DE1065421B - Process for the preparation of alkylated hydropyrazolo [3,4-d] pyrimidines - Google Patents

Description

GERMAN

The invention relates to the production of at least one grouping in the pyrimidine ring

O "'■■ .:

Alkyl - N - C -

having, unsubstituted or unsubstituted in the 1- or 2-position alkylated, unsubstituted in the 3-position and optionally a free or alkyl-substituted one in one of the 4 or 6 positions Hydropyrazolo- [3,4-d] -pyrimidines containing oxy, mercapto or amino groups or unsubstituted in the 6-position with the core of the formula

N ⁵

² N

N N

or their tautomeric forms and their salts. The alkyl radicals in the new compounds are preferred low molecular weight; Particular mention should be made of methyl and isopropyl radicals.

The new compounds show valuable pharmacological properties, especially caffeine-like, i.e. left stimulating and diuretic effect with low toxicity. So has z. B-. [The 2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-pyrazolo- [3,4-d] -pyrimidine has an approximately 6 times greater therapeutic range than theobromine and the is more effective even in absolute doses. They can therefore be used as medicinal products, but are also suitable as intermediate products for the production of medicinal products. They also influence the metabolism. Those compounds of the type mentioned in which a lower alkyl radical is in the 1 _r or 2 position and their salts are particularly valuable.

Particularly noteworthy is the 2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine as well as 1-isopropyl-4,6-dioxo-5,7-dimethyl-4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine.

The new compounds are obtained by methods known per se. You will get if one N-unsubstituted or alkylated 3-amino or monoalkylammopyrazole-4-carboxylic acids unsubstituted in the 5-position, optionally in the form of nitrile or other reactive ones containing an oxo, thiono or imino group functional derivatives with carbonic or formic acid, optionally in the form of their reactive ones functional derivatives at elevated temperature with the proviso that at least one of the Carboxylic acids is modified functionally so that it has a free or monoalkyl-substituted amino group and at least one of the amino groups present in the starting materials is monoalkyl-substituted, or Method of manufacture

of alkylated
Hydropyrazolo [3,4-d] pyrimidines

Applicant:

CIBA Aktiengesellschaft,
Basel, Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney,
Hamburg 36, Neuer Wall 10

Claimed priority:

Switzerland from February 10, April 7, June 1, July 16
and September 28, 1956

Dr. Jean Druey, Riehen,

and Dr. Paul Schmidt, Therwil (Switzerland),

have been named as inventors

if you have N-unsubstituted in the pyrimidine nucleus, in at least one of the positions 4 and 6 is an oxo group and optionally an unsubstituted or in the other alkyl-substituted oxy, mercapto or amino groups or those unsubstituted in the 6-position, in the 1- or Hydro-pyrazolo- [3,4-d] -pyrimidines which are unsubstituted in the 2-position or alkylated, unsubstituted in the 3-position reactive esters of alkanols and optionally alkylated in compounds obtained with an alkyl mercapto group these hydrolyzed to the free oxy group or by reaction with ammonia or alkylamines converted into a free or alkyl-substituted amino group and optionally prepares salts.

Alkyl formamide or N-alkyl carbonic acid amides are preferably used for the first-mentioned reaction on the one hand and 3-aminq-pyrazole-4-carboxylic acid derivatives, e.g. esters, on the other hand. J> the 3-amino-pyrazole-carbpic acid-N-alkylamides and carbonic or formic acid, optionally in the form of their reactive derivatives. The condensation to give the pyrazolopyrimidines is preferably carried out at temperatures above 100 ° C., if appropriate in the presence of diluents and / or condensation agents in an open or closed vessel. The alkylation according to the process takes place by treatment with reactive esters of alkanols, in particular of methanol, such as. B. with alkyl halides or dialkyl sulfates, depending on the used

909,628 / 400

''" ^:: ■ ■■■■■■ · ■ 3 ■ '4

Reaction conditions of one or more of the pyrimidine continue to stir and pull out the solution with a lot of chloroform ring nitrogen atoms and possibly also the stick. The chloroform residue is alkylated from a boiling substance atom in the 1-position. Water can also be recrystallized. 2,5,7-trimethyl-4,6-dioxo-other alkylable groups present can be alkylated, ■ _: 4; 5,6,7-tetrahydro-pyrazolo- [3,4-d] -pyrimidine of the formula such as e.g. B. a mercapto or amino group .. The replacement '5 ■■■. ·. . ,;
tion of an alkyl mercapto group by the oxy group
done by hydrolysis, expediently z. B. by treatment with acids, e.g. B. hydrochloric acid, the one by a
free or alkyl-substituted amino group by treatment with ammonia or alkylamines. ok

Depending on the substituents present in the products of the process, various salts can be prepared. If they have free oxy, mercapto or carboxyl groups, metal salts can be obtained, e.g. B.
by dissolving in alkaline solutions. Connections of basic 15
With a chemical character, as with basic substituents, we form salts with inorganic or organic acids in white crystals with a temperature of 195 to 196 °. As received.

Salt-forming acids come into question, for example: The 4,6-dioxy-pyrazolo-

Hydrohalic acids, sulfuric acids, phosphorus [3,4-d] pyrimidine can be obtained as follows,

acids, nitric acid, perchloric acid; aliphatic, ali- 20 8.5 g ethoxymethylene cyanoacetic esters are brought into 500 cm ^{3 of} cyclic, aromatic or heterocyclic carbonic or alcohol; the solution is then ^{mixed with 2.5 cm 3 of} sulfonic acids, such as form, vinegar, propion, oxal, hydrazine hydrate and amber, glycol, milk, apple, wine, lemon, Refluxed. Ascorbic, oxymalein, dioxymalein or pyruve is evaporated to dryness in vacuo and crystallized from a little water. 3-amino-4-caric acid; Phenylacetic, benzoic, p-aminobenzoic, anthranil, ethoxy-pyrazole of the formula p-oxybenzoic, salicylic or p-aminosalicylic acid; Methanesulfon-, ethanesulfonic-, oxyethanesulfonic-, ethylene- C ₂ H ₅ O OC-sulfonic acid; Toluenesulfonic, naphthalenesulfonic acids or
Sulfanilic acid; Methionine, tryptophan, lysine or arginine. H ₂ N -

Those used as starting materials or for the production of those used as starting materials in the pyrimidine nucleus N-unsubstituted pyrazolo-pyrimidines usable,

4-Steiiung a free or functionally modified _w i _r d as having in white crystals, mp = 102-103 ° 3-carboxyl Amiiiopyrazole be obtained.

z. B. by reacting unsubstituted or substituted 35 50 g of S-amino ^ -carbethoxy-pyrazole and 100 g of urinary a-cyano-a-formyl-acetic acids or their functional material are well mixed and new derivatives, such as theirs, for 40 minutes esters, amidines, amides, i _n a bath of 200 ° heated. The nitriles or nitriles and / or their enol ethers, acetals or melts are then ^{extracted with 400 cm 3 of} hot 1 η sodium hydroxide solution, and mercaptals with hydrazines are obtained. The latter are unfiltered from a little undissolved material and substitute it or can also be acidic with glacial acetic acid with mono-alkyl residues, whereupon a white low-substituted one. As a functional derivative, an α-cyano stroke fails and is sucked off from it. C.C-formyl-acetic acid is obtained, preferably enol ethers of _S o 4,6-dioxy-pyrazolo- [3,4-d] -pyrimidine in white cyan-a-formyl-acetic acid ester, such as. B. the ethoxy stalls, which have not yet melted at 300 °, methylene cyanoacetic acid ethyl ester, is used. The condensation of the pyrazoles proceeds under mild conditions Example 45 λ

in some cases at room temperature and exothermically. 16.8 g of 4-oxy-6-mercapto-pyrazolo- [3,4-d] -pyrimidine

^{You can also be dissolved in 200 cm 3} 2 η-sodium hydroxide solution at a higher temperature and in the presence, and the unit of condensing agents work, such as. B. in solution is slowly stirred with 42 g of dimethyl ■ presence of acids. It is advantageous to add the reac sulfate. The mixture is stirred for 20 hours in the presence of a diluent at room temperature and then stripped with a lot of means, such as an alcohol, toluene or chloroform. From chloroform. , The residue consists of chloroform in the resulting 3-amino-pyrazoles free or a mixture of two compounds of which, which is a functionally modified carboxyl group in the usual j _n Essigester is sparingly soluble and) much Liquor way be transformed. The implementation of the recrystallized. 2,5-Dimethyl-6-methylmercapto-3-amino-pyrazole-4-carboxylic acids or their derivatives 55 4-oxo-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine of the formula with unsubstituted functional amino groups to the
Starting materials N-unsubstituted in the pyrimidine core
takes place analogously to the method according to the invention.

The pyrazolo-pyrimidines described above, their salts or mixtures thereof can, for. B. in 60

Find the form of pharmaceutical preparations use. H ₃ CS LJ \ /

The invention is illustrated in the following examples

described in more detail. The temperatures are given in degrees Celsius. becomes so in white crystals from F. = 203 to 204 ° ". . . , 65 received.

P The 4-oxy-6-mercapto-

A solution of 15.2 g of 4,6-dioxy-pyrazolo- [3,4-d] -pyrazolo- [3,4-d] -pyrimidine can be obtained as follows.

pyrimidine in 200 cm ³ 2 η sodium hydroxide solution is slowly A mixture of 25 g of 3-amino-4-carbethoxy-pyrazole

• 42 g of dimethyl sulfate are added while stirring. Man and 50 g of thiourea is in a bath at 200 ° is then heated for 20 hours at room temperature 70 for 1 hour. You then take the melt

in 400 cm ³ 2 η-sodium hydroxide solution and acidified with glacial acetic acid, 4-oxy-6-mercapto-pyrazolo- [3,4-d] -pyrirnidine precipitating in white crystals which have not yet melted at 300 °.

Example 3

14 g of 4-oxy-pyrazolo- [3,4-d] -pyrimidine are placed in 150 cm ^{3 of} 2 η-sodium hydroxide solution; 30 g of dimethyl sulfate are slowly added to the solution while stirring and the mixture is then stirred for a further 10 hours at room temperature. The solution is then extracted several times with a lot of chloroform and the combined residues are crystallized from a lot of boiling alcohol. This gives two compounds, one of which is sparingly soluble in alcohol and has a mp = 287 to 289 ° and the other dissolves more easily in alcohol and has a mp = 181 to 182 °. The first compound is 2,5-dimethyl-4-oxo-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine and the second 1,5-dimethyl-4-oxo-4,5-dihydro- pyrazolo [3,4-d] pyrimidine of the formulas

CH, -N

N-CH ₃

respectively.

H, C - N

Example 5

A solution of 12.6 g of 4-mercapto-o-oxy-pyrazolo- [3.4 d] pyrrolidine in 150 cm ^{3 of} 2 η-sodium hydroxide solution is slowly admixed with 31.5 g of dimethyl sulfate over the course of 2 hours. The mixture is left to stir for a further 6 hours at room temperature and the alkaline solution is then extracted with a large amount of chloroform. The chloroform residue is recrystallized from a little alcohol and so ίο 2,7-dimethyl-4-methylmercapto-6-oxo-6 ₎ 7-dihydro-pyrazolo- [3,4-d] -pyrimidine of the formula

NS,

N-CH,

The 4-oxy-pyrazolo- [3,4-d] -pyrimidine used as starting material can be obtained as follows:

7.5 g of 3-amino-4-carbethoxy-pyrazole are mixed with 30 cm ^{3 of} formamide; it is then heated in a bath from -190 to 200 ° for 8 hours. It is allowed to cool, a gray crystalline precipitate separating out, from which it is suction filtered. The latter is dissolved in dilute sodium hydroxide solution, the solution shaken with animal charcoal and adjusted with hydrochloric acid to 2 η p _H 3 to 4, which is crystallized from a lot of boiling water to give a white precipitate. The 4-oxy-pyrazolo- [3,4-d] -pyrimidine is obtained in this way in white crystals which have not yet melted at 350 °.

Example 4

15.2 g of 4,6-dioxy-pyrazolo- [3,4-d] -pyrimidine are dissolved in 110 cm ^{3 of} 2 η-sodium hydroxide solution. 25 g of dimethyl sulfate are added dropwise to the solution thus prepared in the course of 4 hours, and stirring is continued for a further 6 hours at room temperature. The alkaline solution is then extracted with a lot of chloroform, with the trimethyl derivative formed as a by-product going into the chloroform phase. To set the aqueous solution to p _H 4, whereupon a white crystalline precipitate, which is again dissolved in sodium hydroxide solution and then precipitated with glacial acetic acid. The resulting precipitate is crystallized several times from boiling water and 4,6-dioxo-5,7-dimethyl-4,5,6,7-tetrahydro-pyrazolo- [3,4-d] -pyrimidine of the formula is obtained

obtained in yellowish crystals with a melting point of 216 to 218 °. The 4-mercapto-6-oxypyrazolo- [3,4-d] -pyrimidine used as a starting material can be obtained as follows. 15 g of 4,6-dioxy-pyrazolo- [3,4-d] -pyrimidine and 50 g of powdered phosphorus pentasulfide are placed in 800 cm ^{3 of} pyridine and heated in a bath at 130 ° for 6 hours. The pyridine is evaporated off in vacuo, the resinous residue is treated with 600 cm ^{3 of} ice water, left to ^{stand for 1} Z ₂ hours at room temperature and then heated on a water bath for 2 hours. After cooling, the precipitate is filtered off with suction. It is dissolved hot in dilute sodium hydroxide solution, treated with animal charcoal, precipitated again using 2η-acetic acid, suction filtered and washed with water and alcohol.
[3,4-d] pyrimidine of the formula

HO
45

is thus obtained in crystals that do not yet exist at 300 ° melted.

Example 6

A solution of 10 g of 2,7-dimethyl-4-methylmercapto-6-oxo-6,7-dihydro-pyrazolo- [3,4-d] -pyrimidine in 80 cm ^{3 of} conc. Hydrochloric acid is heated to boiling for 3 hours. It is then allowed to cool and the white precipitate formed is filtered off with suction. The latter is recrystallized from dilute alcohol. This gives 2,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine of the formula

CH,

N N

CH ₃

in white crystals from m. = 301 to 303 °.

in white crystals from m. = 325 to 327 °

Example 7 Example 10

..1Og 2,7-dimethyl-4-methylmercapto-6-oxo-6,7-dihydro-pyrazolo- [3,4-d] -pyrimidine and 100 cm ^{3 of} liquid ammonia are heated to 100 ° for 6 hours in a closed tube heated. The gray crystals remaining after the ammonia has evaporated are recrystallized from alcohol; thus, 2,7-dimethyl-4-amino-6-oxo-6,7-dihydro-pyrazolo- [3,4-d] -pyrimidine becomes in the formula

NH

O =

N-CH, A solution of 10 g of 1-isopropyl-4,6-dioxy-pyrazolo- [3,4-d] -pyrimidine in 75 cm ^{3 of} 2 η-sodium hydroxide solution is slowly mixed with 14 g of dimethyl sulfate while stirring. It is left to stand through the night and the next morning it is extracted with chloroform. The chloroform residue is recrystallized from alcohol to give l-isopropyl-4,6-dioxo-5,7-dimethyl-4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine of the formula

H ₃ CN

O = I

N N

CH ₃

obtained in white crystals that have not yet melted at 320 °.

If you add alcoholic hydrochloric acid to this, you get its monochlorohydrate, which at 312 ° below Decomposition melts. In a similar way, other salts, such as sulfate, perchlorate, nitrate or methanesulforate, can be obtained.

. Example 8

A solution of 8 g of 2,5-dimethyl-6-methylmercapto-4-oxo-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine in 70 cm ^{3 of} conc. Hydrochloric acid is heated to boiling for 3 hours. After cooling, the resulting white precipitate is filtered off with suction. One crystallizes out. diluted alcohol and thus receives 2,5-dimethyl-4,6-dioxo-4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine of the formula

N N

CH ₃ CH (CH ₃ ) ₂

obtained in white crystals with a temperature of 141 to 142 ° The 2-isopropyl-3-amino-

4-carbamylpyrazole can be obtained as follows.

A solution of 48.8 g of ethoxymethylene malonitrile in

50 cm ^{3 of} alcohol are mixed with 30 g of isopropylhydrazine. The mixture is then heated to boiling for 10 hours, evaporated to dryness in vacuo and crystallized from a large amount of isopropyl ether. 2-Isopropyl-3-amino-4-cyanopyrazole is obtained in this way in white crystals with a melting point of 94 to 95 °. 10 g of the compound thus prepared are ^{mixed with 200 cm 3 of} 2 η-sodium hydroxide solution and 100 cm ^{3 of} alcohol and the solution is heated to the boil for 3 hours. The alcohol is evaporated off in vacuo, allowed to cool and the precipitate which has separated out is filtered off with suction.

The latter is recrystallized from alcohol. This gives 2-isopropyl-3-amino-4-carbamyl-pyrazole of the formula

H, NOC-

H, N-I

CH

CH,

CH,

in white crystals that have not yet melted at 330 °. -'I '' -. . ■ ■,:;

Example 9

8 g of 2,5-dimethyl-6-methylmercapto-4-oxo-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine and 80 cm ^{3 of} liquid ammonia are heated to 100 ° for 20 hours in a closed tube . After the ammonia has been evaporated off, the residue is crystallized from a large amount of alcohol and so 2,5-dimethyl-6-amino-4-oxo-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine of the formula is obtained in white crystals from F. = 215 to 216 °.

10 g of 2-isopropyl-3-amino-4-carbamyl-pyrazole and 20 cm ^{3 of} urea are mixed well and heated in a bath at 200 ° for 1 hour. The hot melt is then placed in 150 cm ^{3 of} ln sodium hydroxide solution, treated with animal charcoal and filtered off with suction. The filtrate is adjusted with hydrochloric acid to p _H 3, whereupon white crystals precipitate. Recrystallization of this precipitate from water gives 1-isopropyl-4,6-dioxy-pyrazolo- [3,4-d] -pyrimidine of the formula

OH

H, C

CH,

HO

CH

in white crystals that have not yet melted at 320 °.

If this is mixed with alcoholic hydrochloric acid, so
its monochlorohydrate is obtained, which melts at 298 ° with decomposition in white crystals with a temperature of 286 to 287 °. . 70 decomposition) ', ι. .

(under

Example 11

9 g of 1-isopropyl-4-oxy-pyrazolo- [3,4-d] -pyrimidine are dissolved in 40 cm ^{3 of} 2 η-sodium hydroxide solution, and 8 g of dimethyl sulfate are slowly added with shaking. A white product precipitates and is sucked off. Recrystallized from water, l-isopropyl-4-oxo-5-methyl-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine is obtained in crystals with a melting point of 162 to 163 °.

Example 12

9.85 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole are refluxed with 25 cm ^{3 of} monomethylformamide for 6 hours. The reaction solution is strongly concentrated. After addition of ether, the 1-isopropyl-4-oxo-5-methyl-4,5-dihydro-pyrazolo- [3,4-d] -pyrimidine crystallizes out and, after recrystallizing once from ether, melts at 161 to 162 ° and with the compound described in Example 11 does not result in mixed melting point depression.

Example 13

10 g of 2-methyl-3-amino-4-carbamyl-pyrazole and 20 g of urea are mixed well and heated in a bath at 200 ° for 3 hours. The hot melt is then placed in 150 cm ^{3 of} ln sodium hydroxide solution, treated with animal charcoal and filtered off with suction. The filtrate is adjusted with hydrochloric acid to p _H 3, whereupon white crystals precipitate. Recrystallization of this precipitate from a lot of water gives l-methyl-4,6-dihydroxypyrazolo- [3,4-d] -pyrimidine of the formula

2-Methyl-3-amino-4-cyano-pyrazole is obtained in this way in white crystals with a melting point of 219 ° to 220 °. 10 g of the compound thus prepared are ³ mit200cm 2N sodium hydroxide solution and 100 cm ³ of ethanol are added, and the solution is heated to boiling for 3 hours. The ethanol is evaporated off in vacuo, allowed to cool and the precipitate which has separated out is filtered off with suction. The latter is recrystallized from ethanol. This gives 2-methyl-3-amino-4-carbamyl-pyrazole of the formula

HpNOC-

OH

HO

35

40

H-NT I N

üJN —I ,

CH ₃

in white crystals from m. = 232 to 234 °.

Claims (1)

Claim: Process for the preparation of the grouping at least once in the pyrimidine ring Alkyl - Ν —C— ^ having, unsubstituted or alkylated in the 1- or 2-position, unsubstituted and unsubstituted in the 3-position optionally in one of the positions 4 or 6 a free or alkyl-substituted oxy-, mercapto- or Hydro-pyrazolo- [3,4-d] -pyrimidines having amino groups or unsubstituted in the 6-position with the core of the formula in white crystals that have not yet melted at 300 ° are. 7.5 g of dimethyl sulfate are added dropwise to a solution of 4.2 g of 1-methyl-4,6-dihydroxy-pyrazo] o- [3,4-d] -pyrimidine in 30 cm ^{3 of 2 η sodium hydroxide solution, and it} stirring is continued for 10 hours. It then provides 2-η sodium hydroxide solution to p _H 9 and pulls out with chloroform. The chloroform residue is recrystallized from a lot of alcohol. 1,5,7-trimethyl-4,6-dioxo -4,5,6,7-tetrahydropyrazolo- [3,4-d] -pyrimidine of the formula H ₃ C O = N- N C ed 55 60 is obtained in this way in white crystals with a m.p. = 230 to 231 °. The 2-methyl-3-amino-4-carbamyl-pyrazole used as starting material is obtained as follows: A solution of 40 g of ethoxymethylene malonitrile in 400 cm ^{3 of} ethanol is mixed with 27 g of methylhydrazine. The mixture is then heated to the boil for 10 hours, allowed to cool and the precipitated product is filtered off with suction. or their tautomeric forms and their salts, characterized in that N-unsubstituted or alkylated 3-amino- or monoalkylaminopyrazole-4-carboxylic acids unsubstituted in the 5-position, if appropriate in the form of nitrile or other reactive ones containing an oxo, thiono or imino group functional derivatives with carbonic or formic acid, optionally in the form of their reactive ones functional derivatives at elevated temperature with the proviso that at least one of the Carboxylic acids is modified functionally so that they have a free or monoalkyl-substituted amino group and at least one of the amino groups present in the starting materials is monoalkylsubstituted is, or that one in the pyrimidine nucleus N-unsubstituted, in at least one of the positions 4 and 6 an oxo group and optionally in the other an unsubstituted or alkyl-substituted oxy, Mercapto or amino groups or those unsubstituted in the 6-position, in the 1- or 2-position unsubstituted or alkylated, in the 3-position unsubstituted hydro-pyrazolo- [3,4-d] -pyrimidines with reactive esters of alkanols and optionally alkylated in compounds obtained with a Alkyl mercapto group hydrolyzes this to the free oxy group or by reaction with ammonia . or alkylamines converted into a free or alkyl-substituted amino group and optionally salts manufactures. © 909 628/400 9.