JP2519178B2 - Process for producing 5- (4-pyridyl) oxazole - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing 5- (4-pyridyl) oxazole which is useful as an intermediate for the production of cephalosporin compounds.

[0002]

2. Description of the Related Art 5- (4-Pyridyl) oxazole (hereinafter referred to as POX) is an important compound as a production intermediate of cephalosporin compounds disclosed in JP-A-61-2780.

As a method for producing such POX, 1) a method of condensing 4-pyridinaldehyde with tosylmethyl isocyanide (Chem. Pharm. Bull., 27.
Vol., 793, 1979) and 2) Aminoisonicotinoylmethane is produced from 4-acetylpyridine and then cyclized with ethyl orthoformate (J. Org. Ch.
em. , 2261, 1980) is known.

However, the above-mentioned method is disadvantageous in that (1) the starting material compound used is expensive, and (2) the reaction step is long, and is not an industrially advantageous production method. I had a problem.

[0005]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a method for industrially producing POX using a raw material compound which is inexpensive and easily available.

[0006]

In view of the above situation, the present inventors have completed the present invention as a result of intensive research to find out a new method for producing POX.

The present invention is shown by the following reaction formula.

[0008]

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(In the formula, R represents an alkyl group)

That is, in the present invention, the isocyanoacetic acid ester (2) is reacted with an active form of isonicotinic acid (3) to give 5- (4-pyridyl) oxazole-4-carboxylic acid ester (4), and then Hydrolyze this and
(4-Pyridyl) oxazole-4-carboxylic acid (5)
In this method, POX (1) is produced by further decarboxylation.

Examples of the alkyl group represented by R in the formulas (2) and (4) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl. Isonicotinic acid activator means a compound having higher reactivity than isonicotinic acid, and examples thereof include acid chloride of isonicotinic acid, mixed acid anhydride with organic acid such as pivalic acid, dicyclohexylcarbodiimide, N-
Examples of the active ester with hydroxybenzotriazole and the complex with Vilsmeier reagent include isonicotinic acid chloride. Such isonicotinic acid activator is usually used in an equimolar amount or more with respect to the isocyanoacetic acid ester. The reaction between the isocyanoacetic acid ester and the isonicotinic acid activator can be carried out in the presence of a base in a suitable organic solvent. The reaction is usually 0 to 50 ° C.
It takes a few hours to a few days. Examples of the base include organic bases such as triethylamine and tributylamine, alcoholates such as tertiary butoxypotassium, and inorganic bases such as alkali metal hydrides such as lithium hydride, preferably triethylamine. The base is usually equimolar or more, preferably about 4 to the isonicotinic acid activator.
Used in double mole. As the solvent, amides such as dimethylformamide and dimethylacetamide, ethers such as tetrahydrofuran and diethyl ether, and halogenated hydrocarbons such as dichloromethane and chloroform can be used. The solvent is used alone or in a mixture, and is usually used in an amount of about 20 parts by weight with respect to 1 part by weight of isocyanoacetic acid ester.

The compound of the formula (4) produced by the above reaction is subjected to a conventional hydrolysis reaction, for example, in the presence of an inorganic base such as sodium hydroxide or lithium hydroxide in water or hydrous alcohol at room temperature to about 50 ° C. for several minutes. The compound of formula (5) can be obtained by reacting for several hours. The inorganic base is usually used in an equimolar amount or more with respect to the compound of the formula (4). The solvent is usually used in an amount of about 2 to about 10 times, preferably about 3 to about 6 times the volume of the compound of the formula (4).

The compound of formula (5) thus obtained is subjected to a conventional decarboxylation reaction, for example, in a solvent such as dimethylformamide or dimethylacetamide, in the presence of a metal powder such as copper powder and an organic base such as pyridine, to about 150 to about 200. About 30 minutes at ℃
Heat for about 5 hours or in a solvent such as glycerin or ethylene glycol at about 150 to about 200 ° C. for about 30 hours.
The target PO can be easily heated by heating for about 5 minutes to about 5 hours.
X can be produced. The amount of the metal powder used is not particularly limited, and generally, with respect to 1 part by weight of the compound of the formula (5),
It is about 0.05 part by weight. Further, the amount of the organic base used is not particularly limited, and it is desirable to make the amount as small as possible for the convenience of post-treatment. Further, the amount of solvent used is not particularly limited,
Usually, about 10 parts by weight is used with respect to 1 part by weight of the compound of the formula (5).

[0014]

EFFECT OF THE INVENTION According to the production method of the present invention, POX can be produced economically advantageously in high yield and in good purity. Therefore, the present invention is an excellent method for producing POX.

[0015]

EXAMPLES The present invention will be described below with reference to examples.

Example 1 Thionyl chloride 27.1 was added to 18.5 g of isonicotinic acid.
ml was added and stirred for 2 hours. 100 ml of diisopropyl ether was added thereto, and the precipitated isonicotinic acid chloride was collected by filtration. Separately, ethyl isocyanoacetate 1
To 3.6 g, 300 ml of dimethylformamide and 67.3 ml of triethylamine were added, and the mixture was ice-cooled. The above isonicotinic acid chloride was added to this solution, and the mixture was stirred with ice cooling for 1 hour. The solvent was distilled off, water was added to the obtained residue, and the mixture was extracted with dichloromethane. The dichloromethane phase was dried over magnesium sulfate and then dried. This was recrystallized from diisopropyl ether to obtain 22.4 g of 5- (4-pyridyl) oxazole-4-carboxylic acid ethyl ester.

IR ν _max ^KBr cm ⁻¹ : 1720, 1630, 159
0. NMR (CDCl ₃ ): δ 1.44 (3H, t, J = 7.0Hz), 4.46 (2
H, d, J = 7.0 Hz), 8.04 (2H, dd, J
= 6.1 Hz, 1.5 Hz), 8.10 (1 H, s),
8.77 (2H, dd, J = 6.1Hz, 1.5H
z).

[Table 1] Elemental analysis C ₁₁ H ₁₀ N ₂ O ₃ Calculated value C60.54, H4.62, N12.84 Experimental value C60.42, H4.71, N12.91 Melting point 51.0 ° C

Example 2 Using 9.9 g of methyl isocyanoacetate instead of ethyl isocyanoacetate, the reaction was carried out in the same manner as in Example 1 to give 5- (4-pyridyl) oxazole-4-carboxylic acid methyl ester 17. 8 g was obtained.

IR ν _max ^KBr cm ⁻¹ : 1720, 1605, 158
0. NMR (CDCl ₃ ): δ 4.00 (3H, s), 8.03 (1H, s), 8.0
6 (2H, dd, J = 6Hz, 1.5Hz), 8.80
(2H, dd, J = 6Hz, 1.5Hz).

Table 2 Elemental analysis C ₁₀ H ₈ N ₂ O ₃ Calculated C58.82, H3.95, N13.72 Found C59.02, H3.98, N13.81 mp 117.6 ° C.

Example 3 23.0 g of 5- (4-pyridyl) oxazole-4-carboxylic acid ethyl ester was prepared in the same manner as in Example 1 except that the solvent was changed from dimethylformamide to tetrahydrofuran and the reaction was carried out at room temperature for 48 hours. Got

Example 4 4.4 g of 5- (4-pyridyl) oxazole-4-carboxylic acid ethyl ester was added to 13 ml of water and 8 parts of sodium hydroxide.
00 mg was added and the mixture was stirred at room temperature for 30 minutes. 10 ml of isopropyl alcohol was added to this, and the precipitated crystals were collected by filtration,
4.2 g of (4-pyridyl) oxazole-4-carboxylic acid sodium salt dihydrate was obtained.

IR ν _max ^KBr cm ⁻¹ : 1600. NMR (D ₂ O): δ 7.88 (2H, dd, J = 1.5Hz, 6.3H
z), 8.20 (1H, s), 8.56 (2H, dd,
J = 1.5 Hz, 6.3 Hz).

[Table 3] Elemental analysis C ₉ H ₅ N ₂ O ₃ Na · 2H ₂ O Calculated value C43.55, H3.66, N11.29 Experimental value C43.28, H3.51, N11.43 Melting point 300 ° C or higher To 4.2 g of soda salt was added 25 ml of water to dissolve it, then 1 ml of acetic acid was added, and the precipitated crystals were collected by filtration to give 5- (4-pyridyl).
3.2 g of oxazole-4-carboxylic acid was obtained.

IR ν _max ^KBr cm ⁻¹ : 1610, 155
0.

[Table 4] Elemental analysis C ₉ H ₆ N ₂ O ₃ Calculated value C56.84, H3.18, N14.73 Experimental value C56.64, H3.37, N14.75 Melting point 260 ° C (decomposition)

Example 5 5- (4-pyridyl) oxazole-4-carboxylic acid (3.2 g) was added to dimethylformamide (35 ml) and copper powder (160).
mg and 1 ml of pyridine were added, and the mixture was heated under reflux for 5 hours. This was ice-cooled, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a usual operation to obtain 4- (5-oxazole) pyridine (1.7 g). This is a standard and I
R, NMR and melting point were consistent.

Example 6 5- (4-pyridyl) oxazole-4-carboxylic acid ethyl ester (10.9 g) was added to water (60 ml) and lithium hydroxide.
After adding 2.1 mg of monohydrate and stirring for 30 minutes, 2.9 ml of acetic acid was added and the precipitate was collected by filtration. This was heated with dimethylformamide, copper powder and pyridine in the same manner as in Example 5 and purified to obtain 3.8 g of 4- (5-oxazole) pyridine. This product had the same IR, NMR and melting point as the standard product.

Claims (2)

(57) [Claims] (1) Formula (5) Characterized by decarboxylating the compound represented by 5
A method for producing-(4-pyridyl) oxazole. 2. A compound represented by the formula CN-CH ₂ CO ₂ R (2) (wherein R represents an alkyl group) is reacted with an isonicotinic acid activator to give a compound represented by the formula (4): (Wherein R represents the same as in formula (2)) and then hydrolyzed to form a compound of formula (5) A process for producing 5- (4-pyridyl) oxazole, which is characterized in that the compound represented by the formula (5) is further decarboxylated.