JPH02268185A - Production of 5-methyl-7-(diethylamino)-s1- thiazolo(1,5-a)pyrimidine and its acid addition salt - Google Patents

Abstract

PURPOSE: To obtain the subject compd. having vasodilator action and platelet aggregation inhibiting action by reacting methylhydroxy-s-triazolopyrimidine and a chlorinating agent in the presence of a chlorinated hydrocarbon and diluting the reaction mixture to adjust the pH thereof.

CONSTITUTION: 1 mol. of 5-methyl-7-hydroxy-s-triazolo(1,5-a)pyrimidine and 0.6-0.9 mol. of a chlorinating agent composed of POCl₃ or PCl₃ are reacted in the presence of a chlorinated hydrocarbon. After the completion of reaction, the reaction mixture is diluted with the chlorinated hydrocarbon and an aq. alkali is added to the diluted soln. to adjust the pH thereof to 1.0-2.0. An org. phase is separated and, if desired, an aq. phase is extracted with the chlorinated hydrocarbon and, according to circumstances, the combined org. phase is reacted with diethylamine and a product is isolated to obtain the objective compd.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 5-methyl-7-dinithylamino-S-)riazolo(1,5-a)pyrimidine and its acid addition salt.

5-Methyl-7-dinithylamino-S-)riazolo(1
, 5-a) Pyrimidine [trapidil (trapidH)
[commercially available as] has vasodilatory and platelet aggregation inhibiting effects.

(Prior art) French patent specification 1.567.021 (DOS5.
956), tribasil is prepared by reacting 5-methyl-7-chloro-3-triazolo(1,5-a)pyrimidine with diethylamine in the presence of water. The reaction mixture thus obtained is evaporated and the separated tribasil is filtered off and then purified using n-hebutane. According to this description, the starting compound (7-chloro derivative) is N.

It can be prepared by reacting the corresponding 7-hydroxy derivative with a phosphorus halide in the presence of N-dimethyl-aniline or N,N-dimethyl-formamide.

A similar process is described in DD 155.068, but in this process the 5-methyl-7-chloro-8-triazolo(1,5-a)pyrimidine intermediate is not separated but left in the reaction mixture. , where it reacts with diethylamine.

Swiss Patent No. 454.153 (CA 1968.
Deaf, 96759), 1 mole of 4-hydroxy-
POCj! s and N.

react with N-diethylaniline at a temperature of 90°C,
4-chloro derivative is achieved. On the one hand, the chlorinating agent is used in high molar excess and acts as a solvent, on the other hand it shifts the equilibrium of the reaction towards the desired product,
N,N-diethylaniline functions as a catalyst. Only these reaction conditions were considered suitable to achieve sufficient yields of the 4-chloro derivative and POCj! s
Alone it is not considered a suitable chlorinating agent for 4-hydroxypyrimidine derivatives.

POCj! s and N, N-dialkylaniline or N.

When N-dialkylformamide is used as the chlorinating agent for the chlorination of 5-methyl-7-hydroxy-s-triazolo(1,5-a)pyrimidine, it is carried out at the continuous flow temperature of the reaction mixture. During the reaction, POCj!
Colored products and tar-like substances form from the s, which contaminate the reaction mixture.

Coloration and tar formation increase with increasing temperature and increasing phosphorus oxychloride usage.

When the reaction is complete, excess phosphorus oxychloride must be removed by distillation, which further contributes to the formation of by-products.

N,N-dialkyl-formamides or N,N-dialkylanilines have high boiling points, so they raise the reflux temperature of the reaction mixture and the removal of these agents must also be carried out at elevated temperatures. These materials are expensive and their reproduction is not possible.

The 7-chloro derivative is removed from the reaction mixture by evaporation of the phosphorus oxychloride, or the reaction mixture is used directly for the preparation of trapidil.

In the course of the reaction with diethylamine, dimeric or trimeric compounds with two or three triazolo-pyrimidine skeletons are produced as by-products, the physical properties of which are very distinct from those of the target compound. Therefore, it is very difficult to remove these from the target compound.

Trapidil can be prepared using several other methods, such as JP-A-56-1.
08.772 and 56-079.674. However, these methods have the disadvantage that the final product cannot be recovered with a yield higher than 26%.

Since tribasil is a pharmaceutical substance, it must meet very high purity standards, but its purification is very difficult. Therefore, several methods have been described for the purification of crude products.

DD 111.632 describes the purification of the crude product obtained by the method of PR 1,567,021. According to this specification, the crude product is alkalinized to pH 9-10 by addition of aqueous alkali, extracted with aliphatic and/or aromatic hydrocarbons or esters at a temperature of 20"C to 60C, and organic crystallized from phase and recrystallized from toluene.

According to another method, the crude product is contacted with a sulfur compound having a reducing action in the presence of water (JP 59-29°69
1) or contacted with an acid (JP 59-39.896),
Alternatively, the crude product is dissolved in a hydrocarbon vehicle and
washed with water at a temperature of 80°C to 80°C (JP 59-
174° 384) or with an aqueous solution of a metal salt (JP 59-29, 689) or with activated carbon (JP 58, 110° 588) and recovered from the organic phase or the crude product is recrystallized from a hydrocarbon solvent in the presence of a carboxylic acid (JP 59
-29.690).

These latter methods are suitable for the purification of relatively pure crude products. If the crude product contains a large amount of contaminants,
By column chromatography method (JP 56-07
9.674 or JP 56-110.588) or DD 111,532, otherwise these latter purification steps may be repeated several times in order to obtain the final product of the desired purity. However, each recrystallization step leads to a loss of more than 10%, which significantly reduces the yield.

The active ingredient content of the final product obtained by known methods is 6
0% by weight and at the end of the purification process the yield of trapidil is approximately 30% by weight based on the starting 7-hydroxy derivative.
~40%. Moreover, the purification step not only reduces the yield but also increases the cost of the final product (labor, expensive solvents,
(solvent regeneration, equipment, etc.).

Known methods are directed to the production and therefore purification of trapidil, however, no method is hitherto known which is satisfactory both in terms of yield and purity.

Our new approach to producing suitably pure products in high yields provides the ability to produce suitably pure products if chlorination and subsequent amination are carried out under suitably mild conditions. This is based on the fact that there is no need to concentrate efforts on purifying the final product in order to obtain it.

[Problem to be solved by the invention]

Thus, a process for the production of trapidil that is simpler and more economical than known processes and can be carried out on an industrial scale, leading to a final product of high purity and thus avoiding complex purification steps. is desired.

Furthermore, there is a need for a process that not only provides a pure product, but also provides a high yield of the desired compound.

[Means to solve the problem]

Surprisingly, the inventors have found that 7-hydroxy derivatives in the presence of chlorinated hydrocarbons
cp<s or POCj! When reacting with a chlorinating agent selected from s, it is not necessary to use this chlorinating agent in a 2-3 molar excess as taught by the prior art;
- The reaction can be completed by using 0.6 to 0.9 mol of chlorinating agent, based on the hydroxy derivative, and there is no need to use a catalyst.

The present invention is also based on the recognition that by adjusting the pH of the reaction mixture to 1.0-2.0, tar-like and colored by-products soluble in organic solvents can be transferred to the aqueous phase.

According to the invention, 5-methyl-7-hydroxy-8-triazolo(1,5-a)pyrimidine is reacted with a chlorinating agent chosen from POCl z and PCBs and the 7-chloro derivative thus obtained is It is reacted with diethylamine and the target compound is recovered from the reaction mixture by methods known per se, optionally in the form of an acid addition salt.

In the process of chlorination, in the presence of chlorinated hydrocarbons, 0.6 to 0
．． A chlorinating agent is used in an amount of 9 molar; the reaction mixture is diluted with chlorinated hydrocarbon; the pH of the solution thus obtained is adjusted to 1.0-2.0 by addition of aqueous alkali; The organic phase is then separated; optionally the aqueous phase is extracted with one or more chlorinated hydrocarbons; the optionally combined organic phases are reacted with diethylamine; and the product is prepared in a manner known per se. or converted into acid addition salts.

The present invention is based on the following findings. That is, when the chlorination of a 7-hydroxy derivative is carried out in the presence of a chlorinated hydrocarbon as a solvent, for complete chlorination of the 7-hydroxy derivative, chlorine per mole of the 7-hydroxy derivative is required. It is sufficient to use the chlorinating agent alone in an amount of 0.6 to 0.9 mol, and there is no need to use a catalyst, if only a high excess of the chlorinating agent is used to obtain the chloro derivative with sufficient yield. This is unexpected since the use of catalysts has previously been suggested.

This feature is that the reaction temperature can be low, undesired side reactions are suppressed, and there is no need to remove excess chlorinating agent.
Mild reaction conditions can be used, with the added advantage that heating of the 7-chloro derivative can be omitted, thus significantly reducing the formation of undesired by-products.

As chlorinated hydrocarbons it is possible to use aliphatic or aromatic chlorinated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, chlorobenzene, dichlorobenzene, or mixtures thereof. Preferred chlorinated hydrocarbons are chloroform and dichloroethane, of which dichloroethane is most preferred.

The reaction is carried out at 80 DEG to 120 DEG C., preferably 95 DEG to 105 DEG C., which generally corresponds to the boiling temperature of the reaction mixture.

The chlorination reaction generally takes 30 minutes to 3 hours, preferably 1 to 2 hours.
Complete in time.

When determining the amount of solvent to be used in the chlorination reaction, consideration should be given to ensuring that the boiling point of the reaction mixture does not fall below 80°C. The solvent or solvent mixture is generally 1:0.02 to 1:4, preferably l:0.5 to 1, relative to the starting chlorinating agent.
:Used in an amount of 2 parts by volume.

After the reaction is complete, the reaction mixture is preferably diluted with one or more chlorinated hydrocarbons. The solvent is used in an appropriate amount for dissolving the 7-chloro derivative. The chlorinated hydrocarbon used for dilution can be the same as defined for the solvent in the chlorination reaction, and the amount of solvent can also be the same amount as used in the chlorination reaction. . (For example, if dichloroethane is used in the chlorination reaction, this solvent or one or more other chlorinated hydrocarbons can be used for dilution.) The present invention is further based on the following findings. There is. That is, when a highly acidic reaction mixture is only slightly made basic by the addition of aqueous alkali, i.e. when its pH is 1.
0 to 2.0 (rather than pH 7 as previously suggested), most of the 7-chloro intermediate remains in the organic phase and by-products and contaminants (at higher ptt) enter the organic phase. coloring substances and tar-like substances that also dissolve)
The solubility equilibrium changes so that the remaining in the aqueous phase.

Therefore, contaminants can be removed very effectively in a very simple manner.

Alkalinization of the reaction mixture is achieved by using alkali metal hydroxide,
This can be done by adding carbonates or hydrogencarbonates, these bases being preferably used in the form of 10-20% by weight aqueous solutions.

After alkalinization, the organic phase is separated. To increase the yield, the aqueous phase can be extracted with chlorinated hydrocarbons or mixtures thereof and the combined organic phase used in the next step.

As chlorinated hydrocarbons it is possible to use the same solvents or mixtures thereof as mentioned as suitable solvents for the chlorination reaction. Extraction can be carried out using any solvent or solvent mixture suitable for dissolving the 7-chloro derivative, such as chlorinated hydrocarbons. The same solvents used as solvents for chlorination can be applied. Preferably, the same solvent or solvent mixture used in the chlorination and/or dilution of the reaction mixture is used for the extraction.

The reaction with diethylamine, in which diethylamine is added directly to the organic phase and the 7-chloro derivative is not recovered from the reaction mixture, is performed not in an aqueous medium as described in PR 1,567,021, but in an organic solvent, i.e. It is carried out in the presence of chlorinated hydrocarbons.

From the point of view of the yield of the final product, it is advantageous not to separate the 7-chloro derivative from the extract, but to use it directly in the next reaction step. Using a chlorinated hydrocarbon, preferably dichloroethane, rather than water as a solvent in the reaction with diethylamine also avoids alkalinization of the reaction medium and can significantly reduce the formation of polymer and dimer and trimer by-products. This is preferable because it can be done.

In the course of the amination, diethylamine is used in a 1.3-4, preferably 1.5-3 molar excess relative to 1 mole of the 7-chloro derivative already formed.

The reaction is carried out at a temperature of 10°C to 40°C, preferably 15 to 35°C.
at a temperature of 0.5 to 3 hours, preferably 1 to 2 hours,
It is preferably carried out with stirring.

The target compound can be separated from the reaction mixture by methods known per se and, if desired, purified.

-m, the reaction mixture is washed with water, evaporated and the residue is dissolved in a suitable solvent such as an aliphatic alcohol (e.g.
isopropanol), ketones (e.g. acetone), esters (e.g. ethyl acetate), or aromatic hydrocarbons (e.g.
For example, benzene, toluene) or the product is isolated in the form of an acid addition salt.

Acid addition salts include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid, etc.), or organic acids such as organic carboxylic acids (e.g. glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, salicylic acid, 0-acetoxybenzoic acid, etc.) or organic sulfonic acids ( For example, it can be formed using methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, etc.).

Any purification technique known in the art can be performed. However, because the final product is more pure than that produced by known methods, fewer purification steps are required, and therefore losses are significantly lower.

Next, the present invention will be explained in more detail with reference to examples, but the scope of the present invention is not limited thereby.

■-1 75g (0.5 mol) of 5-methyl-7-chloro-s-
Triazolo(1,5-a)pyrimidine, 40.5m (
0.45 mol) of phosphorus oxychloride and 10 d of dichloroethane are boiled for 60 minutes at a temperature of 95 DEG to 105 DEG C. under a reflux condenser. 375d of oily reaction mixture
of chloroform and then adjust the pH to about 1 by adding 25.0 g of calcium hydroxide suspended in 175 d of water.

The organic phase is separated and 5-methyl-7-hydroxy-
The s-triazolo(1,5-a)pyrimidine is extracted from the aqueous phase with chloroform (3×20 (ld)). The combined organic extracts are stirred at 40° C. for 1 hour at 113. 9d (1.1 mol) of diethylamine.

To separate diethylamine HCII, the reaction mixture is extracted with distilled water (2×125 m). The organic phase is evaporated under reduced pressure and the residue is then recrystallized from ethyl acetate. The target compound can be further crystallized from the ethyl acetate mother liquor and the washing solution.

Total yield 76.8g (75%), melting point: 103℃~10
5℃0 Active ingredient content: 99.59%, absorbance (A+c
m, 307m): 880° Takashi LJ.

75 g (0.5 mol) of 5-methyl-7-hydroxy-
5-1-riazolo(1,5-a)pyrimidine, 29.7
1i (0,33 mol) nooxychloride IJ 7.1oId
of chloroform and 101d of dichloroethane are boiled at a temperature of 95-105° C. for 90 minutes under a reflux condenser. The pH of the reaction temperature thus obtained was set to 170.
- by addition of 21 g of sodium bicarbonate suspended in water.

The organic phase was separated and the aqueous phase was dissolved in dichloroethane (3X2
00m). Combine the organic phases and
8 m (0.85 mol) of diethylamine are added and the reaction is carried out at 20"C for 1 hour with stirring.

The reaction mixture is extracted with distilled water (2×100 ad) and the organic phase is evaporated. Add dropwise until pH 2. The precipitated hydrochloride is collected by filtration. Yield: 94.3g (78%), melting point: (HCj
) 212°C, active ingredient content 97.46%.

b) Dissolved in 3001d acetone, 85.6 g
' p-toluenesulfonic acid and 150 m acetone are added. The salts are filtered off from the reaction mixture. Yield: 1
50.2g (76%), melting point: 168°C - 173°C,
Active ingredient content: 99.12%.

■-1 Repeat the method of Example 1, but replace Pockm with 0.45
Use molar pcp,s. Total yield: 74.6 g
.

Melting point: 103°C to 105°C, active ingredient content: 98.9
2%.

Stop Comparison ■1 Follow the method of Example 1, but 126m instead of 29.7-
(1,4 mol) of phosphorus oxychloride and N,N-dimethylformamide (2
0d) is used. Yield 62. '2 g, active ingredient content:
78.22%.

The method of the example is carried out, except that after the chlorination reaction, the pi of the reaction mixture is adjusted to 7 by addition of a 40% aqueous suspension of sodium bicarbonate. Yield: 71', 3 g, content of active ingredient: 73.84%.

1 of 1 in Northern Europe DD 155068
00 g (0,66 mol) of 5-methyl-7-hydroxy-s-triazolo(1,5-a)pyrimidine in 78
d (0.85 mol) in phosphorus oxychloride and the mixture is boiled for 1 hour under a reflux condenser.

The pH of the reaction temperature was adjusted to 200 d dissolved in 350 d of water.
adjusted to 6-7 by addition of g potassium carbonate, then 9
6.0 g (135 m) diethylamine are added and the mixture is stirred at 40° C. for 2 hours.

Then 400 g of benzene is added to the reaction mixture and 50 g of sodium hydroxide in the form of a 45% aqueous solution are added to the mixture to make it alkaline to pH 10-11. The benzene phase is steam distilled to evaporate the benzene/water mixture.

The distillation residue is diluted to 40 g with water and 45% by weight sodium hydroxide solution is added until the mixture is homogeneous. 100IE of this alkaline solution! benzene/
Extracted three times with a cyclohexane (1:1) mixture, -
The combined organic phases are evaporated and the product is filtered off. Yield: 81.2 g (61.1%).

Melting point: 100°C to 103°C. Active ingredient content: 87.5
%.

Claims (1)

[Claims] 1,5-methyl-7-hydroxy-s-triazolo (1
, 5-a) 5-methyl-7-diethylamino-s- by treating the pyrimidine with a chlorinating agent selected from POCl_3 or PCl_5 and aminating the 7-chloro derivative thus obtained with diethylamine.
In a method for producing triazolo(1,5-a)pyrimidine or an acid addition salt thereof, 5-methyl-7-hydroxy-s-triazolo(1,5-a)
-a) reacting the pyrimidine with 0.6 to 0.9 mole of chlorinating agent per mole of said 7-hydroxypyrimidine derivative in the presence of one or more chlorinated hydrocarbons; diluting the reaction mixture with one or more chlorinated hydrocarbons; reducing the p of said reaction mixture by adding an aqueous alkali;
H is adjusted to 1.0-2.0 and the organic phase is separated; optionally the aqueous phase is extracted with one or more chlorinated hydrocarbons; optionally the combined organic phases are extracted with diethylamine. and isolating the product or optionally converting the product into an acid addition salt. 2. Dichloromethane as a solvent for the chlorination reaction,
2. A process according to claim 1, wherein dichloroethane, chloroform, chlorobenzene, dichlorobenzene or mixtures thereof are used. 3. Process according to claim 1 or 2, characterized in that the chlorinated hydrocarbon is used in an amount that results in a reaction mixture having a boiling point of between 80<0>C and 120<0>C. 4. The method according to any one of claims 1 to 3, wherein the chlorination is carried out at a temperature of 80<0>C to 120<0>C. 5. The method according to any one of claims 1 to 4, wherein the reaction mixture is diluted with dichloromethane, dichloroethane, chloroform, chlorobenzene, dichlorobenzene or a mixture thereof. 6. The method according to any one of claims 1 to 5, wherein the pH adjustment of the diluted reaction mixture is carried out with an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate. 7. The organic phase obtained after said alkalinization is separated and optionally extracted in dichloromethane, dichloroethane, chloroform, chlorobenzene, dichlorobenzene or mixtures thereof. Method. 8. The reaction between the organic phase and diethylamine is carried out as described in 7-
8. The process according to claim 1, which is carried out using 1.3 to 4 mol of diethylamine per mol of chloro derivative. 9. The amination is carried out at a temperature of 10 to 40°C.
A method according to any one of claims 1 to 8. 10. Process according to any one of claims 1 to 9, characterized in that the reaction mixture obtained after said amination is washed with water, it is evaporated and the residue is crystallized from a suitable solvent. 11. Forming an acid addition salt of the resulting 5-methyl-7-hydroxy-3-triazolo(1,5-a)pyrimidine and recovering it from the reaction mixture.
9. The method according to any one of 9.