WO2006108491A1

WO2006108491A1 - Improved process for preparing oxazole nitriles

Info

Publication number: WO2006108491A1
Application number: PCT/EP2006/002509
Authority: WO
Inventors: Johann Hiebl; Michael Stanek; Jan Hilko Schulte
Original assignee: Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg
Priority date: 2005-04-11
Filing date: 2006-03-18
Publication date: 2006-10-19

Abstract

An improved process for preparing oxazole nitriles of formula (I) in which Ar is aryl or heteroaryl and Rl is H or alkyl , which comprises reacting a corresponding oxazole chloride of formula (II) in which Ar and Rl are as defined above, in a solvent with an alkali metal cyanide in the presence of a phase-transfer catalyst to give the desired oxazole nitrile of formula (I) .

Description

Improved process for preparing oxazole nitriles

Oxazole nitriles such as, for instance, 2- (5-methyl-2- phenyl-1, 3-oxazol-4-yl) acetonitrile, are valuable intermediates in the synthesis of pharmaceuticals which are employed for example for the prophylaxis and/or treatment of diabetes II .

The use of such oxazole nitriles for preparing active pharmaceutical ingredients is disclosed for example in US 6,673,815. In Example 4 of the US patent, 2- (5- πiethyl-2 -phenyl- 1, 3-oxazol-4-yl) acetonitrile is obtained in a yield of 37% from the corresponding chloride by reaction with NaCN in DMSO. The chloride is in this case obtained according to Malamas et al . , J. Med. Chem. 39 (1) , 1996; 237-245, by reacting the corresponding benzaldehyde with 2 , 3-butanedione monoxime and subsequent deoxygenation with phosphorus oxychloride . In WO 02/092084 too, the corresponding chloride is reacted with NaCN in DMSO to give the nitrile. Once again, the yield is very low, not exceeding 50%. According to J. Med. Chem. 2001, 44, pp. 2061-2064, the chloride is reacted with KCN in the presence of KI in DMF to give the desired nitrile. The disadvantage in this case is the use of the costly auxiliary reagent KI.

A further possibility for preparing the nitriles is, according to US 6,673,815, reaction of the corresponding alcohol in accordance with the reference Aesa et al . , Synth. Commun. 1996, 26(5), 909-914 with acetone cyanohydrin in the presence of triphenylphosphine-diethyl azodicarboxylate .

It was an object of the present invention to find an improved process for preparing oxazole nitriles which starts from easily and inexpensively obtainable starting materials, which enables reaction in an efficient and industrially achievable manner and easy purification of the reaction mixture, which affords the desired oxazole nitrile in higher yields.

The present invention accordingly relates to an improved process for preparing oxazole nitriles of the formula

in which Ar is aryl or heteroaryl and Rl is H or alkyl, which comprises reacting a corresponding oxazole chloride of the formula

in which Ar and Rl are as defined above, in a solvent with an alkali metal cyanide in the presence of a phase-transfer catalyst to give the desired oxazole nitrile of the formula (I) .

Oxazole nitriles of the formula (I) are prepared by the process of the invention.

In the formula (I) Ar is aryl or heteroaryl and Rl is H or alkyl . Aryl and heteroaryl mean in this connection aromatic compounds which preferably have 4 to 20 C atoms. The heteroaryl compounds additionally have 1 to 3 heteroatoms from the group of 0, N or S . Possibilities in this connection are monocyclic or polycyclic aromatic groups to which further rings (cycloalkyl, cycloheteroalkyl or heteroaryl) may be fused where appropriate . Examples of such aromatic compounds are phenyl, naphthyl, cyclopentadienyl, indenyl , fluorenyl, indanyl, tetralinyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, indolyl, cumaronyl, quinolinyl, chromenyl , chromanyl, etc.

Preferably aryl means phenyl or naphthyl and heteroaryl pyridyl .

The aryl and heteroaryl radicals may moreover be optionally substituted one or more times. Examples of suitable substituents are alkyl, preferably Ci-C₃-alkyl, alkoxy, preferably Ci-C₆-alkoxy, halogen such as, for instance, chlorine, bromine or fluorine, mono- or polyhaloalkyl , mono- or polyhaloalkoxy, alkenyl , preferably C₂-C₈-alkenyl, optionally substituted phenyl, optionally substituted amine, hydroxy, nitro, carboxyl, carboxylic ester, etc.

The aryl or heteroaryl radical is preferably unsubstituted or substituted once or twice by hydroxy, Ci-C₄-alkyl, C₁-C₄-alkoxy, chlorine, trifluoromethyl or phenyl .

Rl is H or alkyl, where alkyl means saturated or mono- or polyunsaturated, linear, branched or cyclic hydrocarbon chains having 1 to 20 C atoms, preferably having 1 to 8 C atoms. Examples thereof are methyl, ethyl, i-propyl, tert-butyl, cyclohexyl, propenyl, etc.

The inventive preparation of the oxazole nitriles of the formula (I) starts from the corresponding oxazole chloride of the formula (II) .

Ar and Rl in formula (II) are as defined above.

Suitable oxazole chlorides can be prepared as in the prior art as described, for instance, in Chem. Pharm. Bull., 1971, 19, pp. 2050; J. Med. Chem., 1996, 39, pp. 237-245; J. Med. Chem., 2000, 43, p. 995-1010, US 5468760, US 5480896, WO 03/043985, etc. It is particularly advantageous to purify the oxazole chloride, after the reaction of the corresponding oxazole N-oxide with POCl₃ as in the prior art, by- extraction with water and, where appropriate, recrystallization in methanol or a methanol/water mixture, because the purity of the product can be increased considerably thereby in an efficient and industrially achievable manner.

The inventive reaction of the oxazole chlorides of the formula (II) to give the desired oxazole nitriles of the formula (I) takes place in a suitable solvent with an alkali metal cyanide in the presence of a phase- transfer catalyst .

Suitable solvents for the inventive process are aromatic hydrocarbons, which may be optionally halogenated, such as, for instance, toluene, xylenes, chlorobenzenes, etc., or mixtures thereof with water. A mixture of toluene and water is preferably employed as solvent .

Suitable examples of alkali metal cyanide are NaCN, LiCN, KCN, etc.

The cyanide is in this case employed in at least the equivalent amount or in an excess relative to the oxazole chloride.

The cyanide is preferably used in an amount of from 1.0 to 2.5 mol per mol of oxazole chloride and particularly preferably from 1.1 to 1.5 mol per mol of oxazole chloride .

Suitable phase-transfer catalysts are quaternary phosphonium salts such as, for instance, (alkyl) ₄P⁺Hal^", (aryl) ₄P⁺Hal^~, alkylaryl-P⁺HaI^", etc. or quaternary ammonium salts such as, for instance, tetraalkylammonium halides, tetraarylammonium halides, alkylarylammonium halides or cyanides, etc., which are described for example in CM. Starks, CL. Liotta, M. C. Halpern, Phase Transfer Catalysis; Chapman & Hall; New York, 1994. Halide means in this case preferably bromide or chloride. The tetraalkyl moiety consists of four alkyl groups, which may be identical or different, and comprise 1 to 16 C atoms. The aryl moiety may be for example phenyl or benzyl .

Quaternary ammonium salts are preferably employed.

Examples of suitable phase-transfer catalysts are tetrabutylammonium bromide (TBAB) , tributylmethyl- ammonium chloride (TBMAC) , trimethylbenzylammonium chloride, etc.

The phase-transfer catalyst is employed in the inventive reaction in an amount of from 0.001 to 0.1 mol per mol of oxazole chloride. An amount of from 0.01 to 0.05 mol per mol of oxazole chloride is preferred.

The reaction temperature is 50 to 120⁰C, preferably 75 to 90⁰C.

To carry out the process, preferably all the reagents (oxazole chloride, solvent, cyanide, phase-transfer catalyst) are introduced simultaneously and then heated to the desired temperature, preferably while stirring. Alternatively, the cyanide can also be added last, at the desired reaction temperature. After the reaction is complete, the reaction mixture is cooled to a temperature of from 5 to 30⁰C, preferably to 15 to 25°C, and an aqueous base such as, for instance, a dilute Na₂CO₃ or NaHCO₃ solution is added and, after phase separation, the organic phase is, where appropriate after extraction one or more times with the aqueous base, concentrated. The remaining residue is recrystallized where appropriate in a suitable solvent. Examples of suitable solvents for this are diisopropyl ether, tert-butyl methyl ether, methanol, etc.

Oxazole nitriles of the formula (I) are prepared in higher yields compared with the prior art, and in high purity, from easily obtainable precursors in a simple manner which is easy to achieve industrially.

The oxazole nitriles of the formula (I) which are prepared according to the invention are moreover outstandingly suitable for further reaction to give the corresponding oxazole carboxylic esters of the formula

in which Ar is aryl or heteroaryl, Rl is H or alkyl and R2 is alkyl or aryl, for example by converting the appropriate oxazole nitrile into the desired oxazole carboxylic esters in the presence of a mineral acid and of an alcohol of the formula R20H and subsequent hydrolysis with water.

Example 1: Preparation of 2- (5-methyl-2 -phenyl-I₇3- oxazol-4-yl) acetonitrile

a) Preparation of the oxazole chloride

1465 g (13.8 mol) of benzaldehyde, 1244 g (12.3 mol) of 2,3-butanedione monoxime and 4.8 1 of cone, acetic acid were mixed and this mixture was cooled to 4⁰C while stirring. Then, over the course of 100 min, 1500 g (41.1 mol) of HCl gas were passed in at an internal temperature of 4-12⁰C. The reaction mixture was stirred at the same temperature for 1 h and then, at 10-20⁰C, 21 1 of t-butyl methyl ether (MTBE) were added over the course of 45 min. The MTBE addition was initially exothermic. The mixture was then stirred at 5⁰C for a further 30 min and subsequently the resulting solid was filtered off. The solid was washed with MTBE and dried in vacuo at 5O⁰C. Yield: 2498 g of oxazole N-oxide (11.07 mol, 90%).

2220 g of oxazole N-oxide were suspended in 19.9 1 of methylene chloride, and this mixture was cooled to 5°C. Then, over the course of 15 min, 2837 g (18.5 mol) of POCl₃ were added at an internal temperature of 5-7⁰C. Stirring at 5-7⁰C for 3.0 min was followed by slow warming to 40⁰C and stirring at this temperature for 3 h. After cooling to 5⁰C, 34.7 1 of water were added over the course of 2 h. The phases were separated and the organic phase was extracted with 17.3 1 of water.

The organic phase was concentrated in vacuo, and the residue was recrystallized from methanol/water

(14.4 1/14.4 1) and washed with 10 1 of water. Filtration and drying resulted in 1940 g (9.35 mol, 95%) of the oxazole chloride.

b) Reaction of the oxazole chloride

1634 g (7.87 mol) of oxazole chloride, 463 g (9.44 mol) of NaCN, 28 g (0.119 mol) of tributylmethylammonium chloride, 4.9 1 of toluene and 0.24 1 of H₂O were introduced into the reactor, and this mixture was heated at 80-85°C while stirring vigorously for 6 h. After the reaction mixture had cooled to 20⁰C, dilute aqueous Na₂CO₃ solution was added and, after phase separation, the organic phase was extracted twice with dilute aqueous Na₂CO₃ solution. The residue after concentration of the organic phase in vacuo was dissolved in diisopropyl ether, filtered through activated carbon and crystallized. 1435 g (7.24 mol, 92%) of the oxazole nitrile were obtained.

Claims

Claims :

1. An improved process for preparing oxazole nitriles of the formula

in which Ar is aryl or heteroaryl and Rl is H or alkyl , which comprises reacting a corresponding oxazole chloride of the formula

2. The process as claimed in claim 1, wherein the reaction takes place in a solvent from the group of optionally halogenated aromatic hydrocarbons or in a mixture thereof with water.

3. The process as claimed in either of claims 1 or 2 , wherein the cyanide is employed in an amount of from 1.0 to 2.5 mol per mol of oxazole chloride .

4. The process as claimed in any of claims 1 to 3 , wherein a quaternary phosphonium salt or a quaternary ammonium salt is employed as phase- transfer catalyst .

5. The process as claimed in any of claims 1 to 4, wherein the phase-transfer catalyst is employed in an amount of from 0.001 to 0.1 mol per mol of oxazole chloride .

6. The process as claimed in any of claims 1 to 5, wherein the reaction is carried out at from 50 to 12O⁰C.

7. The process as claimed in any of claims 1 to 6, wherein the oxazole nitrile of the formula (I) is isolated by adding, after the reaction has taken place, an aqueous base to the reaction mixture, after which a phase separation takes place, the organic phase is, where appropriate after extraction with the aqueous base, concentrated, and the remaining residue is recrystallized where appropriate.

8. The process as claimed in any of claims 1 to 7, wherein the chloride of the formula (II) employed is prepared by reacting the corresponding oxazole N-oxide with POCl₃, extracting with water and, where appropriate, subsequently recrystallizing in methanol or a methanol/water mixture.

9. The use of oxazole nitriles of the formula (I) prepared as claimed in any of claims 1 to 8 for preparing oxazole carboxylic esters of the formula

in which Ar is aryl or heteroaryl, Rl is H or alkyl and R2 is alkyl or aryl .

10. The use as claimed in claim 9, wherein an appropriate oxazole nitrile of the formula (I) is converted into the desired oxazole carboxylic ester of the formula (II) in the presence of a mineral acid and of an alcohol of the formula R2OH and subsequent hydrolysis with water.