DD220602A1 - PROCESS FOR THE PREPARATION OF CHINOXALIN-2-THIOCARBOXY ACID AMIDES - Google Patents

Abstract

The invention relates to a novel process for preparing the hitherto inaccessible quinoxaline-2-thiocarbonsaeureamide (formula I), which are applicable as intermediates for the preparation of biologically active preparations. The synthesis is carried out by reacting quinoxaline 2-dithiocarboxylic acid esters or their precursors with ammonia, aliphatic primary amines, aliphatic secondary amines or cyclic secondary amines. If 2- (halomethyl) quinoxalines are used as precursors, the nitrogen bases can be added before or after the thiolation.

Description

Field of application of the invention:

The invention relates to a process for the preparation of quinoxaline-2-thiocarboxamides, which are applicable as intermediates for the preparation of biologically active preparations.

Characteristic of the known technical solutions:

Quinoxaline-2-thiocarboxamides are hitherto unknown; Thus, there is still no process for their preparation.

Object of the invention:

The aim of the invention is to find a process for the preparation of quinoxaline-2-thiocarboxylic acid amides, since such compounds are not previously available. _

Explanation of the essence of the invention:

- The object of the invention is to find a method by which the previously inaccessible quinoxaline-2-thiocarbonsäureamide can be produced. ,

Features of the invention:

According to the invention the object is achieved in that quinoxaline-2-dithiocarboxylic acid ester of the general formula II, in . R R is alkyl or substituted alkyl, R ^{3 is} H, OH, alkyl, aryl or hetaryl, R ^{4 is} R ³ , OAalkyl, O-aryl, halogen, NO ₂ or CN, with basic nitrogen compounds of the general formula HNR ¹ R ² , in which R ¹ and R ^{2 may be the} same or different and H, alkyl, cycloalkyl or aralkyl groups which may optionally carry further functional groups, mean or characterize a carbocyclic or heterocyclic ring member, at temperatures up to 25O ⁰ C, as a rule but at 70 ⁰ C to 120 ⁰ C to the quinoxaline-2-thiocarbonsäureamiden the general formula I, in the R ¹ and R ²

₂ fj

^ ^^ G-S-R

R ¹ Ii

, , ^{: v} - s

the same meaning as in the nitrogen base HNR ¹ R ² and R ³ and R ^{4 have} the same meaning as in formula II are reacted. The reaction may be carried out in indifferent solvents of polar or non-polar character or using excess amine as solvent or without solvent by melting the reaction pacemes each without pressure or under elevated pressure.

Instead of the quinoxaline-2-dithiocarboxylic esters, the quinoxaline-2-dithiocarboxylic esters can also be used as their immediate precursor, the quinoxaline-2-dithiocarboxylic acids (formula II with R = H and R ³ , R ⁴ having the same meaning as in the Dithiocarbonsäureestern) or their salts are used, which in turn are not isolated, but after their formation by thiolation according to substituted 2-

(Halomethyl) quinoxalines or their derivatives, are reacted with the nitrogen bases HNR ¹ R ² , wherein the addition of the nitrogen base can also take place before the thiolation. The thiolation of the 2- (halomethyl) quinoxalines or their derivatives and the preparation of the quinoxaline 2-dithiocarboxylic acid esters are described in the patent application WP C 07 D 253 4608 "Process for the preparation of quinoxaline-2-dithiocarboxylic acid esters" of G. Sarodnick, H.Viola, G.Kempter, R.Mayer and J. Jumar.

Exemplary embodiments: Example 1

S-Methyl-quinoxaline-thiocarboxamide Into the low-boiling solution of 1 TI. Methyl S-methyl-quinoxaline -dithiocarboxylate in 10 μl. Propan-1-ol is introduced within 45 minutes of dry ammonia gas in excess. The product, which gradually crystallizes out in the cold, is recrystallised from 1,2-dichloroethane. Yield 40% of theory, mp 194-196 ⁰ C.

Example 2:;

3-Methyl-quinoxaline-2-thiocarboxylic acid N-methyl-amide Methyl S-methyl-quinoxaline -dithiocarboxylate is dissolved in boiling heptane and excess dry methylamine is passed in. The product is filtered off cold and recrystallized. Yield 76% of theory, melting point 127-129 ⁰ C (from ethanol). -

Example 3:

3-Methyl-quinoxaline-2-thiocarboxylic acid N-ethyl-amide Analogous to Example 2 with ethylamine, yield 95% of theory, melting point 148.5-149.5 ° C (from ethanol).

Example 4:

S-methyl-quinoxaline -thiocarbonsäure- ^ ^ N-dimethyl-amide In analogy with Example 2 with dimethylamine, yield 48% of theory, melting point 126-127 ⁰ C (from heptane).

example:

S-Phenyl-quinoxaline-thiocarboxylic acid N-ethyl-amide Analogously to Example 2 from S-phenyl-quinoxaline-dithiocarboxylic acid methyl ester and ethylamine, yield 79% of theory,

Melting point 165-166.5 ° C (from ethanol). , .

Example 6:

S-methyl-quinoxaline - ^ - thiocarboxylic acid-N-butyl-amide, ... ·.

The solution of methyl S-methyl-quinoxaline -dithiocarboxylate in boiling heptane is added with butylamine in a 1.1- to 5-fold molar excess and boiled under reflux for 30 minutes. It is allowed to cool, filtered off and crystallized. Yield 94% of theory, mp 103-104.5 ⁰ C (from heptane).

Example 7:

3-Methyl-quinoxaline-2-thiocarboxylic acid N-isobutyl-amide Analogous to Example 6 with isobutylamine; Yield 74% of theory, mp 110.5-112 ° C (from heptane).

Example 8:!

S-methyl-quinoxaline ^ carbothioic acid-N-cyclohexyl-amide In analogy with Example 6, cyclohexylamine, yield 88% of theory, melting point 175 to 176.5 ⁰ C (from toluene).

Example 9:

3-Methyl-quinoxaline-2-thiocarboxylic acid N, N-diethyl-amide Analogous to Example 6 with diethylamine, yield 56% of theory, melting point 101.5-103 ⁰ C (from heptane).

Example 10:

S-phenyl-quinoxaline-thiocarboxylic acid-N-butyl-amide

Analogously to Example 6 from methyl S-phenyl-quinoxaline -dithiocarboxylate, yield 86% of theory, mp 165-

167 ° C (ausToluen / heptane). , '.

Example 11: - · · · ·

3-Phenyl-quinoxa | in-2-thiocarboxylic acid N-cyclohexyl-amide Analogous to Example 6 from 3-phenyl-quinoxaline-2-dithiocarboxylic acid methyl ester and cyclohexylamine, Yield 83% of theory, melting point 215-216 ° C. (from ethanol) ,

Example 12:

S-Phenyl-quinoxaline ^ -thiocarbonsäurepiperidid analogously to Example 6 from 3-phenyl-quinoxalin-2-dithiocarbonsäuremethylester and piperidine, Yield 78% of theory, melting point 200-202 ⁰ C. (from toluene).

Example 13:

S-methyl-quinoxaline-thiocarboxylic acid piperidide Methyl 3-methylquinoxaline-2-dithiocarboxylate is dissolved in 6 times the mass of toluene and, after addition of the double molar amount of piperidine, refluxed for 2 hours. It is concentrated in vacuo, filtered off with suction and crystallized. Yield 85% of theory, m.p. 148-149 ° C (from toluene / heptane).

Example 14:

3-Methyl-quinoxaline-2-thiocarboxylic acid morpholide

Analogously to Example 13 with morpholine, yield 74% of theory, mp 209-210 ⁰ C (from toluene),.

Example 15:

S-phenyl-quinoxaline ^ -thiocarbonsäuremorpholid

3TL. S-phenyl-quinoxaline-dithiocarboxylic acid methyl ester are dissolved in 50 μl. Ethanol hot dissolved, with 1 TI. Morpholine and heated for 30 minutes under reflux. At room temperature, the product crystallizes, which is purified by recrystallization from ethanol or toluene. Yield 65% of theory, mp 208.5-210 ⁰ C.

Example 16:

S-methyl-quinoxaline ^ -thiocarbonsäurepyrrolidid

The suspension is mixed with 3 μl. Methyl S-methyl-quinoxaline -dithiocarboxylate in 25 μl. Ethanol with 1 TI. Pyrrolidine, heated to boiling for 5 minutes and put the mixture in the refrigerator overnight. The product is filtered off, dried and recrystallized from cyclohexane. Yield 66% of theory, melting point 150-151 ⁰ C.

Example 17:

S-methyl ^ chinoxälin carbothioic acid-N-benzyl-amide

The mixture of 1Tl. Methyl S-methyl-quinoxaline -dithiocarboxylate, 15 parts by weight Ethanol and the 1.5 molar amount of benzylamine is refluxed for 15 to 30 minutes. After cooling, slowly add the same volume of water. The crystallized product is filtered off with suction and purified by recrystallization. Yield 64% of theory, melting point 108-110 ⁰ C (from cyclohexane).

Example 18:

3-methyl-quinoxalin-2-thiocarboxylic acid-N- (2-hydroxy-ethyl) amide

Analogously to Example 17 with 2-amino-ethanol, yield 61% of theory, melting point 181-182 ° C (from methanol).

Example":

S-Phenyl-quinoxaline ^ carbothioic acid-N-benzyl-arnid

Analogously to Example 1 from S-phenylquinoxaline-dithiocarboxylic acid methyl ester, yield 85% of theory, melting point 142.5-144 ° C. (from toluene / heptane). ,

Example 20:

3-phenyl-quinoxaline-2-thiocarboxylic acid N- (2-hydroxy-ethyl) -amide.

Analogously to Example 17 from methyl S-phenyl-quinoxaline -dithiocarboxylate and 2-amino-ethanol, yield 82% of theory, melting point 164-165.5 ° C (from methanol).

Example 21:

S-methyl-quinoxaline ^ -thiocarbonsäurepiperidid

1 TI. S-methyl-quinoxaline -dithiocarboxylic acid ethyl ester and 4Tl. Piperidine is allowed to reflux for 1 hour, after cooling the product precipitated by addition of water, filtered off with suction, dried and crystallized from a toluene-heptane mixture to yield ee 7 4% of theory, melting point 148-149 ° C. ,

Example 22:

S-methyl-quinoxaline ^ -thiocarbonsäurernorpholid

The mixture of 9,6Tl. Sulfur, 30.3TI. Triethylamine, 8,7Tl. Morpholine and 45Tl. Ν, Ν-Dimethyl-formamide is stirred for 20 minutes at room temperature. The solution is then added dropwise of 23.7 parts. 2- (bromomethyl) -3-methylquinoxaline in 150 μl. Ν, Ν-dimethyl-formamide at 20-40 ⁰ C added so quickly that the dark color is barely maintained. One hour after completion of the addition, the reaction mixture is poured onto crushed ice and finally separated from the precipitated reaction product, which is purified by recrystallization from toluene. Yield 43% of theory, melting point 209-21O ⁰ C. '. , ';' - '''.^:; , , '. , , ^{v :} · '. '.

Example 23:

S-methyl-quinoxaline-thiocarboxylic acid N-cyclohexylamide.

To the stirred mixture of 9,6Tl. Sulfur, 30, θΤΙ. Triethylamine and 45 μl. Lösung, Ν-dimethylformamide is added dropwise at 20-4O ⁰ C, the solution of 23.7TI. 2- (bromomethyl) -3-methyl-quinoxalih in 150TI, Ν, Ν-dimethyl-formamide gradually added. One hour after completion of the addition is added with 15Tl. Cyclohexylamine and heated for 2 hours at 90 ° C. After cooling, water is added and the deposited product is recrystallised from toluene. Yield 47% of theory, mp 175- 176.5 ⁰ C. ''^..;'.'''''.'.".-':

Claims (10)

-1- 254 754 Invention claims: '- .1. Process for the preparation of quinoxaline-2-thiocarboxamides, characterized in that quinoxaline-2-dithiocarboxylic acid esters or their precursors are reacted with the nitrogen bases HNR ¹ R ² , the quinoxaline-2-thiocarboxamides being formed directly or using precursors by subsequent thiolation , 2. The method according to item 1, characterized in that the quinoxaline-2-dithiocarboxylic acid esters used as starting materials of the general formula II, where R = alkyl or substituted alkyl, R ³ = H, OH, alkyl, aryl or hetaryl, R ⁴ = R ³ , OAikyl, OAryl, halogen, NO ₂ or CN. ^l 3. The method according to item!, Characterized in that as precursors of quinoxaline-2-dithiocarboxylic the Chirioxalin-2-dithiocarboxylic acids of the general formula II with R = H and R ³ , R ⁴ with the same meaning as in the Dithiocarbonsäureestern (s 2.!) Or their salts are used. · "'.' 4. The method according to item 1 and item 3, characterized in that the quinoxaline-2-dithiocarboxylic acids or their salts used as precursors are not isolated in substance, but immediately after their formation by thiolation of correspondingly substituted 2- (halomethyl) -quinoxalines or whose derivatives are reacted with the nitrogenous bases. 5. The method according to item 1 and item 4, characterized in that when using appropriately substituted 2- (halomethyl) quinoxalines as precursors, the addition of nitrogen bases can also take place before the thiolation. 6. The method according to item 1, characterized in that as nitrogen bases compounds of the general formula HNR ¹ R ² are used, in which R ¹ and R ^{2 may be the} same or different and H, alkyl, cycloalkyl or aralkyl groups, optionally further Functionally groups carry kranins, mean or characterize a carbocyclic or heterocyclic ring portion. 7. The method according to item 1, characterized in that the reactions with the nitrogen bases at temperatures from -80 ⁰ C to 250 ⁰ C, but preferably in the range of 70 ⁰ C to 120 ⁰ C are performed. 8. The method according to item 1, characterized in that the reactions are carried out in indifferent solvents of polar or non-polar character or using excess amine as solvent or without solvent by melting the reactants together. ; 9. The method according to item 1, characterized in that the reactions under a pressure of 1OkPa to 10MPa, but preferably are carried out at atmospheric pressure. 10. The method according to item 1, characterized in that the quinoxaline-2-thiocarboxylic acid amides formed as end products of the general formula I correspond, wherein R ¹ and R ^{2 have} the same meaning as in the nitrogen base ($. Point 6.!) And R ³ and R ^{4 have} the same meaning as in general formula II (see point 2.!).