DE2836902A1 - (1-ALKYLPYRROLYL-2) THIOACETAMIDE AND THE METHOD FOR THEIR MANUFACTURE - Google Patents

Description

SAGAMI CHEMICAL RESEARCH CENTER
Tokyo / Japan

(1-Alkylpyrrolyl-2) -thioacetamides and method to their manufacture

description

The invention relates to new (i-alkylpyrrolyl-2 -) - thioacetamides of formula (I) and a process for the preparation of these new thioacetamides!

I i

(ι)

R is a lower alkyl group with 1 to 4 carbon atoms,

1 2
R and R independently of one another are a hydrogen atom

or a substituted or an unsubstituted alkyl group

12th
or R and R together represent an alkylene group having 3 to 5 carbon atoms which can be interrupted by 0, S or an amino group, and

indicates.

R is a hydrogen atom or a p-toluoyl group

1 2

Preferred alkyl groups represented by R and R are lower alkyl groups that are 1 to 4 carbon contain atoms. These alkyl groups may be substituted with a substituent group such as a phenyl group or an alkoxy group which is not directly involved in the reaction of the synthesis of the thioacetamides or a reaction in the conversion

1 2 ment of thioacetamides. R and R can be used together mean an alkylene group having 3 to 5 carbon atoms contains, and they can therefore be used together with N in the formula

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form a 4- to 6-membered ring. The carbon chain this alkylene group can be interrupted by a hetero atom

12th
be. For example, if R and R together form an alkylene group with 4 carbon atoms which is interrupted by 0, the alkylene group together with N in the formula forms a morpholino group.

The thioacetamides of formula (i) are very useful Intermediate products for the production of various organic compounds, in particular physiologically active compounds, such as pharmaceuticals and agricultural chemicals. These thioacetamides can be technically advantageous, as in will be explained in more detail below.

First, the conversion of these compounds into pharmaceuticals is described in order to increase the usefulness of the compounds of the formula (I) and their advantages over the prior art.

To date, (1-alkylpyrrolyl-2) acetic acids of the formula
—UrIp L.UUÜ

wherein R stands for a lower alkyl group, are known. It. it was reported that (i-alkyl-5-aroylpyrrolyl-2) -acetic acid, by introducing an aroyl group in the 5-position of the Pyrrolyl group of these compounds are obtained, show anti-inflammatory and analgesic effects [j.Med.Chem. 14: 646 (1971); ibid., i £ »172 (1973)]. In particular, it is known that [i-methyl-5- (p-toluoyl) -pyrrolyl-2] -acetic acid is a superior anti-inflammatory and analgesic agent [S.Wong, J.F. Gardocki and T.P. Pruss, J. Pharmalogy and Experimental Therapeutics, 185, 127 (1973)].

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A typical process for the preparation of [1-methyl-5- (p-toluoyl) -pyrrolyl-2] -acetic acid is that (i-methylpyrrolyl-2) acetonitrile or a lower alkyl ester of (i-methylpyrrolyl-2 ) -acetic acid with p-toluoyl chloride in the absence of a catalyst or in the a _n essence of aluminum chloride are reacted to convert it to [i-methyl-5- (ptoluoyl) -pyrrolyl-2] -acetonitrile or a low allyl esters of [i-methyl- 5- (p-toluoyl) -pyrrolyl-2] -acetic acid, and then hydrolyzed the resulting compound (see US Pat. Nos. 3,752,526 and 3,998,844). In this process, since the lower alkyl ester of (1-methylpyrrolyl-2) acetic acid is produced from (1-methylpyrrolyl-2) acetonitrile as a raw material, the basic starting material is (1-methylpyrrolyl-2) acetonitrile. The (i-methylpyrrolyl-2) acetonitrile is prepared, for example, by subjecting 1-methylpyrrole to a Mannich reaction with formaldehyde and dimethylamine to form 1-methyl-2- (dimethylaminomethyl) pyrrole, it with methyl iodide to form of the corresponding methiodide and then reacts the methiodide with sodium cyanide or potassium cyanide [W. Herz and JL Rogers, J.Amer.Chem.Soc., 73 p. 4921 (1951)]. In the final stage of this process, the use of a poisonous compound such as sodium cyanide or potassium cyanide is inevitable and the yield is generally below 50%. It has also been reported that by-products such as 1,2-dimethyl-5-cyanopyrrole are formed in this final cyanation step [JR Carson, JTHortenstine, BEMaryanoff and AJMolinari, J.Org.Chem., 42, 1096 (1977)]. Therefore, this process for the preparation of (1-methylpyrrolyl-2) acetonitrile is technically not advantageous, and the known processes for the preparation of [i-methyl-5- (p-toluoyl) pyrrolyl-2] acetic acid using this compound as a starting material are disadvantageous for this reason.

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Other "known processes for the preparation of (1-alkylpyrrolyl-2) acetic acids, which can be converted to (i-alkyl-5-aroylpyrrolyl-2) acetic acids include the following.

(1) A method in which a 1-alkyl pyrrole with a Diazoacetic acid ester using copper powder as a catalyst to form an (i-alkylpyrrolyl-2) acetic acid ester is implemented [J.Org.Chem., 1j4, 664 (1976)].

(2) A method in which a 1-alkylpyrrole is reacted with a diazo pyruvic acid ester using copper powder as a catalyst to form a (1-alkylpyrrοlyl-2 ^ pyruvic acid ester, the resulting pyruvic acid ester is hydrolyzed, and the hydrolyzate is treated with silver oxide to form (1 -Alkylpyrrolyl-2) acetic acid is oxidized (Chem. Abstr., 51_, 13843 ^e ).

(3) A method in which a 1-alkylpyrrole-2-carboxylic acid is converted into its acid chloride, the acid chloride is reacted with diazomethane to form a diazoketone, and it is dissolved in ethanol using platinum as a catalyst to form an (i-alkylpyrrolyl- 2) acetic acid ester is decomposed [the Arndt-Eistert method, Chem. Abstr., 32, 595 ⁷ (1938)].

(4) A method in which a product obtained in Friedel-Crafts reaction of 1-alkylpyrrole and oxalyl chloride is obtained with an alcohol to form a (1-alkylpyrrolyl-2) -glyoxalic acid ester is treated, the resulting ester is reacted with hydrazine and then the reaction product with potassium hydroxide (Wolff-Kishner reaction) under Formation of an (i-alkylpyrrolyl-2) acetic acid is treated [Liebigs Ann. Chem., 72 ^, 105 (1969)].

The methods (1), (2) and (3) are technically unsuitable because they all use unstable diazo compounds will. The method (4) is not satisfactory because the yield of the Friedel-Crafts reaction in the first Level is low.

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The various known processes for the preparation of (i-alkylpyrrolyl-2) -acetic acids or (i-alkyl-5-aroylpyrrolyl-2) -acetic acids are technically unacceptable because of various difficulties. The procedural stages are complex, the reagents are toxic or unstable, and the yields are low.

In contrast, the (i-alkylpyrrolyl-2) -thioacetamide of the formula (I) produced according to the invention in an industrially advantageous manner and easily converted into the corresponding (pyrrolyl-2) acetic acid derivatives can be converted by simply subjecting it to alkaline hydrolysis. Will connections of formula (i), in which R is hydrogen, among alkaline ones Conditions hydrolyzed, the corresponding (i-alkylpyrrolyl-2) acetic acids can be obtained directly. Will Compounds of the formula (I) in which R is a p-toluoyl group means hydrolyzed under alkaline conditions, the corresponding [i-alkyl-5- (p-toluoyl) -pyrrolyl-2) -acetic acids can be obtained directly.

The alkaline compounds used in the alkaline hydrolysis include common alkaline compounds such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate and quaternary ammonium hydroxide. Of these, the alkali metal hydroxides are preferred because the reaction proceeds smoothly, the yields are high and the cost is low. The reaction temperature for the hydrolysis is at least about 7O ° C, preferably at least 10O ⁰ C. Accordingly, it is water or a water-miscible organic medium having a boiling point of at least 100 ⁰ C, such as dioxane, ethylene glycol, diethylene glycol or diethylene glycol dimethyl ether as reaction medium suitable. The hydrolysis reaction mixture is acidified with an acid to convert the acetate into the free acid form. The subsequent extraction or crystallization can give highly pure (i-alkylpyrrolyl-2) -acetic acids or [i-alkyl-5- (p-toluoyl) -pyrrolyl-2] -acetic acids in high yields (see the following reference examples 6 to 12) .

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The thioacetamides of formula (I) can directly through alkaline hydrolysis to the corresponding useful acetic acid compounds being transformed. Alternatively, the thioacetamides of the formula (I) can easily be converted into the corresponding Acetamides converted by oxidation and then reaction with water or, more simply, oxidation in the presence of water will. The hydrolysis of acetamides can lead to the corresponding acetic acid compounds. If necessary, the Acetamide compounds are subjected to a toluoylation reaction to form compounds which have a p-toluoyl group, introduced in the 5-position. The hydrolysis of the compounds can be the corresponding [i-alkyl-5- (ptoluoyl) -pyrrolyl-2] -acetic acids result (see. Reference Examples 2 to 5 and 13). The oxidation of thioacetamide can can easily be carried out using hydrogen peroxide or a peracid such as ra-chloroperbenzoic acid. if Hydrogen peroxide is used, the oxidation can be caused by the presence of acetic acid or a metal oxide such as Sodium tungstate, are favored or activated.

The compounds of formula (I) which can be easily converted into useful compounds can be safely and economically manufactured from readily available materials, as will be explained in more detail below. The present invention thus exhibits various technical advantages and is free from the various disadvantages of the known methods.

The process for preparing the (i-alkylpyrrolyl-2) thioacetamides of the formula (I) according to the invention is explained in more detail below.

The invention relates to a method for production a (1-alkylpyrrolyl-2) thioacetamide of the formula (I)

CD

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12 5

wherein R, R, R and R ^ have the meanings given above, which is characterized in that one

(a) a 1-acylox; ymethylthio-1-methylthio-2- (i-alkylpyrrolyl-2) ethylene of the formula (il)

NS,

N
E.

wherein R has the meaning given above and R stands for an alkyl or phenyl group, with ammonia or an amine of formula (III)

-j

HN _v (III)

1 2
in which R and R have the definitions given above, to form an (i-alkylpyrrolyl-2) thioacetamide of the formula (I), in which R is a hydrogen atom, and

(b) for the preparation of an [i-alkyl-5- (p-toluoyl) ~ pyrrolyl-2] thioacetamide of the formula (I), wherein R is a p-toluoyl group obtained in the step (a) (i-Alkylpyrrolyl-2) -thioacetamide subjected to a toluoylation reaction.

When R in the formula (II) is an alkyl group, it is preferably an alkyl group having 1 to 4 carbon atoms.

The reaction of the compound of the formula (II) with ammonia or an amine of the formula (III) can be by simple Mixing and stirring of the mixture take place for a certain time. The reaction does not require any special heating or cooling and is generally conveniently carried out at room temperature. Optionally, water or an organic solvent such as methanol, ethanol, 1,2-dimethoxyethane, Dioxane, tetrahydrofuran or diethyl ether, as

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Reaction medium can be used. The amount of amine used is preferably at least 2 molar equivalents. If the amine used is liquid, it can be used in excess, so that it also serves as a reaction medium.

The toluoylation in step (b) of the process according to the invention can be carried out by adding the thioacetamide (R ^ = H in formula I), obtained according to step (a), with p-toluoyl chloride in the presence of a metal halide, such as Aluminum chloride (Friedel-Crafts reaction). In a preferred embodiment, there are equimolar amounts of the metal halide and p-toluoyl chloride in a suitable solvent, such as 1,2-dichloroethane, methylene chloride, nitrobenzene or nitromethane, and the resulting solution is very carefully added to the thioacetamide solution and that Mixture is implemented.

Alternatively, the toluoylation can be carried out by reacting the thioacetamide with a mixed anhydride of p-toluic acid and sulfonic acid.

The toluoylation reaction can also be carried out with acetamide compounds, which correspond to the thioacetamides carried out will.

As previously described, the (1-alkylpyrrolyl-2) -thioacetamides of formula (I) easily according to the invention from the 1-acyloxymethylthio-1-methylthio-2- (1-alkylpyrrolyl-2) -ethylenes of formula (II) are produced. The compounds of formula (II) used can be made easily and safely readily available, known materials as described below. The procedure is as follows shown schematically (the symbols in the formulas have the same meanings as described above).

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[TTL

^ "- ^ - CHO +

(1)

1st stage

CH ₃ SCH ₂ SOCH ₅

(2)

base

-NS

i = c;

(3)

■ SOCH,

2nd stage

(R ⁴ CO) ₂ O

-NS-

(II)

The i-alkylpyrrole-2-carbaldehyde of the formula (1) and the formaldehyde-dimethylmercaptal-S-oxide of the formula (2) readily available, known compounds and their reaction in the presence of a base gives 1-methylsulfinyl-1-methylthio-2- (i-alkylpyrrolyl-2) -ethylenes of formula (3) in high yields. Preferred bases are strong bases, e.g. alkyl metal hydrides, such as sodium hydride, alkyllithium compounds such as butyllithium, alkali metal amides such as lithium diethylamide, Alkali metal alkoxides, such as sodium methoxide, and alkali metal hydroxides, like sodium hydroxide. Alkaline earth metal oxides such as calcium oxide, quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide, and alkali metal carbonates such as sodium carbonate can also be used. The sufficient The amount of base is a catalytic amount and, in general, as the amount of base increases, the reaction is favored

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will. Although the use of a reaction medium is not essential is, if necessary, a medium which does not directly take part in the reaction, e.g., a common one organic solvents such as ethanol, methanol, tetrahydrofuran, dioxane, dimethylformamide and benzene can be used. The reaction proceeds smoothly at room temperature to 150 ° C., and the compound of formula (3) is obtained in high yields.

The reaction of the compound of the formula (3) with the acetic anhydride of the formula (4) gives the 1-acyloxymethylthio-i-methylthio ^ -Ci-alkylpyrrolyl ^^ ethylene of the formula (II). Examples of the acid anhydride are acetic anhydride, propionic anhydride, butyric anhydride and benzoic anhydride. The reaction is preferably carried out in the presence of a weak base such as potassium acetate, pyridine or triethylamine. The reaction is carried out using the two components in almost equimolar amounts. The acid anhydride can be used in excess to serve as a reaction solvent at the same time. The reaction can be carried out in an organic solvent which is inert to the reaction, such as dioxane, toluene or xylene. The reaction is preferably carried out at an elevated temperature. The reaction tempera door is preferably 80 to 150 ° C, more preferably 100 to 150 ⁰ C (comp. Reference Example 1).

As described above, the 1-acyloxy-methylthio-1-methylthio-2- (1-alkylpyrrolyl-2) ethylene of the formula (II) can be prepared safely and effectively from readily available materials, and the compound of the formula (II) can easily be converted according to the invention into the (i-alkylpyrrolyl-2) thioacetamide compounds. The new compounds of the formula (I) can very easily be converted into the corresponding, physiologically active acetic acid derivatives, in particular [i-methyl-5- (p-toluoyl) ~ pyrrolyl-2] acetic acid. The present invention thus represents a significant technical advantage, since the various disadvantages of the known methods are eliminated. "", ","",

The following examples and reference examples illustrate the invention.

Reference example 1

This example illustrates the preparation of the compound of formula (II).

A mixture of 3 »913 g of i-methylpyrrole-2-carbaldehyde, 4.55 g formaldehyde dimethyl mercaptal S-oxide and 670 mg sodium hydroxide is stirred at room temperature for 4 h and then at 55 to 60 ° C. for 10 h. 70 ml of methylene chloride are added and the mixture is washed with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate concentrated under reduced pressure and attached to a column of silica gel using methylene chloride-ethyl acetate (4: 1) chromatographed as eluent; 5.943 g of 1-methylsulfinyl-1-methylthio-2- (1-methylpyrrolyl-2) ethylene are obtained as a light brown oil in a yield of 81%.

IR (neat): 1054 cm

NMR (CDCl ₃ ): S 2.28 (3H, S), 2.65 (3H, S), 3.66 (3H, S), 6.19 (1H, DxD, J = 2.5 and 4, 2 Hz), 6.68 (1H, DxD, J = 1.6 and 2.5 Hz), 7.29 (1H, DxD, J = 1.6 and 4.2 Hz),

7.52 (1H, S)
Mass analysis (relative intensity): m / e 215 (M ⁺ , 36%), 152 (63%), 151 (69%), 137 (100%), 136 (71%), 105 (86%) and 104 ( 46%).

An 803 mg portion of the resulting product is dissolved in 7 ml of acetic anhydride and 700 mg of potassium acetate are added. The mixture is ^{stirred at 115 °} C. for 2 h. 50 ml of methylene chloride are added and the insoluble materials are filtered off. The filtrate is concentrated under reduced pressure. The residue is chromatographed on a column of silica gel using methylene chloride-benzene (1: 9) as the eluent; 708 mg of 1- (acetoxymethylthio-1-methylthio-2- (1-methylpyrrolyl-2) ethylene are obtained as a light brown oil in a yield of 74%.

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IR (pure): 1742, 1570, 1480, 1410, 1260, 1205, 1090, 1060,

1017 cm "" ¹
(NMR (CDCl ₃ , c): 2.02 (3H, S), 2.31 (3H, S), 3.52 (3H, S),

5.27 (2H, S), 6.06-6.16 (1H, M), 6.50-6.60 (1H, M),

6.84-6.91 (1H, M), 6.91 (1H, S) mass analysis (relative intensity): m / e 257 (M ⁺ , 59%), (27%), 137 (100%), 43 (43%). '

The following examples 1 to 9 show the preparation of various compounds of formula (I). The examples 8 and 9 show the preparation of compounds of formula (I) in which R ^ is a p-toluoyl group.

example 1

3 ml of methanol and 0.54 g of a 50% aqueous solution of Dime thy lamin become 286 mg of 1-acetoxymethylthio-imethylthio-2- (i-methylpyrrolyl-2) -ethylene given. The mixture is stirred at room temperature for 24 hours. 20 ml diethyl ether are added and the mixture is washed three times with 20 ml of water. The organic layer becomes over anhydrous Dried sodium sulfate and concentrated under reduced pressure. The residue is on a column made of Florisil (Trademark for magnesium chromatographic silicate) using benzene-methylene chloride (3: 1) as the eluent chromatographed; 176 mg of N, N-dimethyl- (1-methylpyrrolyl-2) thioacetamide are obtained as colorless crystals in a yield of 87%, melting point 108 to 109 ° C. (from diethyl ether).

IR (KBr): 2930, 1525, 1445, 1395, 1317, 1300, 1274, 1232, 1148, 1108, 1087, 1057, 1000, 970, 865, 852, 776,

727 cm " ¹ .
NMR (CDCl ^ o): 3.32 (3H, S), 3.50 (3H, S), 3.64 (3H, S),

4.17 (2H, S), 5.87-5.98 (1H, M), 6.07 (1H, T, J = 3 Hz), 6.58 (IH, DxD, J = 2 and 3 Hz)

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Analysis for

calculated: C 59.30% H 7.74% N 15.37% found: 59.34 7.73 15.19.

Example 2

Example 1 is repeated with the exception that 275 mg of 1-acetoxymeth3'-lthio-1-methylthio-2- (i-methylpyrrolyl-2) -ethylene and 0.22 g of the 50% aqueous dimethylamine solution is used. 136 mg of N, N-dimethyl- (1-methylpyrrolyl-2) -thioacetamide are obtained in this way in a yield of 70%.

Example 3

507 mg of 1-acetoxymethylthio-1-methylthio-2- (i-methylpyrrolyl-2) ethylene v / earth dissolved in 5 ml 1,2-dirnethoxyethane and 1.4 g of a 50% strength aqueous dimethylamine solution were added. The mixture is stirred at room temperature for 24 hours. 30 ml of methylene chloride are added and the mixture is washed three times with 30 ml of water. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is on a Florisil (trademark) column chromatographed using benzene-methylene chloride (3: 1) as eluant; 311 mg of N, N-dimethyl- (1-methylpyrrolyl-2) -thioacetamide are obtained in a yield of 87%.

Example 4

257 mg of 1-acetoxymethylthio-i-methylthio-2- (i-methylpyrrolyl-2) -ethylene are dissolved in 3 ml of methanol and 330 mg of morpholine are added. The mixture is 3 days at Zim-. mertemperature stirred. 20 ml of methylene chloride are added and the mixture is washed three times with 20 ml of water. the organic layer is dried over anhydrous sodium sulfate, concentrated at reduced pressure and attached to a column of Florisil (trademark) using benzene: Methylene chloride (3: 1) chromatographed as the eluent;

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196 mg of (i-methylpyrrolyl-2) thioacetomorpholide are obtained as colorless crystals in a yield of 87%, melting point 134.5 to 136 ° C. (from benzene diethyl ether) ,

IR (KBr): I500, 1440, 1278, 1117, 965, 840, 730 cm " ¹ NMR (CDCl ₃ , S): 3.50-3.64 (2H, M), 3.57 (3H, S) , 3.64-3.80 (4H, M), 4.17 (2H, S), 4.24-4.36 (2H, M), 5.80-5.90 (1H, M), 5 .99 (1H, DxD, J = 3 and 2.3 Hz), 6.51 (IH, DxD, J = 2.5 and 2.3 Hz).
Analysis for C ₁₁ H ₁₆ N ₂ OS

Calculated: C 58.90% H 7.19% N 12.49% S 14.29% found: 59.07 7.17 12.50 14.52.

Example 5

285 mg of 1-acetoxymethylthio-1-methylthio-2- (i-methylpyrrolyl-2) ethylene are dissolved in 3 ml of methanol and 1 ml of 29% ammonia is added. The mixture is stirred for 4 hours at room temperature. 20 ml of methylene chloride are added and the mixture is washed with 20 ml of water twice. The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and attached to a column of Florisil (trade mark) using benzene chroma tographed as Elui grounding agent; 48 mg are obtained (i-Methylpyrrolyl-2) -thioacetamide in a yield of 28%.

IR (KBr): 3350, 3150, 1615, 1440, 1405, 1300, 1235, 950,

742 cm " ¹
NMR (CDCl ₃ , £): 3.48 (3H, S), 4.00 (2H, S), 6.02 (2H, D, J =

2Hz), 6.57 (1H, T, J = 2 Hz)
Mass analysis (relative intensity): m / e 154 (M ⁺ , 36%), 95 (11%), 94 (100%), 42 (12%).

Example 6

207 mg of 1-acetoxymethylthio-1-methylthio-2- (i-methylpyrrolyl-2) ethylene are dissolved in 3 ml of methanol and 380 mg of benzylamine are added. The mixture is 2.4 h at room temperature touched. 20 ml of methylene chloride are added

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and the mixture is washed twice with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and determined by column chromatography [Florisil, n-hexane-benzene (3: 1)] and thin layer chromatography (Silica gel, benzene) purified; 72 mg of N-benzyl- (i-methylpyrrolyl-2) -thioacetamide are obtained as light brown oil in a yield of 28%.

IR (pure): 3310, 2820, 1525, 1496, 1400, 1310, 1118, 725,

700 cm " ¹
NMR (CDCl ₃ , S) '. 3.42 (3H, S), 4.09 (2H, S), 4.77 (2H, D, J = 6 Hz), 5.99 (2H, D, J = 2 Hz), 6.54 ( 1H, T, J = 2 Hz),

7.03-7.28 (5H, M), 7.4 (1H, broad) mass analysis (relative intensity: m / e 244 (M ⁺ , 22%), 95 (2850), 94 (100%), 91 (30%), 81 (10%), 65 (10%).

Example 7

318 mg of 1-acetoxymethylthio-1-methylthio-2- (i-methylpyrrolyl-2) ethylene are dissolved in 3 ml of methanol and 280 mg of n-butylamine are added. The mixture is left at room temperature for 17 hours touched. 20 ml of methylene chloride are added and the mixture is washed with 20 ml of water twice. the organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography [Florisil, n-hexane-benzene (3: 1)] and thin layer chromatography [silica gel, methylene chloride-benzene (1: 9) 3 cleaned; 76 mg of N-butyl- (1-methylpyrrolyl-2) thioacetamide are obtained as a colorless oil in a yield of 29%.

IR (neat): 3300, 2950, 2925, 1530, 1415, 1310, 1085, 716 cm " ¹ NMR (CDCl ₃ , 8): 0.86 (3H ₁ T, J = 6 Hz), 1.06-1 .66 (4H, M), 3.44 (3H ₁ S), 3.56 (2H, Q, J = 7 Hz), 4.04 (2H, S), 6.03 (2H,

D ₁ J = 2 Hz), 6.58 (1H, T, J = 2 Hz) mass analysis (relative intensity): m / e 210 (M ⁺ , 29%, 95 (30%), 94 (100%).

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Example 8

10 ml of 1,2-dichloroethane are added to 0.92 g of aluminum chloride and, while stirring and cooling with ice, 1.04 g of p-toluoyl chloride are added dropwise in an argon atmosphere. The resulting, light red solution is added dropwise, while cooling with ice, to a solution of 1.235 g of N, N-dimethyl- (i-methylpyrrolyl-2) -thioacetamide in 10 ml of 1,2-dichloroethane. After the addition, the mixture is stirred at room temperature for 40 minutes and then under reflux for 15 minutes. The resulting solution is introduced into a mixture of 5 ml of 3.5% strength hydrochloric acid and 35 ml of ice-water and extracted three times with 50 ml of methylene chloride. The organic layers are combined and washed successively with 70 ml of an aqueous solution of N, N-dimethylaminopropylamine, 100 ml of 2% hydrochloric acid, 50 ml of an aqueous solution of potassium carbonate and 60 ml of an aqueous solution of sodium chloride. The resulting organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on a column of Florisil using n-hexane-methylene chloride (2: 1) as the eluent; obtained 196 mg of N, N-dimethyl [i-methyl-5- (ptoluoyl) -pyrrolyl-2] -thioacetamid as colorless crystals in a yield of 10%, mp. 122.5 to 123.5 ⁰ C (from acetone -tfasser).

IR (KBr): 2910, 1618, 1605, 1488, 1456, 1376, 1274, 1112, 1042,

885, 751 cm " ¹
NMR (CDCl ₃ , 6) '. 2.42 (3H, S), 3.30 (3H, S), 3.54 (3H, S), 3.96

(3H, S), 4.22 (2H, S), 6.00 (1H, D, J% 4 Hz), 6.68 (1H, D, J = 4 Hz), 7.24 (2H, diffuse D, J = 8 Hz, 7.73 (2H,

diffused D, J = 8 Hz)
Mass analysis (relative intensity): m / e 300 (M ⁺ , 37%) , 212 (100%), 120 (22%), 119 (32%), 91 (27%), 88 (46%).

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example

1.21 g of p-toluoyl chloride are added dropwise to a suspension of 1.0 g of aluminum chloride in 10 ml of 1,2-dichloroethane, while stirring and cooling with ice. The resulting, light red solution is added dropwise, while cooling with ice, to a solution of 1.004 g of (1-methylpyrrolyl = -2) -thioacetomorpholide in 10 ml of 1,2-dichloroethane. After the addition is complete, the mixture is stirred at room temperature for 50 minutes and then under reflux for 3 minutes. The resulting mixture is introduced into a mixture of 20 ml of 1N hydrochloric acid and 30 ml of ice-water and extracted three times with 100 ml of methylene chloride. The organic layers are combined and successively with 50 ml of a 10bigen aqueous solution of Ν, Ν-dimethylaminopropylamine, two 100 ml parts of 0.1N hydrochloric acid, 100 ml of an aqueous solution of potassium carbonate and two 100 ml parts of an aqueous solution of sodium chloride blew. The resulting organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on a column of Florisil using benzene-methylene chloride (1: 2) as the eluent; 203 mg of [1-methyl-5- (p-toluoyl) -pyrrolyl-2] -thioacetomorpholide are obtained as a red oil which is crystallized from diethyl ether with the formation of pale yellow crystals. The yield is 13%, melting point 154.5 to 155.5 ° C. (from benzene diethyl ether).
IR (KBr): 3000, 2945, 2830, 16O2, 1490, 1457, 1377, 1276, 1265, 1219, 1205, 1110, 1020, 884, 875, 826, 748,

600 cm " ¹
NMR (CDCl ₃ , <£): 2.36 (3H, S), 3.48-3.79 (6H, M), 3.87 (3H, S),

4.20 (2H, S), 4.26-4.36 (2H, M), 5.94 (1H, D, J = 4 Hz), 6.60 (1H, D, J = 4 Hz), 7.18 (2H, diffuse D, J = 8 Hz),

7.65 (2H, diffuse D, J = 8 Hz, mass analysis (relative intensity): m / e 342 (M ', 32%), 213 (1796), 212 (10050, 130 (29 ° / o), 120 (1796), 119 (41%), 91 (3296), 86 (24%), 65 (11%).

909 * 10/083?

Analysis ^ rC ₁₉ H ₂₂ N ₂ O ₂ S

Calculated: C 66.64% H 6.48% N 8.18% S 9.36% found: 66.74 6.44 8.04 9.35.

The following Reference Examples 2 and 5 show the acetamides which correspond to the thioacetamides of the formula (i).

Reference example 2

155 mg of N, N-dimethyl- (i-methylpyrrolyl-2) -thioacetamide are dissolved in 7.5 ml of methanol and 8.5 mg of sodium tungstate are added. 0.28 ml of a 30% strength aqueous solution of hydrogen peroxide v / earth was gradually added with stirring and cooling with ice. The mixture is stirred for 2 hours while cooling with ice. Then 20 ml of water are added and the mixture is extracted three times with 30 ml of methylene chloride. The organic layers are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column made of Florisil using benzene-methylene chloride (1: 2) as the eluent; 103 mg of N, N-dimethyl- (i-methylpyrrolyl-2) acetamide are obtained as light yellow crystals in a yield of 73%, melting point 97 ° to 98 ° C. (from diethyl ether).
IR (KBr): 2910, 1646, 1497, 1394, 1320, 1298, 1236, 1207, 1127, 1090, 854, 826, 726, 719 cm "* ¹

NMR (CDCl ₃ , <T): 2.90 (3H, S), 3.02 (3H, S), 3.55 (3H, S), 3.60 (2H, S), 5.88 (1H , M), 5.98 (ifl, T, J = 3 Hz), 6.51 (1H, DxD, J = 2 and 3Hz)

Analysis for C ₉ H ₁₄ N ₂ O

Calculated: C 65.03% H 8.49% N 16.85% found 65.16 8.43 17.06.

Reference example 3

150 mg N, N-dimethyl (i-methylpyrrolyl-2) - thioacet- amide are dissolved in 3 ml of acetic acid and 0.1 ml of a 30% aqueous solution of hydrogen peroxide is added. The mixture is stirred for 1 hour at room temperature. 15 ml of water are added and the mixture is washed three times with 30 ml of methylene

009810/0837

Chloride extracted. The organic layers are united, dried over anhydrous sodium sulfate-anhydrous potassium carbonate and concentrated under reduced pressure. The residue is chromatographed on a column made of Florisil using ethyl acetate as the eluent; you get 28 mg of N, N-dimethyl- (i-methylpyrrolyl-2) -acetamide in a yield of 20%.

Reference example 4

10 ml of 1,2-dichloroethane are added to 1.0 g of aluminum chloride and, while stirring and cooling with ice in an argon atmosphere, 1.0 g of p-toluoyl chloride is added dropwise. The resulting, light red solution is added dropwise, while cooling with ice, to a solution of 876 mg of N, N-dimethyl- (i-methylpyrrolyl-2) -acetamide in 10 ml of 1,2-dichloroethane. After the addition, the mixture is stirred at room temperature for 15 minutes and under reflux for 10 minutes. The mixture is treated in the same way as in Example 8; 421 mg of N ", M-dimethyl- [i-methyl-5- (p-toluoyl) -pyrrolyl-2] -acetamide are obtained in the form of pale yellow crystals in a yield of 28%. In addition, 170 mg of unreacted acetamide, which is used as Starting material was used, recovered; m.p. 130 to 132 ° C (from carbon tetrachloride diethyl ether).
IR (KBr): 2910, 1649, 1614, 1497, 1458, 1373, 1270, 1146,

886, 757 cm " ¹
NMR (CDCl ₃ , /?): 2.37 (3H, S), 2.95 (3H, S), 3.02 (3H, S),

3.68 (2H, S), 3.90 (3H, S), 5.95 (1H, D, J = 4 Hz),

6.60 (1H, D, J = 4 Hz), 7.17 (2H, diffuse D, J = 8 Hz),

7.66 (2H, diffuse D, J = 8 Hz) mass analysis (relative intensity): m / e 284 (M ⁺ , 16%), 212

(100%), 120 (17%), 119 (1796), 91 (16%), 72 (15%) analysis for C ₁ -H ₂₀ N ₂ O ₂

Calculated: C 71.81%, H 7.09%, N 9.85% found: 71.40 6.95 9.63.

909810/0837

Reference example 5

500 mg of N, N-dimethyl- (i-methylpyrrolyl-2) -acetamide are dissolved in 3 ml of 1,2-dichlorobenzene and 700 mg of p-toluoyl chloride are admitted. The mixture is refluxed for 4 hours in an argon atmosphere. The mixture is at reduced Pressure concentrated and 50 ml of methylene chloride are added to the residue. The mixture is successively with 30 ml a 10xigen aqueous solution of Ν, Ν-dimethylaminopropylamine, 30 ml of 3.5% dilute hydrochloric acid and 30 ml washed with an aqueous potassium carbonate solution. The resulting organic layer is dried over anhydrous sodium sulfate, concentrated at reduced pressure and on a column of Florisil using benzene as the eluent chromatographed; 49 mg of N, N-dimethyl [imethyl-5- (p-toluoyl) pyrrolyl-2] acetamide are obtained in a yield of 7%.

The following Examples 6 to 13 illustrate the Production of acetic acids corresponding to the thioacetamides of the formula (I) or the corresponding acetamides.

Reference example 6

10 mg to about 205 ml of a 25 ° £ aqueous solution of potassium N, N-dimethyl (i-methylpyrrolyl-2) was added and the mixture is -thioacetamid 19h then stirred for 1 h at 130 ⁰ C at 115 ° C and. Then it is heated 2 hours at 140 to 150 ⁰ C under reflux and cooled to room temperature. The reaction mixture is acidified to pH 2 with 1N dilute sulfuric acid and extracted three times with 100 ml of ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure; 154 mg of (1-methylpyrrolyl-2) acetic acid are obtained in the form of light brown crystals in a yield of 98%. Samples for analysis are prepared by recrystallization from carbon tetrachloride; Mp 114 -5 ⁰ C in the literature ⁽⁴ "mentioned value: 113 ° C). [. + Chem.Abstr, 32.595 ⁷ O938)].

909610/0837

IR (KBr); 3300-2500, 1695, 1503, 1418, 1395, 1350, 1310, 1250, 1198, 1101, 1090, 1058, 1012, 930, 805, 777, 722, 712, 701, 659, 632 cm " ¹

NMR (CDCl ₃ , ei); 3.56 (3H ₁ S), 3.64 (2H, S), 6.07 (2H, D, J = 2 Hz), 6.59 (1H, T, J = 2 Hz)

Analysis for C ₇ HoNO ₂

calculated; C 60.42% H 6.52% N 10.07% found: 60.45 6.41 9.90.

Reference example 7

10 g of a 25% aqueous solution of potassium hydroxide to 297 mg N, N = dimethyl (~ i methylpyrrolyl-2) was added and the mixture is -thioacetamid 2 hours over an oil bath at 150 heated to 16O ⁰ C to reflux, "The The reaction mixture is treated in the same manner as in Reference Example 6; 226 mg of (i-methylpyrrolyl-2) acetic acid are obtained.

Reference Examples 8 to 11

Reference Example 7 is repeated with the exception that 36Ο mg of (i-methylpyrrolyl-2) thioacetomorpholide, 245 mg (i-methylpyrrolyl-2) «thioacetamide, 341 mg of N-butyl- (i-methylpyrrolyl-2) thioacetamide or 403 mg of N = benzyl- (i-methylpyrrolyl-2) -thioacetamide instead of 297 mg of N, N-dimethyl- (1-methylpyrrolyl-2) -thioacetamide are used »This gives (i-methylpyrrolyl-2) acetic acid in an amount of 212, 214, 221 and 219 mg, respectively.

Reference example 12

68 mg of N, N-dimethyl- [i-methyl-5- (p-toluoyl) -pyrrolyl-2] -thioacetamide are dissolved in 10 ml of ethanol and 5 ml of a 1N aqueous sodium hydroxide solution are added. The mixture is refluxed for 24 h. The solution is introduced into 40 ml of ice-water containing 10 ml of 1N dilute sulfuric acid and extracted with diethyl ether. The organic layer is dried over anhydrous sodium sulfate and ' concentrated under reduced pressure. The residue is on

S0i81O / O837

chromatographed on a column of silica gel using methylene chloride as the eluent; obtained 36 mg [i-methyl-5- (p-toluoyl) -pyrrolyl-2] acetic acid in the form of colorless crystals in a yield of 62%, Fp. 156 to -157 ⁰ C (from acetonitrile).
IR (KBr): 2950, 2910, 1698, I63O, I6IO, 1488, 1462, 1379,

1273, 1244, 888, 750 cm " ¹
NMR (CDCl ₃₁ J): 2.37 (3H, S) -, 3.70. (2H, S), 3.89 (3H, S), 6.07 (1H, D, J = 4 Hz) , 6.62 (1H, D, J = 4 Hz), 7.18 (2H, diffuse D, J = 8 Hz), 7.66 (2H, diffuse D, J = 8 Hz),

8.65 (1H, broad).
Analysis for C ₁₅ H ₁₅ NO ₃

Calculated: C 70.02% H 5.88% N 5.44% / found: 70.00 5.84 5.30.

This product is tested by IR, NMR and by a comparative test identified with an authentic sample [prepared according to J.R.Carson et al, J.Med.Chem., t4, 646 (1971)].

Reference example 13

10 ml of a 25% strength aqueous solution of potassium hydroxide are added to 246 mg of N, N-dimethyl- [i-methyl-5- (p-toluoyl) -pyrrolyl-2] -acetamide and the mixture is refluxed for 9 hours. 100 ml of water are added and then 40 ml of 1N dilute sulfuric acid are added to adjust the pH to 3. The solution is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure; 127 mg of [i-methyl-5- (p-toluoyl) -pyrrolyl-2] -acetic acid are obtained in the form of colorless crystals in a yield of 57%.

End of description.

101110/083 *

Claims (1)

Dr. F. Zumstein Sr. - Dr. E. Assmann - 3r. R. Ka _ö r »iysberger Dlpl.-Phys. R. Holzbauer - Dipl -.- lng. F. Xiing ^ iron - Dr. R Zumstein jun. PATENT LAWYERS 8000 Munich 2 · Bräuhausstraße 4 ■ Telephone collective no. 225341. Telegrams Zumpat Telex 529 <) 79 Case F6081-K19 (Sagami) / EM Patent to s ρ r ü c h e . 1J New (i-alkylpyrrolyl-2) thioacetamide of formula (I) wherein R is a lower alkyl group with 1 to 4 carbon atoms, 1 2 R and R independently of one another are a hydrogen atom or a substituted or unsubstituted alkyl group 1 2
or R and R together represent an alkylene group with 3 to 5 carbon atoms which can be interrupted by 0, S or an amino group, and R ^ represents a hydrogen atom or a p-toluoyl group. 2. A compound according to claim 1, wherein R in the formula (I) is a methyl group. 909810/0337 1 2 3. A compound according to claim 1, wherein R and R are in the Formula (I) independently of one another for a hydrogen atom, represent a methyl group, an n-butyl group or a benzyl group. 4. A compound according to claim 1, .Worin R and R in the Formula (I) together with N in the formula is a morpholino group mean. 5. A compound according to claim 1, wherein in formula (I) R is one means. R represents a methyl group and R represents a p-toluoyl group 6. Process for the preparation of an (i-alkylpyrrolyl-2) thioacetamide of formula (I) ■ ν * r CHoC a N ^d ^ -IT ^ 2 R ^R R is a lower alkyl group with 1 to 4 carbon atoms, 1 2 R and R independently of one another are a hydrogen atom or a substituted or unsubstituted alkyl group 1 2
or R and R together represent an alkylene group with 2 to or 3 to 5 carbon atoms, which are replaced by O, S or an amino group can be interrupted, and
■ χ. R ^ denotes a hydrogen atom or a p-toluoyl group,
characterized in that one (a) a 1-acyloxymethylthio-1-methylthio-2- (1-alkylpyrrolyl-2) ethylene of formula (II) N ^ SCH ₂ OCOR R 909810/0837 2336902 R has the meaning given above and R stands for an alkyl or phenyl group, with ammonia or an amine of the formula (III) R ¹ HNv ■ (III) with formation of an (i-alkylpyrrolyl-2 -) - thioacetamide der Formula (I) in which R is a hydrogen atom, and (b) for the preparation of an [i-alkyl-5- (p-toluoyl) -pyrrolyl-2] -thioacetamide of formula (i), wherein R represents a p-toluoyl group obtained in step (a) (i-Alkylpyrrolyl-2) -thioacetamide subjected to a toluoylation reaction. 5509810/0837