DD286355A5 - PROCESS FOR PREPARING SUBSTITUTED 2-AMINO-THIAZOLIN-4-ONE - Google Patents

Abstract

The invention relates to a process for the preparation of substituted 2-amino-thiazolin-4-ones of the formula III in which R 1 is hydrogen, an alkyl or aryl radical and R 3 and R 4 are identical, different or linked together alkyl radicals. Compounds of this type have remarkable pharmacological properties and can also be used as intermediates, e.g. For the preparation of dyes or photographic sensitizers. The title compounds are prepared according to the invention by reacting α-thiocyanato-carboxylic acid derivatives of the formula I (R1H, alkyl or aryl; R2Alkoxy or NH2) with amine salts of the formula II in which R3 and R4 have the abovementioned meaning and HX represents a weak acid, either in solvents such as lower alkanols, haloalkanes or dipolar aprotic solvents at temperatures up to the boiling point of the reaction mixture or without solvents at temperatures in the range between 80 and 120 C. {substituted 2-amino-thiazolin-4-ones; Intermediates; dyes; photographic sensitizers; a-thiocyanato-carboxylic acid derivatives; Amine salts}

Description

The amine salts III can be used both in substance as well as directly in the reaction mixture by combining equimolar amounts of the underlying dialkylamine and the corresponding acid erzgeugt. As the acid component are weak acids, eg. As carboxylic acids such as acetic acid, propionic acid or benzoic acid, while strong acids, eg. As perchloric acid, or the sole use of dialkylamines either lead to the complete absence of Thiazolinonbildung or reduced yields of thiazolinone.

The resulting in the reaction substituted 2-amino-thiazolin-4-one III differ in the case of high-melting compounds when working with alcohols or acetonitrile as a solvent in cooling the reaction mixture optionally after addition of portions of water - in crystalline form, so that their isolation without difficulty is possible (variant A, see Example 1). When using halogenated hydrocarbons as the reaction medium, the resulting reaction mixture is mixed with water and the thiazolinone III is recovered by concentration of the organic phase (variant B, Example 2). The synthesis of thiazolinone III can also be carried out without the use of a solvent. For this purpose, it is heated z. B. the a-thiocyanato-carboxylic acid derivatives I with the dialkylamine Il at 9O ⁰ C (water bath) in substance and purifies the resulting Piodukte in aqueous solution on their hydrochlorides by extraction with chloroform (variant C, Aueführungsbeispiel 3). Furthermore, it is possible to isolate the Aminothiazolinone III in the form of the corresponding salts by the alcoholic reaction solution is veretzetzt with excess acid and the salts are brought by addition of ether for deposition (variant D, Embodiment 4).

Compared to the literature methods for the preparation of 2-dialkylamino-thiazolin-4-ones, the inventive method characterized by the fact that it is technically available (dialkylamines, carboxylic acids) or simply and in good yields synthesizable (a-thiocyanato-carboxylic acid derivatives ) Starting materials and the target product can be obtained in easily realizable catfish

 The invention is explained below with reference to four exemplary embodiments in the form of general working instructions.

Autführungsbeltpiele example 1 Substituted 2-amino-thiazolin-4-ones III by reaction of a-thiocyanato-carboxylic acid derivatives I with dialkylamine salts II

in lower aliphatic alcohols or dipolar aprotic solvents (general procedure, variant A;

Table 1)

The mixture is heated with 10 mmol of thlocyanato-carboxylic acid derivative with 10 mmol of dialkylamine II (or with the equimolar amount of amine

and acid, which underlie the salt II) in 10 ml of the respective solvent 2h. under reflux. The (possibly after addition of portions of water) from the reaction mixture crystalline thiazolinone III are filtered off with suction and from

Recrystallized ethanol / acetone or n-hexane / ethanol. Example 2

Substituted 2-amino-thiazolin-4-ones III by reaction of α-thiocyanato-carboxylic acid esters (I, R ² = OAlkyl) with dialkylamine salts II in halogenated hydrocarbons (general procedure, variant B, see Table 1) 10 mmol a-thiocyanato carboxylic acid ester I (R '= OAlkyl) and 10 mmol of dialkylamine salt II are refluxed in 10 ml of halogenated hydrocarbon for 2 hours. After cooling, the reaction mixture is treated with water, the organic phase separated and the aqueous phase extracted twice with the halogenated hydrocarbon used for the reaction. After washing the organic solutions twice with water, it is dried over sodium sulfate, the solvent i. Vak. and brings the remaining residue by treatment with ethanol for crystallization. The cleaning is carried out analogously to Example 1.

Example 3

Substituted 2-amino-thiazolin-4-ones III Reaction of α-thiocyanato-carboxylic acid esters (I, R ² = OAlkyl) with dialkylamine salts II without solvent (general procedure, variant C, Table 1) 20 mmol of α-thiocyanato-carboxylic acid ester are heated KR ¹ = OAlkyl) with 20 mol of dialkylamine salt II (unless otherwise stated, see Table 1) 2 hrs. at 90 ⁰ C on the water bath. After cooling to room temperature, the Renktionsgemisch is mixed with 50ml dil. Hydrochloric acid, extracted three times with 30 ml of chloroform and discarded the chloroform extracts. After the aqueous phase was made alkaline with dilute ammonia solution (control with pH paper), extracted four times with 30 ml of chloroform, the combined organic phases are dried over sodium sulfate and concentrated i. Vak. on. Crude products, which are obtained in crystalline form, are recrystallized as indicated in Example 1.

Example 4 Substituted 2-amino-thiazolin-4-one hydrochlorides III HCl by reaction of a-thiocyanato-carboxylic acid esters

(I, R ¹ = OAlkyl) with dialkylamine salts II in lower aliphatic alcohols with addition of hydrochloric acid after completion of the reaction (general procedure, variant D, see Table 1)

10 mmol of α-thiocyanato-carboxylic acid ester I (R ¹ = O-alkyl) and 10 mmol of dialkylamine salt II are dissolved in 10 ml of ethanol for 2 h.

refluxed. To the reaction solution is added 2 ml conc. Hydrochloric acid and added in portions after cooling

Diethyl ether. The thiazoline hydrochlorides III HCl precipitated in this way are filtered off with suction, washed with ether

and recrystallized from ethanol.

Table 1 Yields and melting points of the 2-aminothiazolin-4-ones I prepared according to the embodiments

Verb. • Vari Acid derivative I R ² Amine salt Il R ¹ NR ³ R ⁴ solution Y. Mp. • thiazoline-4-one ante R ¹ OEt HNR ³ R ⁴ · HX medium (%) " ( ⁰ o 2-morpholino A H morpholine H morpholino ethanol 48 201-202 (INa) acetate A n-propanol 40 A acetonitrile 40 B tetrachloride 59 carbon B chloroform 27 C without 54 A morpholine · ethanol 46 acetate ²¹ A morpholine ethanol 51 propionate ²¹ A morpholine · ethanol 51 2-morpholino OMe benzoate ²¹ (IIIa) A H morpholine · methanol 22 2-dimethylamino- acetate (IIIb) A ethanol 46 A On-Pr n-propanol 54 2-diethylamino A H NH, n-propanol 51 (HIC) A H morpholine · H morpholino ethanol 22 201-202 2-diisobutylamino OEt acetate CIfId) C H dimethylamine H dimethyl without 55 68-70 2-pyrrolidino acetate amines " (IIIe) O OEt 39 180-182 " 2-piperidino C H diethylamine H diethyl without 55 oil (HIF) OEt acetate cmino 2-dimethylamino-5- C H diisobutyl H diisobutyl · without 23 oil methyl- (IIIg) OEt amine acetate amino 2-Oimethylamino-5- C H pyrrolidine H pyrrolidino without 67 99-101 phenyl (MIh) OEt acetate C H Piperld'n- H piperidino without 60 90-91 OEt acetate C ⁴ ' me dimethylamine me dimethyl without 50 65-66 OEt acetate amino C ⁴¹ Ph dimethylamine Ph dimethyl without 38 130-131 acetate amines)

1 Yields are due to the crude products.

2 By combining fulmolar amounts AmIn and Slure directly produced in reaction.

3 Hydrochloric !.

4 ReaktloniteltBStd.

formula page

-ί-

2a us s

t SCN ^R

HNR ³ R * -HX

-HX -HR ²

NR ³ R *

Claims (3)

1. A process for the preparation of substituted 2-amino-thiazolin-4-ones of the formula III in which R ^{1 is} hydrogen, an alkyl or aryl radical and R ³ and R ^{4 are the} same, different or mutually linked alkyl radicals, characterized in that α-Thiocyanatocarbonsäurederivate of the formula I in which R ^{1 is} hydrogen, an alkyl or aryl radical and R ^{2 is} an alkoxy radical or an amino group, with dialkylamine salts of the formula II in which R ³ and R ^{4 have} the abovementioned meaning and HX is a weak Acid, e.g. As acetic acid, propionic acid or benzoic acid, either in solvents such as lower aliphatic alcohols, for. Methanol, ethanol or n-propanol, haloalkanes, ... Chloroform or carbon tetrachloride, or dipolar aprotic solvents, e.g. As acetonitrile, at temperatures up to the boiling point of the reaction mixture or without solvents at temperatures in the range between 80 and 12O ⁰ C reacted. 2. A process according to item i, characterized in that the dialkylamine salts II are either used in bulk or are produced directly in the reaction mixture by combining equimolar amounts of amine and acid. 3. Method according to item 1, gel is characterized in that the 2-amino-thiazolin-4-ones III are isolated as such or as salts by acid addition to the reaction mixture obtained after completion of the reaction. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of substituted 2-amino-thiazolin-4-ones of the general formula III in which R 'is hydrogen, an alkyl or aryl radical and R ¹ and R ^{4 are the} same, ι, different or linked together alkyl radicals. Compounds of this type possess notable pharmacological properties and may also be useful as intermediates, e.g. For the preparation of dyes or photographic sensitizers. Characteristic of the known technical solutions Substituted 2-amino-thiazolin-4-ones of the general formula III, in which R ¹ , R ³ and R ^{4 have} the abovementioned meaning, have hitherto been (cf.: GC BARRETT, Tetrahedron 36 [1980] 2033, GR NEWKOME and A. NAYAK, Adv. Heterocycl Chem 25 (1979183; SP SING, SS PARMAR, K. RAMAN and VI STENBERG, Chem. Rev. 812 (1981) 175) from suitable acyclic compounds (a-halo-carboxylic acid (derivatives)). and Ν, Ν-dialkylthioureas [HANTZSCH synthesis], see BAM COMRIE, J. Chem. Soc., 1964, 3478; a-mercapto-carboxylic acid derivatives) and Ν, Ν-dialkyl-cyanamide, see, for example, DE 930563, Chem , 52, 1958, 20199) and by substitution reactions on partially saturated thiazoles (reaction of rhodanine with dialkylamines, see, for example, S.SCHEITHAUER and H. HARTMANN, DD WP 633374, Chem. Abstr. 70 (1969) 77979, Z. Chem. 181. Alkylation of 2-amino-thiazolin-4-one, see Yu. G. BASOVA, SM RAMSH and A. IGINAK, Khim., Geterotsikl., Soedin 1981, 1046; Aminolysis of 2-amino-thiazolin-4-one , FR 11.6278, Chem. Abstr. 74 (1971) 100022). These production methods are based on starting materials whose presentation is associated with the processing of highly toxic or easily flammable substances, or lead to product mixtures that can only be separated consuming. Object of the invention The aim of the invention is to produce from industrially available or readily available starting materials in a technically straightforward manner to be implemented 2-amino-thiazolin-4-one, which carry in the 5-position hydrogen, an alkyl or aryl radical and the amine nitrogen two alkyl radicals. Explanation of the essence of the invention The invention has for its object to produce 2-amino-thiazolin-4-ones of the general formula HI with R '= H, alkyl, aryl and R ¹ , R ⁴ = Alkyl «us a-thiocyanato-carboxylic acid derivatives. The object is achieved in that a-thiocytinato-carboxylic acid derivatives of the formula I in which R ^{1 is} hydrogen, an alkyl or aryl radical and R ^{2 is} an alkoxy radical or an amino group, with amine salts of the formula II in which R ³ and R ^{4 represent} identical, different or linked together alkyl radicals and HX a weak acid, either in solvents W <e lower aliphatic alcohols, eg. I). Methanol, ethanol or n-propanol, haloalkanes, ι. As chloroforn or carbon tetrachloride, or dipolaraprotic Solventien, z. As acetonitrile, at temperatures up to the boiling point of the reaction mixture or without solvents at temperatures ranging between 80 and 120 ° C.