DD267632A3 - PROCESS FOR THE PREPARATION OF 2,6-DICHLOR-4,8-DIPIPERIDINO-PYRIMIDO [5,4-D] PYRIMIDINE - Google Patents

Abstract

2,6-Dichloro-4,8-dipiperidino-pyrimido & 5,4-d! Pyrimidine is obtained by reacting 2,4,6,8-tetrachloropyrimido & 5,4-d! Pyrimidine with piperidine, according to the invention before the Amidation a nonionic surfactant is added. The inventive method optimizes the reaction and avoids the formation of decomposition products. The target product is a valuable intermediate of the pharmaceutical industry.

Description

Field of application of the invention

The invention relates to an improved process for the preparation of 2,6-dichloro-4,8-dipiperidino-pyrimido (5,4-d] pyrimidine (I) on an industrial scale.

This compound is a valuable intermediate for cardiovascular drugs, in particular it is required for the synthesis of dipyridamole.

Characteristic of the known state of the art

From DD-PS 105447 the preparation of I from 2,4,6,8-tetrachloro-pyrimido (5,4-dlpyrimidine (II) and piperidine in an inert organic solvent in the presence of Alkulilauge and the workup of the resulting reaction mixture is known ,

It has already been proposed a process for the preparation of I, in which especially the work-up of the reaction mixture is much cheaper 's in DD-PS 105447. In particular, the formation of hydrolysis and decomposition products is prevented by the otherwise very drastic conditions ,

However, studies have shown that, especially in the reaction of the 2,4,6,8-tetrachloro compound with piperidine in the presence of an inert organic solvent on an industrial scale due to the presence of acid halides such as PCIs and POCl ₃ no complete amidation, despite excess use of Piperidine, takes place. Above all, piperidine cleavage products such as 1,5-dichloropentane are found which are lost for the quantitative course of the reaction. Moreover, these products crucially interfere with the progress of the synthesis.

Also, a previously proposed variant of the reaction of II with piperidine hydrochloride or another salt to I in chloroform phase is carried out on an industrial scale not r ..: 'the expected high yield. Time and again, the reaction of II with piperidine or piperidine hydrochloride in the heterogeneous chloroform mixture has a very disadvantageous effect. Also, a change of the solvent or diluent, such as. As chloroform against chlorobenzene or perchlorethylene, gives no other results.

Object of the invention

The aim of the invention is to find suitable conditions for the reaction of 2,4,6,8-tetrachloropyrimido [5,4, -dlpyrimidin II and piperidine or piperidine hydrochloride in chloroformic phase in high yield and quality. It should be assumed especially of technical mixtures of compound II, which still contain acid chlorides are assumed.

Explanation of the essence of the invention

The invention is based on the object, the reaction of 2 4,6,8-tetrachloro-pyrimido [5,4-d] pyrimidine II from the technical synthesis, which mainly contains acid chlorides, in particular PCIs and POCl ₃ , with piperidine or Piperidine hydrochloride, in an inert organic solvent or primarily chloroform, to optimize, avoiding decomposition products.

According to the solution of the problem is achieved in that one adds in the synthesis of Il resulting reaction mixture, consisting of an inert organic phase, primarily CHCi ₃ , unreacted starting material and II, a nichtionogtnes surfactant and thus the partially heterogeneous mixture in the reaction with Piperidine or its hydrochloride homogeneously designed.

The amidation reaction proceeds particularly uniformly in the presence of a nonionic surfactant, without resulting in decomposition products of II or of piperidine, especially not if the reaction is completed by the addition of NaOH.

Oxyethylated alkylphenols or fatty alcohols or mixtures of such surfactants can be used as nonionic surfactants for the process according to the invention.

Preferably, ethoxylated alkylphenols or fatty alcohols are used with 7 to 15 mol, preferably 9 to 12 moles of ethylene oxide.

In general, it is sufficient to add the surfactants in amounts of 0.1 to 10 mol% of the reaction mixture.

In this case, it is advantageous to proceed by boiling the reaction mixture after addition of the surfactant or a mixture of nonionic surfactants and again cooled to temperatures of 15 to 40 ⁰ C, then at these temperatures piperidine or the hydrochloride so admitting that 40 ° C. not be exceeded.

Following this, you cook again and work on already proposed variant.

In the preparation of II is distilled from a reaction mixture of 2,4,6,8-tetrahydroxy-pyrimido [5,4-d | pyrimidine or its disodium salt, triethylbenzylammonium chloride, POCl ₃ and PCIe largely from the phosphorus halides, the residue in an inert organic solvent, adds a non-ionic surfactant or a mixture of non-ionic surfactants, and adds the resulting mixture with piperine, in its hydrochloride and further with caustic soda.

produced by the novel process in almost quantitative yield free of by-products and in high quality. The success of the process is surprising and could not be foreseen since no information was known from the literature that these reactions proceeded in an improved manner by using a surfactant in the amidation of chloroderivatives in organic solvents with piperidine or amines.

embodiments example 1

kg 15001 kg

kg

Example 2

kg

500l kg 1kg kg

10001 kg

kg

2,4,6-Tetrachloropyrimido [5,4-d] pyrimidine are stirred in chloroform and admixed with a Nohn! Phenols ethoxylated with 9 moles of ethylene oxide. The mixture is heated to 60 ⁰ C and stirred for 30 minutes.

It is then cooled to 2O ⁰ C and piperidine is running so that a maximum temperature of 40 "C is not exceeded.

After completion of the addition, the mixture is boiled, cooled again to 2O ⁰ C and completes the amidation by addition of sodium hydroxide solution. The maximum temperature of 40 ^° C should also not be exceeded. The mixture is stirred for 30 minutes at a pH of 10 to 12 and worked as suggested.

Yield: 362 kg IA 98% of theory.

Analytical control:

TLC: eluent: CHCl ₃ , benzene, 100% I, no by-products.

F .: 250 to 251 ° C.

Disodium salt of 2,4,6,8-Telrahydroxy-pyrimido- [5,4-dlpyrimidins be submitted. To this is added with stirring and strong cooling POCl ₃ and then stirred the mixture for 30 minutes. Then one adds PCI ₃ and triethylbenzylammonium chloride and initiates chlorine at 20 to 40 ° C. It must be strongly cooled.

After all PCI _{6 has been} reacted, the mixture is refluxed for 6 hours, the resulting POCl ₃ distilled off, initially under atmospheric pressure and towards the end under vacuum.

The residue is treated with chloroform and an ethoxylated with 9 moles of ethylene oxide nonylphenol and boiled. After cooling to 20 ° C piperidine hydrochloride are added, again the temperature may not exceed 40 ⁰ C. After addition, the mixture is brought to boiling and cooled again to 20 ⁰ C from.

Now a pH of> 10 is set with sodium hydroxide solution and stirred for 30 minutes.

The workup is carried out by adding water and Sauersteiien after boiling with sulfuric acid and phase separation.

The extraction with chloroform is repeated, the combined organic phases are concentrated and precipitated with methanol.

After aspirating and washing, the target product I is obtained in the following yield and quality:

Yield: 208 kg I ^ 86% of theory.

Analytical control:

TLC: eluent as in Example 1, TLC: 100% 1, no side-bonds.

F .: 250 to 251 ° C.

Claims (3)

1. A process for the preparation of 2,6-dichloro-4,8-dipiperidino-pyrimido [5,4-diphyrimidine (I) from 2,4,6,8-tetrachloro-pyrimido [5,4-d] pyrimidine (II ) and piperidine or its hydrochloride in an inert organic solvent by alkalization, characterized in that before the amidation with piperidine or its hydrochloride the Reaktionsgemisnh and solvent an ethoxylated alkylphenol or fatty alkanol having an oxethyl chain of 7 to 15, preferably from 9 to 12, or a mixture thereof, in an amount of 0.1 to 10 molar proportions in%. 2. The method according to claim 1, characterized in that one of a in the preparation of (II) from 2,4,6,8-tetrahydroxy-pyrimido [5,4-d] pyrimidine or its disodium salt, triethylbenzylammonium chloride, POCl _3rd and PCI ₅ resulting reaction mixture, the phosphorus halides largely distilled off, the residue is taken up in an inert organic solvent, to the surfactant or surfactant mixture and added to the resulting mixture with piperidine or its hydrochloride and the reaction completed by the addition of sodium hydroxide solution. 3. Process according to claims 1 and 2, characterized in that the heated with the surfactant or surfactant mixture heated to boiling, cooled to 15 to 40 ⁰ C and after addition of piperidine or its hydrochloride at a maximum of 4O ⁰ C again to boiling.