CA1274828A

CA1274828A - Triazolo(1,5-c) pyrimidines as bronchodilating agents

Info

Publication number: CA1274828A
Application number: CA000516196A
Authority: CA
Inventors: James J. Wade
Original assignee: Riker Laboratories Inc
Current assignee: Riker Laboratories Inc
Priority date: 1984-02-24
Filing date: 1986-08-18
Publication date: 1990-10-02
Anticipated expiration: 2007-10-02

Abstract

ABSTRACT OF THE DISCLOSURE:

Certain triazolo[1,5-c]pyrimidines and their pharmaceutic-ally acceptable acid addition salts are useful as broncho-dilator agents. The compounds may be produced by a process wherein triazolo[4,3-c]-pyrimidines substituted on the 7-position through a nitrogen atom which is part of a heterocyclic ring are rearranged to provide the corres-ponding 7-substituted triazolo[1,5-c]pyrimidines by the catalytic action of an organic base in a protic solvent.

Description

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-llETEROCYCLIC COllPl)lJhlDS ANI) PROCESS
-Technical Field .
The present invention relates to a process for the preparation o~ triazolo[l,5-c]pyrimidines substituted on the 7-position through a nitroyen atom which is part of a heterocyclic ring by the catalytic rearran-~ement of the corresponding substituted triazolo[4,3-c~pyrirnidines.
Triazolo[1,5-c]pyrimidines prepared by such a process are also described.

Back round of the Invention Processes are known for the rearrangement of some of tlle triazolo~4,3-c]pyrimidine compounds of the prior art. For example, United Kingdom Patent No. 898,409 describes the rearrangement of 3-aminotriazolo[4,3-c]-pyrimidines, which may be substituted on the triazolo riny by amino groups, in the presence of acid or inorganic alkali. Emphasis is placed on the use of a relatively large amount of acid.
It is known that the simply substituted triazolo[4,3-c]pyrimidines rearrange readily by the action o~ heat, acid or inorganic alkali (for example, see United Kingdom Patent No. ~98,407). Further, U.S. Patent No.
3,850,932 discloses tlle use of certain bases to rearrange 1,2,4-triazolo[4,3-c]quinazolines substituted in the 5-position by substituted amino to the corresponding 1,2,4-triazolo[1,5-c]cluinazolines. llowever, complex triazolo~4,3-c]pyrimidines are unpredictable in their reactivity. For example, Brown and Nagamatsu, Aust. J.
Chem. 1979, 32(15~5-1593) report that certain triazolo-[4,3-c]pyrimidine.s with condensed nitrogen-containing rings are stable to rearrangement, that is, they do not readily rearrange. F`urthermore, these compounds may be subject to irreversible decomposition in the extended presence of acids or bases.

.

:

The prior art has not recognized and appreciated the catalytic nature of an organic base to effect the rearrangemen~ of triazolo[4,3-c]pyrimidines substituted in the 7-position by a nitrogen atom which is part of a heterocyclic ring to provide the corresponding substituted triazolo[l,5-cJpyrirnidine. Indeed, in view of the basic nature of such triazolo[4,3-c]pyrimidines, it is surprising that the rearrangement may be effected in the presence of an organic base.
The advantages of the process of the present invention include a more rapid rate o~ reaction, improved purity of the product, more convenient reaction workup, reduced danger of decomposition during reaction, and avoidance of the use of relatively large amounts of acids and problems associated with the-ir di~posal. Moreover, employment of an organic base in an organic solvent for the rearrangelnent reaction of the present invention is particularly advantageous. A more rapid and cleaner reaction results if an organic solvent is employed because of the generally very limited solubility of the reactant in water.

Detailed Description of the Invention The present invention relates to a process for the rearrangment of triazolo[~,3-c]pyrimidines substituted on the 7-position through a nitrogen atom which is part of a heterocyclic ring (Formula II) through the action of an organic base to provide the corresponding sub~tituted triazolo[l,5-c]pyrimidine. The present invention also relates to triazolo[l,5-c]pyrimidines prepared by such process.
More specifically, the process of the present invention relates to the preparation of compounds of the Formula I
~5 ~ N ~ N-7 ~ N
R~

~L~7~
. ~
~3--wherein R2 is hydrogen or lower alkyl: P~5 is hydrogen or lower alkyl; and R7 is -N~X, wherein X is oxygen, sulfur, sulfinyl, sulfonyl, methylene, imido or lower N-alkylimido, and R~ is hydrogen, lower alkyl or phenyl, comprising reacting a substituted triazolo[4,3--c]pyrimidine of the Formula II

N~ N~

wherein R2, R5, R7 and R~ are as defined above, in a protic solvent and in the presence of an organic base. Compounds of Formula I and their pharmaceutically acceptable acid addition salts (e.g., those obtained by reacting a compound of Formula I with an inorganic acid such as hydrochloric, sulfuric or phosphoric acid) are useful bronchodilator agents as is described in Applicants' copending Canadian patent application Serial No. 44~,748, filed March 2, 19~4.
Lower al]cyl as used in the instant specification and claims designates straight- or branched-chain alkyl groups containing one to about four carbon atoms.
Preferred lower alkyl substituents are methyl, propyl and ethyl.
The rearrangement reaction of the invention is carried out by heating a compound of Formula II in the presence of at least a catalytic amount of an organic base such as a metal alkoxide or a secondary amine. Primary or tertiary amines may also be used, but they are less preferred. Most preferred are rnetal alkoxides. Compounds of Formula II may be prepared as described in said Canadian Patent application Serial No. 44~,74a.
The rnetal alkoxide is preferably an alkali metal alkoxide such as a sodium or potassium alkoxide, althou~h other metals such as calcium, cesiunl, rubidium, etc. could be used. Preferably, the alkoxide is a lower alkoxide (i.e., an alkoxide containing one to about four carbon ~7~
, ~

atoms) derived from the respective lower alkanol (i.e., an alkanol containing one to about four carbon atoms) such as methanol, ethanol, isopropanol and the like.
When a secondary amine reagent is used, it is r~
preferably the cyclic amine o~ the formula ~IN ~ X, wherein X is as defined above. However, other secondary amines such as di(lower alkyl)amines, for example, N,N-diethyl-amine, N,N-di-n-butylamine and the like, may also be used.
When di(lower alkyl)amines and tri(lower alkyl)amines are used, the reaction rate is slower than when metal alkoxides are used.
The exact amount of base used is not critical, although if very small amounts such as significantly less than 1 mole of catalyst to 100 moles of the triazolo[4,3-c]-pyrimidine reactant are used, the reaction rate may be noticeably reduced. Generally, from 1 to 10 moles of catalyst per 100 moles of reactant will be used.
The method by which the base is generated is not critical. Generally, sodium methoxide is generated in the absence of water. flowever, it can also be obtained by reacting an inorganic base such a.s sodium hydroxide with methanol. In the latter case, traces of water will be present, but have not been observed to reduce yields or purity.
The temperature of the reaction is a variable which may be adjusted to regulate the reaction rate. An increase in the reaction temperature will increase the reaction rate. Since the reaction is carried out in a solvent, the reaction is ~enerally carried out at the reflux temperature of the reaction mixture, and the reflux temperature will vary according to the boiling point of the solvent used. The reflux temperature will ordinarily be slightly lower than the boiling point of the solvent.
- The solvent used will be any protic solvent which dissolves the reactants and is inert to the reaction 74~rc~B

conditions. Preferably, for convenience, the solvent chosen will be the lower alk.anol correspondiny to the lower alkoxide used, for example, methanol if sodium methoxide is used as the base, and ethanol if potassium ethoxide is used as the base. However, this is not necessary, and may be varied if an alterna~ive solvent is desired due to, for example, cost considerations, safety, or a desire to vary the reaction temperature.
The rearrangement reaction is generally surprisingly facile and will be complete in, for example, less than one hour, and, at times, in only a few minutes when the ratio of catalyst to reactant and the reaction temperature are relatively high.
The reaction is essentially quantitative under the preferred reaction conditions, especially on a large scale. The product will ordinarily be isolated by removal of the solvent by distillation or evaporation. Traces of catalyst and other minor impurities may be removed readily by washing the solid product with a solvent such as water, an alkanol or the likeO Alternatively, water may be added to the cooled reaction mixture and the product rnay then be isolated by filtration or extraction.
If desired, the product isolated may be recrystallized. ~uitable recrystallization solvents include a wide variety of organic liquids such as alkanes, for example, cyclohexane, heptane, hexane and the like, toluene; benzene, ethyl acetate; ethanol; and diethyl ether.
The following examples are provided to illustrate various methods of the invention. The examples are not intended to limit the invention.

Example 1 To a solution of 3.00 g (10.8 mmole) of 3,5-diethyl-7-(a~-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine in 5 ml of methanol was added 1.0 ml (0.11 mmole) of a solution of 0.23 ~ of sodium methoxide in lO ml ~ ~7~
~, of methanol. Thin layer chromatogr~phy anal~sis on silicagel, eluting with a mixture of ethyl acetate and dichloromethane (50:50, v/v) or with ethyl acetate alone, showed that the rearrangement reaction was complete after 15 minutes. After a total reflux time of 30 minutes, the solution was evaporated to provide a residue which was suspended in 75 ml of water, followed by filtration and recrystallization with treatment with decolori~ing charcoal from 100 ml of cyclohexane. Two crops of white solid

2,5-diethyl-7-(~-thiomorpholino)-1,2,~-triazolo-[1,5-c]pyrimidine were obtained, total 2.30g (77~ yield).
Both crops gave acceptable analyses: Calculated for C13~19MsS: %C, 56.3, ~H, 6.9: ~N, 25.2; Found: First crop:
%C, 56.5; H, 6.9; ~N, 25.3; Second crop: Found: ~C, 56.0;
~l, 6.9; %N, 25.6.

Example 2 Using the method of F.xample 1, 50 mg (0.17 mmole) of 5-ethyl-3-isopropyl-7-(4-morpholino)-1,2,4,-triazolo-t4,3-c]pyrimidine was reacted in 2 ml of methanol to which had been added 0.4~ ml (0.001~3 mmole) of 0.0037M sodium methoxide in methanol. After 5 minutes of heating the mixture at reflux, and periodically thereafter, the mixture was analyzed by thin layer chromatography on silica gel, eluting with 5~ acetone in ethyl acetate. The reaction was complete after 2.5 hours. The product was determined to be the desired 5-ethyl-3-isopropyl-7-(4-morpholino)-1,2,4-triazolo[l,5-c]pyrimidine by comparison of its chromatogram with that of an authentic sample of the desired product.
~lo significant amount of starting material or impurity was detected.

Examples 3-4 Following the method of Example 2 above, the starting materials of Formula II listed in the Table below were reacted to provide the indicated product~ of Formula I.

- ~7--TAsLE
Substituted Sub~tituted Ex. Triazolo[4,3-c]pyrimidine Triazolo[l,5-c]pyrimidine N of Formula II Product of ~ormula I

l~l3 f 3 C~12 CH2CH3 CH2 N~ N~ N~N-- ~
I~ N /~ N ~N ~\N ~ ~ CH 2 Cll 3 0~ ~ OS ~ complete in 0.42 hours) fH3 . fH3 CH2 CH2CH3 CH,2 N~N~ N~N~ ~

1~\ N /~Nl/\N /~ )- CH 2 C H 3 complete in 2.5 hours) Example 5 In order to examine the effect of base concentration on the rate of reaction, the reaction of Example 3 was repeated using double the mole ratio of base to the triazolo[4,3-c]pyrimidine as described below.
To a refluxing solution of 50 mg (0.17 mmole) of

3,5-diethyl-7-C4~ oxothiomorpholino]-1,2,4-triazolo[4,3-c~-pyrimidine in l.5 ml of methanol was added 0.92 ml (0.0034 mmole) of a 0.0037~1 solution of sodium methoxide in methanol. The reaction was monitored by thin layer chromatography on silica gel, eluting with 5~ methanol in acetone. The reaction was complete after .15 minutes. This reaction rate was observed to be at least twice that of Example 3.

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Example 6 In order to examine the effect of extended reaction time on yield and purity, the reaction of Example 1 was repeated using the same arnounts of reactants. ~ere reaction was continued for two days. The product was again recrystallized from 100 ml of cyc]ohexane to provide 2.27 (76%) of white crystals having a slight yellow tinge. The mother liquors from the recrystallization provided 0.36g (12~) of yellow solid which was chiefly the desired product. Analysis of the product, 2,5-diethyl-7-(4-thiomor-pholino)-1,2,4-triazolo[1,5-c]pyrimidine, was comparable to the product of Fxample 1. Calculated for C13~11gNsS: %C, 56.3; %H, 6.9; %N, 25.2, Found: %C, 56.1; %H, 6.8; ~N, 25.5.
Analysis hy high pressure liquid chromatography of the proucts of Example 1 and this example showed similar patterns (about 1% impurities) in both products.

Example 7 In order to compare the effect of different concentrations of a tertiary amine catalyst, two reactions were run side by side as follows:
To a refl~xing solution of 0.050 g (0.18 mmole) of 3,5-diethyl-7-(4-thiomorpholino)-1,2,4-triazolo[4,3-c]-pyrimidine in 3.0 ml of methanol was added 1.0 ml of a solution of triethylamine in methanol. Reaction A used a 0.01 M solution (0.010 mmole) of triethylamine and reaction used a 0.1 M solution (0.10 mmole) of triethylamine.
Samples were periodically removed and analyzed by thin layer chromatography to determine the extent of reaction. Reaction B was complete after 8 hours. Reaction A was not quite complete after 8 hours, but was complete a~ter 24 hours. The thin layer chromatographic analysis was carried out on silica gel plates, eluting with ethyl acetate.

_9_ Example 8 Example 7 was repeated exactly, except here diethylamine was employed instead of triethylamine, as the catalyst. Corresponding reaction B was complete after 4 hours. Corresponding reaction A was not complete at 2 hours, but was complete after 31 hours.

Example 9 3,5-Diethyl-7-thiomorpholino-1,2,4-triazolo-[~,3-c]pyrimidine (1.~7 kg, 5.3 moles) was dissolved in methanol (2.S L) in a 5 L three neck round bottom flask fitted with a thermometer, mechanical stirrer and condenser. Then, 25% sodium methoxide in methanol (11.6 g) was added in one portion, and the mixture was heated to reflux (65C) for one hour at which time the reaction was judged complete by thin layer chromatography. The reaction mixture was poured into 16 L of cold rapidly stirred water, stirred 30 minutes, and then collected by filtration and washed liberally with water. l`he wet cake was dissolved in 1.5 L of chloroform, the water phase was removed, and the chloroform solution was dried over magnesium sulfate and filtered. The chloroform filtrate was then warmed to 50C, mixed into 20 L of warmed (55C) hexane and allowed to recrystallize while slowly cooling to 25C. The mixture was placed in a freezer (-5C) overnight. The resulting off-white solid was collected by filtration, washed once with hexane, air dried and dried in a vacuum oven at 50C.
This gave 1.28 kg (87.1%) of 2,5-diethyl-7-thiomorpholino-1,2~-triazolo[1,5-c]pyrimidine. The filtrate was concentrated under vacuum and the residue recrystallized from chloroform/hexane as described above. This produced second crop of the desired compound. The combined solids (1.63 kg; 1.~1 kg from this run plus 0.22 kg from a smaller scale preparation) were then recrystallized from cyclohexane (16.3 L, 10 ml/g) to give 1.39 kg ~8S~) of 2,5-diethyl-7-thiomorpholino-1,2,a.-triazolo[1,5-c~pyrimidine.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula:

wherein R2 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; R7 is , wherein X is oxygen, sulfur, sulfinyl, sulfonyl, methylene, imido or lower N-alkylimido;
and R8 is hydrogen, lower alkyl or phenyl; comprising reacting a substituted triazolo[4,3-c]pyrimidine of the formula wherein R2, R5, R7 and R8 are as defined above, in a protic solvent and in the presence of an organic base.

2. A process according to Claim 1, wherein X is sulfur.

3. A process according to Claim 1, wherein R2 and R5 are each ethyl and X is sulfur.

4. A process according to Claim 1, wherein the base is an alkali metal alkoxide.

5. A process according to Claim 1, wherein the base is an alkali metal alkoxide and the solvent is an alkanol.

6. A process according to Claim 1, wherein the reaction is accompanied by heating.

7. A process according to Claim 1, wherein the base is an alkali metal alkoxide, the solvent is an alkanol and the reaction is carried out at the reflux temperature of the reaction mixture.

8. A process according to Claim 1, wherein the reaction is carried out in the presence of from about 1 to about 10 moles of base per 100 moles of said substituted triazolo[4,3-c]pyrimidine reactant.

9. A process according to Claim 7, wherein the reaction is carried out in a lower alkanol solvent.

10. A process according to Claim 7, wherein the reaction is carried out at the reflux temperature of the reaction mixture.

11. A compound of the formula wherein R2 is hydrogen or lower alkyl; R5 is hydrogen or lower alkyl; R7 is , wherein X is oxygen, sulfur, sulfinyl, sulfonyl, methylene, imido or lower N-alkylimido; and R8 is hydrogen, lower alkyl or phenyl.

12. The compound 2,5-diethyl-7-thiomorpholino-1,2,4-triazolo[1,5-c]pyrimidine.

13. A process according to claim 1, wherein said organic base is a catalytic amount of a metal hydroxide or a secondary amine.

14. A process according to claim 13, wherein the secondary amine is of formula wherein X is as defined in claim 1.

15. A process according to claim 13 or 14, wherein said catalytic amount is from 1 to 10 moles of catalyst per 100 moles of said triazolo[4,3-c] pyrimidine.