DE2004713A1 - Nitrofuryl triazolo pyrimidine and process for their preparation - Google Patents

Description

BOEHRINGER MANNHEIM GMBH 'I67O

Nitrofuryl-triazolo-pyritiiiiditte 'and process for their preparation

The invention relates to nitrofuryl-triazolo-pyrimidines of the general formula I

(D

, in which TP represents a triazolopyrimidine ring system and 'R :, R ₀ and R, can be identical or different and are hydrogen, alkyl, halogen, a hydroxyl, alkoxy, acyloxy, amino, alkylamino or acylamino group mean,

and methods of making them.

The new compounds exhibit a surprisingly good antimicrobial Effect both in vitro and in vivo. Since they are also highly effective against Escheriehia coli, they are special suitable for the treatment of urinary tract infections. Their use for the manufacture of drugs with an antimicrobial effect is therefore also the subject of the invention.

The compounds can be prepared in a known manner in which either

a) Furyl * ^ riazolo-pyrimidine 'of the formula II

(ID

in dor TP, .It ₁ , H ,, and R., the abovementioned structure hubon,

101) 8.33 / 1893

nitrided or

b) hydrazones of the formula III or Hl '

(III)

(III)

in which R ^, R ₂ , and R, have the meaning given above and Py together with the group -N = C (forms a pyrimidine ring,

oxidizing cyclized or

c) hydrazides of the formula IV or IV

109833 /

NH-ν:

(IV)

in which R *, R ₂ , R «* and Py have the meaning given above, ·.

cyclized with elimination of water or

d) aminotriazoles of the general formula V

(V)

in which R ^ J has the meaning of R ^ or a Represents 5-nitrofuryl-2 group,

with 1,3-dicarbonyl compounds of the general formula VI

Rj ₁ - CO - CHR ₁₁ - CO - R ₁

(VI)

in which R ^ has the meaning given above, but

only one of the radicals R ₁ J is a nitrofuryl group,

or their reactive derivatives condensed or

e) in diaminopyrimidines of the formula VII

H,

(VII)

in which R> has the above-mentioned meaning,

./■■· BAOOFIIGINÄI.

1098 33/109

-limit closes the triazole ring with nitrous acid and optionally then converts the substituents R ^, R ₂ or Rj into one another in a manner known per se.

The nitration of the furyl-triazolopyrimidines can, for. B. with Nitric acid in sulfuric acid or acetic anhydride can be done at low temperatures. Working in acetic anhydride is special recommended if this causes sensitive substituents, e.g. B. amino groups, are protected at the same time by acetylation. If desired, the acetyl group can subsequently be saponified be split off again.

The ring closure by dehydrating the compounds III or III ¹ is preferably carried out with oxidizing agents such as lead tetraacetate or red lead in glacial acetic acid or benzene. However, other oxidizing agents and solvents can also be used.

The elimination of water from compounds of the formula IV or IV is preferably carried out by heating with water-binding agents such as acetic anhydride, or polyphosphoric acid. In many cases, however, it can already be boiled in higher-boiling, inert ones Solvents such as toluene or xylene take place.

In the implementation of the hydrazino compounds on which structure IV is based with orthoesters the cyclization to the compounds I.

The condensation of the aminotriazoles V with the 1,3 dicarbonyl compounds VI is preferably carried out by boiling in polar solvents after adding some acid. As reactive derivatives of the compounds VI, the nitriles are particularly suitable. A variant of this reaction is also the rearrangement of s-Triazolo [i |, 3-a] -pyrimidines in s-Triazolo- [2,3-a] -pyrimidines, which is also done by cooking in polar solvents with the addition of mineral acids.

109833/1996

The cyclization of the diaminopyrimidines VII is carried out using conventional methods Diazotization conditions, e.g. BV in aqueous solution or suspension with sodium nitrite / hydrochloric acid.

In many cases it is advantageous to have the desired substituents only after the production of the nitrofuryl-triazolo-pyrimidine system made from less sensitive substituents. So · can a hydroxyl group e.g. B. by hydrolysis of an acyloxy group or of a halogen atom or by diazotizing and boiling off an amino group. An amino group becomes preferable during the reaction protected by acetylation or subsequently introduced by aminolysis of a halogen substituent. Conversely, acylamino or acyloxy groups in the usual way by subsequent acylation are produced by amino or hydroxyl groups. The alkoxy radical The easiest way to do this is by alcoholysis of a halogen substituent ™ introduce.

The substances I can be oral and in liquid or solid form - be applied parenterally. The preferred injection medium is Water for use, soft the usual for injection solutions Additives such as stabilizers, solubilizers and / or buffers, contains. Such additives are z. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are z. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), Gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners. For external use, the inventive Substances I can also be used in the form of powders and ointments; they are z. B. with powdered physiologically acceptable Diluents or »usual ointment bases. mixed. ·

The invention is explained in more detail in the following examples.

'./.■'. 109833/1998

2Ü04713

Example 1 3-C5 "nitro-2-furyl) -5 _i 7-dimethyl-3-tria2oloC4 _t 3-a3pyriinidine

3g of 2-hydrazino-4,6-dimethylpyrimidine, mp 164 ° C., are dissolved in 60 ml of a mixture of 80Jfigem, aq. Ethanol and a little glacial acetic acid in the heat, then gives 4.5 g of crude 5-nitro-furan-2-aldehyde to, boils under reflux for 10 minutes, sucks off the orange hydrazone formed and washed it with ethanol-water 1: 1 and dry it. The yield is 5 »2 g.

4.6 g of it with stirring to an at 4O ⁰ C to a suspension of 12 g of lead tetraacetate in 180 ml glacial acetic acid, after about 5 minutes, the solution is decolorized. The solution is then evaporated in a vacuum, the residue is rubbed with water, the undissolved material is filtered off with suction (4.9 g) and this is boiled with dioxane; the clear dioxane extract is evaporated in a vacuum and the evaporation residue is recrystallized from 20 ml of dioxane (using activated charcoal). Are thus obtained 1.6 g of pale yellow crystals of the desired compound from the Pp. 210/212 ⁰ C (dec.).

Example 2

3- (5-Nitro-2-furyl) -5- (and / or 7 -) - methyl-s-triazolo [4,3-a ] - pyrimidine

10 g of crude 2-chloro-4-methylpyrimidine are boiled with 135 ml of ethanol and 35 ml of hydrazine hydrate for 1 hour under reflux, sucked off Undissolved, the piltrate evaporates in a vacuum, dissolves the evaporation residue in 25 ml of water, 50 ml of dioxane are added, 25 ml of 10 n sodium hydroxide solution are added dropwise while cooling with ice, and the dioxane phase is separated and extract the water layer a few more times mib Dioxane after. The combined dioxane extracts are dried at the same time

109833/1998

ι -. ■ -. '■

anhydrous soda, it then evaporates in a vacuum ,, whereby 6.5 g of crude 2-hydrazine-4-methyl-pyrimidine remain.

This hydrazino compound thus obtained is dissolved in a mixture from 50 ml of water and 5 ml of glacial acetic acid add a solution of 8.84 g of 5-nitrofuran-2-aldehyde in 55 BiI.Methanol, left for 1 hour stand at room temperature, the hydrazone formed is sucked off, washes this with 50 $ aqueous: methanol and finally with ether.

The yield is 9.8 g of crude hydrazone.

This is dissolved in 280 ml of hot glacial acetic acid, carrying at 60 ° C with stirring 20.6 g of lead tetraacetate, then still leaves 10 minutes at 6O ⁰ C and then 30 minutes at room temperature continued to stir evaporated dam- into Vacuum, rubs the Evaporation residue is boiled twice with 30 ml of ice water each time, the undissolved material obtained (8 g) boils repeatedly with a total of approx. 500 ml of dioxane, separates from undissolved matter, evaporates the combined dioxane extracts in a vacuum and crystallizes the evaporation residue from 80 ml 90% aqueous Dioxane to give 0.85 g of pale yellow crystals of the desired product. Pp. 282/284 ⁰ C. It was not determined whether the methyl group is in the 5- or 7-position, or whether there is possibly a mixture of isomers.

Example 3 3- (5-Nitro-2-furyl) -6-methyl-s-triazolof4,3-a] pyrimidine

1.28 g of 2-chloro-5-methyl-pyrimidine, melting point 89 ° C., are also boiled 15 ml of ethanol and 4.5 ml of hydrazine hydrate for 1 hour under reflux, after separating off a little undissolved matter, the filtrate is evaporated in a vacuum a, rub the evaporation residue with 2 ml of cold water and thus obtained 0.9 g of crude 2-hydrazino-5-methyl-pyrimidine with a melting point of 143 / 145.degree.

■ "■ · - ■ -0.78 g of it is dissolved in a mixture of 6.5 ml of water and 4 ml of 2N hydrochloric acid gives a solution of 1 g. 5-nitro-furan-2-aldehyde in 11 ml. of methanol, sucks after standing for 1 hour

<- ..:. ■ _. ./. 109833/1996 BADORiQINAL.

the precipitate formed, washed with 50 #, aqueous. Methanol after and thus receives 1.6 g of crude, orange-colored hydrazone.

1.5 g of it are dissolved in 15 ml of glacial acetic acid at 90 ^° C .; at 6O ⁰ C to wear 3.3 g Bleitei? raacetat a stirring, allowed 10 minutes at 60 ⁰ C. for sucking and after 1 hour standing at room temperature, washed with glacial acetic acid and then with ether, and crystallizing the solid product thus obtained (1.15 · g) from 25 ml of a mixture of dioxane-dimethylformamide (l: l) by using activated carbon to obtain 0.85 g of the desired product from the Pp 267/268 ⁰ C as a light yellow material are incurred..

Example 4 3- (5-Nitro-2-furyl) -7-methyl-B-triazolo [4,3-c] pyrimidine

1.24 g of 4-hydrazino-6-methyl-pyrimidine, melting point 141/142 ° C., are dissolved in a mixture of 8 ml of water and 1 ml of glacial acetic acid, and 1.7 g are added 5-nitro-furan-2-aldehyde dissolved in 10 ml of methanol, warmed up briefly on the steam bath and sucks the accumulated, crude hydrazone from (2.17 g) and washes it with 50 # igem aq. Methanol.

1.9 g of this are introduced at 50 ^° C. into a stirred suspension of 5.2 g lead tetraacetate in 40 ml glacial acetic acid, stirred at this temperature for 10 minutes and, after cooling, the desired product is filtered off with suction as pale yellow crystals. Yield: 0.45 g; Mp. 223 ⁰ C (dec.).

Example 5 i,

3- (5-Nitro-2-furyl) -6-methoxy-s-triazolo [4,3-a3-pyrimidine

1.5 g of crude 2-chloro-5-methoxy-pyrimidine, mp. 64 C ⁰ is boiled with 15 ml of ethanol and 4.8 ml of hydrazine hydrate for 1 hour under reflux and drawn after 1 hour Einkühion in an ice bath the precipitated, crude P -Hydrazino-ij-methoxy-pyrimidine (0.9 ß, mp. 131 / 13Λ) from,

HKit; 3 3/1996. BATH ORIGINAL

0.7-5 g of which is dissolved in a mixture of 6 ml of water and 2 ml of 2N hydrochloric acid at 5O ⁰ C, are at this temperature a solution of 0.84 g of 5-nitro-furan-2-aldehyde in 8 ml of methanol to , creating a dark red gelatinous precipitate. This is in the mortar with 10 ml of 50 # something S. Methanol rubbed into an orange-colored substance which can be sucked off, sucked off after standing for 1 hour at room temperature and washed with 50% aqueous. Methanol and washed with ether, 1.4 g of crude hydrazone of p. 186/188 ° C. being obtained. '

This product is dissolved in 18.5 ml of glacial acetic acid, ^{2.75 g of lead tetraacetate are added at 50 °} C., then left to stand for a further 30 minutes at room temperature, then filtered off with suction, washed with glacial acetic acid and ether and the product obtained (1 , 1g) were obtained from 15 ml of dioxane, using activated charcoal, wobei.0,4g the desired substance as a greenish-yellow crystals of Pp. 177/178 ⁰ C. .

B e '1 "s' ρ Τ - θ" Τ- · 6 -5 - ^^

13.9 g of crude 2-amino-4-hydrazino-6-methyl-pyrimidine of melting point 221 ^° C. are dissolved in a mixture of 50 ml of water and 7 ml of glacial acetic acid and heated briefly with a solution of 15.5 g of 5- Nitro-furan-2-aldehyde in 50 ml of methanol on the steam bath, sucks off the precipitated crystals after cooling, rewashes with 50% aqueous methanol and then with ether and thus receives 19.85 g of crude hydrazone. .

This hydrazone is added in portions / with stirring at 50 ° C. to a solution of 40 g of lead tetraacetate in 500 ml of glacial acetic acid. 250 ml of Waeeer, sucks daa insolubles, washed with water and is thus obtained 9.2 g of crude 3- (5-nitro-2-furyl) -5-amino ^ 7-methyls-triazolotiljj-clpyrimidin. '■

A sample of the orange-yellow substance from 70 tiger, aqueous

2ÜÜA713

Dimethylformamide uokristallisiert melts at 325 ⁰ C (Aufseh., From 2Io ° C color change).

Example 7 3- (5 "NitrQ-2-furyl) -5-hydroxy-7-methyl" S "triazolo [i | _t 3" c3pyrimidine

1.3 g of the crude amino compound obtained in Example 6, finely powdered, are mixed with 25 ml of 2N hydrochloric acid and a solution of 0.8 g of sodium nitrite in 8 ml of water is added dropwise between 25 ° and 28 ° C. with stirring, then another 45 is stirred minutes at room temperature, the insolubles filtered off, washed with water and crystallized the substance (0.9 g) in 18 ml of a mixture of dimethylformamide and Dioxanfl: l) using activated charcoal, wherein 0, ¹ Jo g beige yellow crystals of the desired Product with a melting point of 288/291 ° C. (decomposition) was obtained, to which, however, about 5/6 molar equivalents of dimethylformamide have been added.

B e i s ρ i e 1 8

3- (5-Nitro-2-furyl) -5-dichloroacetamido -7-ynethyl-s-triazolo - [4,3-eIpyrimidine

5 g of crude 3- (5-nitro-2-furyl) -5-amino-7-methyl-s-triazolo ^[1 J, 3-c pyrimidin _J (according to Example 6) is heated with stirring in 10 ml α dichloroacetic 30 minutes to 50 to 6O ⁰ C, rubs through with Xther after cooling, sucks off the undissolved material, washes with Xther, dissolves the solid material obtained (6 g) in 20 ml of dioxane, mixed with 170 ml of benzene, removes the Excreted dirt after adding activated charcoal by suction, the clear piltrate evaporates in a vacuum (at 50 ⁰ C bath temperature), rubs the evaporation residue (4.6 g) with 4 ml of benzene, sucks again and thus receives 1.19 g lemon-yellow crystals of the desired product, which contains 1/2 molar equivalent of benzene added. Mp 130/133 ° C.

109833/1996

At s ρ ie 1 9 .

3- (5-Nitro-2-furyl) -5-freeaftido "7-matliyl-s-triazolo'l k ^ -clpyrimidine

2 g raw. 3- (5-Nitro-2-ruryl) -5-amino-7 ^ ynethyl-s-triazolo [4,3-c] pyrimidine (according to Example 6) suspended in 20 ml of glacial acetic acid, stirred with 6 ml of mixed anhydride from acetic acid and formic acid at room temperature, after about 20 minutes solution occurs; Now it is allowed to stand over.Haclt at room temperature, then evaporated (at 3O ⁰ C bath temperature) in a vacuum, rubs the evaporation residue twice with ether and then with benzene, sucks off the undissolved material and thus obtains 0.85 g of the desired product as yellow substance with a ^{melting point of 253 0} G (Aufsch., from approx. 15.5 ⁰ C change).

.. "· ■ - example IO ,

3- (5 "Mitro-2-furyl) -5" amino ~ s-triazoloI ^ _< 3 ~ c3pyrimidine

21 g of 2-amino- ¹ J-chloropyrimidine are boiled with 210 ml of ethanol and 21 ml of hydrazine hydrate under reflux for 5 minutes, then benzene is added and the mixture is evaporated in vacuo, the evaporation ^{residue is boiled off with 1} 100 ml of dioxane, which is an oily one Layer separates. Anhydrous sodium sulphate is added, then suctioned off while hot, the filtrate is evaporated, the evaporation residue is rubbed with 50 ml of isopropanol and thus obtained. Aspirating crude 2-amino-4-hydrazino-pyrimidine (8.6 g, pp. 183/185 ° C); from this substance is made in a mixture of 50 ml of water and 5 ml of glacial acetic acid and a solution of 11.5 g of 5-nitro-furan-2-aldehyde in 50 ml of ethanol by briefly refluxing and. Subsequent cooling in an ice bath for 2 hours produces 19.6 g of crude hydrazone as an acetic acid salt.

This is dissolved in 350 ml of trifluoroacetic acid and with stirring at -5 to. -10 ⁰ C portionwise admixed with 38.6 g of lead tetraacetate and stirred for 15 minutes at this temperature; Now you evaporate at 25 ° C bath temperature in a vacuum, rub the evaporation residue with 300 ml of water, "

. ^J ' 109033/1896

- γι -

Al

sucks off the undissolved matter, adjusts the piltrate to approx. pH 4-5 with sodium acetate, then sucks off the precipitated crystals, washed with water and thus receives 8.65 g of crude 3- (5-nitro-2-furyl) - 5-amino-s-triazolo [4,3-c] pyrimidine; 1 g of it dissolved in 10 ml of dimethylformamide and mixed with 3 »5 ml of water gave an orange. Product (0.63 g), mp. 311 ⁰ C (Barge.).

B e i s ρ i e 1 11 3- (5-nitro-2-furyl) -5-hydroxy-s-triazolo [4 , 3-c] pyrimidine

1.23 g of the crude amino compound according to Example 10 are dissolved in 25 ml of 30% sulfuric acid at 50 ^° C., a little undissolved material is separated off, and a solution of 0.75 g of sodium nitrite in 7.5 »1 of water is added dropwise while stirring, stirred at 5O ⁰ C for 15 minutes after, then filtered, after cooling, the precipitated crystals are filtered off, washed with water and after drying 0.42 g of the desired product, mp. 323 ⁰ C (Barge.) as light yellow crystals.

B e i s ρ i e 1 12 3- (5 "nitro-2-furyl) -5'-formamido-s-triazolo [4,3-c3pyrimidine

2.55 g of crude 3- (5-nitro-2-furyl) -5-amino-s-triazolo [4,3-c] pyrimidine, the preparation of which is described in Example 10, is left with 10 ml for 2 hours at room temperature mixed anhydride of formic acid and acetic acid react, then evaporates in a vacuum, takes up the residue in approx. 20 ml of dioxane, mixed with 80 ml of benzene, sucks off the dirt that has precipitated out and evaporates the clear filtrate at 3O-4O ° C in a bath temperature Vacuum one; the evaporation residue is rubbed with 5 ml of a mixture of isopropanol-dioxane 7: 3 to, can stand for 2 hours, then filtered off and so after drying 1 g of the desired substance of melting point 248 ⁰ C (Barge, from 155 ° C.. Color change) as a yellow product which is contaminated with some 3- (5 ~ nitro-2-fury1) -5-diformamido-s-triazolo [4,3-c] pyrimidine.

109833/1996

'.... ■■ 2U04713

Al

For example 13 .

3 "(5-nitro-2-furyl) -5 ^ (- 7 -) methyl - 7 - ('- 5 -) amino-s -' triazolo · - i ^> 3-a ] pyrimidine (mixture of isomers)

10.2 g of crude 2-hydrazino-4-methyl-6-amino-pyrimidin from Pp. 178 / 18O ⁰ C are dissolved in a mixture of 50 ml of water and 10 ml of glacial acetic acid, then with a solution of 10 g of 5-nitrofuran -2-aldehyde in 50 ml of abs. Ethanol is added and the mixture is briefly refluxed. After cooling, the crystals obtained are filtered off with suction, rewashed, and 19.7 g of crude hydrazone are obtained as the acetic acid salt. "

15.5 g of which one carries portionwise to a stirred suspension of 32 g of lead tetraacetate in 340 ml of glacial acetic acid at 30 ⁰ C, where temperature rise occurs at 36 ⁰ C, then allowed for 15 minutes at 35 ° C. for sucking according _v cooling off, washed with glacial acetic acid and ether and thus obtained 7> 76 g of the desired product as a red-orange mixture of isomers. A sample of 1.6 g of the substance melts after recrystallization from 28 ml of 80 tiger aqueous dimethylformamide at 305.degree. C. (slurry, color change from 240.degree. C.). According to the NMR spectrum, the substance contains a small amount of water. '

/ Be i 3 ρ 1 el 14

3- (5-Nitro-2-furyl) "5" methyl-7 "acetamido-s-triazolo [4,3-a] · » pyrimidine and 3 ^ t5- ⁱ 'nitro "2 - furyT) -5 -acetamido-7-methyl "S" triazolo [4,3 ^ ä] pyrimidine

2.6 g of the crude mixture of isomers of 3- (5-nitro-2 ^ - = furyl) -5-methyl-7-amino- and 5-amino-7-methyl-s-triazolo [4,3-a] pyrimidine , which is prepared according to Example 13, is boiled with 15 ml of acetic anhydride under reflux for 30 minutes, after cooling, the precipitated crystals are filtered off with suction, washed with a little glacial acetic acid and ether and thus 0.87 g of pale yellow product of pp. 260 / 2ßl ° C (Aufsch.) J it is one of the two desired isomeric substances. About 10 ml of ether are added to the acetic anhydride mother liquor and the resulting precipitated

Ί ' 109833/1998

Product (1 g) sucked off after some time and washed with ether. After recrystallization from 16 ml of 80 aqueous dioxane tigern under addition of activated carbon obtained 0, ^ 5 g of the other desired isomeric compound of Pp. 236/211 ⁰ C (Barge.), · Also as light yellow crystals. A definitive assignment of one of the two separate isomeric compounds to a specific form of the isomers was not made.

Example 15

3- (5-nitro-2-furyl) -5-methyl-7-propionamido-s-triazolo [l ⁱ ₁ 3-a] pyrimidine ~ u. 3- (5-nitro-2-furyl) -5-propionamido -7-methyl-striazolo [* J _t 3-a] pyrimidine

2.6 g of the isomer mixture of 3- (5-nitro-2-furyl) -5-methyl-7-amino- (and -5-amino-7-methyl) -s-triazolo [ ¹ l, 3-a] pyrimidine _>, which is prepared according to Example 13, is heated with 15 ml of propionic anhydride for 30 minutes to 150/160 ° C. (bath temperature), after cooling the precipitated crystals are filtered off with suction (1.81 g) and washed with Xther; 0.9 g of the isomer mixture thus obtained is recrystallized from 4 ml of glacial acetic acid to give 0.3 g of the two isomeric forms of the desired product as a lemon-yellow crystals of mp. 209 ⁰ C (dec.) Is obtained.

The one obtained by evaporating the glacial acetic acid mother liquor in a vacuum. Residue is dissolved at 135 ° C in 9 ml of propionic anhydride, the precipitated at 50 ⁰ C crystals filtered off, washed with ether and obtained as 0.5 of the other isomeric form g of the desired compound, also as a lemon-yellow substance. Mp 23O ⁰ C (dec.).

Example. 16

3- (5-Nitro-2-furyJ.) -5-hydroxy-6-methyl- (and 7-hydroxy-6-methyl) -s-triazoloHt ^ -alpyrimidine

1 g of 2-hydrazino-li-hydroxy-5-methyl-pyrimidine of melting point 225/227 C is dissolved in a mixture of 10 ml of water and 5 ml of 2N hydrochloric acid

· ^Λ 109833/1996

200Λ713

then mixed with a solution of 1.2 g of 5-nitro-furan-2-aldehyde in 15 ml of methanol, sucks off the hydrazone (1.9 g) after stirring for 30 minutes at room temperature, washed with 50% aqueous methanol and suspended it in 50 ml of glacial acetic acid; at 80 ⁰ C to wear into this suspension with stirring 3.75 'g lead tetraacetate a, leaving 10 minutes at this temperature then filtered after 1 hour standing at room temperature, the clear filtrate in vacuo an mL evaporated, the evaporation residue is rubbed with 10 Water and the undissolved material (1.8 g) then recrystallized from 12 »1 80 Jfigem aqueous dioxane using activated charcoal, 0.7 g of pale yellow crystals of the desired product being obtained as a mixture of isomers. M.p. 278/280 ° C.

At s ρ I e T 17

3- (5-Nitro-2-furyl) -6-methyl-5- (or -7-) methylamino-striazoloIM, 3-a] pyrimidine

8, ^ g of 2-hydrazino- ¹ J-methylamino-5-methyl-pyrimidine, obtained as a crude product by treating 10 g of 2-chloro-I-methylamino-S-methylpyrimidine with 50 ml of hydrazine hydrate at 100% for 1 1/2 hours ⁰ C and subsequent cooling are obtained, dissolved in a mixture of 52 ml of water and 32 ml of 2N hydrochloric acid, then a solution of 9.3 g of 5-nitro-furan-2-aldehyde in 8MmI of methanol is then blunted with sodium acetate and sucks off the precipitated hydrazone after standing for 1 hour.

After washing with 50 Jiigem, aqueous methanol and with ether 13.6 g of crude hydrazone as fall from Pp. At 173/178 ⁰ C (dec.).

The product obtained in this way, suspended in 196 ml of glacial acetic acid, is admixed with 26.3 g of lead tetraacetate, a clear solution being formed. After standing for 1 hour, it is evaporated in vacuo, the residue is rubbed with 60 ml of water, brought to pH 8 to 9 with ammonia and the material which has separated out is filtered off with suction and washed with water. The resulting (12.6 g) crude product is repeatedly boiled with 90% aqueous dimethylformamide, filtered off with suction while hot, the filtrates are allowed to crystallize after previous treatment with activated charcoal, 3 g dosing

./. 109833/1996

desired product of Pp. 332/335 ⁰ C (Aufsch., from 30O ⁰ C red color) as a yellow substance. It was not established which of the two possible isomers is present.

E.g. pi e 1 18

3- (5-Nitro-2-furyl) -g-methyl-5- (or -T-Qamino-s-triazolo- [4,3-a] pyrimidine

6.8 g of crude 2-hydrazino-4-amino-5-methyl-pyriinidin from Pp. 174/175 ⁰ C, which by 1 1/2 hour treatment of 8 g of 2-chloro-4-amino-5-methyl pyrimidine is obtained with 40 ml of hydrazine hydrate at 100 ^° C., it is dissolved in a mixture of 79 ml of water and 37 ml of 2N hydrochloric acid, then a solution of 8.3 g of 5-nitro-furan-2-aldehyde in 116 ml is added of methanol is filtered after 1 hour standing at room temperature, the precipitated crystals are filtered off, washed with 50 Jfigem aqueous methanol and then with ether and obtains as 12.7 g of crude hydrazone, mp. 264/268 ⁰ C, which was in 212 ml Glacial acetic acid suspended.

With stirring to wear in this suspension 27 »8 g of lead tetraacetate, where the temperature rises to 4O ⁰ C, then stirred for 1 hour at room temperature, then evaporated in a vacuum, are added to the residue 150 ml of water, adjusted with ammonia to ca pH 8 and sucks off the undissolved material. After washing with water and drying, 9> 1 g of crude 3- (5-nitro-2-furyl) -6-methyl-5- (or -7-) amino-s-triazolo [4,3-a] pyrimidine are from obtained pp. 258 / 26O ⁰ C (Barge.).

Example 19

3- (5-Nitro-2-furyl) -6-methyl-5- (or-7-) acetamido-s-triazolo - [4,3 ~ a] pyrimidine

2 g Arainoverbindung according to Example 18 is stirred with 60 ml of acetic anhydride at 13O ⁰ · C ₇ to clear solution occurs (about 20 minutes); After cooling, the mixture is left to stand for 1 hour at room temperature, then the precipitated crystals (0.85 g) are filtered off with suction, washed with acetic anhydride and with Xther and crystallized

τ /. 109833/1998

from 15 ml mixture of dioxane-dimethylformamide (7: 3) with the addition of activated charcoal. This gives 0.56 g of lemon-yellow crystals of the desired substance. Mp 264/266 ⁰ C (premium).

Example 20

3- (5 "Nitro-2-furyl) -5-methyl-7-methylamino- (or -5-methylamino · 7-methyl) -s-triazolo Q \ "3-aJ pyrimidine

A still moist isomer mixture of 2-hydrazino-4-chloro-6-methyl-pyrimidine and 4-hydrazino-2-chloro-6-methyl-pyrimidine {which is added dropwise to 18 g of crude 2,4-dichloro with 24 ml of hydrazine hydrate -6-methyl-pyrimidine dissolved in 180 ml of ethanol, obtained after evaporation of the suspension obtained in a vacuum and trituration of the residue with ice water. Dissolve in a mixture of 150 ml of water and 15 ml of concentrated hydrochloric acid, a solution of 16 g is added 5-Nitro-furan-2-aldehyde in 150 ml of ethanol, boils briefly under reflux, sucks off the precipitated crude hydrazone isomer mixture (19.7 g) after cooling, washed with 50% aqueous ethanol and with ether and carries 11 , 2 g of it at room temperature with stirring in a suspension of 13.2 g of lead tetraacetate in 80 ml of glacial acetic acid, allowed to stir for 15 minutes, sucks off the undissolved material, washes with a little glacial acetic acid to obtain 6.2 g of hydrazone back, but mainly only one of the two isomeric forms of hydrazone. The filtrate is admixed with 100 ml of ether, rubbed with the glass rod until crystallization begins and, after standing for 30 minutes, the crystals which have accumulated are filtered off with suction . After washing with glacial acetic acid, fail), finally with ether alone, 2.72 g of isomeric mixture of 3- (5-nitro-2-furyl) -5-methyl-7-chloro (and 5-chloro) are obtained 7-methyl) -s-triazolo [4,3-a] pyrimidine in a mixing ratio of approx. 1: 1 (estimated from the paper chromatogram / mp. 187 C (list)

1.68 g of it dissolves? one in 30 ml of a mixture of dioxane-methanol! (l: d) dropwise with stirring at 30 ⁰ C 2.2 ml to about 18 Jiigen methanolic methylamine solution, whereupon the temperature rises to 40 ⁰ C, then stirred for 15 Stir for minutes, suck off the resulting crystals, wash with

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Water and then with methanol, and thus obtains 0.45 g. of the desired substance as an orange-red product, mp. 281 ⁰ C (Barge.).

B e i s ρ i e 1 21 5-methyl-7- (5-nitro-2-furyl) -B-triazolo [4,3-c] pyrimidine

5.0 g of 7- (2-puryl) -5-methyl-s-triazolo [ ¹ i, 3-c] pyriinidine are dissolved in 50 ml of concentrated sulfuric acid at room temperature. To this end, 12.8 ml of nitrating acid (9 vol. Percent nitric acid in sulfuric acid) are added dropwise ^{at 0 ° C. with stirring.} Then is stirred for one hour at O ⁰ C and one hour at 0-20 ⁰ C, poured onto ice, brought with sodium carbonate solution to pH 6, in the refrigerator overnight allowed to stand, suction filtered washed und.mit water.

The yield is 4.55 g (71 % of theory ); the melting point after recrystallization from dimethylformamide is 263-268 ° (decomp.). Elemental analysis, IR and NMR spectrum confirm the structure.

The 7- (2-furyl) -5-methyl-striazolo [4,3-c] pyrimidine (melting point 230-232 °) used as starting material can be obtained by conversion of 6- (2-furyl) -i | -hydrazino-2-methyl-pyrimidine with orthoaric acid triethyl ester.

The following compounds are obtained in an analogous manner: 5, S-dimethyl-S-hydroxy -? - (5-riitro-2-fury1) -s-triazolo [4,3-c]

pyrimidine m.p. * 315 ^O (dec.)

The 3-acetoxy-5,8-dimethyl-7- (2-furyl) -s-triazolo [ ¹ i, 3-c] pyrimidine (melting point 226-228 °) used as starting material is obtained by converting 2.5- dimethyl-6- (2-furyl) - ¹ »hydrazino-pyrimidine with ethyl chloroformate to the corresponding Carbaethoxyhydrazinoverbindung (mp. 16O I6I ⁰⁾ and their cyclization using acetic anhydride obtained.

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5-Amino-3.8-dimethyl-7- (5-nitro-2-furyl) -s-triazolo [4 _t 3-c 3 pyrimidine m.p. · ν29Ο ° (ZerB.)

The 5-amino-3,8-dimethyl-7- (2-furyl) -s-triazolo [4,3-c] pyrimidine used as the starting material (Pp. 228-230 °) is obtained by chlorination of 2-acetamido-4- (2-furyl) -5-methyl-6 (lH) -. pyrimidinone, conversion of the chlorine compound thus obtained (p. 155-160 °) with hydrazine hydrate to give 2-amino-4- (2-furyl) -6-hydrazino-5-methyl-pyrimidine (Pp. 220-222 °) and its cyclization by means of triaethyl orthoacetate.

Example 22 7- (5-Nitro-2-furyl) -2,5j8-trimethyl-s-triazolo [1,5-c] pyrimidine

4.2 g of 7- (2-furyl) -2,5,8-trimethyl-s-triazolo [l, 5-c] pyrimidine is suspended in 42 ml of acetic anhydride and with the mixture of 1.53 ml of nitric acid, 42 ml Sulfuric acid and 42 ml of acetic anhydride nitrated at -10 °. The work-up is carried out as in Example 21. The yield is 1.5 g (30 %) ; Pp. 255-260 ° (dec.). Elemental analysis, IR and NMR spectrum confirm the structure.

The 7- (2-puryl) -2,5,8-trimethyl-s-triazolo [l, 5-c] pyrimidine used as starting material (Pp. 224-226 °) is obtained by cyclizing 2,5-dimethyl-6- (2-furyl) -4-hydrazino-pyrimidine obtained by means of acetic anhydride.

Example 23 5- (5-Nitro-2-furyl) -8-methyl-S'-triazolo [4 _> 3-c] pyrimidine

A suspension of 3 g of 2- (5-nitro-2-furyl) -4-hydrazino-5-methyl-pyrimidine in 30 ml of ethyl orthoformate is stirred under reflux for 90 minutes. It is then cooled, diluted with Xther and suctioned off. After washing with Xther and drying, 2.2 g (= 70 % of theory ) of yellow crystals are obtained, which after recrystallization from aqueous dioxane with the addition of dimethylformamide at 185-188 ° with decomposition

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melt. The compound is chromatographically uniform, elemental analysis and spectra confirm the structure.

Example 24 5- (5-Nitro-2-furyl) -7-methyl-s-triazolo [4 »3-c3pyrimidine

7 g of 5- (2-furyl) -7-methyl-s-triazolo [4,3-c] pyrimidine (p. 212-216 °) (prepared by heating 2- (2-furyl) -4-methyl- 6-hydrazino-pyrimidine with ethyl orthoformate) are suspended in 70 ml of acetic anhydride. The nitration mixture, consisting of 2.9 ml of 100 percent strength, is added dropwise at 0 ° with stirring. Nitric acid in 70 ml conc. Sulfuric acid, slowly to. After the addition, the mixture is stirred for one hour, poured onto ice and neutralized with solid bicarbonate. In this manner (45% d. Th. ^S) of a chromatographically uniform, yellow product is 3 »g 9 is that a Pp after recrystallisation from aqueous alcohol with addition of dimethylformamide. Has from 225-227 °. Elemental analysis and spectra confirm the structure.

Example 25 lH-5- (5-nitro-2-furyl) -7-hydroxy-v-triazolo [JJ, 5-d] pyrimidine

10 g of 1H-5- (2-furyl) -7-hydroxy-v-triazolo [JJ, 5-d] pyrimidine (p. 315 ° dec., Prepared by reacting 2- (2-furyl) -4.5 -diamino-6-hydroxy-pyrimidine [Gazz. £ 3, 264/1953] with nitrous acid) are concentrated in 100 ml. Dissolved sulfuric acid with stirring at 10 ° and with a mixture of 4.1 ml 100 percent. Nitric acid in 100 ml conc. Sulfuric acid nitrated at 0 °. After the nitrating acid has been added dropwise, the mixture is stirred for 1 hour, poured onto ice and the amorphous precipitate is isolated. Crystallization occurs when it is boiled in water. This gives 2.0 yellow crystals (= 16 % of theory ) which, after recrystallization from aqueous dimethylformamide, have a decomposition point of 290 °.
Elemental analyzes and spectra confirm the structure.

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Example 26 2- (5-nitro-2-furyl) -5,7-dimethyl-s-triazolo [2,3-a] pyrimidine

0.4 g crude 5- (5-nitro-2-furyl) -2-amino-l, 2,4-triazole, mp. 260/263 ⁰ C boils "to 0.22 g acetylacetone and with .2 ml glacial acetic acid reflux for 1 hour, drawn after cooling, the precipitated crystals from, wäscht.mit glacial acetic acid and with ether and obtained as 0.35 g of the desired substance from the Pp 251/252 ⁰ C;. of the mixed melting point with the generated according to example 1, isomeric Connection, gives a definite depression.

Example 27 2- (5-Nitro-2-fury1) -5,7-dimethy1-s-triazolo [2,3-a] pyrimidine ·

30 mg of the 3- (5-nitro-2-furyl) -5,7-dimethyl-s-triazolo [4,3-a] pyrimidine obtained according to Example 1 are boiled with 2 ml of ethanol and 0.5 ml of 2N hydrochloric acid for 15 minutes under reflux; after cooling, is filtered, the precipitated crystals are filtered off, washed with ethanol and obtained 25 mg of the desired substance from the Pp 251/252 ⁰ C. the mixed melting point with the substance obtained according to Example 26 is without depression.

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Claims (3)

PATENT CLAIMS 1J nitrofuryl-triazolo-pyrimidines of the general formula I. (D in the TP is a triazolo-pyrimidine ring system and R ^, Rp and R, be the same or different can and hydrogen, halogen, an alkyl, hydroxyl, alkoxy, acyloxy, amino, Mean alkylamino * or acylamino group. 2. Process for the preparation of nitrofuryl-triazolo-pyrimidines of the general formula I. (D in the TP is a triazolopyrimidine ring system and R ₁ , Rp and R, be the same or different and can denote hydrogen, halogen, an alkyl, hydroxyl, alkoxy, acyloxy, amino, alkylamino or acylamino group, characterized in that either a) furyl-triazolopyrimidines of the formula II (ID 7th 109833/1996 2UÜ4713 in the TP, R ₁ , R ₂ and R- have the aforementioned meaning or _{t nitrided} b) hydrazones of the formula III or III (III) NH N in the Rl, R ₂ and R _{3 have} the meaning given above and Py together with the group -N = c £ forms a pyrimidine ring, oxidizing cyclized or c) hydrazides of the formula IV or IV ¹ (IV) · / · 109833/1996 NH N (IV) in which R ₁ , R ₂ , R ^ and Py have the meaning given above, cyclized with elimination of water or d) aminotriazoles of the general formula V (V) in which R ₁ ^ has the meaning of R ₁ , or represents a 5-nitrofuryl-2 group., with 1,3-dicarbonyl compounds of the general formula VI Ri ₁ - CO - CHR ₁ , - CO - R, (VI) in which R ₁ J has the meaning given above, but only one of the radicals R ^ is a nitrofuryl group, or their reactive derivatives condensed or e) in diaminopyrimidines of the formula VII NH. (VII) ^ ₁ .— - * 2 in which R _{1 has} the meaning given above » ./. 109833/1996 closes the l'riazole ring with nitrous acid and optionally then converts the substituents R ₁ , R ₂ or R into one another in a manner known per se. 3. Use of nitrofuryl-triazolo-pyrimidines of the general formula I for the preparation of medicaments with antimicrobial effect. 109933/1996