JPS5915919B2 - Method for producing (N-methylpyryl-2)acetothioamide derivative - Google Patents

Description

Detailed Description of the Invention: CH2C<5/R1-(I) l \ ] (wherein R" and R" are hydrogen or a lower alkyl group, and R1 and R2 together with N form a ring can be formed.

) The present invention relates to a method for producing a (N-methylpyryl-2)acetothioamide derivative represented by: In the general formula (I), R1 and R2 may be substituted with a functional group that does not directly participate in the reaction. Therefore, when R1 and R2 are combined with N to form a ring, -N/ is one ()
(R"\R, '--R4 and R5 are alkylene groups, and X is an amino group, an oxygen atom, and a sulfur atom.

) is also included. The compound represented by the general formula (I) can be led to (N-methylpyryru-2)acetic acid represented by the following formula (■) by alkaline hydrolysis according to the following formula (see Reference Examples below).

The compound of formula () is known as an important intermediate for synthesizing physiologically active substances used in medicines, agricultural chemicals, and the like.

For example, (N-methyl-5-aroylpyryl-2)acetic acids, which can be produced by Friedel-Crafts type reaction and hydrolysis of (N-methyl-11pyryl-2)acetate and aroyl chloride, have pronounced anti-inflammatory properties. It has been reported that [J. Med. Chem. ,↓Al646
l,' (1971): Ibid. , 16, 172 (19
73)], among which [N-methyl-5-(p-toluoyl)pyryl-2]acetic acid is known as trimethine [J. PharmacOlOgyandExperim
mentalTherapeutics, l85, 127
(1973)]. The known manufacturing methods for 21(N-methylpyryl-2)acetic acids can be broadly classified as follows.

(1) A method of reacting N-methylpyrrole and diazoacetate using copper powder as a catalyst to obtain (N-methylpyrrole-2) acetate [J. Org. 2, Chem↓A,
664 (1949)]. (2) N-methylpyrrole and diazopyruvate are reacted using copper powder as a catalyst to obtain (N-methylpyryl-2)pyruvate, which is further hydrolyzed and then acidified with silver oxide. 3,
Method for producing (N-methylpyryl-2)acetic acid by
Chem. Abstr. , Ull3843e].

(3) After converting N-methylpyrrole-2-carboxylic acid to its acid chloride, it is reacted with diazomethane to obtain a diazoketone, which is decomposed in ethanol using platinum as a catalyst (N- Methylpyryl-2) Method for producing acetic acid ester [Arndt-Eistert method Chem.
Abstr. , ye, 5957 (1938)] o (4)
Friedel's combination of N-methylpyrrole and oxalyl chloride
The product obtained by the Crafts-type reaction is treated with alcohol to synthesize (N-methylpyryl)glyoxalic acid ester, which is reacted with hydrazine and then treated with potassium hydroxide (Wolf-Kitssyuna reaction).
(N-methylpyryl-2) Method for producing acetic acid [Lie
bigsAnn. Chem. , L2'', 105 (196
9)].

(5) N-methylpyrrole is reacted with dimethylamine and formaldehyde to form a so-called Mannitz base (Mannitzsch reaction), which is then reacted with methyl iodide to form methiodide, and then reacted with sodium cyanide (N- (methylpyrrole)-2-acetonitrile is obtained, and by this hydrolysis (N-methylpyrrole-2)
Method for obtaining acetic acid [J. Anler. Chem. SOc.
, Ldan, 4921 (1951)].

Among these methods, method (1). (2) and (3
) are not suitable as industrial production methods because they all use unstable diazo compounds. Method (4) has a drawback in that the Friedel-Crafts reaction in the first step has a low yield. Method (5) is based on the fact that side reactions occur in the cyanide ion substitution reaction in the second step [J. Org. Che
m. , 1096 (1977)] and highly toxic sodium cyanide, this method is not satisfactory as an industrial production method. As described above, all of the conventional methods for producing (N-methylpyryl-2)acetic acids are difficult to implement industrially. As a result of intensive studies to overcome these drawbacks, the present inventors discovered a method for producing a (N-methylbilyl-2) acetothioamide derivative that is useful as a precursor that can easily lead to the above formula (), This has led to the completion of the present invention.

The method of the present invention, including the synthesis of raw materials, can be expressed as follows. The first step is to react an aldehyde represented by the formula \NΔCHO with formaldehyde dimethyl mercaptal S-oxide represented by CH3SCH2SCH3 in the presence of a strong base.

The strong bases mentioned here include, for example, alkyl lithiums such as butyl lithium, metal hydrides such as sodium hydride,
Metal amides such as lithium diethylamide, metal alkoxides such as sodium methoxide, metal hydroxides such as sodium hydroxide, metal oxides such as calcium oxide, quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide, and sodium carbonate. Examples include metal carbonate salts such as carbonates. The so-called contact amount of the base is sufficient, but if it is used in a large amount, the reaction will be accelerated. The use of a solvent is not an essential requirement, but if desired, substances that do not directly participate in the reaction, such as common organic solvents such as ethanol, methanol, tetrahydrofuran, dioxane, dimethylformamide, benzene, etc., can be used.

The reaction proceeds smoothly at room temperature to 150°C to give the desired product () in high yield. The second step in the above formula is the general formula ()
is reacted with an acid anhydride, preferably in the presence of a base.

In the reaction, it is sufficient to use approximately equimolar amounts of the starting compounds, but an excess of the acid anhydride may be used in conjunction with the action of a solvent. Furthermore, if desired, a solvent that does not directly participate in the reaction, such as dioxane, toluene, xylene, etc., may be used. The reaction is preferably carried out under heating, and the heating temperature is generally 80 to 150°C, preferably 100 to 150°C.
It is ℃. The method of the present invention involves reacting a compound of general formula () with an ammonia or amine compound represented by general formula ().

When the amine used in carrying out the reaction is liquid, an excess amount of the liquid amine can be used in combination with solvent action, but if desired, water or methanol, ethanol, dimethoxyethane, dioxane, tetrahydrofuran, ether, etc. can be added. Common organic solvents may also be used. The reaction temperature is preferably room temperature since no special heating or cooling means are used.
The present invention will be explained in more detail below using Examples and Reference Examples.

Reference Example 1 3.913t of N-methylpyrrole-2-aldehyde and 4.913t of formaldehyde methyl mercaptal S-oxide.
A mixture of 55t and sodium hydroxide 670W9 was stirred at room temperature for 4 hours and at 55-60°C for 10 hours.

After adding 70 ml of methylene chloride, the mixture was washed with 20 ml of water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography [silica gel, methylene chloride monoethyl acetate (4:1)] to obtain 1-methylsulfinyl-11-methylthio-2-( N-methylpyryl-2) Ethylene 5.9437 was obtained as a light brown oil. Yield 77%. IR (Neat): 10540fIL-
1NMR (CDCl3): δ2.28 (3H,.s),
2.65 (3H,.s), 3.66 (3H,.s), 6
．． 19 (1H, .dXd, .J-2.5 and 4.2Hz
), 6.68 (1H, .dXd, .J=1.6 and 2.
5Hz), 7.29 (1H..dXd,.J=1.6 and 4.2Hz), 7.52 (1H..s). Mass spectrometry (
Relative intensity): m/E2l5 (M+, 36%), 152 (
63%), 151 (69%) 137 (100%), 13
6 (71%), 105 (86%), 104 (46%). Reference example 2 1-methylsulfenyl-1-methylthio-2-(N-
Methylpyryl-2) Dissolve 8037!1f of ethylene in 7ml of acetic anhydride and add 700~ of potassium acetate to make 11
The mixture was stirred at 5°C for 2 hours.

After adding 50 ml of methylene chloride and filtering off insoluble matter, the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (silica gel, methylene chloride-benzene).
-acetoxymethylthio-1-methylthio-2-(N-
Methylpyryl-2) Ethylene 708TI19 was obtained as a pale yellow oil. Yield 74%. IR(Neat);1
742, 157011480, 1410, 1260, 1
205, 109011060, 1017cTL-1. N
MR (CDCl3): δ2.02 (3H,.s), 2.
31 (3H.s), 3.52 (3H.s), 5.27 (
2H,. s), 6.06-6.16 (1H1m), 6.
50-6.60 (1H,.m), 6.84-6.91 (
1H,. m), 6.91 (1Hss). Mass spectrometry (relative intensity): m/E257 (M+, 59%), 184 (27
%), 137 (100%), 43 (43%). Example 1 1-acetoxymethylthio-1-methylthio 2-(N-
Methylpyryl-2) 286η of ethylene and 3m of methanol
0.54 t of a 50% aqueous solution of dimethylamine and dimethylamine were added, and the mixture was stirred at room temperature for 24 hours.

After adding 20 ml of ether and washing with water (20 ml x 3 times), it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography [Florisil, benzene monomethylene chloride (3:1)] to obtain N-N-dimethyl (N-methylpyryl-2) acetothioamide (176 η).
was obtained as colorless crystals. Yield 87% o Melting point: 108-1
09°C (from ether) IR (KBr): 293011
525, 1446, 1395, 1317, 1300, 1
274, 1232, 1148, 1108, 1087, 1
057, 100019701865, 852, 776,
727? -1. NMR (CDCl3): δ3.32(3
H,. s), 3.50 (3H,.s), 3.64 (3H
、． s), 4.17 (2H,.s), 5.87-5.9
8 (1H1m), 6.07 (1H.t,.J=3Hz)
, 6.58 (1H.dXd,.J=2 and 3Hz). C
, calculated value as Hl4NS: Cl59.3O:H, 7.
74:Nll5.37%. Measured value: Cl59.34:H, 7.73:Nll5. l
9%. Example 2 1-acetoxymethylthio-1-methylthio-2-(N
-Methylpyryl-2) Example 1 except that 275η of ethylene and 0.22y of a 50% aqueous solution of dimethylamine were used.
In the same manner as N-N-dimethyl (N-methylpyryl-2
) Acetothioamide 136 was immediately obtained.

Yield 70% o Example 3 1-acetoxymethylthio-1-methylthio-2-(N
-Methylpyryl-2) Dissolve 507η of ethylene in 5m2 of 1-2-dimethoxyethane, and dissolve 50% of dimethylamine.
1.47 g of an aqueous solution was added and stirred at room temperature for 24 hours.

After adding 30 ml of methylene chloride and washing three times with 30 ml of water, the mixture was dried over anhydrous sodium sulfate. After concentrating under reduced pressure, it was separated by column chromatography [Florisil, benzene monochloromethylene (3:1)] to obtain N-N-dimethyl (
N-Methylpyryl-2) Acetothioamide 311 was obtained. Yield 87%. Example 4 1-acetoxymethylthio-1-methylthio 2-(N-
Methylpyryl-2) 257~ of ethylene and 3 m of methanol
1, add morpholine 330Tn9 and incubate at room temperature.
The mixture was stirred for several days.

Add 20ml of methylene chloride and wash with water (20ml x 3
After drying with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was separated by column chromatography (Florisil, benzene monomethylene chloride (3:1)) to obtain (N-methylpyryl-2) acetothiomorpholide 196. Yield 87%. Colorless crystal Melting point: 134.5-136°C (from benzene-ether) IR (KBr): 1500, 144011278, 1
117, 965, 840, 730CTfL-1. NMR
(CDCl3): δ3.50-3.64 (2H..m)
, 3.57 (3H,.s), 3.64-3.80 (4H
1m), 4.17 (2H,.s), 4.24-4.36
(2Hvm), 5.80-5.90 (1H1m), 5.
99 (1H,.d><D..J=3 and 263Hz),
6.51 (1H.dXd..J=2.5and2.3H
z). Calculated value as CllHl6N2OS: C, 58.9O; Hl7. l9;Nll2.4
9;Sll4.29%. Measured value: C, 59. O7:Hl7. l7;Nll2.5
O: Sll4.52%. Example 5 1-acetoxymethylthio-1-methylthio-2-(N
-Methylpyryl 2) Ethylene 285 ~ methanol 3
1 ml of 29% aqueous ammonia was added thereto, and the mixture was stirred at room temperature for 4 hours.

Add 20ml of methylene chloride and wash with water (20TLI x 2
times) and then dried with anhydrous sodium sulfate? did. After concentration under reduced pressure, it was separated by column chromatography (Florisil, benzene) (N-methylpyryl 2'). Acetothioamide 48η was obtained. Yield 28%. IR (KBr):
33501315011615, 144011405,
130011235, 950, 742c-Rn-1. N
MR (CDCl3): δ3.

48 (3H18), 4.00 (2H,.s), 6.02
(2H,.d,.J-2Hz), 6.57 (1H,.
t. J-2Hz). Mass spectrometry (relative intensity): m/El5
4 (M+, 36%), 95 (11%), 94 (100%
), 42 (12%). Example 6 1-acetoxymethylthio-1-methylthio-2-(N
-Methylpyryl-2) Ethylene 207~ to metal 3m
1, 380 mg of benzylamine was added thereto, and the mixture was stirred at room temperature for 24 hours.

After adding 20 ml of methylene chloride and washing with water (20 ml x 2), it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, separation was performed using column chromatography (Florisil, n-hexane-benzene (3:1)) and thin layer chromatography (silica gel, benzene) to obtain N-benzyl (
N-Methylpyryl-2) Acetothioamide 72 was obtained as a light brown oil. Yield 28% 01R (Neat
):33101282011525, 1496, 140
0, 1310, 1118, 725, 700 cm-1. N
MR (CDCl3): δ3.42 (3H,.s), 4.
09 (2H,.s), 4.77 (2H..d,.J-6
Hz), 5.99 (2H, .d, .J-2Hz), 6.
54 (1H, .t, .J-2Hz), 7.

03-7.28 (5H,.m), 7.4 (1H,.br
0ad). Mass spectrometry (relative intensity): m/E244 (M+
, 22%), 95 (28%), 94 (100%), 91
(30%), 81 (10%), 65 (10%). Example 7 1-acetoxymethylthio-1-methylthio 2-(N-
Methylpyryl - 2) 318 ethylene and 3 m of methanol
2, and 280 ~ of n-butylamine were added thereto, followed by stirring at room temperature for 17 hours.

After adding 20 ml of methylene chloride and washing with water (20 ml x 2), it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was separated by column chromatography [Florisil, n-hexane-benzene (3:1)] and thin layer chromatography [silica gel, methylene chloride benzene (1:9)] to obtain N-butyl ( N-Methylpyryl-2) Acetothioamide 76 was obtained as a colorless oil. Yield 29%
. IR (Neat): 3300, 2950, 2925,
153011415, 1310, 1085, 716? −
1NMR (CDCl3): δ0.86 (3H,.t,.
J=6Hz), 1.06-1.66 (4H,.m), 3
．． 44 (3H,.s), 3.56 (2H,.q,.J-7Hz), 4.04 (2H,.s), 6.03 (2H1
d,. J=2Hz), 6.58(1H,.t,.J=2
Hz). Mass spectrometry (relative intensity): m/E21O (M+,
29%), 95 (30%), 94 (100%). Reference example 3N-N-dimethyl(N-methylpyryl-2)acetothioamide 205 Immediately 25% potassium hydroxide aqueous solution 10
ml was added, and the mixture was stirred at 115°C for 19 hours and at 130°C for 1 hour.

The mixture was further heated under reflux at 140-150°C for 2 hours, and then cooled to room temperature. The mixture was made acidic (PH2) with 1N dilute sulfuric acid and extracted with ethyl acetate (100ml x 3 times).

The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 154 pieces of (N-methylpyryl-2)acetic acid.
Yield 98%. The analytical sample was recrystallized from carbon tetrachloride. Light brown crystal Melting point: 114.5°C (Literature value *113°C) [*Chem. Abstr. , 32, 59
57 (1938)] IR (KBr): 3300-250
011695, 1503, 1418, 1395, 135
011310, 1250, 1198, 1101, 109
011058, 1012, 930, 805, 7JMoV, 7
22, 712, 701, 659, 632? -1. NMR
(CDCl3): δ3.56 (3H.s), 3.64 (
2H,. s), 6.07 (2H, .d, .J = 2 pressure),
6.59 (1H..t.J=2Hz). C7H,NO2
Calculated value: C, 60.42: H, 6.52: N, 1
007.10.07%.

Claims (1)

[Scope of Claims] 1 (N-methylpyryl-2)keteneacyloxymethylcaptal represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing (N-methylpyryl-2) acetothioamide derivatives represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^ 2 is hydrogen or a lower alkyl group, R^1 and R^2 can be combined with N to form a ring, and R^3 is an alkyl group or a phenyl group. ].