JPS61225182A - Production of thiazole derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as a cardiac inexpensively in high yield, by reacting a thiazole derivative with a compound such as pyridine and a compound such as 2,2,2-trichloroethyl chloroformate, etc., and reacting the reaction product with sulfur, etc. CONSTITUTION:A thiazole derivative shown by the formula I (R1 is H, hydroxyl group, lower alkyl, aryl, acyl, amino, lower alkylamino, arylamino, etc.; R2 is H, or lower alkyl) is reacted with a compound shown by the formula A-X<1> [A is group shown by the formula II (X is halogen; n is 1-3); X<1> is halogen] and a compound shown by the formula R3-H (R3 is nitrogen-containing hetero ring residue) at normal pressure under a temperature condition of environment by using preferably equimolar amounts of the compound shown by the formula I and the compound shown by the formula A-X' and >= an equimolar amount of the compound shown by the formula R3-H to give a compound shown by the formula III (R3' is dihydro derivative residue of nitrogen-containing hetero ring). Then, this compound is reacted with sulfur, or reacted with zinc and oxidized, to give the aimed compound including a novel compound shown by the formula IV.

Description

[Detailed description of the invention] [Industrial application field] The present invention is based on the general formula T Ru.

Some of the compounds of general formula T obtained by the production method of the present invention are new compounds, and some have myocardial contractile action,
Must be useful as a cardiotonic agent.

[Prior art] As a method for synthesizing thiazole derivatives, Japanese Patent Publication No. 5B-29
No. 953, JP-A-49-49969, JP-A-59-1
A common method is to react a thioamide with an α-herocarbonyl compound as disclosed in No. 93878 and the like. In all of these, a nitrogen-containing heterocyclic residue is introduced into an α-herocarbonyl compound before the reaction with a thioamide.

[Problems to be Solved by the Invention] However, the method of producing a deazole derivative by reacting an α-halocarbonyl compound containing a nitrogen-containing heterocycle with a thioamide has a poor yield, and an improvement has been desired.

"Means to Solve the Problems" As a result of intensive research, the present inventors succeeded in obtaining easily and in high yield a deazole derivative having a nitrogen-containing heterocycle at the 5-position, and completed the present invention. did.

That is, the present invention provides a compound of the general formula (1) [wherein R+ and R2 have the same meanings as above], a compound of the general formula AX', and a compound of the general formula R3-H [wherein R3 has the same meaning as above]. A deazole characterized by reacting a compound with the same meaning] to obtain a compound of the general formula ■, reacting the compound of the general formula ■ with sulfur, or reacting the compound of the general formula ■ with zinc, followed by oxidation. This relates to a method for producing a derivative.

The compound obtained by the production method of the present invention is represented by the general formula (2) above, and the meanings and examples of the words used to define each symbol in this formula will be explained below.

"Lower" means a group having 1 to 6 carbon atoms unless otherwise specified.

Examples of "lower alkyl groups" include methyl, ethyl,
n-propyl, 1so-propyl, n-butyl, 1so
-butyl, tert-butyl, n-pentyl, n-hexyl and other straight-chain or branched alkyl groups.

Examples of the "aryl group" include phenyl, 1-lyl,
xylyl, mesidel, cumenyl, bifdenyl and lower alkyl groups, lower alkoxy groups, halogen atoms,
Examples thereof include groups substituted with an acyl group, a cyano group, a hydroxyl group, and the like.

Examples of the "acyl group" include formyl, acedel, propionyl, succinyl, glutaryl, valmitoyl, acryloyl, phthaloyl, and the like.

A "lower alkylamino group" is an amine group substituted with a lower alkyl group, such as methylamino, eddylamino, isopropylamino, n-hexylamino, and the like.

The "arylamino group" is an amino group substituted with an aryl group, and includes anilino, toluidino, xylidino, and the like.

The "acylamino group" refers to an amino group substituted with an acyl group, such as acedelamino and benzoylamino.

"Nitrogen-containing heterocyclic residue" is a 5- to 6-membered monocyclic or fused ring residue containing a nitrogen atom, and is an unsubstituted or lower alkyl group, lower alkoxy group, halogen atom, or aldehyde monocyclic group. , a cyano group, a nitro group, an acyl group, a hydroxyl group, or the like.

For example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinazolinyl, phthalazinyl, acridinyl, methylpyridyl, methoxypyridyl, chloropyridyl, formylpyridyl, cyanopyridyl, nitropyridyl, acedelpyridyl, human' Roxypyridyl, Me1
-xyquinolyl, methylpyridazinyl, piperidino, piperazino, etc.

Some of the compounds obtained by the production method of the present invention may exist in tautomeric forms. For example, a compound of general formula T having a hydroxyl group adjacent to the nitrogen atom of the pyridine ring may exist in the following two forms.

The definition of the compound of the general formula (1) above includes all of these tautomers.

The manufacturing method of the present invention will be explained in detail below.

First, a known thioamide represented by general formula V and general formula I
Using a known halocarbonyl compound represented by V, Organic React
ion) Vol. 6, p. 382, Willie (Richard)
H, Wile V) 1951, Special Publication 1973-342,
A thiazole derivative represented by the known general formula (2) is produced by the method disclosed in No. 111 and the like.

V IV II [wherein R+ and R2 have the same meanings as above] Next, a known thiazole derivative of the general formula (1) and a compound of the general formula A-X' [
In the formula, A, X' do not have the same meaning as above] and the general formula R3-H [R3 has the same meaning as above]
A deazole derivative represented by the general formula (2) is obtained by reacting the known compound.

I II This reaction is carried out by combining approximately equimolar amounts of the compound of the general formula (1) with the compound of the general formula , preferably by stirring for 1 to 7 hours.

In addition, examples of solvents that can be used in this reaction include di-1-lyls such as acedelpyridi, ethers such as tetrahydrofuran, and halogenated hydrocarbons such as dichloromethane. may be used as a solvent.

Examples of compounds having nitrogen-containing heterocyclic residues include pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, acridine, phenazine, lower alkyl groups, lower alkoxy groups, halogen atoms, Derivatives of these nitrogen-containing heterocyclic compounds having substituents such as a cyan group, nitro group, aldehyde group, acyl group, hydroxyl group, etc., such as 3-methoxypyridine, 3-chloropyridine, pyridine-3-aldehyde, 2]tinitrile, 3
-acetylpyridine, methyl nicodinate, 3-nitropyridine, 3-hydroxypyridine, 6-medoxyquinoline, 3-methylpyridazine and the like.

Next, by removing A, which is the residue of the general formula AX' bonded to the 5-position of the compound of the general formula (1), that is, the halogenated ethoxycarbonyl group, the compound of the general formula T is obtained.

Various methods can be considered for this reaction, and the following methods are common.

The compound of general formula (2) and sulfur are removed by heating to make them unreact. That is, the compound of general formula (1) and about 5 times its amount of finely ground sulfur are heated and stirred at normal pressure at 120 to 2000°C for 0.15 to 8 hours, preferably at 140 to 180°C for 5 hours. A compound of general formula (2) can be obtained by

In this case, it is not usually necessary to use a solvent, but dimethylformamide, dimethyl sulfoxide, etc. may be used. When a solvent is used, the amount of sulfur may be about half of the amount of the compound of general formula (1).

(2) Alternatively, the compound of general formula (2) and sub-M) may be reacted under heated conditions to be removed. In this case, since the substituent at the 5-position remains a dihydro-residue, further oxidation is required to obtain the desired compound of general formula (2). That is, the compound of general formula
The reaction is allowed to proceed for 4 hours, preferably for 2 to 3 hours at 50-60°C.

Next, an oxidizing agent such as 2,3-dichloro-5,6-dicyazbenzoquinone (DDQ) is added, and further 30-80'
The compound of general formula (2) can be obtained by stirring at C for 1 to 4 hours, preferably at 50 to 60 DEG C. for 2 to 3 hours. As the solvent in this reaction, nitriles such as acetonitrile, ethers such as tetrahydrofuran, sulfoxides such as dimethyl sulfoxide, and amides such as dimethylformamide can be used.

II I The compounds of general formula (■) and general formula (■) can be purified using lower alcohols such as methanol, ethanol, and isopropanol, carbons such as acetone, halogenated hydrocarbons such as chloroform, and ethyl acetate. This can be carried out by a recrystallization method using carboxylic acid esters, aromatic hydrocarbons such as benzene, ethers such as diethyl ether, nitriles such as acetonitrile, etc.

Alternatively, column chromatography using silica gel,
It may be carried out by flash column chromatography or thin layer chromatography. For column chromatography, the silica gel used every other month is 100 to 2
For flash column chromatography, silica gel 60 (Art9385) (manufactured by Merck & Co., USA), thin layer In the case of chromatography, silica gel with an average pore size of 60 A and prepared to emit fluorescence at 254 nm, such as Merck C-plate silica gel 60F (US Mel = 14
- Manufactured by RI Co., Ltd.) is preferred.

Incidentally, the compound of general formula (1) may be used in the next reaction without being purified.

In addition, in some cases, substituent R1, which can be obtained particularly easily and with high yield among the compounds of general 2. For example, a compound having a hydroxyl group may be prepared and then converted by a conventional method to form substituent R1. .

As the compound of general formula 1 obtained by the production method of the present invention,
Examples include the following compounds.

・4-Methyl-5-(4-pyridyl)-thiazole 04
-Methyl-5-(4-pyridyl)-2(3H)-thiazolone・4-methyl-5-(3-methyl-4-pyridyl)
-2(3H)-thiazolone 4-methyl-5-(3-chloro-4-pyridyl)-2
(3H)-thiazolone 4-methyl-5-(3-cyano-4-pyridyl)-2
(3-old-thiazolone 4-methyl-5-(3-formyl-4-pyridyl)-
2(3H)-thiazolone 4-methyl-5-(3-acetyl-4-pyridyl)-
2(3H)-thiazolone 4-medyru-5-(4-pyridazinyl)-thiazole 04-Methyl-5-(4-pyridazinyl)-2(3H)
-thiazolone 4-methyl-5-(3-methyl-4-pyridazinyl)
-2(3-former-thiazolone・4-methyl-5-(3-acetyl-4-pyridazinyl)-2(311)-thiazolone o4-methyl-5-(4-quinolyl)-thiazole・4
-Methyl-5-(4-quinolyl)-2(3-old-thiazolone 4-methyl-5-(6-methyl-4-quinolyl)-2(3H)-thiazolone 02.4-dimethyl-5 -(4-pyridyl)-thiazole 02-〇-hexyl-4-methyl-5-(4-pyridyl)-thiazole 2-amino-4-methyl-5-(4-pyridyl)-thiazole 02-methylamino -4-Methyl-5-(4-pyridyl)-thiazole・4-methyl-5-(4-pyridyl)-thiazole-2
-Anilide 02-acetyl-4-methyl-5-(4-pyridyl)-
Thiazole 02-mercapto-4-methyl-5-(4-pyridyl)
-Thiazole・2-ethylmercapto-4-methyl-5-(4-pyridyl)-thiazole [Function] According to the production method of the present invention, compared to the conventional production method, 1) the starting material is easily available, and 2) the reaction It has excellent industrial properties such as easy operation and high yield of the target compound.

For example, 2-hydroxy-4-methyl-5-(4-pyridyl)- disclosed in JP-A-59-193878.
When producing 2(3-old-thiazolone (Example 35)),
1-(4
-pyridyl)-2-propanone is difficult to handle, but chloroacetone, which is the starting material of the present invention, is easy to handle. In addition, in the manufacturing method of JP-A No. 59-193878, the starting material trade is 6.7
5jJ yields 0.2 g (yield 2.0%) of the target substance, whereas in the production method of the present invention, the starting material 12.5j;
] to target substance 4. Op (yield 19.0%) can be obtained.

It was found in the following pharmacological tests that some of the general compounds (2) obtained by the production method of the present invention increase myocardial contractile force.

Pharmacological test The effect on left atrial specimens of guinea pigs was tested according to the method described in Basic Course on Drug Development V: Pharmacological Testing Methods (Middle), p. 534 (1971). Specifically, a 7-week-old Hartley male guinea pig (weight: 350 g) was stunned by head blowing, the heart was removed, and the heart was injected into Krebsu-Henseleit's solution (sodium chloride 6, 92C1, potassium chloride -18), which had been sufficiently oxygenated. = 0.35g, calcium chloride 0.28g, magnesium sulfate 0.29g, acidic potassium phosphate 0.16g, sodium bicarbonate 2.1g, glucose 1.8g, add distilled water for pouring, and make the total amount 1000 g. The left atrial specimen was suspended in a Magnus chamber at 30-32°C, and the isometric contractions were measured using a pen-written oscillograph via a strain pressure amplifier connected to an FD pickup. Recorded.

For electrical stimulation, stimulation frequency: 0.5 cps, stimulation time: 5
m5eC, stimulation voltage: Current stimulation was performed under conditions of 20% increase in threshold. The nutrient solution was a Talegas-Henseleit solution, and a mixed residue of 95% oxygen and 5% carbon dioxide was constantly aerated. The effect of each specimen was tested 60 to 90 minutes after the generated tension stabilized. The results are shown in Table 1 below.

Table 1 Effect on Guinea Pig Left Atrium Specimens The following devices, etc. were used in the above pharmacological tests. Magnus device [newly manufactured by Natsume Seisakusho], pen-written oscillograph, D pickup, strain pressure amplifier, electrical stimulation device [all manufactured by Nihon Kohden].

[Example] Next, the present invention will be described in more detail by showing examples, but the present invention is not limited thereto. In addition, the following equipment was used for the measurement. Melting point (MP-1 type) [manufactured by Yamato Rigaku], mass spectrometer S) (Toro type 0), infrared absorption (IR)
(Model 260-10) [all new products made by Hitachi], nuclear magnetic resonance (NMR) ([X-270] "made by JEOL Ltd.").

Example 1 (1) Reference intermediate compound: 4-methyl-2(3-formerly-thiazolone) 1.5 J of water, 125 q of potassium thiocyanate, 92.5 ml of talolacetone (), and 30 ml of sodium bicarbonate were mixed with occasional shaking. It was left under ambient temperature conditions for 10 days.
20 g of activated carbon was added and left at ambient temperature for 2 hours. After removing the activated carbon, the title compound was extracted with ether as colorless needle-like crystals.
7 g (yield 41%) was obtained.

Melting point: 103-104°C (n) Intermediate compound: 4-methyl-5-[1-(2,2,
Preparation of 2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridyl]-2(3H)-thiazolone 1.6 g of pyridine was dissolved in 20 ml of dry acetonitrile and dissolved in 2,2,2-trichloro under ice-water cooling. Add ethyl chloroformate 4.68 (] dropwise and leave it at that temperature for 5
Stir for a minute. 4-Methyl-2(3-old-thiazolone 2g)
Add it little by little in its solid state and let it cool for 40 minutes under ice-water cooling.
9. Stirred for 3.5 hours at ambient temperature. The precipitated crystals were collected monthly, washed with acetonitrile, and then recrystallized from ethanol to obtain 2 g (yield: 31%) of the title compound as colorless needles.

Melting point: 174-175°C Nuclear magnetic resonance spectrum (CDCf3, TMS,
δ): 2.06 (3H, S) 4.28
(1tLdd)190 (/It(,s+m) 6.
95 (2H, d) 9.72 (1N, 5) KBr-1° Infrared absorption spectrum 1 ~ (cm) -ax 34.50.3200.3060.1730.1680
．． 1640ω04-methyl-5-(4-pyridyl)-2
(Preparation of 3-old-thiazolone 4-medyru-5-[1-(2,2,2-trichloroethoxycarbonyl 2(3-old-thiazolone) 12.5 g and 7 g of sulfur was dissolved in 87 d of dimethylformamide at 140°C for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with 2N hydrochloric acid (40%).
Extraction was carried out at ~50%, and insoluble matter was removed. ) Wash the door solution with chloroform and The pH was adjusted to 7 to 8 with a normal aqueous solution of sodium and lithium hydroxide, and the precipitated yellow grains were dried and recrystallized from ethanol using activated carbon to obtain the title compound as pale yellow crystals (yield 61.5%). Obtained.

Melting point: 269-271°C Nuclear magnetic resonance spectrum (CDCl3, TI3, δ
).

2.25 (3+33) 7.31 (2H, d)
8.55 (2H, d) 11.6 (IH, 5)
KBr-1.

Infrared absorption spectrum ν (cm).

aX 3450, 3000.1670.1590.1570 Compounds of Examples 2 to 7 were produced by performing the same treatment as in Example 1.

Example 2 (1) Intermediate compound: 4-methyl-5-[1-(2,2,
2-trichloroethoxycarbonyl)-3-methyl-1
,4-Dihydro-4-pyridyl]-2(3H)-thiazolone Preparation of 4-methyl-2(3-former-thiazolone 2.303jJ,3
-Methylpyridine 3.9 (7,2,2,2-trichloroethyl chloroformate 5.51 m!!) was used to obtain 1.96 g (yield 25.5%) of the title compound as white crystals.

Melting point: 173-174°C Nuclear magnetic resonance spectrum (CDCl3.T1・Is, δ
).

1.64 (311,s) 2.08 (
31L s) 4.09 (IN, d) 4.
76 ~5.01 (3H, m)6.77 (IH,
S) 6.94 (IIL d) 9.6
1 (III, 5) KBr-1° infrared absorption spectrum 1 ~ (Cm).

aX 3170, 3050.2880.1730.1700.
1650(ii) 4-methyl-5-(3-methyl-4-
Preparation of pyridyl)-2(3-old-thiazolone) 4-medyru5- [1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridyl]-2(311)- Using 1 g of Deazolone and 5 g of sulfur, 429 mo of the yellow crystal title compound was prepared.
(yield 79.8%).

Melting point: 203.5-205°C nuclear magnetic resonance spectrum (DI4SO-66, TI·Is, δ).

1.90 (3N, s) 2.26 (3H, s)
7.27 (1H, d) 8.41 (1H, d) 8
．． 51 (IH, S) 11.45 (IH, bs)
KBr-1° infrared absorption spectrum ν (Cm).

max 3000, 2840.2680.1660.1590 Example 3 (D intermediate compound: 4-methyl-5-[1-(2,2,2
-trichloroethoxycarbonyl)-3-chloro-1,
Preparation of 4-dihydro-4-pyridyl]-2(3 former-thiazolone) 4-Methyl-2(311)-thiazolone 0158(1,
Using 138mf! of 3-chloropyridine 1.14(],]2,2.2-trichloroethylchloroformate, 1.324q of the title compound as white crystals (yield 65.5%)
)Obtained.

Melting point: 181-183°C Nuclear magnetic resonance spectrum (CD(, f3, TMS
, δ).

2.11 (3H,S) 4.4
0 (Ill, d) 4.78-5.11 (3H
, m) 6.97 (IH, s) 7.17 (1H,
d) 9.89 (1N, 5)KBr-1
゜Infrared absorption spectrum ν (Cm).

max 3190, 3060.2880.1730.1670.
1640(r+) Production of 4-methyl-5-(3-'7 Rolow 4-Hirishi JL/)-2(3H)-deazolone 4-Methyl-5-[1-(2,2,2-1 helichloro ethoxycarbonyl)-3-chloro-1,4-dihydro-
Using 404 mo of 4-pyridyl]-2(3-thiazolone and 202 mg of sulfur), 132 mo of the title compound in the form of brown flaky crystals (yield 58.4%) was obtained.

Melting point: 199-200.5°○ Nuclear magnetic resonance spectrum (DMSO-ds, T-IS, δ); 1.
99 (3,H,s) 7.50 (IH,d)8
．． 55 (IH, d) 8.72 (IH, 5) 1
1.63 (Ill, bs) KBr −1.

Infrared absorption spectrum 1-1 (cm).

aX 3010, 2840.2720.1670.1620.
1580 Example 4 (1) Intermediate compound: 4-medyru5-[1-(2,2
,2-trichloroethoxycarbonyl)-3-cyano-
Preparation of 1,4-dihydro-4-pyridyl]-2(311)-thiazolone 0.58 g of 4-methyl-2(311)-thiazolone, 3
- 1.06 g of cyanopyridine, 1.38 m of 2,2.2-1~lichloroedyl chloroformate! ! Using this method, 1.208 g (yield 61.2%) of the title compound as white crystals was obtained.

Melting point: 139-140'C Nuclear magnetic resonance spectrum 1-1 (CDCJ3, TMS
, δ): 2.17 (3H, s) 4.53
(Month 1.d)/1.96 (2H,s) 5.1
9 (IH, dd) 7.04 (IH, d) 7.6
9 (IH, 5) 10.35 (1.5 per month) KBri.

Infrared absorption spectrum ν (cm).

aX 3150, 3030.2950.2870.2225.
1740.1'650(n) 4-)(chill-5-(
3-Schiff/-4-pyridi/1. z) Preparation of -2(3-former-thiazolone) 4-Methyl-5-[1-(2,2,2-trichloroethoxycarbonyl)-3-cyano-1,4-dihydro-4
-Pyridyl]-2(3-thiazolone 7,893()) and sulfur 3,95q were used to obtain 1.362 g (yield 31.3%) of the title compound in the form of light brown needle-like crystals.

Melting point: 257-258°C Nuclear magnetic resonance spectrum (DH3O-d6, TMS
, δ); 2.09 (3H,S) 7.60 (I
H, d) 8.83 (IH, d) 9.06 (I
H, 5) 11.80 (IH, bs) KBr-1° infrared absorption spectrum ν (cm).

aX 3010, 2840.2740.2220.1695.
1580 Example 5 (1) Intermediate compound: 4-Mediru 5-[1-(2,2
,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridazinyl]-2(3-formerly-thiazolone) 1.15q of 4-methyl-2(311)-thiazolone,
Using 1.45m of pyridazine and 2,2.2-trichloroT-methylchloroform-1-2.7f7, 2.05q of the title compound as white crystals (yield 55%) was obtained.

Melting point: 138-140°C Nuclear magnetic resonance spectrum (CDCl3, TMS, δ
); 2.10 (3H, s) 4.15 (IH, d
) 4.94 (2H, S) 5.05 (1N, dd
)6.90 (IH,S) 7.19 (IH,d)
9.95 (ill, 5) KBr -1 Infrared absorption spectrum ν (cm).

aX 3200, 1750.1670 (n) 4-Methyl-5-(4-pyridazinyl)-2(3
Preparation of pre-thiazolone 2.05 g of 4-methyl-5-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridazinyl]-2(3H)-thiazolone and 1.0 g of sulfur.
Using Og, 0.2q (yield: 19%) of the title compound as pale yellow crystals was obtained.

Melting point: 245-247°C Nuclear magnetic resonance spectrum (DI(SO-d6.TMS)
, δ).

2.31 (3H, S) 7.58 (IH, dd)
9.16 (1H, dd) 9.23 (廿, dd)
11.80 (IH, 5) 3000, 2830.2700.1670 Example 6 (1) Intermediate compound: 4-methyl-5-[1-(2,2,
2-trichloroethoxycarbonyl)-3-methyl-1
, 4-dihydro-4-pyridazinyl]-2(3H)-thiazolone 1.15 g of 4-methyl-2(3-formerly-thiazolone, 1.8 g of 3-methylpyridazine, 2,2.2-trichloroethylchloro) Using formate 2.76d, 2.19g (yield 57%) of the title compound as pale yellow crystals was obtained.

Melting point: 85-87°C Nuclear magnetic resonance spectrum (DI-1sO-d6.TMS
, δ): 1.92 (3H,S) 2.01 (3
H, S) 4.38 (1M', d) 5.05 (
2H, s) 5.17 (IH, dd) 7.15 (
IH, d) 11.05 (111,5) KBr −1.

Infrared absorption spectrum ν (cm).

aX 3200, 1730.1660 (1) Production of 4-methyl-5-(3-methyl-4-pyridazinyl)-2(3-former-thiazolone) 4-medy-5-[1-(2,2,2-trichloroethoxy) carbonyl)-3-methyl-1,4-dihydro-
4-pyridazinyl]-2(3-old-thiazolone 1.75 g
Using 0.9 g of sulfur and 0.9 g of sulfur,
．． 44 g (yield 47%) was obtained.

Melting point: 248-249°C Nuclear magnetic resonance spectrum (D) IsO-ds, TMS
, δ); 1.94 (3H,s) 2.62 (3
H, s) 7.58 (IH, d) 9.11 (
IH, d) 11.60 (111,5) KBr-1° infrared absorption spectrum ν (cm).

aX 3000, 2840.2710.1660 Example 7 (1) Intermediate compound: 4-medyru-5-[1-(2,2
,2-trichloroethoxycarbonyl)-L4-dihydro-4-quinolyl]-2(3-formerly-thiazolone production 4-
Using 0.115q of methyl-2(3-former-thiazolone), 0.258g of quinoline, and 0.30d of 2,2.2-trichloroethylchloroformate, the m2 compound of yellow crystals was
02 mg (yield 24.4%) was obtained.

Melting point: 120'C or higher Nuclear magnetic resonance spectrum (CDCl3.TMS, δ)
;2.16 (3H,S) 4.78 (IH,
d) 4.99 (2H,s) 5.44 (IH
, dd) 7.1-7.6 (4H, m) 8.1-8
．． 4 (IN, m) 10.28 (IH, m) KBr-1° infrared absorption spectrum 1~l ν (cm).

aX 3160, 3030.2950.2860.1730.
1650(ii) 4-methyl-5-(4-quinolyl)-
2 (Preparation of 3-former-thiazolone 4-methyl-5-[1-[2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-quinolyl]
-2(311)-thiazolone 1.341jJ and sulfur 1
．． Using 7g, 0.481g of m2 compound of yellowish white crystals
(yield: 62.1%).

Melting point: 237-23B, 5°C nuclear magnetic resonance spectrum (DI-ISO-66, TMS, δ).

1.94 (3tLs) 7.5
3 (ill, d) 7.67~8.13 (4H
, m) 8.94 (IH, d) 11.69 (I
N, 5) KBr-1° infrared absorption spectrum ν (cm) - aX 3000, 2830.2700.16B0.1620.
1570 Example 8 (1) Intermediate compound: 4-Mejiru-5-[1-(2,2,
Preparation of 2-trichloroethoxycarbonyl-dihydro-4-quinolyl]-2(3N)-deazolone 4-methyl-2(3H)-thiazolone 0,5760,
6-Medoxyquinoline 1,592C], 2,2.2-
Trichloroethyl chloroformate 1.38m! ! was used to obtain 548 mg of white crystal m2 compound (yield: 24
．． 4%> obtained.

Melting point: 187-189°C Nuclear magnetic resonance spectrum (CDCl3, TNS, δ
).

2, 14 (3H, s) 3.78 (3H,
s) 4,70 (IH, d) 4.93 (2H
, s) 5, 34 (1H, dd) 6.62 (
IH, d) 6, 85 (IH, dd) 7.21
(IH, d) 8,07 (IH, d) 10.
06 (IH, S)KBr-1.

Infrared absorption spectrum 1-1 (cm).

aX 3200, 3070, 2950, 2850, 1
720, 1650. 1620(ii) 4-Methyl-5-(6-medoxy-4-quinolyl)-2 (3H
)-thiazolone 4-Methyl-5-[1-(2,2.2-trichloroethoxycarbonylquinolyl]-2(311)-thiazolone 430m(If
Using 215 mg of sulfur and 215 mg of sulfur, 2
03...q (yield 78%) was obtained.

Melting point: 223-224°C Nuclear magnetic resonance spectrum (DMSO-d6, TNS,
δ); 1,97 (3tl, s) 3.89 (
3H, s) 7, 28 (formerly L d) 7.
47 (IH, d) 7, 47 (old (, dd)
8.01 (111, d) 8, 76 (IH
, d) Br-1 at 11.62 (IH, S).

Infrared absorption spectrum ν (cm).

aX 3140, 3020, 2860, 2720, 1
690, 1680. 1620 Example 9 (+) Intermediate compound: 4-methyl-5-[1-(2,2
．． Preparation of 4-methyl-2(3-old-diazolone 3.05(J, pyridine-3- Using aldehyde 5.675 (), the same treatment as in Example 1 (1) was performed, and recrystallization from ethanol gave 2,342 g of m2 compound as light yellow crystals (yield: 29.7
%>Obtained.

Melting point: 185-186°C Nuclear magnetic resonance spectrum (CDCJ3, TMS
, δ): 2, 18 (3H, s) 4.63 (
IH, d) 5.03 (2H, s) 5.3
3 (old (, dd) 7.08 (IH, d) 7
．． 90 (IH, S) 9.53 nth, S)
10.21 (11-1,5)KBr-1° infrared absorption spectrum ν (cm).

aX 3290, 3080.2970.2920.2850.
1740° 1670, 1610 (n) Intermediate compound: 4-methyl-5-(1N-3-formyl-1,4-dihydro-4-pyridyl)-2(3-old-
Production of thiazolone 1,821q of 4-methyl-5-[1-(2,2,2-trichloroethoxycarbonylpyridyl]-2(3-formerly-thiazolone) and 0,3 g of zinc powder were mixed in 30 ml of a 50% aqueous solution of tetrahydrofuran.
1 and flowed rapidly for 6.5 hours. During this time, the pH was constantly adjusted to 3 to 4 with 2N hydrochloric acid, and 1.
Added 2g. After cooling, the insoluble matter was removed, the pH was adjusted to 7 with a 2N aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with methanol, and the precipitate was separated. Further, the washed methanol solution was distilled off under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel chromatography (filling agent: Wakogel C-200, @opening solvent: chloroform:methanol-20:1), and the above-mentioned precipitate was purified. In addition, recrystallization from methanol yielded 259 mg (yield 25.4%) of the title compound in the form of pale yellow needle-like crystals.
Obtained.

Melting point: 180.5-182.5°C Nuclear magnetic resonance spectrum (D) 130-d6, TMS, δ
); 1,99 (3N, s) LSI (
1 t1, d) 4, 79 (11-1, dd) 6
．． 22 (11Ldd)7, 23 (IIL d)
8.95 (IH, bs) 9, 05 (old L
s) 10.66 (IH, s)KBr
-1.

Infrared absorption spectrum ν (Cm).

3350, 31B0, 3060, 1640, 1
630. 1580Qi9 Preparation of 4-methyl-5-(3-formyl-4-py1-nodyl)-2(3H)-thiazolone 4-Methyl-5-(IH-
3-formyl-1,4-dihydro-4-pyridyl)-2
To a suspension solution to which 240 mg of (311)-azolone was added,
2,3-dichloro-5,6-dicyano-p- at ambient temperature
245 mg of benzoquinone was added and stirred for 15 minutes. The solvent was distilled off under reduced pressure, the residue was extracted with 2N hydrochloric acid, and the insoluble materials were removed. Wash the liquor with ether, neutralize with 2N aqueous sodium hydroxide solution, extract with ethyl acetate,
Dry with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 182 mg of the title compound as yellow-white crystals (yield 7639
%)Obtained.

Melting point: 225-226°C Nuclear magnetic resonance spectrum (DHSO-66, TI4S
, δ).

1,93 (3H, S) 7.51 (IH, d
)8,80 (1H, d) 8.97 (IH,
S) 10, 12 (1H, S) 11.70 (I
H, b) KBr-1.

Infrared absorption spectrum ν (cm).

aX 2990, 2830, 2700. 1675, 1
620. 1595 Example 10 (1) Intermediate compound: 4-Mediru-5-[1-(2,2
．． 2-1-lichloroethoxycarbonyl)-3-acetyl-1,4-dihydro-4-pyridyl]-2(3-
Production of thiazolone 4-methyl-2 (3 former-diazolone 1.15+11,3
-Acetylpyridine 2.2mN, 2,2.2-trichloroethylchloroforme-1-2. Using 76 power,
The same treatment as in Example 9 (1) was performed to obtain 2.27 (yield: 48%) of the title compound as white crystals.

Melting point: 170.5-171.5°C Nuclear magnetic resonance spectrum (CDCf3, TMS, δ);
2, 25 (3tL s) 2.33 (3H, s
)4,66 (IH, d) 4.95 [IH,
S) 5, 30 (IH, dd) 7.05 (
Month 1, d) 8, 05 (IH, s) 10.00
(111, s)KBr-1.

Infrared absorption spectrum ν (Cm).

aX 3240, 1750. 1680 (i'i) Intermediate compound: 4-methyl-5-(IH-3-
acetyl-1,4-dihydro-4-pyridyl)-2(3
Production of former-thiazolone 4-medyru-5-[1-(2,2.2- 1-lichloro-1-oxycarbonyl)-3-acetyl-1,4-dihydro-4-pyridyl]-2(3-old-thiazolone 2.0
The same treatment as in Example 9 (ii) was carried out using CI and 1.4 g of zinc powder, and 0.74 g (yield 74%) of the title compound as = 38 = white crystals was obtained 1
child.

Nuclear magnetic resonance spectra (DMSO-ds, TMS)
, δ) 11.97 (311,s) 2.07 (
311, s) 4.53 (monthly 1. d) /1.
74 (114, dd) 6.18 (IN□dd)
7.42 (old) 1 d) 8.56 (IN
, S) 10.59 (IH, 5) KBr-1° infrared absorption spectra] ~ le v (cm).

aX 3300, 3160.1660.16000104-methyl-5-(3-acedel-4-pyridyl)-2(3H
)-Deazolone 4-Methyl-5-(IH-3-acetyl-1,4-dihydro-4-pyridyl)-2(3N)-Deazolone 0.7
The same treatment as in Example 9 Qii) was carried out using 0.67 g of dicyanobenzoquinone () to obtain 0.16 g of the title compound as white crystals. ] (Yield 23%) was obtained.

Melting point: 198-199°C Nuclear magnetic resonance spectrum (DMSO-ds, TMS
, δ).

1.88 (3H,S) 2.47 (3H,S)
7.45 (old), d) 8.71
(IH, d) 8.88 (old 1.S) 11.5
1 (IN, S) in Br-1° infrared absorption spectrum 1~l ν (cm).

aX 3000, 2830.2700.1690.1620 [
Effects of the Invention] The method for producing deazole derivatives of the present invention is excellent as an industrial production method because deazole derivatives can be produced in good yield by simple operations using starting compounds that are easy to handle.

Claims (1)

[Claims] 1) General formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼... I [In the formula, R_1 is a hydrogen atom, a hydroxyl group, a lower alkyl group,
Aryl group, acyl amino group, lower alkylamino group, arylamino group, acylamino group, mercapto group or lower alkylmercapto group, R_2 is a hydrogen atom or lower alkyl group, R_3 is a nitrogen-containing heterocyclic residue] In the manufacturing method of the thiazole derivative represented by the formula III, a compound of the general formula -X' [wherein A is a mathematical formula, chemical formula, table, etc.] (X is a halogen atom, n is an integer of 1 to 3) X' is a halogen atom that is the same as or different from X] and A compound of the general formula R_3-H [in the formula, R_3 has the same meaning as above] is reacted to form the general formula II ▲ Numerical formulas, chemical formulas, tables, etc. has the same meaning as above, and R_3' represents a dihydro residue of a nitrogen-containing heterocycle] was obtained, and the compound of general formula II was reacted with sulfur, or the compound of general formula II was reacted with zinc. A method for producing a thiazole derivative characterized by post-oxidation.