DE1962261C3 - Process for the preparation of 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido [5,4-d] pyrimidine - Google Patents

Description

characterized in that 2,6-bis (chlorosulfonyl) -4,8-dipiperidino-pyriniiocK [5,4-d] -pyrimidine the formula

QO ₂ S

optionally in the presence of a tertiary amine and / or a solvent with diethanolamine at a temperature of more than 100 ° C.

The invention relates to a new method of manufacture of 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine the formula

HOH ₂ CH ₂ C

HOH ₂ CH ₂ C

which has excellent vasodilatory dilation of the coronary arteries.

The method according to the invention is characterized in that that 2,6-bis (chlorosulfonyl) -4.8-dipiperidino-pyrimido [5,4-d] pyrimidine the formula

ClQ ₂ S

optionally in the presence of a tertiary amine and / or a solvent with diethanolamine at a temperature of more than 100 ° C
40. The end product can be obtained if the compound of formula II with double or more, CH ₂ CH ₂ OH preferably with a four-fold or more molar

Amount of diethanolamine at temperatures between "1 100 and 120 ° C for a longer period of time. The response time

45 can be reduced by increasing the reaction temperature - CH ₂ CH ₁ OH. For example, the reaction takes place at

about 200 ^° C. completely in about one hour.
In the above reaction, the amount of diethanolamine can be decreased by thus adding a tertiary amine such as pyridine or chboline to the reaction mixture.

An inert solvent can be used for the reaction organic solvents such as tetrahydrofuran, decahydronaphthalene, toluene or xylene can be used. However, it is also possible to use excess diethanolamine as a solvent.

There are two known processes for the preparation of 2,6-bis (diethanolamino) -4,8 - dipiperjdino * pyrimido [5,4 - d] pyrimidine. According to the method of 60 German Auslegeschrift 1116676, a 2,4,6,8-Te-SO ₂ CI (II) trahalogenpyrimido [5,4-d] pyrimidine, which is replaced by Kon

densation of 5-amino orotic acid with urea (cf. DE-PS 8 45 940) and halogenation of the resultant 2,4,6,8-Tetrahydroxypyrimido [5,4-d] pyrimidines er-6s is held, only reacted with piperidine in order to introduce the piperidino groups in the 4- and 8-positions, and the reaction product is then reacted with diethanolamine to reduce the diethanolamino-

to introduce groups in the 2 and 6 positions.

From the German Auslegeschrift 11 Sl 806 another process for the preparation of 2,6-bis (diethanolamino) - 4,8 - dipiperidino - pyrimido [5,4 - d] pyrimidine is known, in which one first the more reactive halogen atoms in 4- and 8-Stcilung a 2 _> 4,6,8-Tetrahalogen-pyrimido [5,4-d] pyrimidine replaced by reaction at low temperature by unsubstituted or substituted mercapto or hydroxyl groups and then the halogen atoms in 2- and 6- Position is exchanged for diethanolamino groups by reaction with diethanolamine at elevated temperature and the groups in the 4- and 8-position of the compound thus obtained are converted into piperidino ribs by reaction with piperidine, working at a higher temperature than when reacting with diethanolamine. However, this process is far inferior to that of the German Auslegeschrift 1116676, since not only is a high temperature required, but also the product can only be obtained in a lower yield.

The German Auslegeschrift 11 Sl 806 discloses Reactions to replace the unsubstituted or substituted mercapto or hydroxyl groups in 2,4,6,8-position on the pyrimido [5,4-d] pyrimidine ring are bound by amino radicals; however, these reactions may take the particular form indicated above Case difficult to produce 2,6-bis- (diethanolamino) - 4,8 - dipiperidino - pyrimido [5,4 - d] pyrimidine can be used. It can e.g. B. no 2,6-bis (diethanolamino) - <', S-dipiperidinopyrimido [5,4-d] pyrimidine if you have a 2,6-bis- (alkylmercapto) - 4,8 - dipiperidino - pyrimido [5,4 - d] pyrimidine, obtained by chlorination and subsequent Reaction with piperidine from a 2,6-bis- (alkyI-mercapto) -4,8 - dihydroxypyrimido [5,4 - d] pyrimidine was used as starting material and reacts with diethanolamine at high temperature. This is probably because there are alkyl mercapto groups react only with difficulty in the 2- and 6-position with diethanolamine. When the reaction is through If the temperature is forced to increase further, the piperidino groups are in the 4- and 8-positions also replaced by diethanolamino groups, or decomposition occurs.

So far has been considered the most beneficial method for Production of 2,6-bis (dJäthanolamino} -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine, that in the German

Auslegeschrift II16676 described by 2,4,6,8-Te-

trahalogen - pyrimido [5,4 - d] pyrimidines starting

Procedures viewed. It has now been shown, surprisingly, that

das = 2,6-bis- (diethanolamino) -4,8-dipiperidino-pyrirni-

do [5,4-d] pyrimidine from 2,6-bis (chiorsulfonyl) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine can be obtained by the process according to the invention kana. It is surprising that the compound of the formula H, the groups other than halogenate in the 2- and 6-positions carries, with diethcnciarnin without peanuts on the Piperidino groups can be implemented in the 4- and 8-position and that also the compound in good yield is obtained.

The compound used as the starting material for the Method of the invention used is new. she can, however, easily be made from -i.S-dihydroxy- ^ o-dimercaptopyrimido [5,4-d] pyrimidine can be obtained in the manner shown in the table. 4,8-dihydroxy-2,6-dimercapto-pyrimido [5,4-d] pyrimidine can advantageously by customary methods according to the information in GB-PS 7 99177 and DE-PS 1093801 to be produced. From example 25 These patents show that 2-methylthio-6-thio-8-hydroxypyrimido [5,4-d] pyrimidine from 2-methylthio-5-aminopyrimidinecarboxylic acid (6) and ammonium rhodanide is obtainable according to the following reaction:

C NH ₂

N C

IH + NH ₄ SCN -

/ ^c \ / ^c \ / 'sy \ /

CH ₃ SN COOH CH ₃ SNC

H \ / H C.
I. I. ⁵ I. I. I.
N C. Il
* c N ' \ H
I. I.
C ²

H
C.

Tautomerism C C

CH ₃ SNC

OH

To prepare 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido [5,4-d] pyrimidine, the above specified starting materials of Example 25 of GB-PS 7 99 177 or DE-PS 10 93 801 by 5-amino-4-hydroxy-2-methylthio-pyrimidinecarboxamide (6) and replaced a dithiocarbamate.

OH

C.
\

NH ₂

I Il
cc

CH ₃ SN CONH ₂

H ₅ C

C ₂ H ₅

N-C-SH

HjC ₂

C ₂ H ₅

H ₅ C ₂ -OC-SNa OH

C N SH

NCC

I Il I

CCN

CH ₃ SNC

OH

5 6

These two starting materials are in the description. In addition, the reaction product lalls in

Exercise of GB-PS 7 99177 on page 2 in lines 60 of its tautomeric form under the following on page 1.

to 78, after which amides of the free pyrimidine left column, below, of GB-PS 799177 indicated

carboxylic acids- {6) (loc. cit., lines 75 to 78) with dithio- general formula

carbaminates (loc. cit., line 64) are implemented S

CNR ₇

? · Ι -ΐ

C- * C ⁹ N

/ \ s / \, o / \ R ₅ NCR ₃

wherein R _{3 is} a hydrogen atom (page 1, line 33), R ₄ . a Wasserstoifatoni (page 1, line 36), R ₅ an A! ky! - thiogroppe (page 1, line 42), z. B. a methylthio group (see. Example 25), R ₆ a hydroxyl group (page 1, line 44 and 45) and R _{7 can be} a sulfur atom (page 1, line 46).

Dealkylation of the methylthio group can then

take place according to the method, • "ie it is described in the work of FHS C urd and DN R> L-.fe ards ο η, Joum. Chem. Soc 1955, pages 1853 to 1858, in particular page 1857, paragraph 4

The technical progress achieved by the process according to the invention is shown in the table below emerged:

Tabel

Process of the invention: overall yield 30.4% or more

Example 2a ₂

OH

H ₃ CS

CONH ₂

Yield 82.2% H ₃ CS

Example 2 b

87.7%

OH

Example 2 c

PClj + POCl ₃ 87%

Example 2d Example 2e

Cl ₂ 96% ClO ₂ S

SO ₂ Cl

Examples 1 or 2

HN

C ₂ H ₄ OH

C ₂ H ₄ OH HOH ₄ C,

75.2 or 78.5% ν '

/ HOH ₄ C ₂

Process according to DE-AS 1116 676: overall yield 25.9%

OH

HO

NH ₂

COOH

DE-AS 11 16 676
Example 2

PClj + POCI ₃

DE-PS 8 45 946 Example 2

Yield 90%

DE-ASIl 16 676
Example 28

Cl

58%

- nrY

95%

DE-ASIl 16 676 Example 28

C ₂ H ₄ OH

HN

C ₂ H ₄ OH

52.4%

HOH ₄

C, I

C ₂ H ₄ OH

C ₂ H ₄ OH

(I)

OH

HO

OH

C ₂ H ₄ OH

C ₂ H ₄ OH

HOH ₄ C ₂

Process according to DE-AS 1151 806: overall yield 163%

DE-PS 8 45 946 Example 2

OH

OH

NH,

HO

COOH

Yield 90%

HO

OH

DE-ASIl 16 676
Example 2

PCI ₅ + POCI,
58%

GB-PS 807826
Example 18

C ₂ H _S SH
96%

SC ₂ H ₅

DE-ASIl 16 676
Example 22 a
C ₂ H ₄ OH

DE-AS 11 51 806
Example 2 a

C ₂ H ₄ OH

SC ₂ M ₅ /

50% HOH ₄

C ₂ H ₄ OH - [JC ₂ H ₄ OH

1 ^N

C ₂ H ₄ OH 67% HOH ₄ C ₂ I ί Τ C ₂ H ₄ OH

NH

example 1

2,6-bis (diethanolamino) -4> 8-dipiperidinopyrimido [5,4-d] pyrimidine

A mixture of 300 mg of 2,6-bis- (chlorosulfonyl) -4,8-dipiperidino-pyrimide [5,4-d] pyrimidine and 1.3 g of diethanolamine was heated on an oil bath to below 110 ° C. for 5 hours or reacted at 20O ⁰ C for 45 minutes. After standing in the cold, the reaction mixture was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate, and then the chloroform was evaporated under reduced pressure. The resulting viscous red-brown residue was triturated with a small amount of acetone, and 230 mg (75%) were obtained , 2%) of the product obtained, which was filtered off. It was recrystallized from ethyl acetate. Fine, distinctly yellow needles with a melting point of 160 to 162 ° C. were obtained. No depression of the melting point could be found when the product obtained was mixed with an authentic sample which had been produced by another method.

Example 2

2,6-bis (diethanolamino) -4 »8-dipiperidinopyrimido [5,4-d] pyrimidine

A mixture of 1 g of 2,6-bis {chlorosulfonyl) -4.8-dipiperidino-pyrimido [5,4-d] pyrimidine and 10 g of diethanolamine was stirred for 72 hours at 120 ⁰ C. After standing in the cold, the reaction mixture was poured into 50 ml of chloroform evacuated. The chloroform layer was then washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure. 800 mg (78.5%) of the crude product were obtained. This was purified by column chromatography on silica gel with 25% methanol-ethyl acetate as the eluent. The eluate was concentrated and 615 mg (60.3%) of the product were obtained as yellow crystals with a melting point of 161 to 163.degree.

The starting material was prepared as follows:

a,) In 10 ml of pyridine, 100 mg of 5-amino-4-hy-

droxy - 2 - methylthiopyrimidinecarboxamide - (6) and 2.2 g of N.N'DJäthyldithäocarbaniinsäurs-diethy! - dissolved amine salt and the solution heated under reflux overnight. The one containing the reaction product Liquid was concentrated and 3 ml of water was added to the black-brown thus formed Residue added. After the pH of the mixture by adding acetic acid to 4 to 5 10 ml of ether was added to the mixture and shaken well Allow the mixture to stand for about an hour at room temperature, and the crystals which separated out were filtered off and washed twice with 0.5 ml of water each time.

so The crystals thus obtained were in 10 ml of 3normal dissolved in aqueous ammonia. Activated charcoal was added to the mixture, and the charcoal as well as undissolved ones Ingredients filtered off. The filtrate was washed with acetic acid weakly acidified, and the precipitating light yellow crystalline precipitate was filtered off and washed twice with 1 ml of water each time and dried obtained 80 mg (61.5%) 4,8-dihydroxy-6-mercapto-2-methylthio-pyrimido [5,4-d] pyrimidine.

a ₂ ) 0.38 g of carbon disulfide were added to a sodium alcohol solution obtained by adding 0.115 g of metallic sodium to 3 ml of ethanol. 50 mg of S-Anwio ^ -hydroxy ^ -methylthiopyrmudincarboxamide- (6) and 5 ml of pyridine were added to the yellow solution thus obtained, and the mixture was refluxed for 18 hours. The solution was then cooled to room temperature and the precipitated crystals were collected 1 ml of water was added to crystals and the pH of the

Mixture adjusted to about 4 by adding acetic acid. The light yellow crystals thus obtained were filtered off, washed twice with 0.5 ml of water and dried. 53.4 mg of 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido [5,4-d] -pyrimidine were obtained in a yield of 82.2%.

b) A solution of 46 g of metallic sodium in 600 ml of anhydrous methanol was fed with 80 g of dried hydrogen sulfide, whereupon the methanol was distilled off under reduced pressure. 1000 ml of anhydrous ethylene glycol were added to the residue and the mixture was heated and concentrated at a reduced pressure of 70 to 80 mm Hg until the temperature of the solution was about 135 ° C., whereupon the solution was cooled. In the so prepared ethylene glycol solution of anhydrous? 80 g of 4,8 - dihydroxy-6 - mercapto - 2 - methylthiopyrimido [5,4 - d] pyrimidine were suspended in sodium hydrogen sulfide and the mixture was stirred at room temperature for 30 minutes while slowly adding hydrogen sulfide, and then carefully adjusted the temperature in order to prevent foam development. slowly increased to 155 to 160 ^° C., whereupon the stirring was continued for a further 6 hours at this temperature with the addition of hydrogen sulfide. 800 ml of methanol were then added to the reaction mixture, which had cooled after the reaction had taken place, and the mixture was stirred for 10 minutes and the yellow crystals thus obtained were filtered off and washed with 200 ml of methanol. The crystals of the sodium salt of 4,8-dihydroxy-2,6-dimercaptopyrimido- [5,4-d] pyrimidine thus obtained were then heated to 80 to 85 ° C. with the addition of 2000 ml of water in order to dissolve them; insoluble matter was filtered off. The filtrate was adjusted to pH 4 with acetic acid at a temperature not exceeding 40 ° C. The solution was then aerated for about 30 minutes, after which filtered crystals of the product were washed first with 320 ml of water and then with 160 ml of methanol. After drying for one hour with hot air at 70 to 80 ° C., 66 g of 4,8-dihydroxy-2,6-dimercapto-pyrimido [5.4-d] pyrimidine (yield 87.7%) were obtained.

c) A mixture of 4 g of 4,8-dihydroxy-2,6-dimercapto-pyrimido [5,4-d] pyrimidine, 22 g of phosphorus pentachloride and 120 ml of phosphorus oxychloride was 30 minutes refluxed on an oil bath. The reaction mixture became under reduced pressure concentrated and from the residue the excess phosphorus pentachloride as much as possible at about 70 ° C sublimed off under reduced pressure. By adding 5 ml of chloroform to the residue, it became 4,8-dichloro-2,6-bis (chlorosulfeno) pyrimido [5,4-d] pyrimidine precipitated The precipitate was filtered off. The yield was 5.1 g (87%) of the product with a melting point of 198 to 199 ° C.

Analysis door C ₆ N ₄ -SCI ₄ :
Calculated:

C 21.67, N 16.77, Cl 42.48, S 19.20%; found:
C 21.57, N 16.57, Cl 42.05, S 19.40%.

d) To a solution of 350 mg of 4,8-dichloro-2,6-bis (chlorosulfono) pyrimido [5,4-d] pyrimidine in 10 ml of dry dioxane was added 0.8 ml of piperidine dropwise

to added with stirring and cooling. The reaction mixture was further left at room temperature for one hour and stirred for a further 30 minutes at 50 ° C. and then concentrated. The residue was then dissolved in 50 ml of chloroform dissolved, and the solution was made three times with each

■ Washed 10 ml of water. The solution was thereafter dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure. The product was precipitated from the residue thus obtained by adding 1 to 2 ml of ethyl acetate. The crystals were collected by filtration and washed with a small amount of ethyl acetate washed and dried. There was 370 mg (67%) of 4,8-dipiperidino-2,6-bis- {piperidinosulfeno) -pyrimido- [5,4-d] pyrimidine obtained with a melting point of 165 to 167 ° C.

Analysis: C ₂₆ H ₄₀ N ₈ S ₂ :
Calculated:

C 59.06, H 7.62, N 21.19, S 12.13%; found:

C 58.90, H 7.36, N 20.76, S 11.86%.

e) In a suspension of 100 mg of 4,8-dipiperidino-2,6-bis (piperidinosulfeno) -pyrimido [5,4-d] pyrimidine in 7 ml of water-methanol (5: 2) mixture became chlorine gas Initiated for 2 hours with stirring and ice cooling. The yellow crystals obtained were filtered off with Washed with water and dissolved in 50 ml of chloroform. The solution thus obtained was three times with 10 ml 3% aqueous sodium bicarbonate solution and then washed three times with 10 ml of water each time. The solution was then dried over anhydrous sodium sulfate. The dehydrated solution became that Crude product by evaporating the chloroform under reduced pressure and triturating the residue obtained in crystal form with 2 ml of ethyl acetate. The crystals were filtered off and with a small Amount of ethyl acetate washed. 90 mg (96%) of 2,6-bis (chlorosulfonyl) -4,8-dipiperidino-pyrimido- [5,4-d] pyrimidine were obtained obtained with a melting point of 208 to 209 ° C (decomposition).

Analysis: Q ₆ H ₂₀ N ₆ S ₂ O ₄ Cl ₂ :
Calculated:

C 38.79, H 4.07, N 16.96, S 12.94, Cl 14.31%; found:

C 39.27, H 4.46, N 16.39, S 12.49, Cl 14.05%.

Claims (1)

Claim: Process for the preparation of 2,6-bis (diethanolaniino) -4,8-dipiperidino-pyrimido [S, 4-d] pyrimidine formula CH ₂ CH ₂ OH HOH ₂ CH ₂ C CH ₂ CH ₂ OH