DD208355A1 - PROCESS FOR THE PREPARATION OF THIAZOLO (4,5-D) PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of substituted thiazolo (4,5-d) pyrimidines. Such compounds can gain importance for the production of pharmaceuticals, pesticides and dyes. With the invention is to be achieved to produce the hitherto unknown thiazolo (4,5-d) pyrimidines of the specified substituent pattern easily and from readily accessible starting materials. This is effected according to the invention by reacting cyanimidocarbonic acid ester salts with chloroacetylurethane to give thiazoles which are cyclized to give thiazolo (4,5-d) pyrimidine-5,7-diones and subsequently to the 5,7-dichlorothiazolo (4,5-d) d) pyrimidines are chlorinated. The invention is applicable in the chemical and pharmaceutical industry.

Description

242301 5

VEB CHEMICAL COMPANY BITTERFELD Bitterfeld, 25.7.1982

; , 2270

Process for the preparation of thiazo-lo / 4,5-di-7- pyrimidine. Field of application of the invention

Substituted thiazole Oj / ^ VS-d ^ pyrimidines may be important as intermediates for the preparation of Pharraazeutike ', dyes and pesticides, or even potential bio-, z.'B, fungicides or Bakterizide.sein.

Characteristic of the known technical solutions

The syntheses for thiazolo- _J / 4,5-dy'pyriraidine described in the literature are based on a heterocyclic compound which is either a thiazole or a pyriraidin derivative, and is converted to the condensed heterocycle V by a subsequent reaction

For these syntheses relatively complicated and technically difficult to access heterocyclic starting compounds or intermediates are necessary.

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Related substances, which differ from the compounds erfindungsgeraäßen by the type and position of substituents aer, but based on your gleichaiheterocyclischen body; are essentially produced by two processes:

a) Brorabarbituric acid or derivatives thereof are converted by thioaraidene to thiazolo ^ s-dTpyrimidin-S ^ -diones

(eg, He., Ch., in. Act a 1943, 26 ~ 366-3) ", 4,6-dialkyl-substituted thiazolo / 4 ₄ 5-d7-pyridine 3-diazine-5-dione are also available from aminouracil derivatives and mustard oils or chlorocarbonyl sulfenyl chloride. eg OE-OS 2 038 9221 DS-OS 2 223 42I) V

b) Aminothiazolecarboxylic esters or amides react with isocyanates to give substituted thiazolo ^ jS-d / 'pyrimidine-SjT (z; B ^r , - Tetrahedron Letters 1968, 1385-9).

All these methods do not use technically readily; available starting or intermediate products,

Aim of the invention

The aim of the invention is to develop a process which in a simple manner the preparation of thiazoles ^ ', S-d /' pyriaidin. enables derivatives of readily available starting materials,

Darlegun g of the "essence _m s of the invention.

This object is achieved in accordance with the invention by "alkylating alkali metal salts of cyanimidocarbonic acid derivatives of the general formula I in a polar solvent, if appropriate in the presence with triethylamine, to the substituted triazoles of the general formula II and then adding these after prior isolation or but without

242301 5

Isolation can be cyclized in one pot to the thiazolo / 4 ", 5-Oy ⁷ pyriraidine-5,7-diones of general formula III This cyclization can be carried out either in a solvent by basjs: he catalysts, for example triethylamine in alcohol, sodium alcoholate in Alcohol or aqueous alkali or by dry heating of the thiazoles II to .150-200 ⁰ C for 0.5 to 2 hours.

The compounds of general formula III can be converted by literature methods by means of phosphorus oxychloride / oimethyl aniline in the new S ^ -Dichlorthiazolo ^ jS-d / ^ pyrimidines of general formula IV.

Implementation Examples Example 1

4-Affinol-2-ethylthio-5-N-bis (ethoxycarbonyl) carbamoyl-7-tiazole A solution of 17 g (0.1 mmol) of potassium methyl cyanimidoditanate carbonate in 150 ml of ethanol is added with 16.6 g (0.1 mol ) Chloroacetylurethane. It is stirred for 30 min under reflux, filtered from the precipitated halide, treated with 2 ml of triethylamine and again heated under reflux for 2-5 min. The precipitate which precipitates on cooling is filtered off with suction and recrystallised from ethanol.

Yield: 16 g (51.5 % of theory )

Analogously, for example, it is possible to obtain:

4-AiHino-2-n-propylthio-5- ^ N- (ethoxycarbonyl) carbamoyl-7thiazo] (From Kaliura n-propyl cyanisnidodi-thiocarbonate) Yield: 11, S g (40 % of theory ); F 132 to 137 ⁰ C (ethanol /

Water)

"4-Araino-2-isopropylthio-5-" N- (ethoxycarbonyl-carbamoyl) -thiazc (from potassium isopropyl-cyanimidodithiocarbonate) Yield: 15.7 g (55 % of th.); F "114" to 118 "^0" C (benzene /

Cyclohexar

* -. 242301

-2-allylthio-5- ^ N- (ethoxycarbonyl) thiazole (from potassium allyl cyaniraidodithiocarbonate)

Yield: 12 g (42 % d, Th); F 115-119 ⁰ C (carbon tetrachloride)

4 ~ Araino-2-benzylthio-5- ^ W- (ethoxycarbonyl) carbamoyl-7-thiazole (from potassium benzyl cyanimidodithiocarbonate) Yield: 14.3 g (42.5 % of theory ) (ethanol)

4-Amino-2-ethoxy-5- / ^< N- (ethoxycarbonyl) carbaraoylthiazole (from S-Sodium O-ethyl cyanimidoditic carbonate) Yield: 10.1 g (39 % of theory ); F 130 to 131 ⁰ G (water)

Example 2

2-methylthio-thiazolo ^ 4 ^! , 5-dJ7pyrii3idin-5v7-dione 26.1 g (0.1 mol) of 4 ~ amino-2-methylthio-5- £ N- (ethoxycarbonyl) carbamoyl / 'thiazole are heated two hours at 180 ⁰ C dry.

The residue remaining is the cyclized crude product.

Exploits 21.5 g (quantitative); F from 310 ⁰ C Zers.

Analogously, for example, can be obtained:

- 2-n ~ P'ropylthlo- thiazolo ^ 4 _"# 5-dJ7pyriffiidin - 5,7-dione Yield: 24.3 g (quantitative); F 22S to 233 ⁰ C.

2-isopropylthio-thiazolo ^ 4,5-d / pyriflidin-5,7-dione. Yield: 20.2 g (83 % d, Th.); F 247 to 248 ⁰ C

2-allylthio-thiazolo _2/4 , Sd / 'pyriaidin-S ^ - exploiter 21.5 g (89 % of theory ); F 220 to 225 ⁰ C

2-Benzylthio-thiazolo _J / 2r, 5-d7p-pyrimidine-5, 7-dione Yield: 29.1 g (quantitative); F 275 to 280 ⁰ C

2-ethoxythi

Yield? 21.3 g (quantitative); F from 235 ⁰ C Zers.

242

Example 3

2-Benzylthio-tbiazolo / 4 → 5-dicyclo-imidino-5,7-dione 33.7 g (0.1 mol) of amino-Z-benzylthio-O-N- (etboxycarbonyl) -carbaraoyl / thiazole are used in 400 ml of ethanol and, after addition of 10 ml of triethylarain, refluxed for 15 hours; the precipitate which separates out is filtered off with suction while hot, washed several times with hot ethanol and dried.

Yield: "22.1 g (76 % of theory )

Example 4> y 2-Methylthio-thiazolo / 4,5-d / pyris-idine-5,7-dione 34 g (0.2 mol) of potassium methyl-cyanimidodithiocarbonate are dissolved in 300 ml of ethanol. Are added 33.2 g (0 ^ 2 mol) of chloroacetylurethane, stirred for 30 min under reflux, added rait 20 ml of triethylamine and stirred again for 15 hours under reflux. It is filtered off with suction while hot, washed with hot ethanol and with water and dried. Yield: 18 g (42 % of theory )

Example 5

2-Methylthio-thiazolo ^ 4,5-d] 7-pyridium-5,7-dione 25.1 g (0.1 mol) 4-Ag) ino-2-methylthio-5- _J / N- (ethoxycarbonyl) - / After cooling, the mixture is acidified with acetic acid, filtered off with suction, washed with ethanol and dried in a solution of 4.5 C_, y (0.2 gram atoms) of sodium in a solution of sodium bicarbonate : 18.5 g (86 % d, Th.)

Example 6

5,7-dichloro-2-raethylthio thiazol0j / 4.5-dy ^r pyriraidin To 21.5 g (0.1 mol) of 2-methylthio-thiazolo _J /4,5-d_7pyrimidi.n-5,7-dion in 150 ml of phosphorus oxychloride are added 24.2 g (0.2 mol) of dimethylaniline. The mixture is refluxed for three hours, excess phosphoric acid chloride is distilled off, the residue is brought to ice, the resulting crude product is filtered off with suction, washed with water and crystallized from ethanol / benzene, etc.

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Yield: 19.5 g (75 % of theory ):

Analogously, for example, it is possible to obtain:

5,7-dichloro-2-n-propylthio-thiazolo / 4,5-d / pyrimidine Yield: 25.2 g (90 % of Th,); F 61 to 62 ⁰ C (methanol / water)

% _'S 5-c [7PY risiidin · yield: 25.5 g (91% of theory ά..); F68 to 69 ⁰ C (methanol / water)

5,7-Di-chloro-Z-allylthio-t hi azolo / 4,5-d7pyrimidine din Yield: 18.1 g (S5 % d, Th.) ^! : F 6.1.5 ⁰ C (ethanol / water)

, Ö-d / 'pyrimidine

( Water)

Yield: 18.7 g (57 % of theory) :: F 133 to 135 ⁰ G (ethanol /

5 'Yerfahren according to item 1, characterized in that the thermal cyclization of the (thiazoles of general formula II to the' Ihiazolo / i-jS-d / pyrimidine-S ^ -diones of the general formula III in the temperature range of 120-200 " C, preferably at 160-190 ° C, is carried out within 0.5 to 2 hours.

For this 1 page formulas

Po mer! "Sheet

c = sr - c s sr

H ₁ -C ₀ QCOHECO 5 2

- Ή

II

III

Cl.

IV

S - alkyl, - alkeayl, benzyl X = S, O Me = alkali metal

Claims (2)

1. Yerfahren for the preparation of 5,7-dichloro-Shiazolo- / 4,5-d / -pjriinidinen the general Porsiel IY, in which X is sulfur or oxygen and H. alkyl, alkenyl or benzyl, characterized in that alkali metal salts of cyanide derivatives of cocarbonic acid of general formula I in which E and X are as defined above and Me is an alkali metal, with chloroacetylurethane in polar solvents, optionally in the presence of triethylamine, to the substituted (") thiazoles of the general formula II be alkylated, which can be either after previous isolation by ^: thermal treatment or by basic catalysts in a polar solvent or without isolation in the. Solution by basic catalysts to the Ihiazolo / 4,5-d / pyrimidine-5,7-dienes, which cyclizes all-. Pormel III common with phosphorus oxychloride / dimethylaniline in the 5 ₃ 7- Diohlor-thiäzolo / 4,5-4 / pyrimidines are converted · 2. Have you seen point 1, characterized by being one? Catalysts for the cyclization of the thiazoles of ( f) general formula (I). the 2ma2olo / 4,5-4 / pyri: midi- ¹ ^ 5, -7-di.enen the general! Formula. Ill basic condensing agents such as .Sriethylamine in alcoholic solution ,. Alcoholic alcoholic solution or aqueous alkali solution used.