WO2006108493A1 - Process for preparing oxazole carboxylic esters - Google Patents
Process for preparing oxazole carboxylic esters Download PDFInfo
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- WO2006108493A1 WO2006108493A1 PCT/EP2006/002511 EP2006002511W WO2006108493A1 WO 2006108493 A1 WO2006108493 A1 WO 2006108493A1 EP 2006002511 W EP2006002511 W EP 2006002511W WO 2006108493 A1 WO2006108493 A1 WO 2006108493A1
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- Prior art keywords
- formula
- oxazole
- nitrile
- employed
- carboxylic esters
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Definitions
- Oxazole carboxylic esters such as, for instance methyl 2- (5-methyl-2 -phenyl -1, 3-oxazol-4-yl) acetate, are valuable intermediates in the synthesis of pharmaceuticals employed for example for the prophylaxis and/or treatment of diabetes II.
- oxazole carboxylic esters for preparing active pharmaceutical ingredients and the preparation thereof is disclosed for example in WO 01/79202, in which for example first methyl 3-oxovalerate is reacted with methyl orthoformate to give methyl 3-methoxy-2- pentenoate which is then brominated by conventional methods such as, for instance, reaction with bromosuccinimide, followed by condensation with an appropriate amide such as, for instance, a benzamide to give the desired oxazole carboxylic ester, the condensation step proceeding, for instance as in Example 14, in a yield of 43%.
- the present invention accordingly relates* to a process for preparing oxazole carboxylic esters of the formula
- Ar is aryl or heteroaryl
- Rl is H or alkyl
- R2 is alkyl or aryl, which comprises converting an oxazole nitrile of the formula
- Oxazole carboxylic esters of the formula (I) are prepared by the process of the invention.
- Ar is aryl or heteroaryl
- Rl is H or alkyl
- R2 is alkyl or aryl .
- Aryl and heteroaryl mean in this connection aromatic compounds preferably having 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 .
- aromatic compounds examples include phenyl, naphthyl, cyclopentadienyl, indenyl, fluorenyl, indanyl, tetralinyl, pyrrolyl, furyl , thienyl, pyridyl, pyrimidinyl , indo ⁇ yl, cumaronyl, quinolinyl, chromenyl, chromanyl , etc .
- Aryl is preferably phenyl or naphthyl and heteroaryl pyridyl .
- the aryl and heteroaryl radicals may moreover be optionally substituted one or more times .
- suitable substituents are alkyl, preferably Ci-C ⁇ -alkyl, alkoxy, preferably Ci-C 6 -alkoxy, halogen such as, for instance, chlorine, bromine or fluorine, mono- or polyhaloalkyl, mono- or polyhaloalkoxy, alkenyl, preferably C 2 -C 8 -alkenyl, optionally substituted phenyl, optionally substituted amine, hydroxy, nitro, carboxyl, carboxylic esters, etc.
- the aryl or heteroaryl radical is preferably unsubstituted or substituted once or twice by hydroxy, Ci-Ci-alkyl, Ci-C 4 -alkoxy, chlorine, trifluoromethyl or phenyl .
- Rl is H or alkyl, where alkyl means saturated or tnono- 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.
- R2 is alkyl or aryl, where alkyl in turn 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 .
- Aryl has the abovementioned meaning, but in the case of R2 aryl is preferably phenyl .
- R2 is particularly preferably a saturated, linear or branched alkyl radical having 1 to 6 C atoms.
- a further possibility is to prepare the oxazole nitriles employed according to the invention in analogy to WO 01/79202 from, for example, 3-ethoxy-2- pentenenitrile which is then brominated by conventional methods, such as, for instance, reaction with bromosuccinimide, after which a condensation takes place with an appropriate amide such as, for instance, a benzamide to give the desired oxazole nitrile.
- Reaction of the oxazole nitrile to give the carboxylic ester takes place according to the invention in the presence of a mineral acid and of an alcohol of the formula R2OH and subsequent hydrolysis.
- Suitable mineral acids in this case are, for example, HCl, H 3 PO 4 , p-toluenesulfonic acid, H 2 SO 4 etc.
- HCl can in this case be employed as gas or as alcoholate, where appropriate anhydrous solution.
- the amount of acid employed, based on nitrile, is at least one mol per mol of nitrile, preferably 1.5-3 mol per mol of nitrile and particularly preferably 1.8 to 2.2 mol per mol of nitrile.
- alcohols employed are alcohols of the formula R20H where R2 is as defined above.
- Alcohols of the formula R2OH in which R2 is a saturated, linear or branched alkyl radical having 1 to 6 C atoms are particularly preferred.
- the alcohol serves in this case both as solvent for the nitrile or for the hydrochloric acid and as ester component.
- the amount of alcohol based on nitrile is at least 1 to about 5 mol per mol of nitrile. It is also possible if desired to use larger excesses of alcohol .
- the oxazole nitrile is introduced into the appropriate alcohol of the formula R20H and then, at a temperature of 20 to 60°C, preferably of 30 to 50 0 C, the mineral acid, for example sulfuric acid, is metered in.
- the reaction mixture is then stirred for some time (a few minutes up to several hours) at 50 0 C to the reflux temperature.
- the reaction can be checked for example by GC - the reaction solution is cooled to 10 to 3O 0 C, and water is added. In this case, from 1 to about 5 mol of water is added per mol of nitrile. Larger excesses of water can also be employed if desired.
- the reaction mixture is then worked up by adding a basic aqueous solution such as, for instance, an NaHCO 3 solution, until the pH of the reaction solution is in the basic range, after which the reaction mixture is extracted with a suitable conventional extractant such as, for instance, CH 2 Cl 2 , tert-butyl methyl ether etc.
- a suitable conventional extractant such as, for instance, CH 2 Cl 2 , tert-butyl methyl ether etc.
- the organic phases are then concentrated to isolate the carboxylic ester.
- Reaction of the oxazole nitrile to give the corresponding carboxylic ester can also, however, take place by metering an anhydrous alcoholic HCl solution or an HCl gas/alcohol/H 2 0 mixture into an alcoholic solution of the nitrile.
- the • subsequent procedure takes place as indicated above.
- Oxazole carboxylic esters of the formula (I) are prepared by the process of the invention in high yields and high purity from easily obtainable precursors in a simple manner which can easily be achieved industrially.
Abstract
A process for preparing oxazole carboxylic esters of the formula (I) in which Ar is aryl or heteroaryl, Rl is H or alkyl and R2 is alkyl or aryl, which comprises converting an oxazole nitrile of the formula (II) in which Ar and Rl are as defined above, in the presence of a mineral acid and of ' an alcohol of the formula R20H, and subsequent hydrolysis with water, into the desired oxazole carboxylic esters of the formula (I) .
Description
Process for preparing oxazole carboxylic esters
Oxazole carboxylic esters such as, for instance methyl 2- (5-methyl-2 -phenyl -1, 3-oxazol-4-yl) acetate, are valuable intermediates in the synthesis of pharmaceuticals employed for example for the prophylaxis and/or treatment of diabetes II.
The use of such oxazole carboxylic esters for preparing active pharmaceutical ingredients and the preparation thereof is disclosed for example in WO 01/79202, in which for example first methyl 3-oxovalerate is reacted with methyl orthoformate to give methyl 3-methoxy-2- pentenoate which is then brominated by conventional methods such as, for instance, reaction with bromosuccinimide, followed by condensation with an appropriate amide such as, for instance, a benzamide to give the desired oxazole carboxylic ester, the condensation step proceeding, for instance as in Example 14, in a yield of 43%.
According to Malamas et al . , J. Med. Chem. 39 (1), 199,6; 237-245, the corresponding oxazole carboxylic esters are obtained by reacting the corresponding benzamide with 4-chloroacetoacetate at the reflux temperature. Malamas et al . refer in this connection to EP 0 177 353, in which variously substituted oxazole acetates are obtained by reacting the corresponding amides and 4-chloroacetoacetate in yields of only 28 to about 35%.
It was an object of the present invention to find a novel process for preparing oxazole carboxylic esters, which starts from easily and inexpensively obtainable starting materials and which enables the products employed to be reacted in an efficient and industrially achievable manner.
The present invention accordingly relates* to a process 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, which comprises converting an oxazole nitrile of the formula
in which Ar and Rl are as defined above, in the presence of a mineral acid and of an alcohol of the formula R2OH, and subsequent hydrolysis with water, into the desired oxazole carboxylic esters of the formula (I) .
Oxazole carboxylic esters of the formula (I) are prepared by the process of the invention. In the formula (I), Ar is aryl or heteroaryl, Rl is H or alkyl and R2 is alkyl or aryl .
Aryl and heteroaryl mean in this connection aromatic compounds preferably having 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 , indoϊyl, cumaronyl, quinolinyl, chromenyl, chromanyl , etc .
Aryl is preferably 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-Cβ-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 esters, etc. The aryl or heteroaryl radical is preferably unsubstituted or substituted once or twice by hydroxy, Ci-Ci-alkyl, Ci-C4-alkoxy, chlorine, trifluoromethyl or phenyl .
Rl is H or alkyl, where alkyl means saturated or tnono- 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.
R2 is alkyl or aryl, where alkyl in turn 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 .
Aryl has the abovementioned meaning, but in the case of R2 aryl is preferably phenyl . R2 is particularly preferably a saturated, linear or branched alkyl radical having 1 to 6 C atoms.
The inventive preparation of the oxazole carboxylic esters of the formula (I) starts from an oxazole nitrile of the formula (II) .
Oxazole nitriles of the formula (II) and their preparation are disclosed in the literature, for example US 6,673,815. In Example 4 of the US patent, 2-
(5-methyl-2-phenyl-l, 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 subsequently deoxygenating with phosphorus oxychloride .
A further possibility for preparing the nitriles is according to US 6,673,815 the 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 . A further possibility is to prepare the oxazole nitriles employed according to the invention in analogy to WO 01/79202 from, for example, 3-ethoxy-2- pentenenitrile which is then brominated by conventional methods, such as, for instance, reaction with bromosuccinimide, after which a condensation takes place with an appropriate amide such as, for instance, a benzamide to give the desired oxazole nitrile.
An improved variant for preparing the oxazole nitrile is reaction of the corresponding chloride compound of the formula
with an alkali metal cyanide in a suitable solvent, for example toluene, by means of phase-transfer catalysis.
Reaction of the oxazole nitrile to give the carboxylic ester takes place according to the invention in the
presence of a mineral acid and of an alcohol of the formula R2OH and subsequent hydrolysis.
Suitable mineral acids in this case are, for example, HCl, H3PO4, p-toluenesulfonic acid, H2SO4 etc. HCl can in this case be employed as gas or as alcoholate, where appropriate anhydrous solution.
The amount of acid employed, based on nitrile, is at least one mol per mol of nitrile, preferably 1.5-3 mol per mol of nitrile and particularly preferably 1.8 to 2.2 mol per mol of nitrile.
The alcohols employed are alcohols of the formula R20H where R2 is as defined above. Alcohols of the formula R2OH in which R2 is a saturated, linear or branched alkyl radical having 1 to 6 C atoms are particularly preferred.
The alcohol serves in this case both as solvent for the nitrile or for the hydrochloric acid and as ester component.
The amount of alcohol based on nitrile is at least 1 to about 5 mol per mol of nitrile. It is also possible if desired to use larger excesses of alcohol .
In the process of the invention, for example, the oxazole nitrile is introduced into the appropriate alcohol of the formula R20H and then, at a temperature of 20 to 60°C, preferably of 30 to 500C, the mineral acid, for example sulfuric acid, is metered in. The reaction mixture is then stirred for some time (a few minutes up to several hours) at 500C to the reflux temperature. After the reaction is complete - the reaction can be checked for example by GC - the reaction solution is cooled to 10 to 3O0C, and water is added. In this case, from 1 to about 5 mol of water is added per mol of nitrile. Larger excesses of water can also be employed if desired.
The reaction mixture is then worked up by adding a basic aqueous solution such as, for instance, an NaHCO3
solution, until the pH of the reaction solution is in the basic range, after which the reaction mixture is extracted with a suitable conventional extractant such as, for instance, CH2Cl2, tert-butyl methyl ether etc. The organic phases are then concentrated to isolate the carboxylic ester.
Reaction of the oxazole nitrile to give the corresponding carboxylic ester can also, however, take place by metering an anhydrous alcoholic HCl solution or an HCl gas/alcohol/H20 mixture into an alcoholic solution of the nitrile. The • subsequent procedure takes place as indicated above.
Oxazole carboxylic esters of the formula (I) are prepared by the process of the invention in high yields and high purity from easily obtainable precursors in a simple manner which can easily be achieved industrially.
Example 1: Preparation of methyl 2- (5-methyl-2 -phenyl- 1, 3-oxazol-4-yl) acetate
1 g (0.005 mol) of 2- (5-methyl-2-phenyl-l, 3-oxazol~4- yl) acetonitrile was introduced into 8 ml of methanol and, while stirring at 4O0C, 1.6 ml of H2SO4 (96% pure) were added dropwise over the course of 45 min. The reaction was checked by GC. The mixture was subsequently stirred under reflux for 9 h and then, after cooling to 25°C, stirred with 6 ml of H2O. Subsequently, 60 ml of saturated aqueous NaHCO3 solution were added to the reaction mixture until the pH was in the basic range (pH 9-10) . The reaction mixture was then extracted three times with 50 ml of CH2Cl2 each time, and the collected organic phases were concentrated in a rotary evaporator. 1.1 g (95%) of methyl 2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) acetate were obtained.
Claims
1. A process 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, which comprises converting an oxazole nitrile of the formula
in which Ar and Rl are as defined above, in the presence of a mineral acid and of an alcohol of the formula R2OH, and subsequent hydrolysis with water, into the desired oxazole carboxylic esters of the formula (I) .
2. The process as claimed in claim 1, wherein HCl,
H3PO4, p-toluenesulfonic acid or H2SO4 is employed as mineral acid.
3. The process as claimed in claim 2, wherein HCl is employed as gas or as alcoholate, optionally anhydrous solution.
4. The process as claimed in any of claims 1-3, wherein the amount of acid employed is at least 1 mol per mol of nitrile.
5. The process as claimed in any of» claims 1-4, wherein the amount of alcohol R2OH employed is at least 1 to 5 mol per mol of nitrile.
6. The process as claimed in any of claims 1-5, wherein the oxazole nitrile of the formula (II) is introduced into the appropriate alcohol of the formula R2OH and subsequently, at a temperature of from 20 to 600C, the mineral acid is metered in, after which the reaction mixture is stirred at 5O0C to the reflux temperature and, after the reaction is complete, cooled to 10 to 3O0C, and water is added.
7. The process as claimed in any of claims 1-6, wherein the reaction mixture is worked up by adding a basic aqueous solution until the pH of the reaction solution is in the basic range, and subsequently extracting the reaction mixture with an extractant, after which the organic phase is concentrated to isolate the carboxylic ester.
8. The process as claimed in any of claims 1-7, wherein an oxazole nitrile of the formula (II) that has been prepared by reacting the corresponding chloride compound of the formula
with an alkali metal cyanide in a solvent by means of phase-transfer catalyst is employed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ATA599/2005 | 2005-04-11 | ||
| AT5992005 | 2005-04-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006108493A1 true WO2006108493A1 (en) | 2006-10-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2006/002511 WO2006108493A1 (en) | 2005-04-11 | 2006-03-18 | Process for preparing oxazole carboxylic esters |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006108493A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1139940A (en) * | 1966-09-30 | 1969-01-15 | Ici Ltd | Oxazole derivatives |
-
2006
- 2006-03-18 WO PCT/EP2006/002511 patent/WO2006108493A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1139940A (en) * | 1966-09-30 | 1969-01-15 | Ici Ltd | Oxazole derivatives |
Non-Patent Citations (1)
| Title |
|---|
| HUNG H-K ET AL: "THE TOTAL SYNTHESIS OF 4-DEOXY-D,L-DAUNOSAMINE", CANADIAN JOURNAL OF CHEMISTRY, NATIONAL RESEARCH COUNCIL. OTTAWA, CA, vol. 56, 1978, pages 638 - 644, XP002934384, ISSN: 0008-4042 * |
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