WO2013160322A1

WO2013160322A1 - Process for synthesis of 4-methyloxazole-5-carboxamide

Info

Publication number: WO2013160322A1
Application number: PCT/EP2013/058426
Authority: WO
Inventors: Jocelyn FISCHER; Philippe Karrer; Letizia VOLPE; Werner Bonrath
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2012-04-25
Filing date: 2013-04-24
Publication date: 2013-10-31
Anticipated expiration: 2014-10-25
Also published as: CN104203930A; EP2841424A1; CN110229115A

Description

PROCESS FOR SYNTHESIS OF 4-METHYLOXAZOLE-5-CARBOXAMIDE

Field of Invention

The present invention is concerned with a novel process for synthesis of 4-methyl- oxazole-5-carboxamide (OXA), which is a valuable intermediate in the synthesis of pyridoxine (vitamin B₆).

Background of Invention

Several processes for the manufacture of pyridoxine have already been described. A summary of the most important ones is to be found, e.g., in Ullmann's Encyclopedia of Industrial Chemistry, fifth edition, 1996, vol. A 27, p. 533-537. For the industrial synthesis of pyridoxine there is now used nearly exclusively the approach described by Kondratyeva, G.Y., Khim. Nauka Promst. 2, 666 (1957), in which approach the pyridine ring is obtained by a Diels-Alder reaction of oxazoles with maleic acid or its derivatives. A particularly preferred oxazole in the synthetic pathway is 5-cyano-4- methyl-oxazole (OXN).

US 5,910,594 describes the manufacture of 5-cyano-4-lower alkyl-oxazole by dehydrating, in an aprotic organic solvent, a 5-carbamoyl-4-lower alkyl-oxazole with silicon tetrachloride in the presence of an amine. According to the disclosure of US 5,502,212 OXAs are dehydrated to the corresponding OXNs with an N,N- disubstituted formamide and cyanuric chloride in a polar, aprotic organic solvent. The yield of OXN from the corresponding OXA is 99.4% in theory. Nothing, however, is disclosed on the preparation of OXA. Although Ullmann's Encyclopedia (see above), page 533, mentions the transformation of ethyl 4-methyl- oxazole-5-carboxylate into OXA no reference for this reaction comprising any reaction conditions including yield and purity is given.

It was, therefore, an object to find a method of preparation of OXA in high yield under attractive conditions for industrial synthesis.

Summary of Invention

In accordance with the present invention it has been found that 4-methyl-oxazole-5- carboxylate can be converted into OXA with high yields (90% and more) by reacting with a high concentration of aqueous ammonia.

Therefore, the present invention provides a process for synthesis of 4-methyl- oxazole-5-carboxamide (OXA) which comprises reacting a compound of formula (I) with a high concentration of aqueous ammonia:

(I)

Wherein Ri is H or Ci-io alkyl.

Detailed Description of Invention

In the present invention, the term "Ci-io alkyl" as used refers to branched or unbranched, cyclic or non-cyclic, saturated alkyl comprising 1 -10 carbon atoms. Preferably, the "Ci-io alkyl" is C1-4 alkyl, including but limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methyl cyclopropyl and cyclobutyl. More preferably, the "Ci-io alkyl" is methyl or ethyl. The present invention provides a process for synthesis of 4-methyl-oxazole-5- carboxamide (OXA) which comprises reacting a compound of formula (I) with a high concentration of aqueous ammonia:

0

Wherein Ri is H or Ci-io alkyl.

The high concentration of aqueous ammonia useful in the reaction may be ammonia solution in water which has a concentration of at least 15wt%, preferably at least 28wt%, more preferably at least 30wt%, and the most preferably at least 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 42wt%, 45wt%, 48wt%, 50wt%, 52wt% or 55%. In one embodiment of the process, the aqueous ammonia useful in the reaction has a concentration between 28wt% and 50wt%, more preferably between 30wt% and 45wt%, even more preferably between 30wt% and 40wt%.

The amount of the aqueous ammonia useful in the reaction is not critical and can vary in a wide range. Preferably, the aqueous ammonia is used in an amount of the ammonia in the range of 1 mol to 10 mol, more preferably in the range of 2 mol to 8 mol, and the most preferably 5 mol to 8 mol, per 1 mol of the compound of formula (I).

Preferably, the reaction is carried out in the presence of a catalyst, which may be selected from the group consisting of ammonium salts, quaternary ammonium salts and alkali metal phosphates.

Examples of ammonium salts are those of formula NH₄X wherein X is the anion of an inorganic acid such as a hydrogen halogenide, sulphuric acid and phosphoric acid, or of a strong organic acid well-known in the art, such as, carboxylic acids (mono-, di-, tri-, polybasic) such as formic acid, acetic acid, trifluoro-acetic acid and citric acid.

Quaternary ammonium salts as catalyst are represented by formula [N(R¹)₃R²]X, wherein R¹ is C-i-do alkyl; R² is hydrogen or d-C-io alkyl and X is the anion of an inorganic or organic acid as defined above.

Alkali metal phosphates may be mono-, di- and tribasic (MeH₂PO₄, Me₂HPO₄, Me₃PO₄) and the metal is preferably sodium or potassium.

The preferred catalysts useful in the reaction are ammonium halogenides, and the most preferred catalyst is ammonium chloride.

The amount of catalyst in the reaction is not critical and can vary in a wide range. Preferably, it is present at least in a molar amount in the range of 0.01 to 0.5, more preferably in the range of 0.025 to 0.2, relative to the compound of formula (I).

The reaction may be conveniently carried out under pressure and temperature conditions typical for reactions in aqueous ammonia and well-known to those skilled in the art. Preferably, the reaction is carried out at a temperature of 10°C to 25°C, more preferably 20°C, under an atmospheric pressure.

Optionally, the reaction may be carried out in a solvent. The solvent is any solvent known in the art, including but not limited to alcohol such as methanol, ethanol, isopropanol and mixture thereof.

Optionally, the reaction is carried out under an inert gas atmosphere such as e.g. under nitrogen or argon or mixtures thereof. The reaction may be completed in less than 20 hours, normally in 5 to 15 hours. After the reaction, the produced OXA may be easily isolated from the reaction mixture by crystallization. The isolated OXA, optionally after further purification, can be converted into pyridoxine and its acid addition salts according to methods well-known in the art.

As a raw material of the reaction, the compound of formula (I) may be produced by the method known in the art, such as the methods described in patent publications US 35381 10, IN 177708, US 4026901 and US2009143346.

The process of the present invention is very simple and has advantages of high yield (up to 97%), short reaction time (about 10 hours), and short crystallization time of the produced OXA from the reaction mixture (about 2 hours).

The present invention is illustrated further by the following Examples. These Examples are not intended to limit the invention in any way. Examples

Example 1 : Preparation of OXA with 25% aqueous ammonia

In a 1000 ml steel autoclave, 155.15 g ethyl 4-methyl-oxazole-5-formate (OXE) (1.0 mol) and 340 g ammonia solution (5 mol, 25% in water) were added and stirred for 11 h at 20°C. The product OXA precipitated during the reaction. The suspension was cooled down to -16°C and stirred for 7 h to obtain 123 g of off white to slightly yellow crystals with a purity of 96.4% (±1.2) (GC), yield 94% (±1.7). Example 2: Preparation of OXA with 30% aqueous ammonia

In a 1000 ml steel autoclave, 155.15 g OXE (1.0 mol) and 382 g ammonia solution (6.7 mol, 30% in water) were added and stirred for 12 h at 20°C. The product OXA precipitated during the reaction. The suspension was cooled down to -16°C and stirred for 15 min. to obtain 123.7 g of off white to slightly yellow crystals with a purity of 96.5% (±0.7) (GC ), yield 94.7% (±1.2). Example 3: Preparation of OXA with 35% aqueous ammonia

In a 1000 ml steel autoclave, 155.15 g OXE (1.0 mol) and 365 g ammonia solution (7.5 mol, 35% in water) were added and stirred for 12 h at 20°C. The product OXA precipitated during the reaction. The suspension was cooled down to -16°C and stirred for 30 min to obtain 122.1 g of off white to slightly yellow crystals with a purity of 98.2% (±0.7) (GC), yield 95.1 % (±1.2).

Example 4: Preparation of OXA with 45% aqueous ammonia

In a 1000 ml steel autoclave, 155.15 g OXE (1.0 mol) and 337 g ammonia solution (10 mol, 45% in water) were added and stirred for 10 h at 20°C. The product OXA precipitated during the reaction. The suspension was cooled down to -16°C and stirred for 7 h to obtain 126.1g of off white to slightly yellow crystals with a purity of 97.2% (±2) (GC), yield 97.2% (±2.5).

Example 5: Preparation of OXA with 55% aqueous ammonia

In a 250 ml steel autoclave, 38.8 g OXE (0.25 mol) and 96.4 g ammonia solution (3.12 mol, 55% in water) were added and stirred for 10 h at 20°C. The product OXA precipitated during the reaction. The suspension was cooled down to -16°C and stirred for 7 h to obtain 31.3 g of off white to slightly yellow crystals with a purity of 98.3% (±1) (GC), yield 97.6% (±1.5). Example 6: Preparation of OXA with 35% aqueous ammonia in ethanol starting from purified OXE

Into a 500 ml steel autoclave equipped with stirrer, pressure controller and temperature controller, 17.3 g ammonia (100%, 1020 mmol) was added within 20 minutes under stirring (500 rpm) to a mixture of 21.9 g OXE (96.3%, 136 mmol), 31.1 g water (1728 mmol) and 20.8 g ethanol (99.9%, 357 mmol). The internal temperature was maintained at 5°C during the addition of the reactant. The reaction mixture was heated to 30°C and the internal temperature was held at 30°C under 9.0 bars for about 20 hours. The reaction mixture was cooled down to -20°C and stirred (300 rpm) during 10 hour. The crystals were filtered and dried at 50°C, 20 mbar overnight. The mother liquor was evaporated under reduced pressure (15 mbar, 50°C) and the residue was dried at 50°C, 20 mbar. 17.2 g OXA was obtained with a purity of 98.7 % (¹H NMR). The crude yield was 87.6% based on OXE and the selectivity 87.9%. The isolated yield was 74.0 %. Example 7: Preparation of OXA with 35% aqueous ammonia in ethanol starting from crude OXE

Into a 500 ml steel autoclave equipped with stirrer, pressure controller and temperature controller, 17.3 g ammonia (100%, 1020 mmol) was added within 20 minutes under stirring (500 rpm) to a mixture of 24.0 g OXE (87.8%, 136 mmol), 31.1 g water (1728 mmol) and 20.8 g ethanol (99.9%, 357 mmol). The internal temperature was maintained at 5°C during the addition of the reactant. The reaction mixture was heated to 30°C and the internal temperature was held at 30°C under 9.0 bars for about 20 hours. The reaction mixture was cooled down to -20°C and stirred (300 rpm) during 10 hour. The crystals were filtered and dried at 50°C, 20 mbar overnight. The mother liquor was evaporated under reduced pressure (15 mbar, 50°C) and the residue was dried at 50°C, 20 mbar. 17.2 g OXA was obtained with a purity of 99.9 % (¹H NMR). The crude yield was 92.3% based on OXE and the selectivity 92.5%. The isolated yield was 68.2 %.

Example 8: Preparation of OXA in a mixture of aqueous ammonia and ethanol catalyzed with ammonium chloride starting from purified OXE

Into a 500 ml steel autoclave equipped with stirrer, pressure controller, temperature controller, 17.3 g ammonia (100%, 1020 mmol) was added within 20 minutes under stirring (500 rpm) to a mixture of 21.9 g OXE (96.3%, 136 mmol), 0.4 g ammonium chloride (7 mmol, 99.5%), 31.1 g water (1728 mmol) and 20.8 g ethanol (99.9%, 357 mmol). The internal temperature was maintained at 5°C during the addition of the reactant. The reaction mixture was heated to 30°C and the internal temperature was held at 30°C under 9.0 bars for about 20 hours. The reaction mixture was cooled down to -20°C and stirred (300 rpm) during 10 hour. The crystals were filtered and dried at 50°C, 20 mbar overnight. The mother liquor was evaporated under reduced pressure (15 mbar, 50°C) and the residue was dried at 50°C, 20 mbar. 17.2 g OXA was obtained with a purity of 98.9 % (¹H NMR). The crude yield was 94.2 % based on OXE and the selectivity 98.3 %. The isolated yield was 87.4%.

Example 9: Preparation of OXA in a mixture of aqueous ammonia and ethanol catalyzed with ammonium chloride starting from purified OXE

Into a 500 ml steel autoclave equipped with stirrer, pressure controller and temperature controller, 17.3 g ammonia (100%, 1020 mmol) was added within 20 minutes under stirring (500 rpm) to a mixture of 21.9 g OXE (96.3%, 136 mmol), 0.7 g ammonium chloride (99.5%, 14 mmol), 31.1 g water (1728 mmol) and 20.8 g ethanol (99.9%, 357 mmol). The internal temperature was maintained at 5°C during the addition of the reactant. The reaction mixture was heated to 30°C and the internal temperature was held at 30°C under 9.0 bars for about 20 hours. The reaction mixture was cooled down to -20°C and stirred (300 rpm) during 10 hour. The crystals were filtered and dried at 50°C, 20 mbar overnight. The mother liquor was evaporated under reduced pressure (15 mbar, 50°C) and the residue was dried at 50°C, 20 mbar. 17.2 g OXA was obtained with a purity of 99.9 % (¹H NMR). The crude yield was 96.6% based on OXE and the selectivity 97.7%. The isolated yield was 85.4 %.

Claims

1. A process for synthesis of 4-methyl-oxazole-5-carboxamide which comprises reacting a compound of formula (I) with a high concentration of aqueous ammonia:

(I)

Wherein Ri is H or Ci-io alkyl.

2. The process of claim 1 , wherein the high concentration of aqueous ammonia has a concentration of at least 25%.

3. The process of claim 1 , wherein the high concentration of aqueous ammonia has a concentration of at least 30%.

4. The process of claim 1 , wherein the high concentration of aqueous ammonia has a concentration of at least 35%.

5. The process of any one of claims 1 -4, wherein the aqueous ammonia is used in an amount of the ammonia in the range of 1 mol to 10 mol, preferably in the range of 2 mol to 8 mol, and the most preferably 5 mol to 8 mol, per 1 mol of the compound of formula (I).

6. The process of claim 1 , wherein the reaction is carried out in the presence of a catalyst.

7. The process of claim 6, wherein the catalyst is selected from the group consisting of ammonium salts, quaternary ammonium salts and alkali metal phosphates.

8. The process of claim 6, wherein the catalyst is ammonium halogenides, preferred ammonium chloride.

9. The process of any one claims 6-8, wherein the catalyst is added into the reaction in a molar amount in the range of 0.01 to 0.5, relative to the compound of formula (I).

10. The process of claim 1 , the reaction is carried out at a temperature of 10°C to 25°C under an atmospheric pressure.