JPS5813587A - Oxazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula 1 (R is lower alkyl, phenyl, naphthyl or phenyl bearing 1-3 substituents selected from lower alkyl, halogenated lower alkyl, lower alkoxy, nitro and cyano groups; Y is O, S; n is 2, 3) and its salt. EXAMPLE:2,3,5,6-Tetrahydro-2-(4-methylphenoxymethyl)imidazo[2,1-b]oxaz ole. USE:Local anesthetic. Or its used as a preventive or remedy for thrombosis. PREPARATION:A halide of formula 2 (X is halogen) or epoxy compound of formula 3 is made to react with a diamine of formula 4 to give a compound of formula 5. Then, the product is made to react with carbon disulfide to form a compound of formula 6. Further, an alkyl halide of formula 7 (R' is halogen) is made to act on the product to give a compound of formula 8, on which a base is made to act to give the compound of formula 1.

Description

[Detailed description of the invention] Induction- relates to novel oxazole derivatives.

The oxazole derivative of the present invention is a novel metal material that has not been described in any literature, and is represented by the following general formula (1).

[The wing in the formula is a lower γ-alkyl group, phenyl group, naphthyl group,
Or as a substituent, a lower alkyl group, a lower alkyl group, a lower tekoxy group, a lower alkylthio group, a 1F1 group,
Represents a phenyl group that may have 1 to 1 group selected from the group consisting of a cyano group, a halogen atom, and a FeJLA/group, Y represents an oxygen atom or a sulfur atom, and n represents 8 or 8. ,] The compound represented by the above general formula (1) has a local anesthetic effect and an anti-inflammatory effect, and is used as a local anesthetic, a preventive or therapeutic drug for blood test values, etc.

Each group represented by the above general formula (1m K) is specifically as follows.

Lower alkyl groups - methyl, ethyl, bicarbonate, imbupyr, butyl% t@rt-butyl, pentyl, hexamethyl group, etc.

Naphthyl group - d-naphthyl group, I-naphthyl group.

Halogen atoms...-, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.

(lower alkyl group --) so-fluoromethyl.

Tosopu W-rei methyl, Tofyo talolomethyl, Shiso-do methyl, Yuki-Fluo ■ ethyl,! ,! - diflu quaternary 1 thyl, 8. meaning, silylfluoroethyl group, etc.

Lower alkoxy groups - methoxy, ethoxy, propoxy, impropoxy, butoxy V% t@rt-butoxy, pentyloxy, hexyl group, etc.

Lower alkylthio group --1methylthio, ethylthio, pbiJ? Ramio, imp 1 virthio, butylthio, tar
t-butylthio, munthylthio, hemucylthio groups, etc.

As a substituent, a group consisting of a lower alkyl group, an 8-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a cyano group, a halogen atom, and a phenyl group or 6II
Phenyl group -Mh- which may have one exposed group
- Phenyl, snow-methylphenyl, 8-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-prokPrufeel.

4-V propyl phenol, 1.4-dimethyl phenol, 1.1.4-) so methyl phenyl, mushroom, hatake, butto so menal phenyl, fi, 8. II-) Menalphenyl.

Fluoromethylphenyl, l-trifluoromethanalphenyl, 4-trifluoromenalphenyl, I-
) Hibiki Pro Menal Huel, @-) Soyu WW Methyl Buel, Lo) Hibiki So Do Methylphenyl, Tomi-Methoxyphenyl% 8-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-propo diphenyl,
4-4 tsubupaku poxifu 4/% 4-butoxifutur, 4-electro-rt-butofondiphenyl, snow-methylthiophenyl, S-methylthiophenyl, 4-methylthiophenyl, 4-nonal-4-methylthio Phenyl.

3-Methyl-4-methylthiophenyl, deuterophene JLk, IB-nitrophenyl, 4' = Jl-,)
Lofuel,! -cytenophenyl, 3-cytenophenyl, 4-cyTnophenyl, 1-taII lophel.

8-fluorophenyl, 4-bromphenyl, raccoon.

8-cyta uvx phenyl, 2.4-cyta ww phenyl.

4-difluorophenyl, 4-diprophenyl, 4-diprophenyl, 4-phenyl, 8-phenylphenyl, 4-phenylphenyl.

The compounds of the present invention can be obtained from various types of Il! One example of the most preferred example is the method shown below.

(1) (to))1
-Y-cImQICH*-MH(CHs)IINI1
0H (6, [In the formula, X represents a halogen atom, W represents a halogen atom, and the wings and Y are the same as above.] That is, the compound of the present invention is a well-known metal halide having the general formula 0 or having the general formula A known epoxy compound represented by (3) is reacted with a known cyanide rich in general formula (4), and then a compound represented by general formula (I) obtained is reacted with carbon disulfide. A long time ago, we obtained the general formula (
6) It is produced by reacting the compound represented by the formula (n'''e) with an alkyl halide represented by the general formula (n'''e), and finally reacting the resulting metal compound represented by the general formula (1) with a base. .

Compound of general formula (ri or (3) and compound of general formula (4) -
The reaction with is carried out in a regular solvent. solvent'
1::.

:11 Various organic solvents can be used as long as they do not adversely affect the reaction. Ethers, aromatic hydrocarbons such as benzene, toluene, xylene, etc., enal acetate, etc. can be mentioned (in Japanese)
Or use of the chemical compound of 0) and the chemical compound of general formula k) in Korea, especially limited to 51! Although it can be selected as appropriate within a wide range, usually the latter is at least an equal amount to the former.
It is preferable to use 6 to 7 times the amount of 4J, although the reaction can be carried out either at high temperature or under heating.

The boiling point of the cylinder part ff1E'C [The reaction proceeds suitably and generally ends at 1 to 1.h1iaii degrees.

-1 formula) metal compound and carbon disulfide! The IL reaction is carried out without a solvent or in a suitable solvent. IL as a solvent
A wide variety of organic solvents may be used as long as they do not cause any adverse effects.Specifically, the lower alcohols, ethers, aromatic hydrocarbons, etc. are exemplified. These w
Among the 1P compounds, the lower alcohols are especially: tI7F. The combination of the metal compound of the general formula CI and carbon disulfide may be appropriately selected within a wide range, but it is usually preferable to mix the latter in at least an equimodal amount with respect to the former. It is better to have a layer of equimolar to bulk threatening amount 0
The reaction temperature is not particularly limited and can be carried out under water cooling, at room temperature, or under heating, but usually at around room temperature
After reacting for about B hours, add the solvent, and then heat the pot at home at 160~1sO''1o11 degrees.
The reaction between the compound of general formula (-) and the metal compound of general formula (7) is generally carried out in an organic solvent. As a medium, use a wide range of solvents that do not have a negative effect on the reaction (specifically lower alcohols such as methanol and ethanol).
Examples include halogenated hydrocarbons such as carbon chloride, methylene chloride, chloride, T7ton, and tetrakpm furan. The use of the compound of general formula (6) and the compound of general formula
You can choose the appropriate amount within the range, but usually the latter is about 10 times the amount of the former, and the amount of the latter is about 1. i
It is preferable to use an amount as high as -s.The reaction proceeds whether under cooling, at room temperature, or under heating, but is preferably carried out at room temperature. jK time is usually 1-1
・Time 111111Ev&i.

When reacting with the compound Km group of the general formula (to)), use lower γk such as methanol, ethanol, and impropatol in an organic solvent that does not adversely affect the reaction.
-J＠/[, ethylamine, tetrakF, etc., or in water. As the #1 group, conventionally known ones are widely used. List organic bases such as sodium carbonate, inorganic bases such as potassium carbonate, strium bicarbonate, etc. The amount of Ifrtp base to be used is not particularly limited, but it is usually used in an amount of 44/- to 4-fold molar amount, preferably in an amount of 4- to 6-fold molar amount, relative to the compound of formula <111. The reaction can be carried out under cooling, at room temperature, or under heating, but it proceeds suitably at room temperature = about 10°C.The IL reaction time is usually 1 to 10°C.
It takes about an hour.

The compound of the present invention is prepared by cleavage.

The compound of the present invention obtained by
For example, it is easily purified in a single form from a reaction mixture by solvent extraction, recrystallization, force extraction, etc.

The compounds of the present invention can easily form salts with common pharmacologically acceptable acids. Such acids include, for example, inorganic acids such as sulfuric acid, nitric acid, II1 acid, and hydrobromic acid; It's time to fix the acid.

Next, reference examples and examples of the compounds of the present invention are listed.
The compound of the present invention is shown as a variant in I et al.
I don't think there is anything that could cause electrical damage.

Reference Example 1 Add 866 m/m of methanol to an ethylene-cyaden S4 furnace and heat to 60 - 0°C while preparing a methanol solution of %t, s-epoxyprobyl (4-methyl 7 ether) ether $/t. - was added dropwise over 1 hour. After the completion of the 0 dropwise addition, the solvent was refluxed for an hour, and then the solvent and 31 #J of ethylene diytν were retained under reduced pressure, leaving a residue of 1- -1-(4-methylphenoxy)-
Meaning - Proper tools are available.

1-(1-Ttnoethylteelectron))-It obtained above
- (4-Methylphenoxy) - Dissolve this residue in ethanol 160- without separating the panol and add carbon disulfide spirit @ mJF to form a precipitate. Leave it for 1 hour. After that, the precipitate was collected using a decantation machine, heated gradually to 1°C on an oil bath, and further heated to 1°C.
Continue heating at ℃ for 1 hour. Add impropanol snow/Om/ to this reaction product while it is hot, collect the precipitated crystals after cooling, and recrystallize from impropanol/methanol to obtain a melting point of 141-14. l-[2-hydroxy-Hatake-(
4-Methylphenoxy)propyl2-idendasyridinethione 819 is obtained.

Example 1 Preparation of 2,s, black, @-tetrahydro-2-(4-methylphenol dimethyl)imidazo(Ll-b)oxazole 1-(lazy-highFOxy-8-(4-methylphenoxy)propyl2) -Idenda syridine thione Todoroki f, II-
Add sml of methyl chloride into 1,412,100 wl and stir at room temperature for 1 hour. The precipitated crystals are collected by filtration, and these crystals are
Water with 969 carbonic acid dissolved in it and 100 rrd of acetic acid ethyl ester! Add to the mixture and stir for 10 minutes.

Separate the organic layer, dry (MgSOn), and add 100 ml of inpropyl alcohol to the oily substance obtained by condensation.
was added and refluxed for 8 hours. The resulting crystals were recrystallized from ethyl acetate-isopropyl ether! ! , ml, 5. @-tetrahydro-goose-(4
-Methylpheno4Pvmethyl)imidazo(1,1-b
) Obtain oxamizol.

Melting point: 111s-117℃ ′、′.

Examples 2 to 8 described in Table 1 below in the same manner as Example 1
The compound is obtained.

Table 1 Example 9 3.・、Cheetetrahydro! -7Elthiomethyl-lll-Okifyo Zoro(11,1-1)BiWt Jin・
Production of hydroiodide salt 1-(Hydroxy Hatake-Fuelthioprobil)
Perhydrobin 9t Gin-Naon Hatakero and iodide Menal Hatake m/ are added with acetone 1@(IgmjK) and stirred at room temperature for 1 hour. The precipitated crystals are collected, and the crystals are mixed with ethanol 166 m/ and 18 Mei-an Rei. The mixture was added to a boiler containing 10 m/ml of industrial water and stirred for 8 hours.The crystals obtained by concentrating IILtPfIt were recrystallized from ethyl acetate-ethanol.

Cheetetrahydro-phenylthiomethyl-SH-oxyzozoro[1]bivtsP-hydriodide was obtained, melting point 18 mm - 1s11℃, described in the following table in the same manner as in Example. The compounds of Examples 10 to 14 are obtained.

Announcement May 27, 1980 Mr. Commissioner of the Japan Patent Office 1, Indication of the case 1988 Patent Application No. 11'58 No. 3, Relationship with the person making the amendment Patent applicant Bo Nikinsha Okata Kinyu Factory 4, agent, Heiwa Building, 2-10 Hirano-cho, Higashi-ku, Osaka Phone: 06-203
-0941 (6521) Patent Attorney 13 Branch, English Near ° Supplementary LE (7) Subject - Invention in Book 0IIPjll
Am8, Contents of Amendment As shown in the attached sheet, Contents of Amendment 1: The structural formula described on page 19 of the specification is corrected as shown below.

c and above)

Claims (1)

[Claims] ■ General formula [The formula Shenho is a lower alkyl group, a phegoryl group, a naphnal group,
Or, as a substituent, a group returned from the group consisting of a lower alkyl group, a 6th grade lower γ group, an exclusive group, a lower alkoxy group, a lower thylkylthio group, a 1tro group, a cyano group, an octagen atom, and a phenyl group. Indicates a phenyl group that may have t-S numbers of. Y represents an oxygen atom or a sulfur atom, and 1F represents 2 or 8.] Temuwaakire ink oxfyo sol derivatives and salts thereof.