DE1106331B - Process for the preparation of pyrazolo [3, 4-d] pyrimidines - Google Patents

Description

GERMAN

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

R ₃

N "

R ₂

N-

N N '

wherein R _{1 is} an alkyl, alkenyl, oxyalkyl or cycloalkyl radical, such as. B. a methyl, ethyl, isopropyl, butyl, amyl, hexyl, cyclopentyl or cyclohexyl radical, R _{2 is} a hydrogen atom or an alkyl group, R _{3 is} a halogen atom, such as a chlorine or bromine atom, an alkoxy group , a free or alkylated mercapto group, a free or by alkyl, cycloalkyl, alkenyl, oxyalkyl or aminoalkyl radicals mono- or disubstituted amino group or an optionally further heteroatoms having alkylenimino group and R _{4 is} a hydrogen or halogen atom, an alkoxy group or a represents free mercapto or amino group, and the 5- and / or 7-alkyl, oxyalkyl and aminoalkyl derivatives of pyrazolo [3,4-d] pyrimidines in which R ₃ and / or R _{4 represent} a free mercapto group, and the salts of these compounds.

Examples of substituents of an amino group in the 4-position are: methyl, ethyl, propyl, Isopropyl, butyl, amyl, hexyl, cyclopentyl, cyclohexyl, allyl, butylene (1,4), pentylene (1,5) or 3-aza or oxapentylene (1,5) radicals.

The new compounds have valuable pharmacological properties. So they show a coronary dilation and diuretic as well as central action. They also have anti-tumor and what the halogen compounds as for that, also antibacterial and antifungal properties. The new connections should therefore be used as a remedy. But they are also, and this is particularly true for the halogen and mercapto compounds too, valuable intermediates for the manufacture of medicinal products.

Particularly valuable in terms of their pharmacological Properties are the compounds of the formula

Method of manufacture
of 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 30th, June 13th 1958, January 22nd
and April 3, 1959

Dr. Jean Druey, Riehen,

Dr. Paul Schmidt, Therwil,

Dr. Kurt Eichenberger and Dr. Max Wilhelm,

Basel, Switzerland),
have been named as inventors

Mono- or dimethyl, ethyl, propyl or butylamino group represent, especially 2-isopropyl-4-mercapto- or -amino-pyrazolo [3,4-d] pyrimidine.

The examination of the new connections, taking into account their effect on the coronary vessels the toxicity compared to theophylline, showed that the therapeutic index of these pyrazolo- [3,4-d] pyrimidines is higher than that of theophylline.

The new connections are obtained by

that one 3-amino-pyrazole-4-carboxylic acids of the general formula

H ₂ N

NR ₁

R ₃

N "

NR ₁

N "" N

and their salts, in which R _{1 is} a lower alkyl radical, especially a methyl, ethyl, propyl, butyl or amyl radical, and R _{3 is} the amino or mercapto group or a mono- or di-lower alkyl-amino group, such as one in which R ₁ and R _{2 have} the meaning mentioned at the beginning, or their functional derivatives are reacted with formic acid or the functional derivatives of formic acid or carbonic acid, provided that at least one of the two carboxyl groups is functionally modified so that it contains an unsubstituted amino group, and then in obtained Pyrazolo [3,4-d] pyrimidines alkylated a free hydroxyl group present in the 4-position in a manner known per se or by a halogen atom or a free or substituted one

109 58O / 4OT

3 4

Mercapto or amino group replaced or a free zolo [3,4-djpyrirnidine to be converted. These connections

Hydroxy group in the 6-position in a manner known per se can also be used as by-products in the implementation of

alkylated or by a halogen atom or a free compound with alkyl mercapto groups with Am-

Replaced mercapto or amino group and optionally moniak or amines occur.

In a manner known per se, halogen atoms for alkoxy groups can be exchanged or a halogen atom in the 4-position can be replaced by one, depending on the substituents present in the groups or free mercapto or amino groups. If they have mercapto groups, metal-substituted mercapto or amino groups can be replaced or salts can be obtained, e.g. B. leach a free or substituted mercapto group in the 4-position by dissolving in alkali. Compounds of a basic character form salts with inorganic or organic acids through a free or substituted amino group or io. Examples of possible free mercapto groups in the 6-position by a free salt-forming acids are: amino group replaced or a free mercapto group in hydrohalic acids, sulfuric acids, phosphorus-4-position converted into an alkyl mercapto group and / or acids, nitric acid, perchloric acid; aliphatic, alicy- or obtained 4- and / or 6-mercapto- or alkyl-clic, aromatic or heterocyclic carboxylic or mercapto-pyrazolo [3,4-d] pyrimidines in the 5- and / or 15 sulfonic acids, such as ants -, vinegar, propion, oxal, 7-position alkylated 4- and / or 6-thiono compounds amber, glycol, milk, apple, wine, lemon, converts and / or obtained free compounds into ascorbin -, oxymalein, dioxymalein or pyruvine their salts or salts obtained in the free compounds acid; Phenylacetic, benzoic, p-aminobenzoic, anthranil, transferred. p-oxybenzoic, salicylic, or p-aminosalicylic acid; Methane-acid used for reaction with the S-amino-pyrazoM-carbon- 20 sulfonic, ethanesulfonic, oxyethanesulfonic, ethylene sulfonic acids or their functional derivatives; Toluenesulfonic, naphthalenesulfonic acids or sulfonic acids are primarily functional derivatives of formic fanilic acid; Methionine, tryptophan, lysine or arginine, acid, ζ. B. formamide; or carbonic acid, such as urine The 1-substituted substance required as starting materials, thiourea, guanidine, halocarbonic acid esters, pyrazoles are obtained by x-cyano-carbonic acid dihalides, e.g. B. phosgene, cyanates, e.g. B. 25/3-oxopropionic acids, optionally in the form of their funk-Alkalicyanate, isocyanates, z. B. alkyl isocyanates, or tional reactive acid and / or oxo derivatives isothiocyanates. In the case of the N-monosubstituted hydrazines, which on the N'-nitrogen-free form or carbonic acid derivatives carry the substance atom of a 3-amino-pyrazol-4-carboxylic acid residue that can be split off by hydrolysis, the resulting open-chain products are condensed Acid derivatives containing amino groups, such as the amide. 30 treated with hydrolyzing agents and at the same time In such reactions, initially open-chain or subsequently closes the pyrazole ring.
Intermediates, such as B. Pyrazolyl- (3) -isocyanate, The other starting materials are known or can be formed. These can, if necessary, also be obtained from methods known per se,
potential 3-amino-pyrazoles are formed, e.g. B. The invention is carried out in the following examples from 3-carbamyl-pyrazoles by Hoffmann degradation. 35 described in more detail. The temperatures are given in Celsius - the condensation of the aminopyrazoles to the pyra- grades,
zolopyrimidines are preferably carried out at temperatures Example 1
above 100 ° C, if necessary in the presence of

thinners and / or condensation agents in an open 19.7 g of l-isopropyl-S-amino ^ carbäthoxy-pyrazole or closed vessel. +0 den in 50 cm ³ formamide for 5 hours in a bath of In the compounds obtained free oxy- 200 to 210 ° are heated. After cooling, you suction groups by conventional halogenation, for. B. with phosphorus from the precipitated, crystalline precipitate and acid halides, such as phosphorus oxychloride or penta- crystallized this for purification from boiling ethyl chloride, against halogen atoms, such as chlorine or bromine atoms, alcohol. 2-isopropyl-4-hydroxy-pyrazolo [3,4-d] pyrimidine exchanged or in a manner known per se, for. B. by 45 of the formula
Treatment with phosphorus pentasumd, transformed into mercapto groups. Halogen atoms can be found in more usual
Way against alkoxy groups or free amino or
Exchange mercapto groups, e.g. B. through implementation
with alcoholates, thiourea, metal salts of sulfur 50

hydrogen or with ammonia. A halogen atom in NN CH ₃
4-position can be obtained in crystals by a substituted mercapto; F. 229 to 230 °.
or replace amino group, e.g. B. by reaction with 10 g of 2-isopropyl-4-hydroxy-pyrazolo [3,4-d] pyrimidine metal salts of mercaptans or with amines. and 15 g of phosphorus pentasulphide are added to 100 cm ^{3 of} pyridine. Free mercapto groups can be added by treatment with 55 ° and heated in a bath at 130 ° for 4 hours, reactive esters of the corresponding alcohols. The hot pyridine solution is then poured to 1000 cm ³ . The reactive esters used are water, after which a brown precipitate of strong, inorganic or organic acids precipitates on standing. The latter is dissolved in dilute sodium hydroxide solution, e.g. B. the hydrohalic acids, sulfuric acid or treated with animal charcoal, precipitated by means of dilute organic salt sulfonic acids, z. B. Aryl sulfonic acids, acidic to 60 and obtained after recrystallization from ethanol call. Finally, free or substituted 2-isopropyl-4-mercapto-pyrazolo [3,4-d] pyrimidine of the mercapto groups in the 4-position can be obtained by treatment with formula
Ammonia or amines against amino groups from cjj
To deceive.

It is also possible to obtain 4- and / or 6-mercapto-65 pyrazolo [3,4-d] pyrimidines by treatment with reactive Esters of alcohols not only in the corresponding compounds with etherified mercapto groups, but at the same time also in the 5- and / or

7-position alkylated 4- and / or 6-thionohydropyra-70 in crystals; F. 237 to 239 °.

The starting material is obtained as follows: 8 g of N ₁ -isopropyl-N ₂ -benzylidene hydrazine and 8 g of ethoxymethylene cyanoacetic ester are ^{heated to 80 ° in 50 cm 3 of} benzene for 10 hours. After the solvent has been removed in vacuo, the residue is recrystallized from ethanol. The ^ - (Na-benzylidene-N ^ isopropyl-hydrazino-a-cyano-acrylic acid ethyl ester is obtained in yellow prisms; mp 118 ° to 120 °.

4 g ^ - (Ng-benzylidene-Nj-isopropyl-hydrazinoJ-ix-cyanoacrylic acid ethyl ester is boiled for 2 hours with 10 normal alcoholic hydrochloric acid and the alcohol is then removed by distillation in vacuo. The residue is taken up in 200 cm ^{3 of} 2 hydrochloric acid and the Solution extracted with ether. After the aqueous solution has been separated off, it is made alkaline by adding 2N sodium hydroxide solution. The precipitated base is extracted with ether. After drying and evaporation of the ether, l-isopropyl-S-amino-'l- carbethoxy-pyrazole of the formula

C ₂ H ₅ OOC
H ₂ N

n — ch:

/ CH ₃

XH ₂

Example 2

19.4 g of 2-isopropyl-4-mercapto-pyrazolo [3,4-d] pyrimidine are placed in 150 cm ^{3 of} 1 η-sodium hydroxide solution. The solution is slowly mixed with 16 g of dimethyl sulfate while stirring and then stirred for a further 30 minutes at room temperature. The precipitate is then filtered off with suction and crystallized from ethanol. 2 - Isopropyl - 4 - thiono - 5 - methyl - 4,5 - dihydro pyrazolo [3,4-d] pyrimidine of the formula

H ₃ CN

N ^: N

CH,

N
I.

, CH,

crystallized. 2-Isopropyl-4-dimethylamino-pyrazolo [3,4-d] -pyrimidine the formula

N (CH ₃ ),

is thus obtained in crystals; F. 178 to 180 °.

The alkaline, aqueous filtrate is then extracted with a large amount of chloroform and obtained after evaporation of the chloroform as residue yellow crystals, which are recrystallized from a little isopropyl ether. 2-isopropyl-4-methylmercapto-pyrazolo [3,4-d] pyrimidine the formula

SCH ₃

ν-ch;

N "" N "

CH _R

is thus obtained in white crystals; F. 78 to 79 °.
Example 3

60

10 g of 2-isopropyl-4-methyhnercapto-pyrazolo [3,4-d] -pyrimidine are ^{heated together with 40 cm 3 of} liquid dimethylamine in a sealed tube at 90 ° to 100 ° for 6 hours. After the excess dimethylamine has been evaporated off, the residue is brought into a very little water and expelled with 10 η sodium hydroxide solution. The precipitated oil is taken up in chloroform. The chloroform residue is converted from a lot of isopropyl ether

, CHo

N-CH '

NN CH ₃

is thus obtained in white crystals; F. 138 to 140 °.

Example 4

8.5 g of 2-isopropyl-4-niethylmercapto-pyrazolo [3,4-d] -pyrimidine are ^{heated together with 80 cm 3 of} liquid ammonia in an autoclave to 95 ° to 100 ° for 20 hours. The residue is dissolved in 20 cm ^{3 of} 1N hydrochloric acid, then little that has not been dissolved is suction filtered and the filtrate is treated with 10 η sodium hydroxide solution, a solid precipitate separating out. This is crystallized from ethanol-ether and thus 2-isopropyl-4-aminopyrazolo [3,4-d] pyrimidine of the formula is obtained

NH,

back, which crystallizes from cyclohexane in white flakes; F. 72 to 73 °.

XH,

N — ch:

NN CH ₃

in white crystals; F. 236 to 237 °.
Example 5

5 g of l-methyl-S-amino ^ -carbethoxy-pyrazole are ^{heated to 190 ° with 15 cm 3 of} formamide for 10 hours. After cooling to room temperature, the deposited precipitate is filtered and recrystallized from water. 2-Methyl-4-hydroxy-pyrazolo [3,4-d] -pyrimidine of the formula is obtained

OH

N "V

55 N-CH ₃

in white crystals; F. 193 °.

10 g of 2-methyl-4-hydroxypyrazolo [3,4-d] pyrimidine are ^{heated to 115 ° with 80 g of phosphorus pentasulfide in 200 cm 3 of} pyridine for 6 hours. The pyridine is then removed in vacuo. ^{300 cm 3 of} water are carefully added to the residue. A gray precipitate separates out, which is filtered off and dissolved in 2η sodium hydroxide solution. The 2-methyl-4-mercapto-pyrazolo [3,4-d] pyrimidine of the formula is obtained by adding 2η-hydrochloric acid

SH

N-CH,

N 'Ν

failed. The melting point of this compound is above 350 °.

The starting material is obtained as follows: A solution of 65 g of N ^ methyl-Na-benzylidene hydrazine and 85 g of ethoxymethylene cyanoacetic ester in 500 cm ^{3 of} benzene is refluxed for 10 hours. A precipitate is formed, which is filtered off and recrystallized from ethanol. The / 3- (N ₂ -benzylidene-N ₁ -methylhydrazino) - «- ethyl cyanoacrylate is obtained in pale yellow crystals; F. 155 to 156 °.

80 g of β- (N ₂ -benzylidene-N _a -methyl-hydrazino) -a-cyanoacrylic acid ethyl ester are refluxed for 2 hours with 10 normal alcoholic hydrochloric acid. The solvent is then removed by distillation in vacuo. The residue is taken up in 200 cm ^{3 of} 2N hydrochloric acid and the acidic solution is extracted with ether. After the aqueous layer has been separated off, it is made alkaline by adding 2η sodium hydroxide solution. The precipitated base is extracted by shaking out several times with ether. The residue remaining after the ether extract has been separated off, dried and evaporated is distilled at 130 ° (at a pressure of 0.01 mm of mercury). It becomes l-methyl-3-amino-4-carbethoxypyrazole of the formula

C ₂ H ₅ OOC
H ₂ N

N - CH,

obtained melting at 92 to 93 ^D.

Example 6

To a solution of 10 g of 2-methyl-4-mercaptopyrazolo [3,4-dl pyrimidine in 40 cm ^{3 of} 2 η sodium hydroxide solution, 9 g of dimethyl sulfate are added with stirring at room temperature. After 1 hour, the deposited precipitate is filtered off and recrystallized from ethanol. The 2-methyl-4-methyl-mercaptopyrazolo [3,4-d] pyrimidine of the formula is obtained in this way

SCH ₃

N ■ -— =

N-CH ₃

N N

35

F. 172 to 173 ^:.

Example 7

A solution of 10 g of 2-methyl-4-methylmercaptopyrazolo "3,4-d] pyrimidine and 10 g of propylamine in 100 cm ^{3 of} ethanol is heated to the boil for 6 hours. 5-dihydro-pyrazolo-3,4-d "pyrimidine of the formula

45

CH, -N ■ • - = ™.

15 recrystallized water. The 2-methyl-4-aminopyrazolo is obtained in this way [3,4-d] pyrimidine of the formula

NH ₂

I, N-CH ₃

N "N
The connection melts above 350 °.

Claims (1)

PATENT CLAIM Process for the preparation of pyrazolo [3,4-d] pyrimidines the general formula N \ ™ ^ -R ₂
R _J NR ₁ W N "" wherein R _{1 is} an alkyl, alkenyl, oxyalkyl or cycloalkyl radical, R _{2 is} a hydrogen atom or an alkyl group, R _{3 is} a halogen atom, an alkoxy group, a free or alkylated mercapto group, a free or alkyl, cycloalkyl, alkenyl, Oxyalkyl or aminoalkyl radicals mono- or disubstituted amino group or an alkyleneimino group, optionally containing further heteroatoms, and R ₄ denotes a hydrogen or halogen atom, an alkoxy group or a free mercapto or amino group, as well as the 5- and / or 7-alkyl, oxyalkyl and aminoalkyl derivatives of pyrazolo [3,4-d] pyrimidines, in which R ₃ and / or R _{4 represent} a free mercapto group, and their salts, characterized in that 3-amino-pyrazole-4-carboxylic acids of the general formula HOOC-, r-R, H ₂ N NR ₁ N " N-CH ₃ NN is filtered off and sublimed for purification in a high vacuum; F. 263 to 265 \ The filtrate is evaporated. The residue is recrystallized from methylene chloride-petroleum ether and thus receives the 2-methyl-4-propylamino-pyrazolo [3,4-d] -pyrimidine of the formula NH-CH ₂ -CH ₂ -CH ₃ N ■ = - N-CH ₃ N N in crystals; F. 133 \ The hydrochloride melts 244 to 246 \ " Example 8 15 g of l-ethyl-3-amino-4-cyano-pyrazole are heated with 10 cm ^{3 of} formamide to 190 ° to 200 ° for 10 hours. The deposited precipitate is filtered off and off © 109 · 580 / 40T or their functional derivatives with formic acid or the functional derivatives of formic or carbonic acid with the proviso that at least one of the two carboxyl groups is functional is modified so that it contains an unsubstituted amino group and then obtained in Pyrazolo [3,4-d] pyrimidines have a free hydroxyl group present in the 4-position in a known per se Way alkylated or by a halogen atom or a free or substituted mercapto or amino group replaced or a free hydroxyl group in the 6-position is alkylated in a manner known per se or by a Replaced halogen atom or a free mercapto or amino group and optionally known per se Way halogen atoms for alkoxy groups or free mercapto or amino groups or exchanges Halogen atom in 4-position replaced by a substituted mercapto or amino group or a free or substituted mercapto group in the 4-position by a free or substituted amino group or a free one Mercapto group in 6-position replaced by a free amino group or a free mercapto group in 4-position converted into an alkyl mercapto group and / or obtained 4- and / or 6-mercapto- or alkylmercapto-pyrazolo [3,4-d] pyrimidines into the 4- and / or 6-thiono compounds alkylated in the 5- and / or 7-position converts and / or obtained free compounds into their salts or obtained salts into the transferred to free connections.