DD265760A3 - PROCESS FOR THE PREPARATION OF 2,4,6,8-TETRACHLORPYRIMIDO- [5,4-D] PYRIMIDINE - Google Patents

Abstract

2,4,6,8-Tetrachloropyrimido & 5,4-d! Pyrimidine can be prepared by reacting 2,4,6,8-tetrahydroxypyrimido & 5,4-d! Pyrimidine or its salts with PCl5 or PCl3 and chlorine gas, in the presence of an indifferent solvent , in improved quality and quantity with simultaneously improved technical Verfahrensfuehrung be prepared by carrying out the reaction in the presence of triethylbenzylammonium chloride in an inert organic solvent and the workup is carried out in the presence of a nonionic surfactant. The target product is a valuable intermediate of the pharmaceutical industry.

Description

Field of application of invention

The invention relates to a process for the preparation of 2,4, P, 8-tetrachloropyrimidol5,4-d) pyrimidine (I), which is a valuable intermediate in the pharmaceutical industry.

It is needed above all for the cardiovascular active drug dipyridamole, but also represents the starting compound for other drugs.

Characteristic of the known state of the art From DE-AS 1116676 (cl. 12p 10), the synthesis of 2,4, e, 8-Tetrachlorpyriniido [5,4-d] pyrimidine (I) is known. You go

of 2,4,6,8-tetrahydroxypyrimido (5,4-d) pyrimidine (II) or its disodium salt (Ui) and chlorinated with PCI in POCl ₃ .

It has already been proposed a process for the preparation of I aui Il or Ill, which is necessary for the chlorination PCU from PCIj and Cl ₂ intermediates. The variant of DD-PS 105447 supplies, like the abovementioned methods, I in only about 70 to 75% yield; on

much of the starting compound II or III is destroyed due to the long reaction times. These decomposition products or unreacted starting material significantly interfere with the further progress of the synthesis and give large

Difficulties in the work-up. The thus obtained tetrachloro compound is produced in a poor quality and

must be purified by repeated Umkristallisatlon.

Another shortcoming of the processes described above is that the energy input in the chlorination reaction

must take place continuously, otherwise it comes to the termination of the reaction. This reaction can not be re-initiated, even if new PCI * is added.

B. Cairns and W.O. Kermack and W.O. Kcrmack and N.E. Storey describe in J. Chem. Soc. 1950, p. 1322 ff. And 1951, p. 1390,

that the addition of Hexadecyltrirnethyiamrnoniumbrornld (IV) in the chlorination of 3-hydroxy-2-naphthoic acid or in 4-hydroxy-quinolinoquinoline yield increasing. This effect was surprising according to the authors and could not be explained. The addition of IV to the chlorination of Il and Ill, respectively, was without effect, on the contrary, it was even a yield reduction in Il by 6% and in III by 8% detectable. A generality that IV is to be used as a chlorlerungungspromoting agent, it is not derivable. At the same time it is not deducible that quaternary

Ammonium salts cause such effects. On the basis of own, extensive investigations could by a simple Exchange of IV for another compound with relevant properties in the chlorination did not yield the desired results Yield increase can be achieved. J. Dochx in Byntheais 1973 (8) p. 441 to 456 describes the effects of the use of quaternary ammonium salts

organic syntheses. He also examined and described oubffiitutionsreaktionen, but without the hinwels that quaternary

Ammonium salts in the chlorination reaction yield increase .d act and thus allow a general applicability. The addition of quaternary ammonium salts in the cases mentioned in the literature was purely coincidental, universal Rules can not be established and do not suggest a solution to the problem. Another shortcoming with the addition of IV to the chlorination of Il or Ill is the formation of fission products in comparison

for conversion without IV by about 10 ^ bIs 15% higher. The fission products are mainly concerned with the

connection

^V ,

σοοι

which, with other compounds, adversely affects the further progress of syntheses, especially those which lead to cardiovascular agonists or antiplatelet drugs. The separation of the secondary compound, starting from V, is complicated by the similar chemical properties.

Object of the invention

The aim of the invention is to provide an improved chlorination process of 2,4,8,8-tetrahydroxypyrimido-1,6,4-d) pyrimidine II or its disodium salt III in terms of egg size and quality.

Dcrlegunq the essence of the invention Dc. It is the object of the present invention to provide a process for the preparation of 2,4, e, 8-tetrachloropyrimido (5,4-d)

To develop pyrimidine I, where I In improved quality and quantity obtained and the Verf (management is technically better controlled overall.

According to the invention, the object is achieved by reacting the chlorination mixture consisting of

2,4, e, 8-Tetrahydroxypyrimidol6,4-d) pyrimidln Il or its disodium III and PCI »in POCl ₁ or an inert organic solvent, Triethylbenzylt.rr .. ~ nonium chloride (V") is added and the reaction mixture Boiled for 4 to 8 hours, preferably β hours, at reflux and worked up the mixture in the presence of a nichtionofetnen surfactant.

The procedure according to the invention is carried out so that VI in amounts of 0.01 to 1%, based on the substance to be chlorinated, the Reaction <used. The chlorination to the tetrachloro compound is carried out according to the invention at temperatures of 60 to 1 S C. / or extracts

at the boiling point of the respectively used inert organic solvent or of POCU.

Suitable inert organic solvents are, for example, halogenated aliphatic and aromatic hydrocarbons,

such as carbon tetrachloride, tetrachloroethane, perchlorethylene, chlorobenzene, toluene, xylene or dichlorobenzene

The required for chlorination PCI ₆ can either be added directly to the reaction mixture or presented in or Reaction mixture in a proposed manner from PCI) are prepared by introducing chlorine, wherein Vl already in the mixture

can be present.

As non-ionic Tens'de are suitable Oxethylierungsprodukte of alkylphenols ^ and / or rettalkoholen with a Ethylene oxide chain between 7 and 12, preferably 9. The 2,4, e, 8-tetrachloropyrimido [5,4-d] pyrimidine I prepared by the process according to the invention is obtained in improved form Yield and quality. It is surprising that while the reaction times are shortened and ReaKilonsunteribrechung, for example, conditionally

by discontinuous energy supply, no more reaction interruption occurs.

Ausführungsbolsplele

Example 1 160kg of disodium salt of 2,4,6,8-tetrahydroxypyrimido [6,4-d] pyrimidine was stirred while cooling

one after the other with 6001 POCI ₁ and

378 kg of PCI ₁ offset. You give to that

1 kg of triethylbenzylammonium chloride and passes at 20 to 4O ⁰ C 195 kg of chlorine, which must be strongly cooled.

Then it is heated to boiling and stirred for β hours under reflux. Thereafter, the POCI ₁ becomes initial

distilled off under atmospheric pressure and towards the end in vacuo, with a temperature of about 115 to 125 ⁰ C against

At the end of the vacuum distillation should be achieved. After cooling to 40 to 60 'C is mixed with

10001 chloroform, heated to 60 to 60 ^c C and separates the chloroform phase. The residue is again with

Extracted 5001 chloroform. The combined organic phases are concentrated and after cooling at 15 to 20 ° C.

Stirred for 1 hour. The precipitated chlorine derivative is filtered off, the filtrate is concentrated again, cooled and abgesauyt and dried under exclusion of moisture.

Yield: 149 kg Δ 88% of the theory. Analytical control: TLC: eluent: CHCl ₁ , benzene 100% 2,4,6,8-tetrachloropyrimido | 5,4-d] pyrimidine, no by-products.

Fp.25e-268 ° C.

Example 2

kg of 2,4,6,8-tetrahydroxypyrimido [5,4-d] pyrimidine are added successively with 1000 l perchlorethylene.

For this, kg of PCI ₆ and kg of triethylbenzylammonium chloride are added and boiled for 6 hours at reflux.

In Anechli'G the resulting POCIi is distilled off under atmospheric pressure to 115 ⁰ C, then it is still in the vacuum, laughter-treated.

C. and remaining mixture is cooled to 10.degree. C. and water is added slowly at this temperature, during which it is necessary to cool constantly so that the temperature does not exceed 15.degree. C., kg of an ethoxylated phenol ethoxylated with 9 moles of ethylene oxide is added and unreacted is separated Starting product from.

The lower organic phase is separated distilled to about 350 liters and cooled.

The precipitated target product is aspirated, nachgowaschen and dried under exclusion of moisture. Yield: 149 kg Δ 88% of theory. Analytical control: TLC: eluent: CHCl ₃ , benzene 100% 2,4, e, 8-tetrachloropyrimido [5,4-d] pyrimidine, no minor or

decomposition products

Mp 256-258 ⁰ C.

Disodium salt of 2,4,6,8-Tetrahydroxypyrimidoi5,4-d) -pyrimidine are slowly added to a mixture

out

Toluen and

PCIt, given. By cooling while a temperature of 20 to 30 "C is maintained. After that you give Triothylbenzylammonium chloride and the mixture is heated to 120 to 125 ⁰ C. It is 6 hours with stirring and Reflux cooked. Subsequently, the resulting POCl under atmospheric pressure is distilled to a temperature of 115 to

118 ° C from. Dan Rückelend cools to 10 to 15'C and fills in

Toluen on. The solution is slowly dripped into 10 to 15 ° C water, then the mixture is added

an ethoxylated with 12 moles of ethylene oxide nonylphenol and separates the organic phase. In 1er aqueous

Phase remains unreacted starting material, the organic phase contains no insoluble constituents. After Abdeatillieren of the toluene up to half of the output volume is cooled again and

Stirred for 1 hour at 10 to 15 "C. The precipitated target product is filtered off with suction and dried in a vacuum oven.

Yield: 155 g A 92% of theory. Analytical control: TLC: eluent: CHCl ₁ , benzene 100% 2,4,6,8-tetrachloropyrimido | 5,4-d] pyrimidine, no by-products, none

decomposition products

 Mp 257-258-C.

Example 4 In a mixture consisting of

g 2,4,6,8-tetrahydroxypyrimido (5,4-d] pyrimidine, ml xylene (technical product),

g Trlethylbenzylammoniumchlorid and 3'8 g of PCI], is introduced with stirring and condenser 19tf g of chlorine, the temperature should not rise above 35 to 40 * C.

Thereafter, the mixture is stirred for 30 minutes at room temperature and 6 hours at 135 to 145 ⁰ C. During the reaction, the boiling point drops to 120 to 130 ⁰ C. Thereafter, the resulting POClj is distilled off under atmospheric pressure, the xylenhaltige phase in 1.51 with water

Dropped g of a 7 mol of ethylene oxide ethoxylated dodecylphenol at 10 to 15 ° C and stirred for 30 minutes. The organic phase is separated, distilled to half, cooled and the precipitated Tetrachlorverbindi / ng sucked off, washed and dried

Yield: 153g ü 90% of theory

 Analytical control:

TLC: eluent: CHCl ₁ , benzene 100% 2,4, e, 8-tetrachloropyrimido (5,4-d] pyrimidine, no by-products, mp: 256-258 ° C.

Example 3 150g

Claims (6)

1. A process for the preparation of 2,4,6,8-TetrachlorpyrJmido (5,4-d) pyrimidine (I) by reacting 2,4,6,8-tetrahydroxypyrimido [5,4-d] pyrimidine (II) or its salts (III) with PCI ₆ , which can also be prepared intermediately from PCI ₃ and Cl ₂ , in the presence of an inert solvent and working up of the reaction mixture in the presence of a nonionic surfactant, characterized in that the chlorination reaction in the presence of triethylbenzylammonium chloride ( Vl) in an inert organic solvent. 2. The method according to claim 1, characterized in that one uses Triathylbenzylammoniumchlorid (VI) in amounts of 0.01 to 1%, based on the substance to be chlorinated. 3. Process according to claims 1 and 2, characterized in that triethylbenzylammonium chloride (Vl) before the train abe or production of the PCI _{5 is} added. 4. The method according to claim 1, characterized in that one uses halide aliphatic ^ or aromatic hydrocarbons, such as carbon tetrachloride, tetrachloro than, chlorobenzene, perchlorethylene, toluene, xylene or dichlorobenzene. 5. The method according to claim 1, characterized in that one carries out the chlorination at 50 to 15O ⁰ C, preferably bui the boiling temperature of the solvent. 6. Process according to claims 1 to 5, characterized in that the chlorination 4 to 8 Sf.inden, preferably 6 hours, performs.