WO2011151163A1 - Process for the preparation of oxadiazoles - Google Patents

Process for the preparation of oxadiazoles Download PDF

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WO2011151163A1
WO2011151163A1 PCT/EP2011/057856 EP2011057856W WO2011151163A1 WO 2011151163 A1 WO2011151163 A1 WO 2011151163A1 EP 2011057856 W EP2011057856 W EP 2011057856W WO 2011151163 A1 WO2011151163 A1 WO 2011151163A1
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formula
compound
solvent
process according
alkyl
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PCT/EP2011/057856
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Emanuele Attolino
Vittorio Lucchini
Gabriele Razzetti
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Dipharma Francis S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the preparation of intermediates with 1 ,2,4-oxadiazole structure, useful in the preparation of biologically active compounds.
  • X is -NH- or -O-; E and G are variously substituted alkyl or aryl residues; or the EX- group is an optionally substituted saturated heterocyclic group containing a nitrogen bond to the oxadiazole.
  • E and G are variously substituted alkyl or aryl residues; or the EX- group is an optionally substituted saturated heterocyclic group containing a nitrogen bond to the oxadiazole.
  • 5-0- substituted 1 ,2,4-oxadiazole derivatives having fungicidal and insecticidal properties are disclosed in WO 95/05368, WO 99/31072 and WO 2009/158257; compounds with 5 -N- substituted 1 ,2,4-oxadiazole structure, used in the treatment of obesity and diabetes, were recently described in WO 2008/081204, WO 2008/081205 and WO 2009/034388.
  • the introduction of the heteroatom X at the 5 position of a 1 ,2,4-oxadiazole core is usually carried out through a substitution reaction by an oxygen-, such as an alcohol, or nitrogen- containing nucleophile, such as an amine or hydrazine, on a compound of formula (B)
  • Y is a leaving group, for example a chlorine atom or the trichloromethyl group; and G is as defined above.
  • a compound of formula (B), wherein Y is a chlorine atom can be obtained for example by reaction of a l ,2,4-oxadiazol-5-one with phosphorous pentachloride (PC1 5 ).
  • Said l ,2,4-oxadiazol-5-one can in turn be prepared for example by acylation of an amidoxime with a suitable anhydride and subsequent cyclization of the resulting intermediate, as reported in WO 95/05368.
  • the amidoxime can be prepared by known methods, for example by reaction of the hydroxylamine with a suitable nitrile.
  • a compound of formula (B), wherein Y is the trichloromethyl group can be prepared according to what described in J. Org. Chem. 2002, 67, 6253-6255, by acylation of an amidoxime with trichloroacetic anhydride and cyclization of the resulting intermediate.
  • substitution reaction in the preparation of a compound of formula (A), wherein X is -NH- or a saturated heterocycle, as defined above, is not easily applicable on an industrial scale, even when using an amine as nucleophile and a 1 ,2,4-oxadiazole, for example of formula (B), wherein Y as leaving group is a trichloromethyl group.
  • Y as leaving group is a trichloromethyl group.
  • US 3,574,222 discloses that substitutions with simple amines on compounds of formula (B), wherein Y is trichloromethyl, take place under rather drastic conditions and in most cases they also afford low yields. In many cases high operative temperatures and very large excesses of the amine, which is also used as the solvent, are required to complete the reaction.
  • R 2 , R 3 and R 4 are as defined in WO 2008/081204 and WO 2008/081205.
  • Object of the invention is a process for the preparation of a compound of formula (II), or a salt thereof, as individual isomer or a mixture thereof,
  • the group is a Ci-C 6 alkyl or aryl group
  • T is absent or is -NH-
  • W and Wi which can be the same or different, are independently hydrogen, an optionally substituted C C 14 alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aryl-Ci-Ci 4 alkyl group or an optionally substituted heteroaryl-Ci-Ci 4 alkyl group; or W and W l s taken together with the nitrogen atom they are linked to, form an optionally substituted saturated heterocyclic ring; comprising the reaction of a compound of formula (III)
  • R is as defined above, with a compound of formula (IV) or a salt thereof, as individual isomer or a mixture thereof, (IV) wherein
  • Q is hydrogen or NH 2 ; and W and Wi are as defined above; in the presence of a solvent, preferably a polar aprotic solvent; and, if desired, the conversion of a compound of formula (II) to a salt thereof or the conversion of the salt to the free compound.
  • a solvent preferably a polar aprotic solvent
  • Ci-C 6 alkyl group which can be straight or branched, is for example methyl, ethyl, propyl, isopropyl or tert-butyl.
  • Ci-Ci 4 alkyl group which can be straight or branched, is for example a Ci-C 6 alkyl group, in particular a Ci-C 4 alkyl group, preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
  • An aryl group is for example phenyl or naphthyl, preferably phenyl.
  • a heteroaryl group can be for example a hetero monocyclic or bicyclic group, containing one or more, preferably 1 , 2 or 3, heteroatoms independently selected from oxygen, sulfur and nitrogen, preferably said group is selected from pyridyl, thienyl or pyrazinyl.
  • An aryl-Ci-Ci 4 alkyl group is for example an aryl-Ci-C 6 alkyl group, preferably benzyl or phenylethyl, more preferably benzyl.
  • a heteroaryl-Ci-Ci 4 alkyl group is for example a heteroaryl-Ci-C 6 alkyl group, wherein the heteroaryl and alkyl portions are for example as defined above.
  • a heterocyclic saturated ring is for example a pyrrolidine, piperidine or morpholine ring.
  • alkyl, aryl or heteroaryl group as defined above, can be substituted by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro and cyano.
  • halogen for example fluorine or chlorine, hydroxy, nitro and cyano.
  • a saturated heterocyclic group can be substituted by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro, cyano and straight or branched C C 14 alkyl optionally substituted with hydroxy.
  • halogen for example fluorine or chlorine, hydroxy, nitro, cyano and straight or branched C C 14 alkyl optionally substituted with hydroxy.
  • a solvent can be selected from e.g. the group consisting of a polar aprotic solvent, for example an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethylsulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example methyl acetate or ethyl acetate; a C 3 -Ci 2 ketone, for example acetone, methyl ethyl ketone or methyl isobutyl ketone; or a mixture of two or more, preferably of two or three of said solvents; preferably a polar aprotic solvent.
  • a polar aprotic solvent for example an acyclic or cyclic
  • a compound of formula (III) can be reacted in the form of a solution thereof in a solvent as defined above in a concentration from about 1 to about 15 M, preferably from about 5 to about 12 M.
  • reaction of a compound of formula (III) with a compound of formula (IV), or a salt thereof can be carried out at a temperature ranging from about 0°C to 70°C, preferably from about 20 to about 40°C.
  • an individual isomer of a compound of formula (II) or (Ha) can be recovered from a mixture of its isomers according to known methods.
  • a compound of formula (IV) is a compound of formula (IV a), or a salt thereof, both as an individual isomer, and as a mixture thereof, having the following structure wherein R 5 is hydrogen or Ci-C 6 alkyl.
  • reaction between a compound of formula (III), as defined above, and a compound of formula (IVa) or a salt thereof, both as an individual isomer, and as a mixture thereof affords a compound of formula (Ila), or a salt thereof, both as an individual isomer, and as a mixture thereof, having the following formula
  • R and R 5 are as defined above.
  • a compound of formula (Ila), as defined above, can be used as an intermediate in a process for the preparation of a compound of formula (I), or a salt thereof, both as an individual isomer, and as a mixture thereof,
  • R and R 5 are as defined above;
  • R6 is hydrogen, halogen or Ci-C 6 alkyl;
  • R 7 is -SO 2 Ra, wherein Ra is Ci-C 4 alkyl, or -CONHRb, wherein Rb is hydrogen, or Ci-C 4 alkyl optionally substituted with hydroxy, according to the process reported in WO 2008/081204 and WO 2008/081205; or with known techniques.
  • a halogen is for example chlorine or fluorine.
  • Ci-C 6 alkyl group is for example as disclosed above.
  • Ci-C 4 alkyl group is preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
  • a mixture of isomers of formula (I), (II), (Ila), (IV) or (IV a) is preferably a racemic mixture thereof.
  • An isomer of a compound of formula (I), (II), (Ila) or (IV), in particular of formula (IVa), can be for example an optical isomer thereof.
  • a further aspect of the invention is therefore a process for the preparation of a compound of formula (I), or a salt thereof, both as an individual isomer or as an isomeric mixture, as defined above, comprising the use of a compound of formula (Ila), or a salt thereof, both as an individual isomer or as an isomeric mixture, obtained according to the process of the invention.
  • a salt of a compound of formula (I), (II) or (IV) is for example a pharmaceutically acceptable salt, typically the hydrochloride, hydrobromide, fumarate, citrate or succinate.
  • the invention provides a process for the preparation of a compound (III), as defined above, comprising the reaction of an amidoxime of formula (V), HN
  • a solvent can be selected from a polar aprotic solvent, such as an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide, or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethylsulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a C 3 -Ci 2 ketone, for example acetone, methyl ethyl ketone, methyl isobutyl ketone; an apolar solvent as toluene; or a mixture of two or more, preferably of two or three of said solvents; preferably the solvent is an apolar solvent.
  • a polar aprotic solvent such as an acyclic or cyclic amide
  • the reaction can be carried out at a temperature ranging from about 20°C to about 100°C, preferably from about 60 to about 80°C.
  • Trichloroacetyl chloride has never been used before in the preparation of a compound (III). This is a reagent commercially available and less expensive than the corresponding anhydride. It has surprisingly been found that, albeit trichloroacetyl chloride is more reactive and less stable than the corresponding anhydride, the process for the preparation of a compound (III) according to the present invention affords the compound (III) with both superior chemical purity, as evaluated by HPLC, and in higher yields than those obtainable according to known processes, for example as disclosed in J. Org. Chem. 2002, 67, 6253-6255 and US 3,574,222.
  • Amidoxime (V) is a known compound and can be prepared with known methods, for example by reaction of the hydroxylamine with a suitable nitrile.
  • the present invention relates to a process for the preparation of a compound of formula (I) or (II), or a salt thereof, both as an individual isomer or as an isomeric mixture, as defined above, comprising the use of a compound (III), or a salt thereof, both as an individual isomer or as an isomeric mixture, obtained according to the process of the invention.
  • Isobutyronitrile (104 g, 1.50 mol) is dissolved in methanol (300 ml), then treated with 50% hydroxylamine aqueous solution (100 g, 1.51 mol) and the resulting solution is heated at 50°C for 18 hours, then under reflux of the solvent for 4 hours.
  • the reaction mixture is then concentrated under reduced pressure, diluted with toluene and coevaporated under reduced pressure. The residue is taken up with toluene while warm, then the solution is slowly cooled to obtain an abundant precipitate.
  • the solid is filtered and washed with toluene to afford 138 g of isobutyroamidoxime in 90% yield.
  • the solution is diluted with toluene and water and the suspension is maintained under stirring for about 30 minutes, then the phases are separated and the organic one is further washed with water.
  • the organic phase is then extracted with 15% HC1 and the acidic aqueous phase is mixed with toluene (200 ml).

Abstract

Process for the preparation of oxadiazoles, useful as intermediates in the preparation of biologically active molecules.

Description

PROCESS FOR THE PREPARATION OF OXADIAZOLES
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of intermediates with 1 ,2,4-oxadiazole structure, useful in the preparation of biologically active compounds.
TECHNOLOGICAL BACKGROUND
Many organic compounds containing the 1 ,2,4-oxadiazole ring have shown high biological activity in a number of fields. In particular the compounds of formula (A)
Figure imgf000002_0001
are mentioned, wherein X is -NH- or -O-; E and G are variously substituted alkyl or aryl residues; or the EX- group is an optionally substituted saturated heterocyclic group containing a nitrogen bond to the oxadiazole. In particular, 5-0- substituted 1 ,2,4-oxadiazole derivatives having fungicidal and insecticidal properties are disclosed in WO 95/05368, WO 99/31072 and WO 2009/158257; compounds with 5 -N- substituted 1 ,2,4-oxadiazole structure, used in the treatment of obesity and diabetes, were recently described in WO 2008/081204, WO 2008/081205 and WO 2009/034388.
The introduction of the heteroatom X at the 5 position of a 1 ,2,4-oxadiazole core, is usually carried out through a substitution reaction by an oxygen-, such as an alcohol, or nitrogen- containing nucleophile, such as an amine or hydrazine, on a compound of formula (B)
Figure imgf000003_0001
wherein Y is a leaving group, for example a chlorine atom or the trichloromethyl group; and G is as defined above.
A compound of formula (B), wherein Y is a chlorine atom, can be obtained for example by reaction of a l ,2,4-oxadiazol-5-one with phosphorous pentachloride (PC15). Said l ,2,4-oxadiazol-5-one can in turn be prepared for example by acylation of an amidoxime with a suitable anhydride and subsequent cyclization of the resulting intermediate, as reported in WO 95/05368. The amidoxime can be prepared by known methods, for example by reaction of the hydroxylamine with a suitable nitrile.
A compound of formula (B), wherein Y is the trichloromethyl group, can be prepared according to what described in J. Org. Chem. 2002, 67, 6253-6255, by acylation of an amidoxime with trichloroacetic anhydride and cyclization of the resulting intermediate.
The use of a compound of formula (B) wherein Y is a trichloromethyl group is preferred over a compound of formula (B) wherein Y is chlorine, both in terms of preparation and reactivity and efficiency.
The substitution reaction in the preparation of a compound of formula (A), wherein X is -NH- or a saturated heterocycle, as defined above, is not easily applicable on an industrial scale, even when using an amine as nucleophile and a 1 ,2,4-oxadiazole, for example of formula (B), wherein Y as leaving group is a trichloromethyl group. For example, US 3,574,222 discloses that substitutions with simple amines on compounds of formula (B), wherein Y is trichloromethyl, take place under rather drastic conditions and in most cases they also afford low yields. In many cases high operative temperatures and very large excesses of the amine, which is also used as the solvent, are required to complete the reaction.
Such a method is obviously poorly efficient, difficult to scale up and sometimes cannot be carried out industrially, also due to the high costs involved with the starting materials and the operative reaction conditions. Furthermore, when the amine is a solid and/or very expensive compound, the process could not be carried out.
Probably due to said reasons, alternative synthetic routes for the preparation of a compound of formula (I) have been investigated, and are reported in the following Scheme. By way of example, in WO 2008/081204, WO 2008/081205 and WO 2009/034388, no compounds of formula (B) are used for the introduction of the heteroaromatic 1 ,2,4-oxadiazole cycle, as it is evident from the Scheme reported hereinbelow
Scheme
Figure imgf000004_0001
(IVa) (I)
wherein R 2, R3 and R4 are as defined in WO 2008/081204 and WO 2008/081205.
The synthesis reported in the above Scheme, which from the starting alkylpiperidine intermediate of formula (IVa) affords a compound of formula (I), suffers however from some basic limitations for a preparation process for use on an industrial scale. In particular, the synthesis is not convergent and involves the troublesome formation of the 1 ,2,4-oxadiazole cycle starting from expensive alkylpiperidine of formula (IVa). Last but not least, said synthetic route makes use of cyanogen bromide, a highly toxic, dangerous gas, particularly when used on an industrial scale.
There is therefore the need for an alternative, more advantageous process for the preparation of 1 ,2,4-oxadiazole derivatives, in particular for the preparation of a piperidine compound of formula (I), and of intermediates useful in its synthesis. Said method should also allow to efficiently carry out the preparation of 5 -N- substituted 1 ,2,4-oxadiazoles by use of safer reagents, to be industrially scaled up and to provide the desired product in high yields.
SUMMARY OF THE INVENTION
An advantageous method has now been found for the preparation of a
5 -N- substituted 1 ,2,4-oxadiazole compound of formula (II)
Figure imgf000005_0001
wherein T, W, Wi and are as herein defined, by means of a process comprising the reaction of a compound of formula (III)
Figure imgf000005_0002
(III)
wherein R is as herein defined, with a compound of formula (IV)
Figure imgf000005_0003
wherein W, Wi and Q are as herein defined, under mild reaction conditions which do not involve any excess of a compound of formula (IV) or high reaction temperatures. The yields obtained under the reaction conditions used are surprisingly very high and the reagents used are safe and easy to handle. This makes the process of the invention advantageous on an industrial scale.
DETAILED DISCLOSURE OF THE INVENTION
Object of the invention is a process for the preparation of a compound of formula (II), or a salt thereof, as individual isomer or a mixture thereof,
Figure imgf000006_0001
(Π)
wherein
the group is a Ci-C6 alkyl or aryl group;
T is absent or is -NH-;
W and Wi, which can be the same or different, are independently hydrogen, an optionally substituted C C14 alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aryl-Ci-Ci4 alkyl group or an optionally substituted heteroaryl-Ci-Ci4 alkyl group; or W and Wl s taken together with the nitrogen atom they are linked to, form an optionally substituted saturated heterocyclic ring; comprising the reaction of a compound of formula (III)
Figure imgf000006_0002
(HI)
wherein R is as defined above, with a compound of formula (IV) or a salt thereof, as individual isomer or a mixture thereof,
Figure imgf000006_0003
(IV) wherein
Q is hydrogen or NH2; and W and Wi are as defined above; in the presence of a solvent, preferably a polar aprotic solvent; and, if desired, the conversion of a compound of formula (II) to a salt thereof or the conversion of the salt to the free compound.
A Ci-C6 alkyl group, which can be straight or branched, is for example methyl, ethyl, propyl, isopropyl or tert-butyl.
A Ci-Ci4 alkyl group, which can be straight or branched, is for example a Ci-C6 alkyl group, in particular a Ci-C4 alkyl group, preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
An aryl group is for example phenyl or naphthyl, preferably phenyl. A heteroaryl group can be for example a hetero monocyclic or bicyclic group, containing one or more, preferably 1 , 2 or 3, heteroatoms independently selected from oxygen, sulfur and nitrogen, preferably said group is selected from pyridyl, thienyl or pyrazinyl.
An aryl-Ci-Ci4 alkyl group is for example an aryl-Ci-C6 alkyl group, preferably benzyl or phenylethyl, more preferably benzyl.
A heteroaryl-Ci-Ci4 alkyl group is for example a heteroaryl-Ci-C6 alkyl group, wherein the heteroaryl and alkyl portions are for example as defined above.
A heterocyclic saturated ring is for example a pyrrolidine, piperidine or morpholine ring.
An alkyl, aryl or heteroaryl group, as defined above, can be substituted by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro and cyano.
A saturated heterocyclic group, as defined above, can be substituted by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro, cyano and straight or branched C C14 alkyl optionally substituted with hydroxy.
A solvent can be selected from e.g. the group consisting of a polar aprotic solvent, for example an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethylsulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example methyl acetate or ethyl acetate; a C3-Ci2 ketone, for example acetone, methyl ethyl ketone or methyl isobutyl ketone; or a mixture of two or more, preferably of two or three of said solvents; preferably a polar aprotic solvent.
A compound of formula (III) can be reacted in the form of a solution thereof in a solvent as defined above in a concentration from about 1 to about 15 M, preferably from about 5 to about 12 M.
The reaction of a compound of formula (III) with a compound of formula (IV), or a salt thereof, can be carried out at a temperature ranging from about 0°C to 70°C, preferably from about 20 to about 40°C.
The conversion of a compound of formula (II) or (Ha) to a salt thereof and the conversion of the salt to a free compound can be carried out according to known methods.
After completion of the reaction, the compound of formula (II) or (Ha), or a salt thereof, can be optionally recovered.
If desired, an individual isomer of a compound of formula (II) or (Ha) can be recovered from a mixture of its isomers according to known methods.
According to a preferred aspect of the invention, a compound of formula (IV) is a compound of formula (IV a), or a salt thereof, both as an individual isomer, and as a mixture thereof, having the following structure
Figure imgf000009_0001
wherein R5 is hydrogen or Ci-C6 alkyl.
According to a further aspect of the invention, the reaction between a compound of formula (III), as defined above, and a compound of formula (IVa) or a salt thereof, both as an individual isomer, and as a mixture thereof, affords a compound of formula (Ila), or a salt thereof, both as an individual isomer, and as a mixture thereof, having the following formula
Figure imgf000009_0002
wherein R and R5 are as defined above.
The compounds of formula (III) and (IV) are known or can be obtained with known methods. In particular, a compound of formula (IVa), as defined above, is commercially available or can be prepared according to what reported in WO 2008/081204.
A compound of formula (Ila), as defined above, can be used as an intermediate in a process for the preparation of a compound of formula (I), or a salt thereof, both as an individual isomer, and as a mixture thereof,
Figure imgf000009_0003
(I) wherein R and R5 are as defined above; R6 is hydrogen, halogen or Ci-C6 alkyl; R7 is -SO2Ra, wherein Ra is Ci-C4 alkyl, or -CONHRb, wherein Rb is hydrogen, or Ci-C4 alkyl optionally substituted with hydroxy, according to the process reported in WO 2008/081204 and WO 2008/081205; or with known techniques.
A halogen is for example chlorine or fluorine.
A Ci-C6 alkyl group is for example as disclosed above.
A Ci-C4 alkyl group is preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
A mixture of isomers of formula (I), (II), (Ila), (IV) or (IV a) is preferably a racemic mixture thereof.
An isomer of a compound of formula (I), (II), (Ila) or (IV), in particular of formula (IVa), can be for example an optical isomer thereof.
A further aspect of the invention is therefore a process for the preparation of a compound of formula (I), or a salt thereof, both as an individual isomer or as an isomeric mixture, as defined above, comprising the use of a compound of formula (Ila), or a salt thereof, both as an individual isomer or as an isomeric mixture, obtained according to the process of the invention.
A salt of a compound of formula (I), (II) or (IV) is for example a pharmaceutically acceptable salt, typically the hydrochloride, hydrobromide, fumarate, citrate or succinate.
A process for the preparation of a compound (III) in high yield and with superior chemical purity has herein surprisingly been found.
According to a further aspect, the invention provides a process for the preparation of a compound (III), as defined above, comprising the reaction of an amidoxime of formula (V), HN
OH (v)
wherein is as defined above, with trichloroacetyl chloride, in the presence of a solvent.
A solvent can be selected from a polar aprotic solvent, such as an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide, or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethylsulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a C3-Ci2 ketone, for example acetone, methyl ethyl ketone, methyl isobutyl ketone; an apolar solvent as toluene; or a mixture of two or more, preferably of two or three of said solvents; preferably the solvent is an apolar solvent.
The reaction can be carried out at a temperature ranging from about 20°C to about 100°C, preferably from about 60 to about 80°C.
Trichloroacetyl chloride has never been used before in the preparation of a compound (III). This is a reagent commercially available and less expensive than the corresponding anhydride. It has surprisingly been found that, albeit trichloroacetyl chloride is more reactive and less stable than the corresponding anhydride, the process for the preparation of a compound (III) according to the present invention affords the compound (III) with both superior chemical purity, as evaluated by HPLC, and in higher yields than those obtainable according to known processes, for example as disclosed in J. Org. Chem. 2002, 67, 6253-6255 and US 3,574,222.
This allows to directly use a compound (III) in the preparation of a compound (II), or a salt thereof, without need for further purification, thus avoiding chromatographic or distillation purifications, which are conversely required in the processes known in the art for the preparation of a compound (II).
Amidoxime (V) is a known compound and can be prepared with known methods, for example by reaction of the hydroxylamine with a suitable nitrile.
According to a further aspect, the present invention relates to a process for the preparation of a compound of formula (I) or (II), or a salt thereof, both as an individual isomer or as an isomeric mixture, as defined above, comprising the use of a compound (III), or a salt thereof, both as an individual isomer or as an isomeric mixture, obtained according to the process of the invention.
The following examples illustrate the invention.
Example 1: Synthesis of isobutyroamidoxime (V, R = isopropyl)
Isobutyronitrile (104 g, 1.50 mol) is dissolved in methanol (300 ml), then treated with 50% hydroxylamine aqueous solution (100 g, 1.51 mol) and the resulting solution is heated at 50°C for 18 hours, then under reflux of the solvent for 4 hours. The reaction mixture is then concentrated under reduced pressure, diluted with toluene and coevaporated under reduced pressure. The residue is taken up with toluene while warm, then the solution is slowly cooled to obtain an abundant precipitate. The solid is filtered and washed with toluene to afford 138 g of isobutyroamidoxime in 90% yield.
Example 2: Synthesis of 3-isopropyl-5-trichloromethyl-l,2,4- oxadiazole (III, R = isopropyl)
Isobutyroamidoxime (V, = isopropyl) (138 g, 1.35 mol) is suspended in toluene (600 ml), and the resulting mixture is heated to 75 °C. Trichloroacetyl chloride (491 g, 2.70 mol) is then slowly added to the reaction mixture drop by drop. After completion of the addition, the reaction mixture is refluxed for 30 minutes, then cooled to 30°C and treated with water. The mixture is kept under stirring for 30 minutes, then the phases are separated and the organic phase is washed in succession first with 5% NaHCO3 aqueous solution, then with water. The organic phase is concentrated under reduced pressure to afford 255 g of compound of formula (II, = isopropyl) with in 82% yield.
Example 3: Synthesis of 3-[l-(3-isopropyl-l,2,4-oxadiazol-5-yl)- piperidin-4-yl]-propanol (Ila, R = isopropyl, R5 = H)
The compound (III), prepared as in Example 2, (100 g, 0.435 mol) is dissolved in dimethylacetamide (42 ml), the solution is added with the 3-piperidin-4-yl-propanol (IVa, R5 = H) (41.7 g, 0.29 mol) and the resulting mixture is kept under stirring for about 48 hours at about 28°C. The solution is diluted with toluene and water and the suspension is maintained under stirring for about 30 minutes, then the phases are separated and the organic one is further washed with water. The organic phase is then extracted with 15% HC1 and the acidic aqueous phase is mixed with toluene (200 ml). The biphasic mixture is slowly added drop by drop with 30% NaOH solution to pH 12, keeping the temperature below 30°C. The phases are separated and the organic one is washed with water and then with a NH4C1 diluted solution. The organic phase is concentrated under reduced pressure to afford 55.3 g of compound of formula (Ila, R = isopropyl, R5 = H) in 75% yield.

Claims

1. Process for the preparation of a compound of formula (Ila), or a salt thereof, either as a single isomer or as a mixture thereof,
Figure imgf000014_0001
(Ila)
wherein is a Ci -C6 alkyl or aryl group; and R5 is hydrogen or Ci-C6 alkyl; comprising reacting a compound of formula (III)
Figure imgf000014_0002
(III)
wherein R is as defined above, with a compound of formula (IV a) or a salt thereof, either as a single isomer or as a mixture thereof,
Figure imgf000014_0003
wherein R5 is as defined above; and, if desired, converting a compound of formula (Ila) into a salt thereof, or a salt of a compound of formula (Ila) into a free compound.
2. Process according to claim 1, wherein the reaction is carried out in a solvent chosen from the group consisting of a polar aprotic solvent; an ether; a chlorinated solvent; an ester; and a C3-C12 ketone; or a mixture of two or more of said solvents.
3. Process according to claim 2, wherein the reaction is carried out in a polar aprotic solvent.
4. Process according to claim 2, wherein the reaction is carried out in a solvent selected from the group consisting of an acyclic or cyclic amide; acetonitrile; and dimethylsulfoxide.
5. Process according to claim 2, wherein the reaction is carried out in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide and N-methylpyrrolidone.
6. Process according to claim 3, wherein a compound of formula (III) is reacted in the form of a solution thereof in the polar aprotic solvent at a concentration from about 1 to about 15 M.
7. Process according to claim 6, wherein the concentration is between about 5 and about 12 M.
8. Process according to claim 1 , wherein the reaction of a compound of formula (III) with a compound of formula (IVa), or a salt thereof, is carried out at a temperature ranging from about 0°C to about 70°C.
9. Process according to claim 8, wherein the temperature ranging from about 20°C to about 40°C.
10. Process according to claims 1 to 9, further comprising the use, as starting material, of a compound of formula (Ha), as defined in claim 1 , in a process for the preparation of a compound of formula (I), or a salt thereof, either as single isomer or as a mixture thereof,
Figure imgf000015_0001
(I)
wherein is a Ci-C6 alkyl or aryl group; R5 is hydrogen or Ci-C6 alkyl; R6 is hydrogen, halogen or Ci-C6 alkyl; R7 is -SO2Ra, in which Ra is Ci-C4 alkyl, or -CONH b, in which Rb is hydrogen or Ci -C4 alkyl optionally substituted by hydroxy.
1 1. Process according to claim 1 , further comprising the preparation of a compound of formula (III), as defined in claim 1 , by a process comprising reacting an amidoxime of formula (V)
F ^NH
OH
(V)
in which R is as defined in claim 1 , with trichloroacetyl chloride, in the presence of a solvent.
12. Process according to claim 1 1, wherein the solvent is chosen from the group consisting of a polar aprotic solvent; an ether; a chlorinated solvent; an ester; a C3-C12 ketone; and an apolar solvent; or a mixture of two or more of said solvents.
13. Process according to claim 1 1 , wherein the solvent is toluene.
14. Process according to claim 1 1 , wherein the reaction is carried out at a temperature comprised between about 20°C and about 100°C.
15. Process for preparing a compound of formula (III),
Figure imgf000016_0001
(III)
wherein R is a Ci -C6 alkyl or aryl group; comprising reacting an amidoxime of formula (V),
Figure imgf000016_0002
with trichloroacetyl chloride, in the presence of a solvent.
PCT/EP2011/057856 2010-05-31 2011-05-16 Process for the preparation of oxadiazoles WO2011151163A1 (en)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3574222A (en) 1965-12-29 1971-04-06 Mallinckrodt Chemical Works Preparation of 5-amino-1,2,4-oxadiazoles
WO1995005368A1 (en) 1993-08-13 1995-02-23 Zeneca Limited Thia- and oxadiazole derivatives and their use as fungicides or insecticides
WO1999031072A1 (en) 1997-12-18 1999-06-24 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
WO2008070692A2 (en) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Bicyclic compounds and use as antidiabetics
WO2008081204A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
WO2008081205A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
WO2009034388A1 (en) 2007-09-10 2009-03-19 Prosidion Limited Compounds for the treatment of metabolic disorders
WO2009158257A2 (en) 2008-06-27 2009-12-30 E. I. Du Pont De Nemours And Company Fungicidal pyridines
WO2010004347A1 (en) * 2008-07-10 2010-01-14 Prosidion Limited Heterocyclic gpcr agonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2575430A1 (en) * 2004-08-03 2006-02-16 Merck & Co., Inc. 1,3-disubstituted heteroaryl nmda/nr2b antagonists
UY30183A1 (en) * 2006-03-02 2007-10-31 Astrazeneca Ab QUINOLINE DERIVATIVES
US20080306116A1 (en) * 2007-06-08 2008-12-11 Christ Andreas D Aryloxazole, aryloxadiazole and benzimidazole derivatives
KR20180096823A (en) * 2009-04-22 2018-08-29 리스버로직스 코퍼레이션 Novel anti-inflammatory agents

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3574222A (en) 1965-12-29 1971-04-06 Mallinckrodt Chemical Works Preparation of 5-amino-1,2,4-oxadiazoles
WO1995005368A1 (en) 1993-08-13 1995-02-23 Zeneca Limited Thia- and oxadiazole derivatives and their use as fungicides or insecticides
WO1999031072A1 (en) 1997-12-18 1999-06-24 E.I. Du Pont De Nemours And Company Cyclohexylamine arthropodicides and fungicides
WO2008070692A2 (en) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Bicyclic compounds and use as antidiabetics
WO2008081204A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
WO2008081205A1 (en) 2007-01-04 2008-07-10 Prosidion Limited Piperidine gpcr agonists
WO2009034388A1 (en) 2007-09-10 2009-03-19 Prosidion Limited Compounds for the treatment of metabolic disorders
WO2009158257A2 (en) 2008-06-27 2009-12-30 E. I. Du Pont De Nemours And Company Fungicidal pyridines
WO2010004347A1 (en) * 2008-07-10 2010-01-14 Prosidion Limited Heterocyclic gpcr agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., vol. 67, 2002, pages 6253 - 6255

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