JPS5835188A - Preparation of 6-chloropurine - Google Patents

Abstract

PURPOSE:To obtain titled compound useful as an intermediate for preparing 6- mercaptopurine, an agent that relieves or prevents malignant tumor such as acute leukemia, etc., by reacting an alkali metal salt of 6-hydroxypurine with phosgene in an inert solvent. CONSTITUTION:6-Hydroxypurine is reacted with usually 1-1.5mol based on the compound of caustic alkali (e.g., NaOH, KOH, etc.) in an aqueous solution at 10-110 deg.C to give an alkali metal salt of 6-hydroxypurine, which is reacted with a phosgene gas (preferably 1-3mol based on the alkali metal salt) in an inert solvent such as dioxane, etc. in an amount to give preferably 1-20 times that of the alkali metal salt at preferably 60-150 deg.C for 2-30hr, to give 6-chloropurine shown by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 6-chlorpurine.

6-Chlorpurine is a compound represented by the following structural formula, and is useful as an intermediate for producing 6-mercaptopurine, which is used as an anti-blood tumor agent for acute leukemia and the like.

As a method for producing 6-chloropurine, a method is generally known in which 6-hydroxypurine is reacted with a large excess of phosphorus oxychloride in the presence of N,N-diethylaniline. (
J, appl, Chem, /, 2゜0ctober
, /ri6λ, 4t3a ~ 4t37p) However, since this method uses a large excess of phosphorus oxychloride, it is necessary to use a reactor made of corrosion-resistant material, and the mixture after the reaction is Yodioxyphosphorus chloride, N, N/-
Since it is necessary to recover diethylaniline, etc., 6-
The recovery operation for chlorpurine is troublesome. For example, the mixture after the reaction is first distilled to recover phosphorus oxychloride,
Next, the system was made basic, N,N/-diethylaniline was extracted and removed with an organic solvent, and this was further acidified to precipitate 6-chloropurine crystals, which were then filtered through ν. will be collected.

In view of the above circumstances, the present inventors have completed the present invention as a result of various studies on an industrially advantageous method for producing 6-chloropurine using 6-hydroxypurine as a raw material.

That is, one gist of the present invention resides in a method for producing 6-chloropurine, which is characterized in that an alkali metal salt of 6-hydroxypurine is reacted with phosgun in an inert medium.

The present invention will be explained in detail below.

The alkali metal salt of O-hydroxypurine that is the object of the present invention is a sodium salt or a potassium salt, which can usually be easily obtained by reacting 6-hydroxypurine with a caustic alkali such as caustic soda or caustic potash. . This reaction is usually carried out by adding 6-hydroxypurine to an aqueous caustic solution and reacting for 10 to ii.

It is carried out at a temperature of °C. The concentration of the caustic alkali aqueous solution is usually 3 to 30% by weight, and the amount of caustic alkali used is usually 7.0 to 30% by weight based on 6-hydroxypurine.
, j moles times. The produced metal salt of ≦-hydroxypurine can usually be recovered by precipitating crystals by concentration crystallization or cooling crystallization, filtering and drying the crystals. It can also be recovered by concentrating the reaction mixture to dryness.

In the present invention, the alkali metal salt of 6-hydroxypurine is reacted with phosgene in an inert medium, and the inert medium usually includes dioxane, cyclic ethers such as tetrahydrofuran, ethylene glycol dimethyl ether,
Aliphatic ethers such as diethylene glycol dimethyl ether, inglovir ether, dibutyl ether,
Aromatic hydrocarbons such as benzene, toluene, and xylenato;
Chlorobenzene, dichlorobenzene, chlorotoluene,
Examples include chlorinated hydrocarbons such as ethylene dichloride. The amount of Kowara's inert solvent used is usually 0.000 to 6-hydroxypurine alkali metal salt. j~30 times by weight, preferably /~20 times by weight.

The reaction temperature is usually IO-100°C, preferably θ~/
! θ℃, and if the reaction temperature is too low, the reaction will not proceed well and 6-chloropurine cannot be obtained in high yield, and if it is too high, there will be no difference in the reaction content. This is not preferred because the reaction must be carried out under pressure.

The reaction of the present invention is usually carried out by bubbling phosgene gas into an inert medium containing an alkali metal salt of 6-hydroxypurine, and the amount of phosgene used is usually 6-hydroxypurine.
- for the alkali metal salt of hydroxypurine, O1/
~j, 0 times by mole, preferably 7.0 to 3.0 times by mole. The ventilation time for phosgene gas varies somewhat depending on the reaction temperature, but is usually about 2 to 30 hours.

The mixture after the completion of the reaction contains by-product sodium chloride or potassium chloride in addition to the target product 6-chlorpurine, but the reaction mixture is usually filled with N2 gas or C
After removing residual phosgene by bubbling inert gas such as O2 gas, 6-chlorpurine is recovered.

The method for recovering 6-chlorpurine is not particularly limited, and various methods can be considered. For example, after filtering the reaction mixture and separating precipitated crystals of sodium chloride or potassium chloride, An example of this method is to distill off the inert medium and concentrate to precipitate 6-chlorpurine crystals, which are then collected by filtration. Also, the reaction mixture, for example! Cool to below θ°C to simultaneously precipitate 4-chlorpurine crystals and sodium chloride or potassium chloride crystals, collect these crystals by filtration, and then collect 6-chlorpurine by washing the crystals with water. It may be a method.

The 6-chlorpurine obtained in this manner is of high purity, but if necessary, it may be subjected to a known purification method, such as recrystallization with hot water, and then recovered as a product.

As described above, according to the present invention, 6-chloropurine can be easily produced using 6-hydroxypurine as a raw material, so it is an industrially extremely advantageous method.

Next, the present invention will be explained in more detail with reference to examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Example (Production example of sodium salt of 6-hydroxypurine) Into a glass reactor equipped with a stirrer, a heating device, and a distillation device, 5 roy (0.5 mol) of a 4 twt% caustic soda aqueous solution was charged and heated to SO℃. After that, add 6-hydroxypurine (Ajinomoto Commercial Product) 6/y (o, s
mol) was added thereto and stirred at the same temperature for 40 minutes. Thereafter, the mixture was reduced to about 3,309 ml of water at a reduced concentration of 100 mmHf.
The mixture was concentrated until distilled out to obtain a mixture containing crystals of sodium salt of 6-hydroxypurine.

Next, this mixture was filtered to separate the crystals, which were then dried to obtain the sodium salt 6 of 6-hydroxypurine.
! 2 were collected.

<Production Example of 6-Chlorpurine> Into a glass reactor equipped with a stirrer, a temperature control device, and a phosgene gas blowing tube, 3/1, 6 f (0, 2 mol) and dioxane 326F and heated to a temperature of go°C. At the same temperature, 0.0 mol of phosgene gas was added to the mixed solution while stirring.
At a rate of 0.6 mol/hr! The blow reaction was carried out for an hour.

After the reaction, N2 gas was introduced into the mixture at a temperature of ♂O℃.
After removing residual phosgene by blowing for a certain period of time, the mixture was filtered through a glass filter while hot to remove salt precipitated in the mixture. Next, the ν liquid was heated to 200 MmH.
Concentrate under reduced pressure of f until the liquid volume becomes about 3θ-,
The precipitated crystals were filtered and dried.The pale yellow crystals were collected and analyzed by liquid chromatography, and it was found that 22% of the 6- It contained chlorpurine, and its yield (based on the sodium salt of 6-hydroxypurine) was 4tj%. Applicant: Mitsubishi Chemical Industries, Ltd.

Claims (1)

[Claims] (1) A method for producing 6-chlorobulin, which comprises reacting an alkali metal salt of 6-hydroxypurine with phosgene in an inert medium.