or hydroxyl
  • R 10 is hydrogen or Ci_ 3 alkyl
  • R 4 is -CONR 8 R 9 , -N(H)C(O)R 11 or -N(H)C(O)NR 8 R 9 , where R 8 and R 9 are independently selected from hydrogen, d- 6 alkyl or C 3 - 7 cycloalkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring which is optionally substituted with one or more hydroxyl groups;
  • R 11 is Cr ⁇ alkyl, C 2 _ 6 alkenyl, C 3 _ 6 cycloalkyl, adamantyl, Cs_ 6 cycloalkenyl, phenyl or a saturated or unsaturated 5-10 membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen, and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halo, carboxyl, Ci_ 6 alkyl, d_ 6 alkoxy, Ci_ 6 alkylthio, Ci_ 6 alkycarbonyl, d_ 6 alkoxycarbonyl, phenyl or -NHC(O)R 2 ; R 2 is Ci_ 6 alkyl, amino or phenyl;
  • R 5 is hydrogen or halo
  • R 6 and R 7 are independently selected from hydrogen or Ci- ⁇ alkyl, or R 6 and R 7 together with the carbon atom to which they are attached form a 3-7 membered saturated cycloalkyl group, or a pharmaceutically acceptable salt thereof.
  • WO2008/010765 also discloses different processes for the preparation of compounds of formula I, especially compound 2- ⁇ 2-Chloro-5- ⁇ [(25)-3- (5-chloro-l'H,3H-spiro[ 1 -benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid e.g. examples 5, 7 and 17.
  • Scheme 1 shows the process as described in example 17 of WO2008/010765.
  • Scheme 1 Process processes for the preparation of 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5-chloro- rH,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid (Ia).
  • R 1 and R 2 may be independently selected from hydrogen, halogen and halomethyl.
  • halomethyl means a methyl, which is substituted with halo as defined above.
  • halomethyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or fluorochloromethyl.
  • One embodiment of the invention relates to a process for the preparation of 2-(2-chloro-5- hydroxy-4-methylcarbamoylphenoxy)-2-methylpropionic acid tert-butyi ester (III) comprising the following steps: a) reacting the chloro diol with 2-bromo-2-methyl-propionic acid tert-butyl ester overnight to obtain the compound of formula II in a suitable solvent, using a suitable base, catalyst and a radical inhibitor; b) cooling the mixture to room temperature, charging a water-immiscible solvent and washing the organic phase with water and dilute aqueous base; c) adding aqueous methylamine under stirring; d) repeated extraction of the aqueous solution with a suitable organic solvent; e) acidification and filtration of the aqueous phase.
  • solvents, bases, catalysts and radical inhibitor may be used in this process.
  • Suitable solvents that may be used in step a) are, but not limited to, NMP, DMSO, DMF, DMI, MEK, MIBK, methanol, ethanol or isopropanol.
  • the solvent in step a) is NMP.
  • Suitable solvents that may be used in step b) are, but not limited to, DCM, MTBE and 2-
  • the solvent in step b) is MTBE.
  • Suitable bases that may be used in step a) are, but not limited to, potassium carbonate, caesium carbonate, potassium tert-butoxidc and sodium hydride.
  • the base is potassium carbonate.
  • Suitable catalysts that may be used in step a) are, but not limited to, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and higher homologous tetra alkyl ammonium halides.
  • the catalyst is tetrabutyl ammonium bromide.
  • Suitable radical inhibitors that may be used in step a) are, but not limited to, 2,6-Di-tert- butyl-4-methylphenol or quinone.
  • the radical inhibitor is 2,6-Di-te/t-butyl-4-methylphenol.
  • Process step a) is performed at elevated temperatures in the range of from 40 to 70 0 C.
  • Reaction steps b) to e) may be performed at room temperature.
  • the acidification in step e) may be performed using for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and salts thereof, citric acid and salts thereof and acetic acid.
  • the reaction time of step a) is about 24 hours.
  • the reaction time of step c) is about 0.5 to 4 hours.
  • the process in scheme 3 is a telescope procedure and avoids isolation and purification of a sensitive intermediate of 4-( 1 -tert-butoxycarbonyl- 1 -methylethoxy)-5 -chloro-2- hydroxybenzoic acid methyl ester (II).
  • Another advantage is that the process maintains by-products in solution and allows perform the desired transformation at a manufacturing scale by avoiding f ⁇ ltrations and evaporation of high boiling impurities at high vacuum.
  • Novel Glycidyl benzene sulfonates and the preparation thereof WO 8800190 describes different optically active derivatives of glycidol.
  • the glycidyl benzene sulfonates described in the present application are novel and contemplated to have a high reactivity with thermal stability.
  • the use of these glycidyl benzene sulfonates in the preparation of compounds of formula I or Ia is likewise novel.
  • One embodiment of the invention relates to novel glycidyl benzene sulfonate compounds of formula IV where R 1 and R 2 may be independently selected from hydrogen, cyano, halogen and halomethyl, with the proviso that one of R 1 and R 2 are not hydrogen when the other of R 1 and R 2 is halogen.
  • R 1 and R 2 may be independently selected from hydrogen, cyano, halogen and halomethyl, with the proviso that one of R 1 and R 2 are not hydrogen when the other of R 1 and R 2 is halogen.
  • R 1 and R 2 may be independently selected from hydrogen, cyano, halogen and halomethyl, with the proviso that one of R 1 and R 2 are not hydrogen when the other of R 1 and R 2 is halogen.
  • R 1 and R 2 may be independently selected from hydrogen, cyano, chlorine, fluorine and trifluoromethyl.
  • R 1 and R 2 are chlorine. In a further embodiment R 1 and R 2 are fluorine. In yet a further embodiment R 1 is hydrogen and R 2 is trifluoromethyl.
  • R 1 is hydrogen and R 2 is cyano.
  • One embodiment of the invention relates to compounds selected from [oxiran-2-ylmethyl]-4-(trifluoromethyl)benzenesulfonate, [oxiran-2-ylmethyl]-2,4-dichlorobenzenesulfonate, [oxiran-2-ylmethyl]-2,4-difluorobenzenesulfonate, and [oxiran-2-ylmethyl]-4-(cyano)benzenesulfonate, or salts thereof.
  • Another embodiment relates to compounds selected from [(5)-oxiran-2-ylmethyl]-4-(trifluoromethyl)benzenesulfonate, [(5)-oxiran-2-ylmethyl]-2,4-dichlorobenzenesulfonate, [(5)-oxiran-2-ylmethyl]-2,4-difluorobenzenesulfonate, and [(5)-oxiran-2-ylmethyl]-4-(cyano)benzenesulfonate, or salts thereof.
  • a further embodiment relates to compounds selected from [(i?)-oxiran-2-ylmethyl]-4-(trifluoromethyl)benzenesulfonate, [(i?)-oxiran-2-ylmethyl]-2,4-dichlorobenzenesulfonate, [(i?)-oxiran-2-ylmethyl]-2,4-difluorobenzenesulfonate, and
  • the process may conveniently be carried out in a solvent, e.g. an organic solvent such as a hydrocarbon or ether (e.g. toluene or MTBE) at a temperature of, for example, -10 0 C or above such as a temperature in the range from -20 0 C to 50 0 C.
  • a solvent e.g. an organic solvent such as a hydrocarbon or ether (e.g. toluene or MTBE) at a temperature of, for example, -10 0 C or above such as a temperature in the range from -20 0 C to 50 0 C.
  • a base such as triethylamine or any other appropriate base such as tertiary amines, N-methyl morpholine or isopropyl-diethyl amine.
  • compounds of formula IV In contrast to glycidyl nosylate, compounds of formula IV, especially compounds of formula IVa, as described above are thermally significantly more stable and lend themselves to manufacture and use at large scale. Their unique combination of stability and high selectivity is currently not covered in commercial compounds of the same type.
  • Another embodiment relates to the use of compounds of formula IV, especially compounds of formula IVa, as defined above, in particular (5)-oxiran-2-ylmethyl 4-
  • One embodiment relates to the use of compounds of formula IV, especially compounds of formula IVa, as defined above, in particular (5)-oxiran-2-ylmethyl 4- (trifluoromethyl)benzenesulfonate, where R 1 is hydrogen and R 2 is trifluoromethyl for the large scale manufacturing of pharmaceutical drugs.
  • One embodiment relates to the use of compounds of formula IV, especially compounds of formula IVa, as defined above, in particular (5)-oxiran-2-ylmethyl 4- (trifluoromethyl)benzenesulfonate, where R 1 is hydrogen and R 2 is trifluoromethyl for the large scale manufacturing of compounds of formula I or Ia.
  • NMR spectra were acquired on Varian Inova 300MHz or 400MHz or Bruker 300MHz and 200MHz spectrometers (as detailed) as solutions in suitably deuterated solvents. Nominal masses were determined either by GCMS or LCMS (as detailed).
  • LCMS were ran on an Agilent binary 1100 HPLC with 80Hz DAD and Multimode ES+APC1 positive ion, Agilent LCMS DSL (negative ion) or a Waters 2790 HPLC equipped with 996 Photo Diode Array detector and Micromass ZMD (single quadropole mass spectrometer with Z- spray interface).
  • GCMS data was acquired using an Agilent 6890 GC coupled to a 5973 MSD, equipped with either EI or CI source.
  • EI EI
  • CI reagent grade methane from BOC gases was used as reagent gas.
  • Chiral HPLC was ran on an Agilent HP-1100 VWD Detector.
  • Each exemplified compound represents a particular and independent aspect of the invention.
  • Stage 2 Preparation 2-(2-chloro-5-hydroxy-4-methylcarbamoylphenoxy)-2- methylpropionic acid tert-butyl ester (III)
  • MTBE solution of intermediate II was charged 6.0 kg methylamine solution (40% w/w in water, 77.3 mol) and the mixture was stirred for 2 h at 20-30 0 C.
  • the aqueous phase was extracted with MTBE (2x5 L, 2x2 L) and degassed for 2-5 h at 20-30 0 C under reduced pressure (20-50 mbar).
  • the pH of the aqueous solution was adjusted to 7.50 by addition of 4 M hydrochloric acid to precipitate the product as white solid.

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

Abstract

La présente invention concerne de nouveaux procédés pour la préparation de composés intermédiaires qui peuvent être utilisés pour préparer des médicaments thérapeutiques. L’invention concerne les intermédiaires ester tert-butylique d’acide 2-(2-chloro-5-hydroxy-4-5 méthylcarbamoylphénoxy)-2-méthylpropionique et glycidylbenzène­sulfonates ou des sels de ceux-ci. Plus spécifiquement, la présente invention concerne les intermédiaires ester tert-butylique d’acide 2-(2-chloro-5-hydroxy-4-méthylcarbamoylphénoxy)-2-méthylpropionique et de nouveaux glycidylbenzènesulfonates de formule IV comme défini ci-dessous, utiles dans la préparation d’acide 2-10-{2-chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-pipéridin]-1'-yl)-2-hydroxypropyl]oxy}-4-[(méthylamino)carbonyl]phénoxy}-2-méthylpropanoïque.
PCT/GB2009/050833 2008-07-14 2009-07-13 Intermédiaires ester tert-butylique d’acide 2-(2-chloro-5-hydroxy-4-méthylcarbamoylphénoxy)-2-méthylpropionique et glycidylbenzène­sulfonates ou sels de ceux-ci et procédé pour la préparation desdits intermédiaires WO2010007408A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8030908P 2008-07-14 2008-07-14
US61/080,309 2008-07-14

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WO2010007408A2 true WO2010007408A2 (fr) 2010-01-21
WO2010007408A3 WO2010007408A3 (fr) 2010-05-06

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015178A1 (fr) * 1996-10-07 1998-04-16 Merck & Co., Inc. Derives de sordarine
WO2008010765A1 (fr) * 2006-07-19 2008-01-24 Astrazeneca Ab Nouveaux composés

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003137885A (ja) * 2001-11-06 2003-05-14 Kanegafuchi Chem Ind Co Ltd 光学活性４−［（オキシラン−２−イルメチル）オキシ］−１ｈ−インドールの精製、単離方法
AU2003272967A1 (en) * 2002-10-28 2004-05-13 Kaneka Corporation Processes for producing optically active n-(2,3-epoxypropan-1-yl)phthalimide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015178A1 (fr) * 1996-10-07 1998-04-16 Merck & Co., Inc. Derives de sordarine
WO2008010765A1 (fr) * 2006-07-19 2008-01-24 Astrazeneca Ab Nouveaux composés

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; CHEN, JIAN ET AL: "A direct HPLC method for the determination of enantiomeric excess of some highly enantiomerically enriched derivatives of chiral glycidols" XP002566947 retrieved from STN Database accession no. 120:68464 & TETRAHEDRON LETTERS , 34(48), 7663-6 CODEN: TELEAY; ISSN: 0040-4039, 1993, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KISHIMOTO, SHIGEKI ET AL: "Purification and isolation of optically active 4-[(oxiran-2-ylmethyl)oxy]-1H-indole by crystallization" XP002566946 retrieved from STN Database accession no. 138:368762 & JP 2003 137885 A (KANEGAFUCHI CHEMICAL INDUSTRY CO., LTD., JAPAN) 14 May 2003 (2003-05-14) *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KLUNDER, JANICE M. ET AL: "Arenesulfonate derivatives of homochiral glycidol: versatile chiral building blocks for organic synthesis" XP002566948 retrieved from STN Database accession no. 110:134989 & JOURNAL OF ORGANIC CHEMISTRY , 54(6), 1295-304 CODEN: JOCEAH; ISSN: 0022-3263, 1989, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; NISHIYAMA, AKIRA ET AL: "Processes for producing optically active N-(2,3-epoxypropan-1-yl)phthalimide" XP002566945 retrieved from STN Database accession no. 140:375066 & WO 2004/037815 A1 (KANEKA CORPORATION, JAPAN) 6 May 2004 (2004-05-06) *
J M KLUNDER ET AL.: "Arenesulfonate derivatives of Homochiral Glycidol: Versatile Chiral Building Blocks for Organic Synthesis" J ORG CHEM, vol. 54, 1989, pages 1295-1304, XP002566944 *

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