DE2037257A1 - Poly-(5-amino-1,3,4-thiadiazol-2-yl) derivs prepn - intermediates for drug and polymer prodn - Google Patents

Abstract

Poly-(5-amino-1,3,4-thiadiazol-2-yl) derivs. of general formula (I) are drug and polymer intermediates. Prepn. is by the following stages: (1) Addn. of acylisothiocyanates to bi- or poly-functional acid hydrazides to convert the hydrazide NH2 to the acylthiosemicarbazide; (2) heating this in polyphosphoric acid or other dehydrating agent cyclises the thiosemicarbazide moiety to a 1,3,4-thiadiazolyl ring giving the diacylaminoodio (1,3,4-thiadiazolyl-(2-21) cpd., from which the acyl groups may be removed by hydrolysis with acid (stage 3) to give the final product (I): (where n is 0-4 pref. 0; R is a bi- or poly-functional 1-20C (pref. 1-8C and esp. 3-6C)-aliphatic or cycloaliphatic hydrocarbon residue or a 1 or 2-ringed aromatic or heterocyclic 6-20 C residue; when n is 0, R is a chemical bond). illustrates the final product when n is 0.

Description

Process for the preparation of amines It is known 5-amino-1,3,4-thiadiazoles of the formula 1) from thiosemicarbazides by acylating and cyclizing the N-acyl-thiosemicarbazides with acetyl chloride, concentrated sulfuric acid or other dehydrating agents, 2) from thiosemicarbazides by condensing with an aldehyde and oxidizing the aldehyde thiosemicarbazones, 3) from a thiosemicarbazide ester salt. Elimination of ammonium salt and alcohol.

Practically only 5-amino-1,3,4-thidiazoles can be produced by the two reactions 1) and 2) with an aromatic residue R.

Reaction 3) also takes place with bifunctional xmidic acid ester salts with compounds of the formula optionally in the tautomeric form may exist. The route via the imidic acid esters, which in turn are produced via the nitriles, is laborious and expensive.

A process has now been found for the preparation of amines of the formula in which n is an integer from 0 to 4, preferably 0 and R is a bifunctional or polyfunctional, preferably bifunctional, aliphatic or cycloaliphatic hydrocarbon radical with 1 to 20, preferably 1 to 8, in particular 3 to 6 carbon atoms, or mono- or binuclear aromatic or heterocyclic hydrocarbon radical with 6 to 20 carbon denotes, or for n = 0 also mean a simple chemical bond, from the di- or poly-ydrazides of the (+2) -basic carboxylic acids of the general Formula R -4COOH) n + 2, in which n and R have the above meaning, and at least n + 2 equivalents of an acyl isothiocyanate of the formula R1CONCS, in which R1 is an aliphatic or aromatic hydrocarbon radical which is characterized in that the acyl isothiocyanate on the di- or polyhydrazide in a known manner in solution or suspension at temperatures between -500C and + 1000C, preferably between n + 20 ° C and + 70 ° C, added.

becomes, the addition product in the presence of decydrating agents at temperatures between OOC and + 20 ° C, preferably .between + 500C and + 1500C, while Is cyclized 0.25 to 5 hours and the resulting bis- or poly (5-acylamino-1,3,4-thiadiazol-2-yl) derivative under the action of aqueous acids at temperatures between + 50 ° C and + 1800C, preferably between + 100 ° C and + 150 ° C for 1 to 24 hours to the corresponding Bis- or poly (5-amino-1,3,4-thiadiazol-2-yl) derivative is saponified.

The course of the process is illustrated by the following reaction equations for bis (5-amino-1, 3, 4-thiadiazol-2-yl) compounds: Regarding reaction equation (2): The addition of isothiocyanates to hydrazides is known for the monofunctional area.

The addition of the acyl isothiocyanate to the bifunctional or

general polyfunctional acid hydrazide occurs in solution or suspension usually at -500C to + 1000C, preferably + 200C to + 700C.

The reaction proceeds with high yields, often quantitative.

The N1, N11-acyl-bis-P4-acylthiosemicarbazides resulting from equation (2) 7 can be easily cleaned by recrystallization, if the temperatures are not too high be applied. In general, none occurs at temperatures below + 1000C Change one; but if, for example, boiling N, N-dimethylformamide is used, then you only need to dissolve small amounts, if you work quickly, if the temperature is prolonged then partial cyclization occurs.

All solvents can be used as a solution or diluent if they do not even with the isothiocyanate at the reaction temperature or react with the hydrazide, e.g. methylene chloride, benzene, chlorobenzene, ether, dioxane 1 Acetone, cyclohexanone, ethyl acetate, n-butyl acetate, N-methylpywolidone, N, N-dimethylformamide, N, N-dimethylacetamide, and others.

The acyl isothiocyanates of the formula R1CONCS do not have to be in pure form can also be used, reaction solutions from e.g.

Ammonium thiocyanate and an acid chloride, as used in methods of organ. Chemie (Houben-Weyl) Volume IX., 1955, page 879 is used will.

R is the radical of a bifunctional or polyfunctional, optionally halogenated or aliphatic, cycloaliphatic, aromatic containing ether or sulfonic groups or heterocyclic carboxylic acid. In the special case of oxalic acid there is no residue R present.

R stands, for example, for the residues of the following acids: succinic acid, adipic acid, Sebacic acid, maleic acid, fumaric acid, acetylenedicarboxylic acid, tetrafluorosuccinic acid, Hexafluoroglutaric acid, octafluoroadipic acid, decafluoropimelic acid, dodecafluororkic acid, Tetradecafluorazelaic acid, hexadecafluorosebacic acid, 1,3-cyclopentanedicarboxylic acid, Hexahydroterephthalic acid, 1,4-phenylenediacetic acid, isqhthalic acid, terephthalic acid, 4,4'-diphenyldicarboxylic acid, 4,4t-diphenylether dicarboxylic acid, 4,4'-diphenylsulfondicarboxylic acid, 4,4'-diphenylmethanedicarboxylic acid, 2,2-bis- (4-carboxyphenyl) -propane, 2,2-bis- (4-carboxyphenyl) -hexafluoropropane, 1,3-bis- (4-carboxyphenyl) -hexafluoropropane, 1,4-bis- (4-carboxyphenyl) -oc-tafluorobutane, 1,6-bis- (4-carboxyphenyl) -dodecafluorohexane, 1,8-bis- (4-carboxyphenyl) -hexadecafluorooctane, 1,4-naphthalenedicarboxylic acid, 2,6-naphthalenedicarboxylic acid, 2,5-thiophenedicarboxylic acid, 2,6-pyridinedicarboxylic acid, 2,6-dimethylpyridine-3, 5-dicarboxylic acid, 2,5-thiazole dicarboxylic acid, 1, 3, 4-oxadiazole-2, 5-dicarboxylic acid, 1, 3, 4-thiadiazole-2, 5-dicarboxylic acid and others

The reaction is not limited to bifunctional acid hydrazides; she can react without difficulty to polyfunctional acid hydrazides, how e.g. the Ilydrazides of trimellitic acid, trimesic acid, mellitic acid and others will.

R1 is an aliphatic or aromatic radical, e.g. the methyl, Xthyl or phenyl radical.

On reaction equation (3): The cyclization with elimination of water is used thermally or under the action of known dehydrating agents Temperatures between about OOC and + 200 ° C, preferably + 500C to 71500C carried out and requires about 0.25 to 5 hours. The dehydrating agents are generally Acids or acid derivatives and at the same time serve as a solution or diluent, e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, polyphosphoric acid ester, phosphorus oxychloride, Mixtures of phosphorus oxychloride and phosphorus trichloride, acetic anhydride, acetyl chloride i.a., preferably polyphosphoric acid and conc. H2S04, possibly in a mixture with inert diluents such as toluene, nitrobenzene, o-dichlorobenzene.

Regarding reaction equation (4): The saponification of the resulting after reaction (3) Bis- (5-acylamino-1,3,4-thiadiazol-2-yl) compounds can be acidic or alkaline Medium. An aqueous, strongly acidic medium is preferred, which dissolves the resulting diamines, e.g.

Hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, Ethanesulfonic acid of medium to high concentration. You choose the concentration preferably so that the diamine that is formed is still just in solution in the hot acid goes; e.g. 40 to 80% sulfuric acid is well suited, depending on the constitution of the Bis- (5-acylamino-1> 3,4-thiadiazol-2-yl) compound requires saponification for example 1 to 24 hours at temperatures of +50 to 1800C, preferably + 100 to + 1500C. After the saponification, the diamine crystallizes out, or it becomes by adding Water. Or alkali precipitated. In each case it is advantageous> Organic acid formed from the diamine saponification by treatment with a alkaline solution (NaOII, NaHC03, Na2C03 etc.). the Diamines, which are generally weakly basic, can be obtained, for example, from aqueous acids, in some cases also from organic solvents, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc., can be recrystallized.

One can work very rationally if one uses cyclization and saponification (Reactions (3) and (4)) summarized, i.e. on the isolation of the diacylamino compound waived; so you can e.g.

in conc. Cyclic sulfuric acid, then the acid concentration by adding water reduce and then saponify.

When using polyfunctional acid hydrazides in the first stage (reaction (2)) compounds are formed that have three, four or more 5-amino-1, 3, 4-thiadiazol-2-yl radicals contain.

If alkyl or aryl isothiocyanates of the general formula R1NCS are used instead of acyl isothiocyanates of the formula R1CONCS in the first stage (reaction (2a)), after reaction (3a), for example in the case of the bifunctional acid hydrazides, N-alkyl or N are obtained -aryl-substituted bis (5-amino-1,3,4-thiadiazol-2-yl) derivatives: R1 has the above meaning. The aliphatic or aromatic radical is optionally substituted here. For example, R1 can be a chlorophenyl, 2-, 3- or 4-nitrophenyl, toluyl or benzyl radical.

The products formed after reactions (3), (3 a) and (4) are Intermediate products for pharmaceuticals and are used to manufacture polymers example 1: 5.9 g of oxalic acid dihydrazide are suspended in 50 ml of dry acetone. 16.4 g of benzoyl isothiocyanate are dissolved in a further 50 ml of dry acetone and in 10 Added minutes at 200C.

The mixture is stirred for 30 minutes at room temperature, then batch 1 is heated Hour at reflux. The mixture is cooled and 20.9 g of N, N'-oxalyl-bis (4-benzoyithiosemicarbazide), which is pure enough for further processing. A sample made quickly from N, N-dimethylformamide recrystallized, has a melting point of 233 ° C.

4.44 g of N, N'-oxalyl-bis- (4-benzoylthiosemicarbazide) are added with 30 g of polyphosphoric acid (84% P205) heated to 12500 for 1 hour. It occurs in subordinate Measure already saponification, which can be seen from the fact that small amounts of benzoic acid sublimate. After cooling down, add 60 ml of water to the contents of the flask, the precipitate is suctioned off and washed several times with hot water or with soda solution digested and washed neutral. 3.9 g of 5,5'-dibenzoylaminodi-1,3,4-thiadiazolyl- (2,2 ') 3.4 g of 5,5-dibenzoylaminodi-1, 3,4-thiadiazolyl- (2.21) are mixed with 10 ml of 80% strength Sulfuric acid heated to 1450C for 10 hours. After cooling, it is made with caustic soda alkaline, sucks off the precipitate and washes neutral with water. 1.5 is obtained g of 5,5'-diaminodi-1, 3, 4-thiadiazolyl- (2.2 '), which for purification from 33% Recrystallized sulfuric acid and washed neutral with bicarbonate solution and water will. The substance has no melting point, it decomposes above 3650C.

Example 2: 20.4 g of hexafluoroglutaric acid dihydrazide, melting point 1640C presented in 115 ml of anhydrous n-butyl acetate. 25.0 grams of benzoyl isothiocyanate are dissolved in a further 115 ml of butyl acetate and this solution for 10 minutes added at 20 ° C. The solution warms up to 4500 and becomes clear. Afterward it is heated to 60 ° C. for 1 hour. The first precipitate appears after 15 to 20 minutes of the reaction product. The mixture is cooled and the precipitate is filtered off with suction and dried at 500C under vacuum. 32.6 g of N, N'lhexafluorglutaryl-bis (4-benzoylthiosemicarbazide) are obtained, which has a melting point of 196 ° C. after recrystallization from n-butanol. By Evaporation of the original solution and recrystallization of the residue can be further 8.6 g with an mp of 191 ° C. can be isolated.

32.6 g of N, N'-hexafluoroglutaryl-bis- (4-benzotlthiosemicarbazide) heated to 125 ° C. for 75 minutes with 315 g of polyphosphoric acid (84% P205). The work-up takes place as in Example 1. This gives 28.5; g 1,3-bis- (5-benzoylamino-1, 3, 4-thiadiazol-2-yl) -hexa fluoropropane with a melting point of 337 ° C.

26.0 g of dibenzoyl compound are mixed with 78 ml of 80% strength sulfuric acid Heated at 1450C for 12 hours. The work-up is carried out as in Example 1. The purification takes place by recrystallization from 50 to 70 point sulfuric acid and washing with Bicarbonate solution and water or by US crystallization from glycol monomethyl ether.

Yield after recrystallization once 12.6 g of 1,3-bis (5-amino-1,3; 4-thiadiazol-2-yl) -hexaflu69 "propane Example 3: 12.5 g of isophthalic acid dihydrazide, suspended in 50 ml of dry acetone, are treated for 15 minutes at 25 C with a solution of 22.0 g of benzoyl isothiocyanate added in 50 ml of acetone. After the dropwise addition, the mixture is stirred at 25 ° C. for 30 minutes and finally refluxed for 1 hour. After cooling, it is filtered off with suction and washed with-little dry acetone and dries. 28.5 g of N, N'-isophthaloyl-bis- (4-benzoylthiosemicarbazide) are obtained, that after recrystallization from dimethylformamide / ethanol had a melting point of 2230C Has decomposition.

20.8 g of N, N'-isophthaloyl-bis (4-benzoylthiosemicarbazide) are with 128 g of polyphosphoric acid (84% P205) heated to 14500 for 60 minutes. After cooling down the batch is replaced with ice water, the precipitate is suctioned off and repeated several times Boiled water.

16.1 g of 1,3-bis (5-benzoylamino-1,3,4-thiadiazol-2-yl) benzene are obtained.

15.4 g of dibenzoyl compound are mixed with 66 inl of 80% sulfuric acid Heated to 1450C for 12 hours1. After cooling, one sets with conc. Alkali lye., sucks off and washes the product neutral with water. 7.4 g of 1,3-bis- (5-amino-1, 3,4-thiadiazol-2-yl) benzene, which for purification from 33% sulfuric acid, if necessary with the addition of some animal charcoal, recrystallized and '.

is washed with bicarbonate solution and water.

Example 4: To 8.9 g of N, N'-oxalyl-bis- (4-benzoylthiosemicarbazide), shown as in Example 1, 80 g of conc. Sulfuric acid was added dropwise with stirring. The mixture is stirred for 1 hour at a falling temperature, the last residues also go Solid in solution. Then 20 ml of water are added dropwise and the mixture is heated the batch 6 hours to 14500. The solution is diluted with ice water, put through Adding alkali alkaline and sucks off the precipitate.

The crude product is washed well and dried. 3.7 is obtained g 5,5'-diamino-di-1,3,4-thiadiazolyl- (2,2 '), which for purification as in Example 1 is recrystallized from 33% sulfuric acid or from 1,2-propylene glycol.

Example 5: 11.16 g of 2,6-dimethyl-pyridine-3, 5-dicarboxylic acid dihydrazide with a melting point of 236 ° C. are suspended in 90 ml of n-butyl acetate at room temperature. 16.6 g of benzoyl isothiocyanate are dissolved in 30 ml of n-butyl acetate and during 15 Added dropwise minutes; the temperature rises to about 30etc. The mixture is then stirred for 1 hour at room temperature and 1 hour at 60 ° C. The Addiffbnsprodukt is sucked cold, washed with n-butyl acetate and dried. It can be further processed in this form will.

10 g of the addition product are poured into 80 g conc. Sulfuric acid entered at room temperature; the temperature rises to about 40 ° C., stirring is continued for 1 hour as the temperature falls. For saponification 20 ml of water are now added and the batch is heated to 145 ° C. for 3 hours. One pours the cooled solution on a little ice and adjust the pH with conc. Caustic soda weak alkaline. The crude 3,5 bis (5-amino-1,3,4-thiadiazol-2-yl) -2,6-dimethyl-pyridine is filtered off with suction and recrystallized from N, N-dimethylformamide for purification. Fp. with decomposition: 339 ° C.

Claims (6)

Patent claims: 1 Process for the preparation of amines of the general formula in which n is an integer from 0 to 4, preferably 0, and R is a bifunctional or polyfunctional, preferably bifunctional, aliphatic or cycloaliphatic hydrocarbon radical having 1 to 20, preferably 1 to 8, in particular 3 to 6 carbon atoms , or mono- or binuclear aromatic or heterocyclic hydrocarbon radical with 6 to 20 carbon atoms, or for n = 0 also mean a simple chemical bond, from the bi- or polyhydrazides of the (n + 2) -basic carboxylic acids in general Formula R - + COOH) n + 2, in which n and R have the above meaning, and at least n + 2 equivalents of an acyl isothiocyanate of the formula R1CONCS, in which R1 is an aliphatic or aromatic hydrocarbon radical, characterized in that the acyl isothiocyanate to the di- or polyhydrazide is added in a known manner in solution or suspension at temperatures between -500 ° C. and + 1000 ° C., preferably between + 200 ° C. and + 700 ° C., the addition product is dehydrated in the presence render agents at temperatures between 0 ° C and + 2000C, preferably between + 500C and + 150 ° C, for 0.25 to 5 hours is cyclized and the resulting bis- or Poly (5-acylamino-1, 3, 4-thiadiazol-2-yl) derivative under the action aqueous acids at temperatures between + 500C and + 1800C, preferably between + 1000C and + 1500C, for 1 to 24 hours to the corresponding bis- or poly- (5-amino-1, 3, 4-thiadiazol-2-yl-) derivative is saponified. 2. The method according to claim 1, characterized in that as dehydrating Agents for the cyclization of the addition products from the di- or polyhydrazides and acyl isothiocyanate polyphosphoric acid or conc. Sulfuric acid can be used. 3. The method according to claim 1, characterized in that for saponification of the bis- or poly- (5-acylamino-i, 3, 4-thiadiazol-2-yl) compounds 40 to 80 Sige sulfuric acid is used. 4. The method according to claim 1, 2 and 3, characterized in that Cyclization and saponification were carried out in the same acid without intermediate isolation the concentration of the acid through before the actual saponification The addition of water is reduced. 5. Amines of the general formula in which n is an integer from 0 to 4, preferably 0, and R is a bifunctional or polyfunctional, preferably bifunctional, aliphatic hydrocarbon radical having 1 to 20, preferably 1 to 8, in particular 3 to 6, carbon atoms, or mono- or binuclear aromatic or heterocyclic hydrocarbon radical with 6 to 20 carbon atoms, or for n = 0 also mean a simple chemical bond. 6. Compounds according to claim 5, wherein in the general formula n is equal to 2 and R is an aliphatic, perfluorinated hydrocarbon radical Means 3 to 8 carbon atoms.