DD299060A5 - PROCESS FOR THE PREPARATION OF 3- (MERCAPTOALKYL) -CHINAZOLIN-2,4 (1H, 3H) -dione - Google Patents

Abstract

The invention relates to a simple process for the preparation of * the general formula I, wherein R1 is H, F, Cl, Br, I, or CH3 in the 6- or 8-position or * {* * 2-Aminobenzoesaeurehydroxyalkylamide; biologically active compounds; immunostimulatory / immuno-restorative substances; Starting substances for potential active substances}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 3- (mercaptoalkyl) quinazoline-2,4 (1 H, 3H) -diones of the general formula I. Such substances can gain importance as biologically active compounds as pharmaceuticals or find use for their preparation. The invention is also of interest to the chemical industry.

Characteristic of the known technical solutions

3- (Mercaptoalkyl) quinazoline-2,4 (1H, 3H) -diones have not yet been described in the patent or chemical literature.

Object of the invention

The object of the invention is the preparation of such compounds from readily available reactants in a simple manner with high yields.

Explanation of the essence of the invention

The object of the invention is to find a technically feasible synthesis route for the preparation of 3- (mercaptoalkyl) quinazoline-2,4 (1H, 3H) -diones of the general formula I or their tautomotors, where R 'is hydrogen or F, Cl, I, Br, CH3 in the 6- or 8-position or 6,7- (OCHa ^ and R ^{2 is} hydrogen or CH3 and η is 1 or 2.

The object is achieved in accordance with the invention by 2H-3,1-benzoxazine-2,4 (1H) -diones of the formula II in which R ^{1 has} the abovementioned meaning, with an aminoalkanol of the general formula III in which R ² and η the above

Have meanings, preferably in an aqueous reaction medium to a compound of general formula IV, wherein R ¹ , R ² and η have the meanings given above, are reacted, then a reaction solution of a C ₁ -C ₃ alkanol, carbon disulfide and potassium or Sodium hydroxide, or sodium or potassium ethylxanthogenate, the reaction mixture is heated, preferably to reflux, then cooled, acidified, the resulting compounds of general formula V, wherein R ', R ² and η have the abovementioned meanings, first with concentrated Mineral acids such as hydrochloric acid or sulfuric acid or mixtures of these mineral acids with glacial acetic acid and / or formic acid and heated by subsequent addition of water to the reaction mixture and reheating under reflux to the; Compounds of general formula I, or their tautomers. wherein R ¹ , R 'and η have the abovementioned meanings, are reacted.

embodiments

The invention will be explained in more detail below with reference to exemplary embodiments.

example 1

a-OMercaptopropy-D-chlorinazoline-1-fluoro-dione (I; R '= R ² = H, η = 2)

24.5 g of 2H-3,1-benzoxazine-2,4 (1H) -dione (II; R ¹ = H) are dissolved in a solution of 12.3 g of 3-aminopropan-1-ol (III; R ² = H, η = 2) and added 45 ml of water with stirring and then heated for 10 min on the boiling water bath (= solution 1).

17.0 g of potassium hydroxide are dissolved in 225 ml of ethanol with heating. To the cooled solution 36ml carbon disulfide are added. Thereafter, the batch is allowed to stand for 15 min in a sealed vessel, combined with the solution 1 and then refluxed under a hood for 3.5 h. Thereafter, about 70-80 mM of the solvent mixture was distilled off, the reaction mixture was acidified after cooling with glacial acetic acid and allowed to crystallize for at least 3 hours. There are 24.3 g of pure crude product V (R = R ² - II, η = 2) from the mp. 174-176 ° C received.

After addition of about 20 ⁿ ml of water to the mother liquor further 4.0 g de almost pure crude can be obtained. Recrystallization is possible from ethanol. 30.0 g of the dry crude product obtained above are under a hood together with 300 ml of conc. Hydrochloric acid refluxed for 2.5 h. In this case, care must be taken to dispose of the escaping HCI vapors. Then, 2.71 ml of water are added to the reaction mixture and the mixture is refluxed for a further 20 h. After cooling, the precipitate is filtered off, dried in air or at about 30-40 ⁰ C in a drying oven.

The recrystallization takes place from propan-1-ol. A "prey pure product: 83% m.p .: 165 -167 ⁰ C..

In a second process variant, 30.0 g of V (R ¹ = R ² = H, η = 2) with the mixture of 30 ml of glacial acetic acid and 12 ml of conc.

Sulfuric acid are heated. After addition of about 330 ml of water, the heating is continued under reflux for 15 h. The work-up and the cleaning takes place as with obipur variant. The yield of almost de pure crude product is 85%.

Pure product: 165-167 ° C (propan-1-ol).

Analogous to this second ancestor variant were u. a. also shown:

e-bromo-SO-mercaptopropyll-quinazolin ^ dH.SHl-dione (I; R ¹ = R ² = H, η = 2), m.p .: 220-221 ⁰ C (glacial acetic acid).

Yield: 84%.

Example 2

3- (2-mercaptopropyl) -chlorazoline-2,4 (1H, 3H) -dione (I; R '= H, R ² = CH ₃ , η = 1)

24.5 g 2 H-3,1-benzoxazine-2,4 (1H) -dione (II; R ¹ = H) are analogously to Example 1 with 12.3 g of 2-amino-propan-1-ol (III; R ² = CH ₃ , η = 1) to solution 2.

Using 17.0 g of potassium hydroxide, 225 ml of ethanol and 36 ml of carbon disulfide (it can also get the appropriate amount of lime methyl to the sowing area) is carried out according to Example 1; combined with the solution 2 and reacted again analogously to Example 1 to de almost pure product V (R ¹ = H, R ² = CH ₃ , η = 1). Recrystallization is possible from methanol.

30.0 g of dry crude product obtained above are described in a completely analogous manner as described in Example 1, to the mercaptopropylquinazoline I (R ¹ = H, R ² = CH ₃ , η - Dumgosetzt heating time with concentrated hydrochloric acid 2h, after addition of water for another 15h. After recrystallization of the dry crude product from toluene, 22.4 g of pure product (yield: 69%) of mp 206-208 ⁰ C are obtained.

Example 3

e-Chloro-3- (3-mercaptopronyl) -clilnazoline-2,4 (1H, 3H) -dione (| - ^ = 6-Cl, R ² = H, π = 2) The preparation is carried out analogously to Example 1 of FIG. 12 5 g of 6-chloro-2H-3.1-benzoxazine-2,4 (1H) -dione, 5.8 g of 3-amino-propan-1-ol, 40 ml of water and 7.0 g of potassium hydroxide, 100 ml of ethanol and 7.5 g of carbon disulfide. Reaction time: 4-4.5h. There are distilled off 35-4OmI of the solvent mixture and filtered the reaction solution. The filtrate is acidified with acetic acid. 9.6 g of crude product V (R '= 6-CI, R ² = H, η = 2) are obtained. After addition of about 150 g of ice to the filtrate woitere be recovered 1.1 g of crude product. Recrystallization of the crude product can be carried out from propan-1-ol. M.p. (pure product): 255-257 ° C.

3.0 g prepared above pure product are reacted analogously to Example 1 or 2 to the crude product I (R ¹ = 6-CI, R ² = H, η = 2).

After recrystallization from propan-1-ol, 1.96 g of pure product are obtained in a yield of 66%.

2 9 9 O <5

_TR 2

N (CH ₂ J _n CHSH

R ^!

H ₂ N (CH ₂ I _n CH (R ² IOH

NH _{2 R} 2

CONH (CH ₂ J _n CHOH

MCH ₂ V ₁ CHOH

Claims (3)

1. A process for the preparation of 3- (merc ^> aptoalkyl) quinazoline-2 _/ 4 (1H, 3H) -diones of general formula I or their tautomers, wherein R ^{1 is} hydrogen or F ₁ Cl, Br, I, CH ₃ in 6- or 8-position or 6,7- (OCH ₃ ) ₂ and R ^{2 is} hydrogen or CH ₃ and η is 1 or 2, characterized in that 2H-3,1-benzoxazine-2,4 (1H) -diones of the general formula II in which R ^{1 has} the abovementioned meaning, with an aminoalkanol of the general formula III in which R ² and η have the abovementioned meanings, preferably in an aqueous reaction medium to give a compound of the general formula IV in which R ¹ , R ² and η have the abovementioned meanings, then reacting a reaction solution of a C, -C ₃ -alkanol, carbon disulfide and potassium or sodium hydroxide, or sodium or potassium ethylxanthogenate zuyibt, the reaction mixture heated, preferably to reflux, then cooled, acidified with customary mineral acids or acetic acid, di e obtained compounds of al! mean formula V, wherein R ¹ , R ² and η have the abovementioned meanings, first heated with concentrated mineral acids such as hydrochloric acid or sulfuric acid or mixtures of these mineral acids with glacial acetic acid and / or formic acid and usually by subsequent addition of water to the reaction mixture and reheating under reflux to the compounds of the general formula I, or their tautomers in which R ¹ , R ² and η have the abovementioned meanings, are reacted. 2. The method according to claim 1, characterized in that from the reactions of the compounds of general formula V with concentrated mineral acids such as hydrochloric acid or sulfuric acid or mixtures of these mineral acids with glacial acetic acid and / or formic acid resulting solid mixtures separated and subsequently by heating in dilute mineral acids in the Compounds of general formula I or their tautomers are converted. 3. The method according to claim 1 and 2, characterized in that the resulting from the reactions of the compounds of the general formula II with those of the general formula III compounds of the general η formula IV without separation m of the reaction solution with the from a C ^ Qj-alkanol , Carbon disulfide and potassium or sodium hydroxide, or sodium or potassium ethylxanthogenate, prepared solution and reacted by refluxing heating to the compounds of general formula V.