WO2009011653A1 - Procédé pour la préparation de produits intermédiaires et utilisation de ceux-ci dans la synthèse de composés de spiropipéridine - Google Patents

Procédé pour la préparation de produits intermédiaires et utilisation de ceux-ci dans la synthèse de composés de spiropipéridine Download PDF

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WO2009011653A1
WO2009011653A1 PCT/SE2008/050876 SE2008050876W WO2009011653A1 WO 2009011653 A1 WO2009011653 A1 WO 2009011653A1 SE 2008050876 W SE2008050876 W SE 2008050876W WO 2009011653 A1 WO2009011653 A1 WO 2009011653A1
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chloro
butyl
formula
compound
hydrogen
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PCT/SE2008/050876
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English (en)
Inventor
Martin Cooper
Barry Elkins
Scott Gibson
Eric Gu
Ian Hassall
Martin Hemmerling
Svetlana Ivanova
Bo-Göran Josefsson
Marguerite Mensonides-Harsema
Eric Merifield
John Pavey
Mike Rogers
Wang Zhengyu
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Astrazeneca Ab
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Priority claimed from PCT/SE2007/000694 external-priority patent/WO2008010765A1/fr
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Publication of WO2009011653A1 publication Critical patent/WO2009011653A1/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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • 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
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
    • 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
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to new processes for the preparation of compounds of formula I, especially the compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • Compounds of Formula I show good CCRl and CCR3 inhibitory activity. In addition they have particularly low affinity for the human ether-a-go-go-related gene (hERG)-encoded potassium channel and therefore are advantageous with regard to safety windows. Compounds of Formula I are useful in the treatment of respiratory diseases such as for example asthma or COPD.
  • respiratory diseases such as for example asthma or COPD.
  • R , 1 is halogen
  • R 5 is hydrogen or halogen
  • R 6 and R 7 are independently selected from hydrogen or Ci- 6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is chlorine or fluorine. In another embodiment R 1 is chlorine.
  • R 5 is hydrogen or chlorine. In one embodiment R 5 is chlorine. In another embodiment R 5 is hydrogen.
  • R 6 and R 7 are independently selected from hydrogen or Ci- 6 alkyl, such as methyl. In a further embodiment R 6 and R 7 are both methyl. In one embodiment R 6 and R 7 are both hydrogen.
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl.
  • Ci -4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or tert-butyl.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • C 3 - 6 Cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl refers to an aromatic or partial aromatic group having 5 to 10 carbon atoms such as for example, phenyl or naphthyl.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl as defined above.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms or as cocrystals, and the present invention encompasses all such forms.
  • Compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate,/?-toluenesulphonate, benzenesulphonate, ethanesulphonate, 2-naphthalenesulfonate, mesytilenesulfonate, nitrate acid, 1,5-naphthalene-disulphonate, p-xylenesulphonate, aspartate or glutamate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, fuma
  • They may also include basic addition salts such as an alkali metal salt for example sodium or potassium salts, an alkaline earth metal salt for example calcium or magnesium salts, a transition metal salt such as a zinc salt, an organic amine salt for example a salt of triethylamine, diethylamine, morpholine, 7V-methylpiperidine, 7V-ethylpiperidine, piperazine, procaine, dibenzylamine, 7V,7V-dibenzylethylamine, choline or 2-aminoethanol or amino acids for example lysine or arginine.
  • basic addition salts such as an alkali metal salt for example sodium or potassium salts, an alkaline earth metal salt for example calcium or magnesium salts, a transition metal salt such as a zinc salt, an organic amine salt for example a salt of triethylamine, diethylamine, morpholine, 7V-methylpiperidine, 7V-ethylpiperidine, piperazine,
  • the present invention relates to a process for the preparation as set out below.
  • the compounds of formula I may be prepared using the process as shown below in schemes 1 to 3.
  • One embodiment of the invention relates to a process for the preparation of spiropiperidine comprising the following steps; a) reacting bocpiperidone with trimethylsulfoxonium iodide to form an epoxy piperidine in the presence of a base and solvent, and b) reacting 2-Bromo-4-chloroanisole with isopropylmagnesium chloride to form the aryl Grignard reagent, which is then reacted with the epoxy piperidine to form a piperidinol (XXXI) in the presence of a catalyst and a suitable solvent, and c) reacting piperidinol (XXXI) with hydrobromic acid to obtain spiropiperidine in a suitable solvent.
  • Suitable bases that may be used for the preparation of the Epoxy pip are, but not limited to,
  • Suitable solvents that may be used for the preparation of the Epoxy pip are, but not limited to, dimethylsulphoxide, THF, diethyl ether, tert-butyl methyl ether, dimethoxyethane, dimethylacetamide, NMP or toluene.
  • Suitable Grignard reagents that may be used in the process for making the aryl Grignard reagent in Scheme 1 include but are not limited to, compounds of formula R y MgR v or R V 2Mg, wherein R y represents Cl, Br or I and R v represents Ci -6 alkyl, C 3-7 cycloalkyl or optionally substituted phenyl such as for example isopropylamagnesium chloride.
  • Suitable catalysts that may be used in the process for making the piperidinol include but are not limited to copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulphide complex, copper (I) iodide or copper (I) cyanide.
  • Suitable solvents that may be used in the process for making the piperidinol include but are not limited to THF, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, toluene or hexanes.
  • Suitable solvents that may be used in the process for making the Spirocycle.HBr include but are not limited to water and acetic acid.
  • Suitable temperatures for the processes in Scheme 1 are of from 0 0 C to 100 0 C.
  • One embodiment relates to the process according to scheme 2 for the preparation of Glycidyl Ether.
  • R 1 may be any substituent providing an ester function such as for example Ci -6 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl, optionally substituted arylalkyl e.g. benzyl, R w is any suitable protection group such as for example PMB and R 5 is hydrogen or halogen.
  • Ci -6 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i
  • R w are, but not limited to, alkyl (e.g. Ci-6 alkyl), ether (e.g. methoxymethyl, tetrahydropyranyl), optionally substituted arylalkyl (e.g. benzyl or para- methoxybenzyl) and silyl groups of formula (R q ) 3 Si- where each R q independently represents an alkyl (e.g. alkyl) or aryl (e.g. phenyl) group, for example, tert- butyldimethylsilyl or triethylsilyl.
  • alkyl e.g. Ci-6 alkyl
  • ether e.g. methoxymethyl, tetrahydropyranyl
  • arylalkyl e.g. benzyl or para- methoxybenzyl
  • Suitable bases that may be used in the process for making the O-R w ester where R w is PMB include but are not limited to cesium carbonate, potassium carbonate, 1,8-
  • Diazabicyclo[5.4.0]undec-7-ene triethylamine, ethyldiisopropylamine or sodium hydride.
  • Suitable solvents that may be used in the process for making the O-R w ester where R w is
  • PMB include but are not limited to dichloromethane, toluene, ⁇ /, ⁇ /-dimethylformamide, N- methylpyrrolidone, tert-butyl methyl ether, methanol, ethanol, isopropanol and acetonitrile.
  • XXXIII include but are not limited to THF, water, methanol, ethanol, isopropanol, or mixtures thereof such as a water / THF mixture.
  • Suitable bases that may be used for the preparation of the compound of formula XXXV are, but not limited to cesium carbonate, potassium carbonate, sodium hydride or potassium tert-butoxide.
  • XXXV include but are not limited to butyronitrile, acetonitrile, toluene, tetrahydrofuran,
  • R u such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i- pentyl, t-pentyl, n-hexyl or i-hexyl, or optionally substituted aryl such as phenyl
  • Suitable epoxides may be glycidyl nosylate, optically pure epichlorohydrin, glycidyl tosylate, glycidyl benzenesulphonate or glycidyl mesylate.
  • Suitable temperatures for the processes in Scheme 2 are of from 0 0 C to 100 0 C depending on the step and the solvent used.
  • Another embodiment of the invention relates to a process for the preparation of the compound of formula XXXV comprising the following steps; d) reacting O-R w ester with methylamine to obtain the compound of formula XXXIII,
  • R 1 may be any substituent providing an ester function such as for example C 1-6 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i- pentyl, t-pentyl, n-hexyl or i-hexyl, optionally substituted arylalkyl e.g. benzyl, R w is any suitable protection group, R 5 is hydrogen or halogen and LG is a leaving group and e) reacting the compound of formula XXXIII with an epoxide to form the compound of formula XXXV,
  • R w is any suitable protection group
  • R 5 is hydrogen or halogen
  • LG is a leaving group
  • a further embodiment relates to a process for the preparation of compounds of formula I according to scheme 3.
  • R 1 is halogen
  • R 5 is hydrogen or halogen
  • R 6 and R 7 are independently selected from hydrogen or Ci- 6 alkyl
  • R w is any suitable protection group
  • R p may be hydrogen or any substituent providing an ester function such as C 1-6 alkyl such as methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl, optionally substituted arylalkyl such as benzyl.
  • Another embodiment of the invention relates to a process for the preparation of the compounds of formula (XXXVIII) comprising the following steps;
  • step f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt.
  • Suitable temperatures for step f) are of from 0 0 C to 110 0 C.
  • a further embodiment relates to a process for the preparation of compounds of formula I comprising the following steps; f) treatment of a solution of the spiropiperidine HBr salt with aqueous ammonium hydroxide to liberate the free base and then reacting this with the compound of formula XXXV in a suitable solvent followed by deprotection to obtain the compound of formula XXXVIII, optionally as a salt, followed by gl) reacting the compound of formula XXXVIII with ⁇ -bromo carboxylic ester in a suitable solvent in the presence of a base at an elevated temperature, and g2) de-esterification with a solution of a base followed by isolation by filtration after pH adjustment to obtain compound of formula I.
  • the compound of formula XXXVIII may be reacted with an ⁇ -bromocarboxylic acid in a suitable solvent in the presence of a base at a temperature of from 55 to 70 0 C. De-esterification would not be needed and the compound of formula ID would be isolated after pH adjustment.
  • XXXVII include but are not limited to ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
  • Suitable solvents that may be used in the process for making the compound of formula XXXVII include but are not limited to ethyl acetate, isopropyl acetate, toluene, THF, ethanol, methanol or isopropanol.
  • XXXVIII where R w is PMB include but are not limited to trifluoroacetic acid, formic acid, acetic acid or hydrochloric acid. Suitable solvents that may be used in the process for making the compound of formula
  • R w is PMB include but are not limited to DCM, toluene, tert-butyl methyl ether or THF.
  • Suitable bases that may be used in the process for making the Ester include but are not limited to cesium carbonate, potassium carbonate or sodium hydride.
  • Suitable solvents that may be used in the process for making the Ester include but are not limited to DMF, NMP, ethanol, methanol or isopropanol.
  • Suitable bases that may be used in the process for making the compound of formula I include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • some ester groups for example where R p is tert-butyl, can be de- esterified with acid and suitable acids which may be used for making the compound of formula I in such cases are TFA, formic acid, acetic acid or hydrochloric acid.
  • Suitable solvents that may be used in the process for making the compound of formula I include but are not limited to water, methanol, ethanol, isopropanol or mixtures thereof such as for example a water / ethanol mixture.
  • Another embodiment of the invention relates to a process for the preparation of 2- ⁇ 2- Chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl] oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid comprising the following steps;
  • Suitable temperatures for the steps f) and h) are of from 0 0 C to 150 0 C.
  • the first recrystallisation from an ethanol / NMP mixture reduces the level of the polymeric impurity to a low level.
  • the second recrystallisation from a water / NMP mixture provides the product in the polymorphic form A.
  • One embodiment relates to compound of formula XXXI, where R 1 is halogen
  • Another embodiment relates to compound 4-(5-Chloro-2-methoxybenzyl)-4- hydroxypiperidine-1-carboxylic acid, tert-butyl ester.
  • a further embodiment relates to compound of formula XXXII where R 5 is hydrogen or halogen
  • One embodiment relates to compound 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-7V- methylbenzamide .
  • a further embodiment relates to a compound of formula XXXIII, where R 5 is hydrogen or halogen and R w is hydrogen or any suitable protecting group, or a salt thereof
  • Another embodiment relates to compound of formula XXXIV, where R 5 is hydrogen or halogen
  • One embodiment relates to compound 5-Chloro-4-(4-methoxy-benzyloxy)-7V-methyl-2- ((S)- 1 -oxiranylmethoxy)benzamide .
  • Another embodiment relates to a compound of formula XXXV, where, R 5 is hydrogen or halogen and R w is hydrogen or any suitable protecting group, or a salt thereof
  • a further embodiment relates to a compound of formula XXXVI, where R is halogen and R 5 is hydrogen or halogen
  • Yet a further embodiment relates to compound 5-Chloro-2- ⁇ [(25)-3-(5-chloro-3H-spiro[l- benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -4-(/?-methoxybenzyloxy)-7V- methylbenzamide .
  • Yet another embodiment relates to a compound of formula XXXVII, where R 1 is halogen, R 5 is hydrogen or halogen and R w is hydrogen or any suitable protecting group, or a salt thereof
  • One embodiment relates to compound of formula XXXVIII, where R 1 is halogen and R 5 is hydrogen or halogen
  • R 1 is halogen
  • R 5 is hydrogen or halogen
  • R 6 and R 7 are independently selected from hydrogen or Ci- 6 alkyl
  • R p R p may be hydrogen or any substituent providing an ester function such as for example C 1-6 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, t-pentyl, n-hexyl or i-hexyl, optionally substituted arylalkyl e.g. benzyl
  • One embodiment relates to compound 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, tert-butyl ester.
  • the invention further relates to the use of the intermediates in the preparation of compounds of formula I, especially 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid.
  • One embodiment relates to the use of compounds of formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (ID), and salts thereof, or compounds selected from 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid, tert-butyl ester, 5-Chloro-2-hydroxy-4-(4-methoxybenzyloxy)-N-methylbenzamide,
  • Each exemplified compound represents a particular and independent aspect of the invention.
  • Method B Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 ⁇ particle size,
  • Solvent A 15 mM NH 3 /water
  • Solvent B acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.
  • THF (10 L) was added to the concentrate and solvent was distilled off to leave a solution of l-oxa-6- aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF, 1.8 kg, 51.2% w/w, 0.92 kg contained weight, 86% yield.
  • Step 2 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
  • 2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ.
  • a catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr 1 SMe 2 ) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.
  • the reaction mixture was warmed to between 25 and 30 0 C and stirred at this temperature for around 20 min.
  • the layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg).
  • the organic phase was concentrated under vacuum at 40 - 45 0 C to 2-3 L total volume then heptane (8 kg) added to the solution over a period of 30 min.
  • 5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester is heated under reflux in a mixture of hydrobromic acid and acetic acid to form the hydrobromic acid salt of the 5-chlorospiropiperidine.
  • Aqueous hydrobromic acid (48% w/w, 62 ml) was added dropwise to a stirred mixture of 4-(5-chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester (20 g, 56 mmol) and acetic acid (40 ml) over a period of 40 min at a temperature of between 40 and 50 0 C. Stirring was continued at this temperature for a further 30 - 40 min on completion of the addition. The reaction mixture was then heated to reflux for between 6 and 8 h when HPLC analysis showed complete reaction.
  • Step 4 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester.
  • the product suspension was cooled to 0 to 5°C, the solid was collected by filtration, washed with methanol (2 x 200 ml) and dried under vacuum at 50 - 60 0 C.
  • the crude solid (342 g) was re-slurried in methanol (3.4 L) then collected by filtration and dried under vacuum at 50 - 60 0 C to afford 5-chloro-2-hydroxy-4-methoxybenzoic acid methyl ester as a solid (316.6 g, 86.5%).
  • Aluminium chloride (531 g, 4.0 mol) and toluene (3.45 L) were charged to a reaction vessel and stirred.
  • Dodecanethiol (966 g, 4.8 mol) was added over 25 min and the mixture stirred to give a solution then heated to 40 to 50 0 C.
  • a solution of 5-chloro-2-hydroxy-4- methoxybenzoic acid methyl ester (345.0 g, 1.6 mol) in toluene (3.45L) was then added over 2 h at 40 to 50 0 C.
  • the reaction mixture was maintained at this temperature for a further 2 h following the addition when less than 1.0% starting material remained.
  • the crude product (53.5 g, 75%) was suspended in acetonitrile (250 ml), heated to reflux and held for 15 min, cooled to 40 0 C then held for 1 h.
  • the solid was collected by filtration, washed with acetonitrile (2 x 25 ml) then dried under vacuum at 50 0 C to provide 5-chloro-2-hydroxy-4-(4- methoxybenzyloxy)benzoic acid methyl ester as a solid 42.9 g (60%).
  • Step 10 2- ⁇ 2-Chloro-5- ⁇ [(2S)-3-(5-chloro-3H-spiro[l-benzofuran-2,4'-piperidin]-l '-yl)-2- hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid.
  • the filter cake was slurry washed with water (1 x 135 ml and 1 x 540 ml), ethanol (270 ml), TBME (135 ml), treated with ethanol (1 L) at 60 0 C for 18 h and then filtered.
  • the filter cake was washed with ethanol (135 ml).
  • the solid was dried overnight in a vacuum oven at 50 0 C to give the titled zwitterion as polymorph A (102.3 g; 80% over 2 steps)
  • the resulting solid (5 g) was slurried in NMP (50 ml) and heated to 60 0 C and held at between 60 and 65 0 C for 30 min with stirring. Water (50 ml) was charged to the resulting solution over a period of 35 min, maintaining the temperature between 60 and 65 0 C, which caused crystallization of the product. After a further 30 min at this temperature the slurry was cooled to ambient temperature then held at this temperature for 30 min. The mixture was further cooled to between 0 and 4 0 C and held for 30 min. The solid was collected by filtration, washed with water (25 ml), ethanol (25 ml), pulled dry on the filter then dried in a vacuum oven at 60 0 C.
  • the title compound exhibits at least the following characteristic X-ray powder diffraction (XRPD) peaks (expressed in degrees 2 ⁇ ) (the margin of error being consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) - see the United States Pharmacopeia Convention. X-Ray Diffraction, General Test ⁇ 941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089):
  • the diffractogram is shown in figure 1 of patent application WO2008/010765.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux procédés pour la préparation de composés de la formule I, particulièrement du composé d'acide 2-{2-chloro-5-{[(2S)-3(5-chloro-1'H, 3H-spiro[1-benzofuran-2,4'-pipéridin]-1'-yl)-2-hydroxypropyl]oxy}-4-5[(méthylamino)carbonyl]phénoxy}-2-méthylpropanoïque et de nouveaux produits intermédiaires utiles pour la préparation de ceux-ci.
PCT/SE2008/050876 2007-07-17 2008-07-16 Procédé pour la préparation de produits intermédiaires et utilisation de ceux-ci dans la synthèse de composés de spiropipéridine WO2009011653A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SEPCT/SE2007/000694 2007-07-17
PCT/SE2007/000694 WO2008010765A1 (fr) 2006-07-19 2007-07-17 Nouveaux composés

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WO2009011653A1 true WO2009011653A1 (fr) 2009-01-22

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PCT/SE2008/050876 WO2009011653A1 (fr) 2007-07-17 2008-07-16 Procédé pour la préparation de produits intermédiaires et utilisation de ceux-ci dans la synthèse de composés de spiropipéridine

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010144571A1 (fr) * 2009-06-10 2010-12-16 Sepracor Inc. Agonistes inverses et antagonistes de l'histamine h3 et méthodes d'utilisation associées
WO2012163848A1 (fr) 2011-05-27 2012-12-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques destinés au traitement de la maladie de crohn
WO2013060865A1 (fr) 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux marqueurs d'infiltrat leucocytaire de rosacée et utilisations de ceux-ci
CN110387064A (zh) * 2019-07-12 2019-10-29 西安工业大学 一种混合型低碱性受阻胺光稳定剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005295A1 (fr) * 2002-07-08 2004-01-15 Astrazeneca Ab Nouvelles spiropiperidines ou spiropyrrolidines tricycliques
WO2005049620A1 (fr) * 2003-11-20 2005-06-02 Astrazeneca Ab Nouveaux composes
WO2005054249A1 (fr) * 2003-12-05 2005-06-16 Astrazeneca Ab Nouveaux composes
WO2005061499A1 (fr) * 2003-12-22 2005-07-07 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite des recepteurs de chimiokines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW513418B (en) * 1996-07-31 2002-12-11 Otsuka Pharma Co Ltd Thiazole derivatives, their production and use
SE0302755D0 (sv) * 2003-10-17 2003-10-17 Astrazeneca Ab Novel compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005295A1 (fr) * 2002-07-08 2004-01-15 Astrazeneca Ab Nouvelles spiropiperidines ou spiropyrrolidines tricycliques
WO2005049620A1 (fr) * 2003-11-20 2005-06-02 Astrazeneca Ab Nouveaux composes
WO2005054249A1 (fr) * 2003-12-05 2005-06-16 Astrazeneca Ab Nouveaux composes
WO2005061499A1 (fr) * 2003-12-22 2005-07-07 Astrazeneca Ab Nouveaux spiroderives tricycliques en tant que modulateurs de l'activite des recepteurs de chimiokines

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010144571A1 (fr) * 2009-06-10 2010-12-16 Sepracor Inc. Agonistes inverses et antagonistes de l'histamine h3 et méthodes d'utilisation associées
CN102803268A (zh) * 2009-06-10 2012-11-28 桑诺维恩药品公司 组胺h3反相激动剂和拮抗剂及其使用方法
WO2012163848A1 (fr) 2011-05-27 2012-12-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques destinés au traitement de la maladie de crohn
WO2013060865A1 (fr) 2011-10-28 2013-05-02 Galderma Research & Development Nouveaux marqueurs d'infiltrat leucocytaire de rosacée et utilisations de ceux-ci
CN110387064A (zh) * 2019-07-12 2019-10-29 西安工业大学 一种混合型低碱性受阻胺光稳定剂及其制备方法

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