JPS59510B2 - Pyridine powder - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing pyridine derivatives, and its purpose is to produce novel pyridine derivatives that exhibit excellent anti-inflammatory (including anti-rheumatic) and analgesic effects and are useful as pharmaceuticals or synthetic intermediates thereof. The point is to obtain the following.

The gist of the invention is illustrated by the general formula below.

[In the formula, X1 and X2 are hydrogen, alkyl group,
represents an alicyclic or aromatic ring formed by combining a cyano group, a carbamoyl group, or both, and w is a halogen or 2
Y and Y2 each represent hydrogen, an alkyl group, an alkoxy group, a halogen, or a benzene ring formed by combining both (however, CHRCOOH represents a benzene ring formed by Y1 and Y2). ), R represents hydrogen or alkyl, R/ represents alkyl, and (0) represents that it can be an oxide. ] That is, the method of the present invention is a pyridine derivative substituted with a halogen (e.g., bromine, chlorine, etc.) or having a nitro group at the 2- or 4-position, or its N-oxide by hydrolysis to form a carboxylmethyl group or α - A phenyl compound [] having a group that becomes an alkylcarboxylmethyl group is reacted to produce phenoxypyridine derivatives or their N-
The purpose is to obtain oxide [1].

The raw material compound pyridine derivative [] of the present invention has one or two identical or different substituents, that is, an alkyl group (e.g.
methyl, ethyl, propyl, isobutyl, etc.), a cyano group, or a carbamoyl group, and the pyridine ring may be fused with an aromatic ring such as a benzene ring or an alicyclic ring such as a cyclopentyl ring or a cyclohebutyl ring. You can leave it there.

The phenyl compound [] to be reacted has a CHRCOOR' group (
R and R' have the same meanings as above), and have an alkyl group (e.g., methyl, ethyl, propyl, isobutyl, etc.), an alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.) and a halogen (e.g. , chlorine, bromine, etc.).
It may have ~2 substituents. In the method of the present invention, a pyridine derivative or its N
- It is carried out by condensing a phenyl compound [] to an oxide [].

The reaction is usually carried out without a solvent or in an inert solvent (e.g. pyridine, dimethylformamide, dimethylacetamide,
dimethyl sulfoxide, nitrobenzene, methanol,
(e.g., ethanol) at room temperature to the boiling point of the solvent. In addition, when phenols or naphthols are used, it may be considered to use a metal catalyst such as cupric oxide or copper powder as a catalyst to promote the reaction. Further, in the case of a liquid raw material compound, it can also be used as a reaction solvent. The pyridine derivatives or their N-oxides obtained through the above reaction steps are further subjected to hydrolysis.

The hydrolysis carried out here can be carried out by following the method usually used to convert an ester compound into the corresponding carboxylic acid, and can be carried out in water or other water-containing solvent with an acid (e.g., hydrochloric acid, sulfuric acid, hydrogen bromide, etc.). It is carried out using an alkali (e.g., alkali hydroxide, alkali carbonate, alkali hydrogen carbonate, etc.) at room temperature or under heating. In addition, while using N-oxide as a raw material compound,
When N-oxide is not the target compound, it is possible to appropriately reduce it before and after each step as necessary to obtain the corresponding pyridine derivative. The product of the process of the invention may be prepared in a suitable alkali metal salt (e.g. sodium, potassium, etc.), alkali metal salt (e.g. calcium, barium, magnesium) as required for separation, purification or formulation.
It can be converted into other aluminum salts etc. according to conventional methods. The thus obtained pyridine derivatives and their salts exhibit excellent anti-inflammatory (including anti-rheumatic) or analgesic effects and are novel compounds useful as pharmaceuticals or synthetic intermediates thereof.

When these are used as medicines, either oral administration in the form of tablets, capsules, powders, etc., or parenteral administration in the form of injections, suppositories, etc. can be adopted. Example 1 4-nitropyridine N-oxide 5.37, ethyl 2
-(4-hydroxyphenyl)propionate 7.35
7. A mixture of 7.857 potassium carbonate powder and 55 ml of anhydrous dimethylformamide was heated at 80 to 90°C for 1 hour.
Then, the mixture is reacted at 100 to 110°C for 1 hour.

After distilling off dimethylformamide under reduced pressure, water was added to the residue and extracted with methylene chloride. The extract was washed with a 10% aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried, and methylene chloride was distilled off, yielding crude ethyl 2-[4-(
9.67% of 4pyridyloxy)phenyl]propionate N oxide is obtained. This product was subjected to alumina column chromatography and silica gel column chromatography to obtain a purified product of 7.0y. ．． CCl IR:ν 4CT! l-11740114801ma
x124011205.

Purified product 17 was dissolved in 10 ml of 20% potassium hydroxide aqueous solution and left at room temperature for 10 minutes.

After acidifying with acetic acid, salting out with sodium chloride and extraction with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried, and methylene chloride was distilled off to give 2[4-(4
850 η of -pyridyloxy)phenyl]propionic acid N-oxide are obtained. Recrystallization from 99% ethanol/ethyl acetate shows Mp2O6-207°C.

Elemental analysis: Calculated value as Cl4Hl3O4N Cl64.86:Hl5. O5; N, 5.40 Experimental value Cl64.97; Hl5. ll;N5.52. NujOl-1 1R:ν 鞞- ~1900~, 1700, Max
Example 2 2-bromo-6-methylpyridine 2.247, ethyl 2
-(4-hydroxyphenyl)propionate 2.53
7. A mixture of 2.77 g of potassium carbonate powder and 25 ml of anhydrous dimethylacetamide is reacted at 180-185°C for 16 hours.

After distilling off dimethylacetamide under reduced pressure, water was added to the residue and extracted with benzene. The extract is washed with water and a 2N aqueous sodium monohydroxide solution, dried, and benzene is distilled off to obtain 1.27 g of crude ethyl 2-[4-(6-methyl-2-pyridyloxy)phenyl]propionate. On the other hand, the benzene extraction mother liquor was acidified with hydrochloric acid, extracted with ether, the extracted portion was esterified by adding an ether solution of diazoethane, washed with an aqueous sodium hydroxide solution, then dried, and the ether was distilled off, resulting in crude ethyl 2-[ 4-(6-methyl-2
-pyridyloxy)phenyl]propionate 2.17
is obtained. The purified product 2.157 was combined with the previously obtained 1.27 and subjected to silica gel column chromatography to obtain purified product 2.157 from the benzene to 10% ester/benzene eluate. CClIR:
ν 4 (1-JMo V1-11735, 145002 Ma
x Purified product 2.157 in 20% potassium hydroxide aqueous solution 10
ml and 10 ml of 95% ethanol and left at room temperature for 1 hour.

Ethanol was distilled off under reduced pressure, water was added to the residue to make it acidic with hydrochloric acid, and the precipitated oil was dissolved with sodium hydrogen carbonate. After washing with methylene chloride and treatment with activated carbon, the mixture was acidified with hydrochloric acid and extracted with ether. After washing the extract with water and drying, the ether was distilled off to obtain 1.57 g of 2-[4-(6-methyl-2-pyridyloxy)phenyl]propionic acid as an oil. j This oily substance 1.
457 was dissolved in 30 ml of an aqueous sodium hydroxide solution, washed with ether, and 1.1 equivalent mole of calcium chloride was added to precipitate 2-(4-(6-**methyl-2-pyridyloxy)phenyl)propionate calcium salt. Take a lot and wash with water. Concentrate the mother liquor to obtain calcium salt, with a total of 1.
The calcium salt monohydrate of 59y is obtained. Mp273
~275℃R: νNUjOlCTIl-1340011
5700max1 Example 3-5 The reaction was carried out in the same manner as in Example 2 using pyridine as the reaction solvent to obtain the following compound.

2-[4-(3-pyridyloxy)phenynolipropionic acid N-oxide, Mpl 39-140°C (recrystallized from acetone).

IR:νNUjOlcTL-1~1950~1700
0max elemental analysis: Calculated value as Cl4Hl2O4N C, 64.86: Hl5. O5:N5.4O Experimental value C65. O7; Hl5. 12; Nl5.7O 2-[6-(2-pyridyloxy)-2-naphthyl]propionic acid, Mpl 97-198°C (recrystallized from ethanol).

IR:νNUjOl? -1250011950, Max
Elemental analysis: Calculated value as Cl8Hl5O3N C, 73.70: Hl5. l5; N, 4.78 Experimental value Cl73.52; Hl5. l6:N, 5,02 2-[3-methoxy-4-(2-pyridyloxy)phenyl]propionate calcium salt tetrahydrate, Mpl58
°C (decomposed) (recrystallized from water).

Examples 6 to 17 The following compounds were obtained by carrying out the same reaction treatment as in Example 2.

In the above table, Me represents a methyl group, and in the X1 and X2 columns, for example, 4-Me represents that the 4-position of the pyridine ring is substituted with a methyl group. ]1 tree example 18~
28 The reaction was carried out in the same manner as in Example 1 or 3 to obtain the following compound 9.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. represents a ring, Y_1 and Y_
2 represents hydrogen, an alkyl group, an alkoxy group, a halogen, or a benzene ring formed by combining both (
However, the CHRCOOR' group may be present on the benzene ring formed by Y_1 and Y_2. ), R represents hydrogen or alkyl, and R' represents alkyl. A method for producing a pyridine derivative, which comprises hydrolyzing a compound represented by the above formula or its N-oxide to obtain a corresponding carboxylic acid. 2 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, X_1 and X_2 each represent hydrogen, an alkyl group, a cyano group, a carbamoyl group, or an alicyclic or aromatic ring formed by combining the two, Represents a halogen or a nitro group substituted at the 2- or 4-position. [In the formula, Y_1 and Y_2 are each hydrogen, an alkyl group, an alkoxy group, a halogen, or a benzene formed by combining the two. represents a ring (however, the CHRCOOR' group is Y
It may be on the benzene ring formed by _1 and Y_2. ), R represents hydrogen or alkyl, and R' represents alkyl. [In the formula, X_1, X_2, Y_1, Y_2, R and R
' represents the same meaning as above. A method for producing a pyridine derivative, which comprises obtaining a compound represented by the formula or its N-oxide, and then hydrolyzing it to obtain the corresponding carboxylic acid.