DE1153023B - Process for the preparation of 4-hydroxy-pyrazolo [3,4-d] pyrimidines - Google Patents

Description

GERMAN

PATENT OFFICE

C23977IVd / 12p

REGISTRATION DATE: APRIL 26, 1961

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: AUGUST 22, 1963

The invention relates to a process for the preparation of 4-hydroxy-pyrazolo [3,4-d] pyrimidines the general formula

OH

where Ri is a hydrogen atom, an alkyl, hydroxyalkyl or oxaalkyl radical, R2 is a hydrogen atom or a lower alkyl radical and R3 is a optionally by halogen atoms or hydroxyl groups or lower alkyl or alkoxy groups substituted phenylalkyl or diphenylalkyl radical means, and of their salts.

Ri is, for example, a lower alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, pentyl (1), pentyl (2), pentyl (3), 2-methyl-butyl (3) or hexyl radical, a 3-oxapentyl or 5-oxaheptyl (2) radical or a lower hydroxyalkyl radical, such as a hydroxyethyl radical. In the mentioned Alkoxy groups are the alkyl radicals, in particular lower alkyl radicals, e.g. B. the mentioned.

The lower alkyl radical R2 is primarily the Methyl radical in question.

R3 denotes in particular a lower phenylalkyl radical, in which the alkylene radical z. B. is a methylene, ethylene or propylene radical. R ₃ is e.g. B. an optionally, as indicated, substituted 1- or 2-phenylethyl, 1-phenylpropyl or phenylmethyl radical or a diphenylmethyl radical.

The new compounds have valuable pharmacological properties. In particular, they are Coronary-expanding effective. The new compounds can thus be used as remedies, in particular at Circulatory disorders of the heart muscle, but also as intermediate products for the production of such remedies to serve.

The new compounds are superior to known compounds with the same direction of action. For example, l-methyl-4-hydroxy-6-p-chlorobenzyl-pyrazolo [3,4-d] pyrimidine, the 1 - isopropyl - 4 - hydroxy - 6 - (3 ', 4', 5 '- trimethoxyphenylmethyl) Pyrazolo [3,4-d] pyrimidine and the 1 - [1'-ethoxy-butyl- (3 ') -4-hydroxy-6-benzyl-pyrazolo [3,4-d] pyrimidine on the isolated rabbit heart in the Langendorff experimental setup in the manufacturing process of 4-hydroxy-pyrazolo [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 May 11, 1960 and April 4, 1961

(No. 5403 and 3931)

Dr. Paul Schmidt, Therwil, Dr. Kurt Eichenberger and Dr. Max Wilhelm, Basel (Switzerland),

have been named as inventors

^m

at a concentration of 1 y / ml an increase in the coronary flow of 40, 50 or 50% and at a concentration of 10 y / ml an increase of 90, 90 or 120%, while that according to the method of the German Auslegeschrift 1056613 available 1 - isopropyl -A- diethylamino pyrazolo [3,4-d] pyrimidine effected in a concentration of 1 y / ml and 10 y / ml only an increase of 20 or 60%. In addition, 1-isopropyl-4-hydroxy6-p-chlorobenzyl-pyrazolo [3,4-djpynmidine was found to be 5 times more effective in vivo in cats than 1-isopropyl-4-diethylamino-pyrazolo, which was obtained according to the method of German Auslegeschrift 1056613 - [3,4-d] pyrimidine.
Particularly valuable as a coronary-expanding agent

are compounds of the general formula

Ri

wherein Ri is a hydrogen atom, a lower alkyl radical, e.g. B. the methyl, ethyl, propyl, iso-

309 668/321

propyl, butyl (2>, 3-methyl-butyl (2) -, pentyl (2) or pentyl (3) group, .a lower hydroxyalkyl radical, such as the hydroxyethyl radical, or a lower oxaalkyl radical, such as the 3-oxapentyl group, R _{2 is} a hydrogen atom and R3 is a lower phenylalkyl radical, especially the phenylmethyl radical, it being possible for the phenyl radicals to be substituted as shown above, and the salts of these compounds.

The compounds of the general formula are also particularly valuable

b) an S-amino ^ -cyan-pyrazole of the general formula

OH

15th

where Ri is a lower alkyl radical, R2 is a hydrogen atom and R3 is an unsubstituted or phenyl radical by chlorine atoms, methoxy or methyl groups represents mono-, di- or trisubstituted benzyl radical, and their salts.

Particular mention should be made of 1-isopropyl-4-hydroxy - 6 - ρ - chlorobenzyl - pyrazolo [3,4 - d] pyrimidine, the 1 - isopropyl - 4 - hydroxy - 6 - m - methoxybenzyl pyrazolo [3,4 - d] pyrimidine, the 1 - isopropyl - 4 - hydroxy-6- (3 ', 4', 5'-trimethoxyphenylmethyl) -pyrazolo- [3,4-d] pyrimidine and the 1- [pentyl- (3 ')] -4-hydroxy-6-benzylpyrazolo [3,4-d] pyrimidine and its salts.

The new compounds are obtained when either in a manner known per se

a) a 3 - amino - pyrazole - 4 - carboxylic acid of the general formula

45

or their esters or halides or their amide, optionally in the presence of a condensing agent with a carboxylic acid of the general formula R3 - COOH or its esters, halides or imino ethers or their Anhydride or amide or their sulfur derivatives or with their amidine or nitrile with the proviso that the condensation is carried out in the presence of ammonia if at least one of the carboxy groups is not functionally modified in this way. that it has a nitrogen atom, and then possibly obtained as an intermediate, 3-Amino-pyrazole derivatives substituted on the amino group by optionally heating to higher temperatures or by in the presence of ammonia Heating with a condensing agent or cyclized

with a carboxylic acid of the general formula R3 - COOH or its esters, halides, Imino ethers or their anhydride converts, the cyano group in the compound thus obtained in the 4-position by heating with an alkali hydroxide and an oxidizing agent converted into the amide group, with the pyrimidine ring being closed at the same time, or c) a 4-oxo-pyrazolo [3,4-d] oxazine of the general formula

CR ₃

heated with ammonia or
d) a 4-hydroxy-pyrimidine of the general formula

OH

CO-R ₂

wherein X is a free or etherified mercapto group or a halogen atom, with a Hydrazine of the general formula

Ri-NH- NH-R ₄ ,

in which R4 denotes a hydrogen atom or an acyl group, reacts and optionally hydrolyzes the acyl group before or at the same time as the ring closure or
e) a 6-hydrazino-4-hydroxypyrimidine of the general formula

OH

heated with an acid of the general formula R ₂ - COOH or a reactive functional derivative of such an acid

and optionally subsequently obtained free compounds with bases into their salts or obtained Salts converted into the free compounds.

The reaction according to procedure a) can ζ. B. be done so that the 3-amino-pyrazole-4-carboxylic acid or an ester or a halide thereof with the amide, thioamide, nitrile or amidine a carboxylic acid of the general formula 5 R3 - COOH or an S-amino-pyrazole- ^ carboxamide with a carboxylic acid of the general formula R3 - COOH, its anhydride or one Esters, halides, imino ethers, thioimino ethers or their amide, thioamide, amidine or nitrile, depending on the substances used, ammonia is also added.

The condensation is preferably carried out at an elevated temperature, optionally in the presence of Diluents and / or condensation agents, in open or closed containers. Surprisingly it was found that the reaction is very advantageous when using the 2-position through the remainder Ri and in the 5-position through the remainder K3 substituted 3-amino-pyrazole-4-carboxylic acid ester, e.g. ß. the alkyl ester, and a nitrile the general Formula R3 - CN runs, where expediently a condensing agent, preferably an alkali metal, ζ. B. sodium, optionally in the form of its amide, hydride or an alcoholate, or another strong base such as trimethylbenzylammonium hydroxide is used. Here is also the use of diluents such as benzene, toluene, xylene or ethers, advantageous.

In procedure b), the oxidizing agent used for converting the cyano group into the Carbamyl group for example hydrogen peroxide in question.

In the reaction according to procedure c), the acid amide is formed as an intermediate. That as Oxazine used as starting material is z. B. by dehydration from 4-carboxy-pyrazoles of the general formula

The invention is described in more detail in the following examples. The temperatures are in Degrees Celsius.

example 1

2.3 g of finely ground sodium are introduced into a melt of 50 g of p-chlorobenzyl cyanide and 9.9 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole. The mixture is then heated to 110 ° to 120 ° for 4 hours with stirring, treated with 100 cm ^{3 of} alcohol after cooling and evaporated to dryness in a vacuum. The residue is taken up in 150 cm ^{3 of} 2N sodium hydroxide solution. The alkaline solution is extracted with chloroform to separate off undissolved material and then adjusted to a pH value of 5 to 6 with 6N hydrochloric acid, a solid product precipitating out. The latter is recrystallized from alcohol. This gives l-isopropyM-hydroxy-op-chlorobenzyl-pyrazolo [3,4-d] pyrimidine of the formula

OH

CH ₂

in colorless crystals with a melting point of 181 ° to 182 ° (yield: 6 g).

Example 2

HOOC
R ₃ COHN

R ₂

40

z. B. by means of anhydrides, such as acetic anhydride, obtained.

In procedure e), the acid of the general formula R2 - COOH is preferably used in In the form of a reactive derivative such as the anhydride, the amide or optionally one Orthoesters are used.

The reactions mentioned are carried out in a customary manner, if appropriate in the presence of diluents and / or condensing agents and / or catalysts, with ordinary or optional carried out at elevated temperature.

The hydroxy compounds obtained can be converted into their salts with bases, eg. B. in theirs Metal salts such as alkali metal salts e.g. B. sodium or potassium salts, are converted, e.g. B. by Treatment with appropriate bases, e.g. B. with alkali hydroxides. The salts for their part can be convert into the free oxy compounds, expediently by treatment with acids.

The starting materials are known or can be prepared by methods known per se.

16.8 g of 2-isopropyl-3-amino-4-carbonamido-pyrazole are refluxed for ^{10 hours in 60 cm 3 of} p-chlorobenzyl cyanide. After cooling, it is strongly concentrated in a vacuum. The residue is mixed with 2 η sodium hydroxide solution and extracted twice with chloroform. The alkaline aqueous solution is treated with charcoal and filtered. The filtrate is adjusted to pH 6 with 5η hydrochloric acid, whereupon the 1-isopropyl ^ -hydroxy-o-chlorobenzylpyrazolo [3,4-d] pyrimidine described in Example 1 precipitates (yield: 7 G).

Example 3

2.3 g of sodium are added in small pieces to a solution of 8.5 g of 2-methyl-3-amino-4-carbethoxy-pyrazole in 50 cm ^{3 of} benzyl cyanide and the mixture is then heated to 110 ° to 120 ° with stirring. To

The reaction mixture is cooled for 4 hours, and 100 cm ^{3 of} ethanol are added. The solution is evaporated to dryness in vacuo. ^{150 cm 3 of} 2 η sodium hydroxide solution are added to the residue and the excess benzyl cyanide is extracted with chloroform. The aqueous phase is by adding

5 η-hydrochloric acid adjusted to a pH value of 5 to 6, whereby a solid precipitate separates out, which one filtered off and recrystallized several times from ethanol.

The l-methyl - ^ - hydroxy-o-benzyl-pyrazolo [3,4-d] pyrimidine is obtained the formula

OH

CH ₂

CH ₃

in crystals; M.p. 236 to 237 ° (yield: 6 g). Example 4

A mixture of 8.5 g of 2-methyl-3-amino-4-carbethoxy-pyrazole and 50 g of 3,4,5-trimethoxy-benzyl cyanide is heated to 110 ° and 2.3 g of sodium are added in small pieces with stirring . After 4 hours, the reaction mixture is cooled, 150 cm ^{3 of} ethanol are added and the mixture is then evaporated in vacuo. ^{150 cm 3 of} 2 η sodium hydroxide solution are added to the residue and the mixture is extracted with chloroform. The aqueous phase is separated off and adjusted to a pH of 5 to 6 by adding 5η hydrochloric acid. A precipitate separates out, which is recrystallized from chloroform-petroleum ether. In this way, the l-methyl-4-hydroxy-6- (3 ^ 4 ^ 5'-trimethoxy-phenyl-methyl) -pyrazolo [3,4- d] pyrimidine of the formula

OH precipitates which, after recrystallization from alcohol, melts at 195 ° to 196 ° (yield: 5.6 g).

Example 6

30 g of p-ethoxybenzyl cyanide and 9.9 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole are heated to 60 ° and mixed with 2.3 g of sodium in small pieces. The mixture is then heated to 110 bis for 4 hours 120 °, lets it cool down, destroys the excess

ίο Sodium with alcohol and evaporate to dryness in a vacuum. The residue is taken up in 200 cm ^{3 of} 2 η sodium hydroxide solution, and it is ^{extracted with 200 cm 3 of} chloroform to separate off excess ethoxybenzyl cyanide. The aqueous alkaline solution is treated with activated charcoal and filtered. The clear filtrate is adjusted to pH 6 with 5η hydrochloric acid, whereupon 1 - isopropyl - 4 - hydroxy - 6 - ρ - ethoxybenzyl - pyrazolo [3,4-d] pyrimidine of the formula

OH

C2H5O ■

CH ₂

CHCCHs) ₂

CH ₃ O

CH ₂

OCH ₃

obtained in crystals of melting point 245 ° (yield: 5.5 g).

Example 5

50 g of 3,4,5-trimethoxy-benzyl cyanide and 9.9 g of 2-isopropyl-3-amino -4-carbethoxy-pyrazole are heated to 80 ° and mixed with 2.3 g of sodium in small pieces. The mixture is then heated for 4 hours at 110 ° to 120 °, allowed to cool, the excess sodium is destroyed with alcohol and evaporated to dryness in vacuo. The residue is taken up in 200 cm ^{3 of} 2N sodium hydroxide solution, and it is ^{extracted by shaking with 200 cm 3 of} chloroform to separate off excess trimethoxybenzyl cyanide. The aqueous alkaline solution is treated with activated charcoal and filtered. The clear filtrate is adjusted to pH 6 with 5N hydrochloric acid, whereupon l-isopropyl-4 - hydroxy - 6 - (3 ', 4', 5 '- trimethoxy - phenyl - methyl) pyrazolo [3, 4-d] pyrimidine of the formula precipitates which, after recrystallization from alcohol, melts at 175 ° to 176 ° (yield: 6.2 g).

Example 7

13.8 g of sodium are added in small pieces to 200 cm ^{3 of benzyl cyanide, followed by 63.3 g}

2-sec-butyl-3-amino-4-carbethoxy-pyrazole. The mixture is heated to 110 to 120 ° in about 30 minutes and stirred then continue at this temperature for another 5 hours.

After cooling, absolute alcohol is added and the mixture is concentrated in vacuo. To the arrears one gives dilute sodium hydroxide solution and extracted with chloroform. The aqueous alkaline solution is treated with activated charcoal and filtered. The clear filtrate is adjusted to pH 6 with 5 η hydrochloric acid, whereupon the l-sec-butyl-4-hydroxy-6-benzylpyrazolo [3,4-d] pyrimidine the formula

OH

CH ₂

CH

/ \ CH ₃ C ₂ H ₅

OH

OCH ₃

CH ₃ O

CH ₂

OCH ₃

CH (CHs) ₂ separates out, which, after recrystallization from alcohol, melts at 154-155 ° (yield: 53.8 g).

Example 8

4.6 g of sodium and then 17 g of 2- [pentyl- (3 ')] -3-amino-4-carbethoxy-pyrazole are added to 66 cm ^{3 of benzyl cyanide.} The mixture is heated to 110 to 120 ° in about 30 minutes and stirred at this temperature for a further 5 hours. After cooling, absolute alcohol is added and the mixture is concentrated in vacuo.

Dilute sodium hydroxide solution is added to the residue and the mixture is extracted with chloroform. The alkaline aqueous solution is treated with activated charcoal and filtered. You put the clear filtrate with 5η-hydrochloric acid to pH 6, whereupon the 1 - [pentyl- (3 ')] - 4-hydroxy-6-benzyl-pyrazolo [3,4-d] -pyrimidine the formula

OH

-CH ₂

C ₂ H ₅ C ₂ H ₅

CH ₂

40

45

CH ₂ -CH ₂ -OH

separates, which melts after recrystallization in alcohol at 194 ° to 195 ° (yield: 17 g).

The used as starting material 2 - (S-hydroxyethyl) - 3 - amino -A- carbethoxy pyrazole is prepared as follows:

101.5 g of ethoxymethylene cyanogen acetate and 66 g of 70% strength / 3-hydroxyethyl hydrazine are ^{heated to boiling in 700 cm 3 of} alcohol for 10 hours. It is then evaporated in vacuo and the residue is distilled in vacuo. 2 - (^ - Hydroxy-ethyl) -3-amino-4-carbethoxy-pyrazole of the formula

55

6o

Example 10

2.3 g of finely ground sodium are introduced into a solution of 9.9 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole in 100 cm ^{3 of m-methoxy-benzyl cyanide.} The mixture is then heated to 110 ° to 120 ° for 4 hours with stirring, treated with 100 cm ^{3 of} alcohol after cooling and evaporated to dryness in a vacuum. The residue is taken up in 150 cm ^{3 of} 2 η sodium hydroxide solution, the alkaline solution is extracted by shaking with chloroform to separate off undissolved material and then adjusted to a pn value of 6 with 6N hydrochloric acid, after which a greasy product precipitates. This is recrystallized from a little alcohol. This gives l-isopropyl-4-hydroxy-6 - (m-methoxy-benzyl) -pyrazolo [3,4-d] pyrimidine of the formula

separates, which, after recrystallization in absolute alcohol, melts at 144 to 145 ° (yield: 7.47 g).

Example 9

To 250 cm ³ of benzyl cyanide is added 20.7 g of sodium in small pieces and then 59.7 g of ² S 2 _(j e-hydroxy-äthyi) -3-amino-4-carbethoxy-pyrazol. The mixture is heated to 110 to 120 ° in about 30 minutes and stirred at this temperature for a further 5 hours. After cooling, absolute alcohol is added and the mixture is concentrated in vacuo. Dilute sodium hydroxide solution is added to the residue and the mixture is extracted with chloroform. The alkaline aqueous solution is treated with activated charcoal and filtered. The clear filtrate is adjusted to pH 4 with 5η hydrochloric acid, whereupon the 1- (/ S-hydroxyethyl) -4-hydroxy-6-benzyl-pyrazolo [3,4-d] pyrimidine of the formula

OH

CH ₂ CH ₂ OH

boils at 0.6 mm Hg at 180 ° and melts at 89 to 91 °.

OCH ₃

in colorless crystals with a melting point of 155 to 158 ° (yield: 6.9 g).

Example 11

2.3 g of sodium are added in small pieces to 15 g of 2- [l'-ethoxy-butyl (3 ^/ )] - 3-amino-4-carbethoxy-pyrazole and 50 g of benzyl cyanide and the mixture is heated to 100 bis for 4 hours while stirring 110 °. After cooling, 150 cm ^{3 of} ethanol are added, the mixture is evaporated to dryness in a vacuum and, after the addition of 150 cm ^{3 of} 2N sodium hydroxide solution, the residue is extracted with chloroform. The aqueous solution is acidified with hydrochloric acid and extracted with chloroform. The residue remaining after drying and evaporation of the solvent is crystallized from methanol-water and the 1 - [l'-ethoxy-butyl- (3 ')] -4-hydroxy-6-benzyl-pyrazolo [3,4- d] pyrimidine of the formula

CH ₂

CH ₂ CH ₃

CH ₂ - OC ₂ H ₅

in crystals; F. III to 112 ° (yield: 7.8 g).

The 2- [l'-ethoxybutyl- (3 ')] -3-amino-4-carbethoxy-pyrazole used as starting material is made as follows:

50 g of l-ethoxy-butyl- (3) -hydrazine and 70 g of ethoxymethylene cyanogen acetate are boiled ^{in 40 cm 3 of alcohol for 3 hours.} The solvent is then removed by evaporation in vacuo and distilled

309 668/321

the residue in a high vacuum. The compound mentioned boils at 120 to 125 ° / 0.1 mm.

Example 12

2.3 g of sodium are introduced into a mixture of 8.5 g of 2-methyl-3-amino-4-carbethoxy-pyrazole and 50 g of p-chlorobenzyl cyanide. The mixture is then heated to 110 ° for 4 hours, allowed to cool, 150 cm ^{3 of} ethanol are added and the mixture is evaporated to dryness in a vacuum. 150 cm ^{3 of} 2N sodium hydroxide solution are added to the residue and the mixture is extracted with chloroform. The aqueous solution is filtered and adjusted to a ρπ value of 5 to 6 with 2N hydrochloric acid, whereupon 1-methyl-4-hydroxy-6-chlorobenzyl-pyrazolo [3,4-d] -pyrimidine of the formula

OH

sated. This gives 4-hydroxy-6-benzyl-pyrazolo [3,4-d] pyrimidine of the formula

CH ₂

CH ₂

CH ₃

which precipitates after recrystallization from dimethylformamide-water melts at 268 to 270 ° (yield: 4.9 g).

Example 13

in colorless crystals with a melting point of 290 to 292 ° (yield: 6.2 g).

Example 15

40 g of o-methoxybenzyl cyanide and 9.9 g of 2-isopropyl-S-amino ^ -carbethoxy-pyrazole are heated to 60 ° and mixed with 2.3 g of sodium in small pieces. The mixture is then heated for 4 hours on HO to 120 °, allowed to cool, the excess sodium is destroyed with ethanol and evaporated to dryness in vacuo. The residue is taken up in 200 cm ^{3 of} 2 η sodium hydroxide solution, and it is ^{extracted with 200 cm 3 of} chloroform to separate off excess o-methoxybenzyl cyanide. The aqueous alkaline solution is treated with activated charcoal and filtered. The clear filtrate is made with 5N hydrochloric acid. to pH 6, whereupon 1 - isopropyl - 4 - hydroxy - 6 - (ο - methoxybenzyl) - pyrazolo [3,4-d] pyrimidine of the formula

OH

OCH ₃

CH ₂

2.3 g of sodium are introduced in small pieces into a mixture of 8.5 g of 2-methyl-3-amino-4-carbethoxypyrazole and 50 g of 2,3-dimethoxy-benzyl cyanide. The mixture is then heated to 110 ° for 4 hours, allowed to cool, 100 cm ^{3 of} methanol are added and the mixture is evaporated to dryness. 100 cm ^{3 of} 2 η sodium hydroxide solution are added to the residue and the mixture is extracted with chloroform. By adding 2N hydrochloric acid to the

The l-methyl-4-hy- 40 precipitates in the aqueous alkaline solution, which after recrystallization from ethanol droxy - 6 - (2 ', 3' - dimethoxy - phenyl - methyl) - pyr- melts at 157 to 159 ° (yield: 7.1 g). azolo. [3,4-d] pyrimidine of formula Example 16

CH (CHs) ₂

OH

H ₃ CO OCH ₃

CH ₂

from which, after recrystallization from alcohol, melts at 190 ° to 191 ° (yield: 5.2 g).

Example 14

4.6 g of sodium are finely comminuted in 100 cm ^{3 of} benzyl cyanide and 15.5 g of S-amino-i-carbäthoxypyrazole are added. The mixture is then heated for 4 hours with stirring to 110 ° to 120 °, after cooling, 150 cm ^{3 of} ethanol are added and the mixture is evaporated to dryness in a vacuum. The residue is taken up in 150 cm ^{3 of} 2 η sodium hydroxide solution, the alkaline solution is extracted by shaking with chloroform to separate the undissolved material and then adjusted to a pH of 4 to 5 with 6N hydrochloric acid, a solid product precipitating out. The latter is recrystallized from a lot of ethanol 50 g of 2-methyl-3-methoxy-benzyl cyanide and 9.9 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole are heated to 60 ° and mixed with 2.3 g of sodium in small amounts Staggered pieces. The mixture is then heated for 4 hours at 110 ° to 120 °, allowed to cool, the excess sodium is destroyed with ethanol and evaporated to dryness in vacuo. The residue is taken up in 200 cm ^{3 of} 2 η sodium hydroxide solution, and it is ^{extracted with 200 cm 3 of} chloroform to separate off excess 2-methyl-3-methoxy-benzyl cyanide. The aqueous alkaline solution is treated with activated charcoal and filtered. The clear filtrate is adjusted to pH 6 with 5-hydrochloric acid, whereupon l-isopropyl-4-hydroxy-6- (2'-methyl-3'-methoxy-benzyl) -pyrazolo [3,4-d] pyrimidine of the formula

OH

H ₃ CO CH ₃

CH ₂

precipitates, which melts after recrystallization from ethanol at 150 to 15Γ (yield: 7 g).

Example 17

20 g of diphenylacetonitrile and 19.7 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole are heated to 70 ° and mixed with 2.3 g of sodium in small pieces. The mixture is then heated for 4 hours at 110 ° to 120 °, allowed to cool, the excess sodium is destroyed with ethanol and evaporated to dryness in vacuo. 300 cm ^{3 of} water are added to the residue, and 2η hydrochloric acid is used to adjust the pn value to 3, whereupon a solid precipitate separates out. The latter is sucked off, boiled with a lot of petroleum ether to separate any starting material that is still present, and the portion not dissolved in petroleum ether is recrystallized from ethanol. 1 - isopropyl -A- hydroxy - 6 - (diphenylmethyl) -pyrazolo [3,4-d] pyrimidine of the formula

OH

CH (CH3) 2

is obtained in this way in white crystals with a melting point of 226 ° to 227 ° (yield: 12 g).

Example 18

2.3 g of sodium are finely ground in 50 cm ^{3 of} benzyl cyanide and 11.45 g of 2- [3'-methyl-butyl- (2 ')] -3-amino-4-carbethoxy-pyrazole are added. The mixture is heated for 4 hours with stirring to 110 ° to 120 °, after cooling, 100 cm ^{3 of} ethanol are added and the mixture is evaporated to dryness in vacuo. The residue is taken up in 150 cm ^{3 of} 2 sodium hydroxide solution, the alkaline solution is extracted by shaking with chloroform to separate off undissolved material and then adjusted to pH 3 with 6 η hydrochloric acid, a solid product precipitating out. The latter is recrystallized from a little ethanol. This gives 1 - [3 '- methyl - butyl - (2')] - 4 - hydroxy - 6 - benzyl - pyrazolo [3,4-d] pyrimidine of the formula

OH

CH-CH (CHs) ₂

CH ₃

in colorless crystals with a melting point of 157 to 158 ° (yield: 7 g).

Example 19

1.65 g of sodium are placed in 50 cm ^{3 of} anhydrous toluene, then heated to 120 ° with thorough stirring and slowly at this temperature a solution of 7 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole in 19 g of p -Chlorobenzyl cyanide was added dropwise. The mixture is then heated to 130 ° for 5 hours with stirring, mixed with 24 cm ^{3 of} alcohol after cooling and evaporated to dryness in vacuo. The residue is taken up in 100 cm ^{3 of} 2N sodium hydroxide solution, the alkaline solution is extracted by shaking with toluene to separate the undissolved material and then adjusted to a pH of 5 to 6 with 6N hydrochloric acid, a solid product precipitating out. The latter is recrystallized from a little alcohol. This gives l-isopropyl-4-hydroxy-6- (p-chlorobenzyl) pyrazolo [3,4-d] pyrimidine of the formula

OH

CH ₂

in colorless crystals with a melting point of 181 ° to 182 ° (yield: 1.6 g).

Example 20

19.7 g of 2-isopropyl-3-ammo-4-carbethoxy-pyrazole and 45.6 g of p-chlorobenzyl cyanide are ^{heated to 190 ° for 4 hours in 250 cm 3} with ammonia at 0 ° saturated methanol. The reaction solution is then evaporated, 350 cm ^{3 of} 2N sodium hydroxide solution are added and the mixture is extracted with chloroform. The aqueous alkaline component is filtered through charcoal and adjusted to a pn value of 6 with 6η hydrochloric acid, whereupon the 1 - isopropyl - 4 - hydroxy - 6 - (ρ - chlorobenzyl) pyrazolo [3,4 - d] pyrimidine is deposited is eliminated (yield:

0.24 g).

Example 21

To 22.75 g of p-chlorobenzyl cyanide in 150 cm ^{3 of} chloroform and 8.7 cm ^{3 of} absolute alcohol, dry hydrochloric acid is passed in at -10 ° until saturation, left to stand overnight at room temperature and then the reaction solution is evaporated in vacuo at a maximum of 30 ° a. The residue, containing the imino ether hydrochloride, is dissolved in chloroform and this solution is added dropwise to a solution of 19.7 g of 2 - isopropyl - 3 - amino - 4 - carbethoxy - pyrazole in 100 cm ^{3 of} chloroform and refluxed for 12 hours. The crystals separated out during the reaction are filtered off with suction and the filtrate is evaporated to dryness. This residue is dissolved in 200 cm ^{3 of} methanol, which has previously been saturated with ammonia at 0 °, and heated in a closed tube to 70 to 80 ° for 4 hours. The reaction solution is then evaporated to dryness and the residue is heated at 180 ° for 10 hours. The reaction product is extracted with chloroform and 2N sodium hydroxide solution. The alkaline-aqueous portion is adjusted with 6η-hydrochloric acid to a pn value of about 6, whereupon the 1 - isopropyl - 4 - hydroxy - 6 - (ρ - chlorobenzyl) - pyrazolo [3,4- d] pyrimidine precipitates (yield: 0.55 g).

Example 22

To 34.2 g of p-chlorobenzyl cyanide in 250 cm ^{3 of} chloroform and 13 cm ^{3 of} alcohol, dry hydrochloric acid is passed in until saturation at -10 °, left to stand overnight at room temperature and then the reaction solution is evaporated at a maximum of 30 °. The back

standing, containing the imino ether hydrochloride, is dissolved in 200 cm ^{3 of} chloroform, a suspension of 16.9 g of 2-isopropyl-3-amino-4-carbonamidopyrazole in 1800 cm ^{3 of} chloroform is added and the mixture is refluxed with stirring for 10 hours . The undissolved material is filtered off and the filtrate is evaporated to dryness. The residue consists of crude 2-isopropyl-3- [a-ätooxy- / Hp-chlorophenyl) -äthylidenamino] -pyrazole-4-carboxamide of the formula

H ₂ NOC I. CH
/ \ Il CH ₂ -C = N
OC ₂ H ₅ / \
CH ₃ N CH ₃

After the dropwise addition, stirring is continued for 1 hour at 10 ° and then for a further 2 hours at room temperature. For working up, water and dilute hydrochloric acid are added and the mixture is extracted with ether. The ether solution is dried and evaporated. The residue is rubbed with water and then recrystallized from acetone-petroleum ether. The 2- isopropyl-3- (p-chlorophenyl-acetylamino) -4-carboxypyrazole of the formula is obtained in this way

CH ₃ CH ₃

a) This amide is heated to 180 ° for 10 hours. The residue is extracted with 2N sodium hydroxide solution and chloroform. The aqueous alkaline component is adjusted with 6 η-hydrochloric acid to the pn value 6, whereupon the 1-isopropyl-4-hydroxy-6-p-chlorobenzyl-pyrazolo [3,4-d] -pyrimidine described in Example 1 separates out (yield: 6.1 g).

b) The above amide is refluxed for 30 minutes with a solution of 18 g of sodium in 315 cm ^{3 of methanol.} After filtering the reaction solution, it is evaporated and the residue is extracted with water and chloroform. The aqueous alkaline solution is neutralized with 6N hydrochloric acid, whereupon the 1-isopropyl-4-hydroxy-6-chlorobenzyl-pyrazolo [3,4-d] pyrimidine described in Example 1 precipitates out (yield: 16.5 g).

Example 23

8 g of 2-isopropyl-3-amino-4-carbamyl-pyrazole with "25 g of p-chlorophenylacetic acid amide

Heated to 200 ° for 3 hours. After cooling, the reaction product is extracted with 150 cm ^{3 of} 1N sodium hydroxide solution and chloroform. The aqueous alkaline part is acidified with 6η hydrochloric acid, whereupon the 1-isopropyl-4-hydroxy-6- (p-chlorobenzyl) pyrazolo [3,4-d] pyrimidine separates out (yield: 3.3 g).

Example 24

6.1 g of 1 - isopropyl - 4 - oxo - 6 - (ρ - chlorobenzyl) - pyrazolo [3,4-d] oxazine are mixed with 50 cm ^{3 of} benzene and 15 cm ^{3 of} liquid ammonia in a closed tube at 100 to 110 ° for 8 hours heated. 2N sodium hydroxide solution is then added to the reaction mixture, and the benzene solution is separated off. The alkaline aqueous solution is adjusted to a pH of about 6 with 6 η-hydrochloric acid, whereupon the "1-isopropyl-4-hydroxy-6-p-chlorobenzyl-pyrazolo [3,4-d] -pyrimidine precipitates ( Yield: 0.6 g).

The 1-isopropyl used as the starting product

4 - oxo - 6 - (ρ - chlorobenzyl) - pyrazolo [3,4 - djoxazine is made as follows:

A solution of 92.7 g p is added dropwise to 84.5 g of 2-isopropyl-3-amino-4-carboxy-pyrazole in 375 cm ^{3 of} absolute dioxane and 40 cm ^{3 of} pyridine at a temperature between 10 and 15 ° with stirring -Chlorophenylacetic acid chloride in 125 cm ^{3 of} dioxane.

9.7 g of 2-isopropyl-3- (p-chlorophenyl-acetylamino) -4-carboxy-pyrazole are heated with 30 cm ^{3 of} acetic anhydride for 3 hours while stirring at 100 ° to 110 °. After evaporation of the reaction solution, the residue is recrystallized from ether-petroleum ether.

The l-isopropyM-oxo-o-ip-chlorobenzyl) pyrazolo [3,4-d] oxazine is obtained in this way the formula

CH ₂

CH ₃ CH ₃

Example 25

A solution of 55.8 g of p-chlorophenylacetic ^{acid chloride in 75 cm 3 of} dioxane is added dropwise with stirring to 45.5 g of 2-isopropyl-3-amino-4-cyano-pyrazole in 325 cm ^{3 of} absolute dioxane and 24 cm ^{3 of pyridine} a temperature between 10 and 15 °. After the dropwise addition, the mixture is stirred for a further 1 hour at 10 ° and then for a further 2 hours at room temperature. After adding 100 cm ^{3 of} water and 200 cm ^{3 of} 2 η-hydrochloric acid, the 2-isopropyl-3- (p-chlorophenyl-acetylamino ^ -pyrazolecarboxylic acid nitrile of the formula) crystallizes

CH ₂ -CO-NH

7.95 g of 2-isopropyl-3- (p-chlorophenyl-acetylamino) -4-pyrazole-carboxylic acid nitrile are heated to 70 ° for 10 hours ^{with 27.2 cm 3 of} 10% potassium hydroxide solution and 102 cm ^{3 of 3% hydrogen peroxide.} The reaction solution is then filtered and acidified to pH 5 with 2N hydrochloric acid, whereupon the l-isopropyl-4-hydroxy-6- (p-chloro-

benzyl) pyrazolo [3,4-d] pyrimidine precipitates (yield: 6.2 g).

Example 26

1 - Isopropyl - 4 - hydroxy - 6 - (α - phenyl - propyl) - pyrazolo [3,4-d] pyrimidine the formula

OH

32.6 g of sodium are dissolved in 900 cm ^{3 of} n-butyl alcohol, and a solution of 70 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole and 108 g of p-chlorobenzyl cyanide in 100 cm ^{3 of} n-butanol is added refluxed for 5 hours. The reaction solution is then mixed with 1.210.5 η sodium hydroxide solution and extracted with toluene. The aqueous alkaline solution is made neutral with 5 η-hydrochloric acid, whereupon the l-isopropyl-4-hydroxy-

6 - (p - chlorobenzyl) - pyrazolo [3,4 - djpyrimidine precipitates out, which after recrystallization from alcohol separates (yield: 11.5 g).

Example .27

16.5 g of sodium are ^{finely pulverized in 120 cm 3 of} toluene in a 750 cm ³ sulfurizing flask at a bath temperature of 130 °. Then 240 cm ^{3 of} thiophene-free benzene are added. At this constant boiling at 89 ° solution, 70 g of 2 are - isopropyl - 3 - amino - 4 - carbethoxy - pyrazol in 182 g of p-chlorobenzyl cyanide to (duration of the dropping, 2 ¹ Iz hours; bath temperature 120 ° C; internal temperature 88 to 90 ° ). After the dropwise addition, the mixture is refluxed for a further 10 hours while stirring.

For working up, 250 cm ^{3 of} absolute alcohol are added and the mixture is evaporated to dryness. The residue is taken up in 1.21 liters of N sodium hydroxide solution and extracted three times with 200 cm ^{3 of} toluene. The alkaline solution is adjusted to a pH of 5 to 6 with 5 η hydrochloric acid; the crystalline precipitate is filtered off.

This crystalline filter material is dissolved in 340 cm ^{3 of} alcohol. The solution is treated with charcoal and filtered. While cooling with ice, the 1-isopropyl-4-hydroxy-6-ρ-chlorobenzyl-pyrazolo [3,3-d] pyrimidine crystallizes (yield: 65 g).

Example 28

19.7 g of 2-isopropyl-3-amino-4-carbethoxypyrazole and 30.4 g of p-chlorobenzyl ^{cyanide are heated at 105 ° for 5 hours with 3 cm 3 of} a 40% solution of trimethylbenzylammonium hydroxide in isobutanol. After cooling, the reaction solution is extracted with 1 η sodium hydroxide solution and toluene. The aqueous alkaline solution is adjusted to pH 6 with 6 η-hydrochloric acid, whereby the 1 - isopropyl - 4 - hydroxy - 6 - ρ - chlorobenzyl - pyrazolo [3,4-d] pyrimidine separates out (yield: 0, 6 g).

Example 29

melts at 142 to 143 (yield: 3.8 g).

Example 30

A solution of 19.7 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole and 45 g is added to 4.6 g of pulverized sodium in 85 cm ^{3 of absolute toluene with stirring at a temperature of 90 to 95 °}

jS-phenyl-propionitrile in 30 cm ^{3 of} absolute toluene. The mixture is then stirred for a further 5 hours at 90 to 95 °. For working up, 50 cm ^{3 of} alcohol are added and the mixture is evaporated to dryness. The residue is extracted with 1 η sodium hydroxide solution and toluene. The alkaline aqueous solution is made neutral with 6η-hydrochloric acid, the 1-isopropyl-4-hydroxy-6- (| S-phenyl-ethyl) -pyrazolo [3,4-d] -pyrimidine of the formula ^ '

OH

- CH ₂ - \

CH ₃ CH ₃

precipitates, which, after recrystallization from alcohol, melts at 124 to 125 ° (yield: 8.7 g).

Example 31

From m-hydroxybenzyl cyanide and 2-isopropyl-3-amino-4-carbethoxy-pyrazole obtained by the method described in Example 1 after recrystallization l-isopropyl-4-hydroxy from alcohol - 6 - (m - hydroxybenzyl) - pyrazolo [3,4-d] pyrimidine of the formula

A mixture of 19.7 g of 2-isopropyl-3-amino-4-carbethoxy-pyrazole and 49.5 g is added to 4.6 g of powdered sodium in 85 cm ^{3 of absolute toluene at a temperature of 90 to 95 ° with stirring} α-phenyl-butyronitrile. The mixture is then stirred for a further 5 hours at 90 to 95 °. For working up, 50 cm ^{3 of} alcohol are added and the mixture is evaporated to dryness. The residue is extracted with 1 η sodium hydroxide solution and toluene. The aqueous alkaline solution is adjusted with 6N hydrochloric acid to a pn value of about 6, whereupon the

CH ₂

OH

in white crystals with a melting point of 226 to 227 °

309 668/321

Claims (1)

PATENT CLAIM: Process for the preparation of 4-hydroxypyrazolo [3,4 - d] pyrimidines of the general formula 10 15th wherein Ri is a hydrogen atom, an alkyl, hydroxyalkyl or oxaalkyl radical, R _{2 is} a hydrogen atom or a lower alkyl radical and R3 is a phenylalkyl or diphenylalkyl radical optionally substituted by halogen atoms or hydroxyl groups or lower alkyl or alkoxy groups, and their salts, characterized in that way in itself known, either a) a 3-amino-pyrazole-4-carboxylic acid of the general formula or their esters or halides or their amide, optionally in the presence of one Condensing agent with a carboxylic acid, of the general formula R3 - COOH or their esters, halides or imino ethers or their anhydride or amide or their Sulfur derivatives or with their amidine or nitrile under the proviso that the condensation is carried out in the presence of ammonia, if not at least one of the carboxy groups is functionally modified to be a nitrogen atom having, and then possibly obtained as intermediates, substituted on the amino group 3-amino-pyrazole derivatives by heating, optionally carried out in the presence of ammonia cyclized to higher temperatures or by heating with a condensing agent or b) a 3-amino-4-cyano-pyrazole of the general formula 60 with a carboxylic acid of the general formula R3 - COOH or its esters, Halides, imino ethers or their anhydride converts in the compound thus obtained die'Cyangruppe in 4-position by heating with an alkali hydroxide and an oxidizing agent converted into the amide group, at the same time the pyrimidine ring is closed, or c) a 4-oxo-pyrazolo [3,4-d] oxazine of the general formula heated with ammonia or d) a 4-hydroxypyrimidine of the general formula OH CO - R ₂ in which X stands for a free or etherified mercapto group or a halogen atom, is reacted with a hydrazine of the general formula Ri-NH-NH-R ₄ , in which R _{4 is} a hydrogen atom or an acyl group, and optionally hydrolysed the acyl group before or at the same time as the ring closure or
e) a 6-hydrazino-4-hydroxypyrimidine of the general formula JN-NH ₂ heated with an acid of the general formula R ₂ - COOH or a reactive functional derivative of such an acid and optionally 'subsequently obtained free compounds with bases in their salts or obtained salts converted into the free compounds. Documents considered: German Auslegeschrift No. 1 056 613. © 309 668/321 8.63