JPS63222171A - Production of triazolopyrimidine amino derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful in photographic field and physiologically active field, in high selectivity, by using a triazolopyrimidine halogen derivative as a raw material and reacting the material with ammonia in the presence of a copper catalyst under specific reaction condition. CONSTITUTION:The objective compound of formula II is produced by using a triazolopyrimidine halogen derivative of formula I (R1 is H or lower alkyl; R2 is H, <=8C alkyl, aralkyl, alkenyl or allyl; X is Cl, Br or I) as a raw material and reacting the material with ammonia at 100-300 deg.C, especially 160-270 deg.C under an ammonia partial pressure of >=1atm. and preferably <=10atm. The starting compound of formula I is novel substance which can be synthesized e.g. by reacting a triazole derivative of formula III with an alkoxy-substituted acrylic acid derivative of formula IV (R6 is lower alkyl; R4 is H, etc.) in the presence of a base catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing triazolopyrimidine amino derivatives. More specifically, the present invention relates to a method for producing a triazolopyrimidine amine derivative represented by the following general formula (1).

A compound having a triazolopyrimidine skeleton represented by the general formula (Ilff) is a compound useful in the field of photography or as a substance exhibiting physiological activity. For example, US Pat. No. 3,271,401 describes a compound represented by the following formula, which is said to be useful as an antifog stabilizer for photographic silver halide emulsions.

On the other hand, Japanese Patent Publication No. 51-7677 describes that triazolopyrifazine derivatives are important as substances that show activity against bronchial pain, reduce fat in the body, or have an appetite-reducing effect. ing.

Among these important compounds, compounds having an amino group in the triazolo ring contain nitrogen atoms in the triazolo ring and the pyrimidine ring, and therefore many difficulties arise in the introduction of nitrogen atoms, and therefore complicated synthetic methods are used. In particular, the synthesis becomes more complicated when an alkyl group is introduced into the pyrimidine ring and a different amino or aminoalkyl group is introduced into the triazolo ring.

For example, Japanese Patent Publication No. 51-7677 discloses the following reaction.

S-c! bird ↓ SS-bleaching ↓ Shima 4 RicA S exposed ↓ +N Peng - N Tori・40 t+c11K.

The present invention was achieved as a result of research into a method for easily and inexpensively producing the compound represented by the general formula (m).

That is, the present invention relates to a triazolopyrimidine halogen derivative represented by the following general formula (I) r, where - is a hydrogen atom or a lower alkyl] and ammonia in the presence of a copper catalyst at a temperature of 100 to 300°C. This is a method for producing a triazolopyrimidine amino derivative represented by the following general formula [1], characterized in that the reaction is carried out at a temperature and a partial pressure of ammonia of at least 1 atm.

The inventor previously discovered Kl! #As No. 61-117645, the following general formula [! ] Triazolopyrimidine halogen derivative [I
] and an amino compound represented by the following general formula [■'] R, NH, ...... [■] at a temperature in the range of 100 to 300°C. We have proposed a method for producing triazolopyrimidine amino derivatives represented by the following general formula [Ding].

This proposed method is an excellent method for producing triazolopyrimidine amino derivatives, as it can selectively introduce an amino group or an alkylamino group despite the presence of a compound.

In this method, when 8 is a hydrogen atom, the amine compound [1] is ammonia.

In the case of using this ammonia, the present invention achieves a higher conversion rate by keeping the partial pressure above a certain level, maintaining the reaction temperature within a specific range, and carrying out the reaction in the presence of a copper catalyst. This was achieved based on the knowledge that the desired product could be obtained with a high selectivity.

According to the present invention, since the reaction can be carried out at a much lower pressure and under much milder conditions, the cost required for a reaction apparatus can be greatly reduced, and therefore its industrial value is extremely large. Furthermore, the fact that a high conversion rate and selectivity can be maintained means that separation and purification of the target product can be performed extremely easily and at low cost.

In the triazolopyrimidine halogen derivative of general formula CI) used as a starting material in the method of the present invention, the bird represents a hydrogen atom or a lower alkyl group.

Such alkyl groups may be branched or straight-chained, and lower alkyl groups having 5 or less carbon atoms are generally used, preferably those having 4 or less carbon atoms. Examples of such lower alkyl groups include methyl group, ethyl group, n
-propyl group, fi-butyl group, and n-amyl group.

The symbol represents a hydrogen atom, an alkyl group, an aralkyl group, an alkenyl group, or an allyl group having 8 or less carbon atoms.

The alkyl group may be branched or straight chain, and preferably has 5 or less carbon atoms.

Examples of such alkyl groups include methyl group, ethyl group,
Examples include n-propyl group, n-butyl group, and n-amyl group.

The alkenyl group may have at least 8 carbon atoms and at least a double bond, and may be branched or linear.

Preferably, it has 5 or less carbon atoms, such as vinyl group, aryl group, C-cz-cmwcH, methallyl group, and the like.

The aralkyl group has 8 or less carbon atoms, and includes, for example, a benzyl group or a benzyl group substituted with a halogen, an aqueous group, a methoxy group, or the like. Examples of the allyl group include a phenyl group or a phenyl group substituted with a methyl group, a methoxy group, a halogen, a hydroxyl group, a cyano group, a thiomethyl group, or the like.

Furthermore, in the general formula m, X is a chlorine atom.

A bromine atom or an iodine atom is shown, and an internal filler atom or a bromine atom is preferred from an economic standpoint.

The starting material of the present invention has the general formula [! ] The compound is
As far as the inventors know, this is a new substance and can be produced by various methods. One of the methods is the following method previously proposed by the present inventor.

That is, a triazole derivative represented by the following general formula [v] and a triazole derivative represented by the following general formula [Vl
-a) or (Vl-b) R111-〇-cH=c-C-R, ・-・-・・-・-
[V)-a) (R,, -o-), cH-CH-C-R,
-------・------・-rV)b) and at least one selected from the group consisting of alkali metal hydroxides, carbonates, and amides. A triazolopyrimidine halogen derivative represented by the following general formula rI[) can be obtained by carrying out the reaction at a temperature of -20 to 350°C in an aprotic polar solvent in the presence of a basic catalyst. However, the method for producing the starting material is not limited to these methods.

In the general formula (IF), X is a chlorine atom.

A bromine atom or an iodine atom is shown, and the inner ring atom or bromine atom is preferred from an economic standpoint.

As the copper catalyst used in the present invention, in addition to metal steel, -valent and divalent compounds of steel can be used. Examples of ligands that form copper compounds include the following.

(1) β-diketone anion (2) Aliphatic-2-alicyclic- or aromatic-carboxylic acid anion or organic sulfonic acid anion Those corresponding to β-diketone anion include acetylacetone anion, acetopropylketone anion,
In addition to β-diketones such as acetobutyl ketone, β-diketonate esters such as acetoacetate anion are also included.

Examples of aliphatic carboxylic acids as aliphatic carboxylic acid anions include formic acid, acetic acid, and propionic acid.

In addition to monocarboxylic acids such as butyric acid and valeric acid, polycarboxylic acids such as ironic acid and fumaric acid can be mentioned.

Preferred examples of the alicyclic carboxylic acids include hydrobenzoic acid and naphthenic acid, and preferred examples of the aromatic carboxylic acids include benzoic acid, toluic acid, and various heptalic acids.

The amount of the copper catalyst having a ligand as described above is preferably 10<-2> mol or more, particularly preferably 2*10<-2> mol or more per 1 mol of the compound of the general formula rI). The upper limit of the amount of catalyst is as long as it does not inhibit the reaction #)! Although it is not in #, it is determined by itself from an economic standpoint.

In the method of the present invention, the amount of ammonia relative to the starting material m is not limited to WK as long as it does not generally inhibit the reaction, and may be less than 1 mol or more than 1 mol per 111 mol of the starting material. . However, amounts of 1 molar and higher are generally preferred.

There is no upper limit in general, but it is self-limited for economic reasons.

Although it is important to use the above-mentioned total amount of ammonia for the reaction, the reaction requires the supply of a certain amount of ammonia, and is preferably carried out at an ammonia partial pressure of at least 1 atmosphere or more. If the temperature is lower than this, side reactions will occur,
The conversion rate to the target amine compound rI[) tends to be low, and the selectivity also tends to be low. There is generally no upper limit to the reaction pressure; the higher the pressure, the better.

However, from the point of view of the fabrication equipment, it is not preferable to have a high amperage pressure, and generally a pressure of 300 atm or less, preferably 100 atm or less is used.

However, the reaction takes place when the partial pressure of ammonia is below 20 atm.
The process progresses well at a pressure of 49 K 15 atm or less, especially 10 atm or less.

The reaction in the method of the present invention is generally preferably carried out in a solvent, and in that case, it is preferable to use a 5- or 6-membered ring nitrogen-containing compound as the solvent. It is particularly advantageous to use aromatic nitrogen-containing compounds. Examples of these include:

Vitol pyrazole imidasol 1
,2.3-) Riazole N-methylvirolitotsu L
2+4-) Lian-ruthiazole Pyridine Bicolimbilitazine Pyrimidine Ochusujin Pirashiisinnoline
7 Talazine Medium 6 Zoline Medium Noquinaline These solvents are used in an amount of 0.1 to 100 per part by weight of the starting material 6 triazo a pyrimidine halogen derivative (I).
It is desirable to use 0 parts by weight, preferably in the range of 0.5 to 500 parts by weight.

In carrying out the method of the present invention, the reaction temperature is generally 120°C.
~300℃, preferably 140℃~280℃, special KtF
Preferably it is 160°C to 270°C. If the reaction temperature is lower than the above range, the reaction is difficult to occur, and if the reaction temperature is higher than this range, the formation of a starting acid and the separation of the product layer will occur, which is not preferable.

In the reaction of the present invention, the reaction time is relatively short when the reaction temperature is high within the above range, and relatively long when the reaction temperature is low. Generally 1 minute ~
100 hours, preferably 5 minutes to 50 hours. For example, at a reaction temperature of about 220°C, a few hours is sufficient for the synthesis of most compounds.

The reaction of the present invention can be carried out either batchwise or continuously, or a combination thereof.

According to the above method, the target triazolopyrimidine amino compound (II) can be easily obtained in high yield and achieved in a 2-tl polymer. -propyl-6-methyl-4,5-
Synthesis of dihydro-triazolo(1,5)pyrimidine; Contents: 2-brome 4- as starting material in a 1001 t/titanium autoclave. I-propyl-6-methyl-4.5-dihydro-triazolo[, S) bi17 midine (I) 1, OJ's 30 d ON-methylpyrrolidone steel CTI) 0.1911 of acetylacetone was charged, and after nitrogen substitution, ammonia was added to 1. It was introduced at a partial pressure of 0 atmospheres. The reaction was carried out at 200°C for 4 hours.

Analysis results by liquid chromatography showed a conversion rate of 93% and a 2-week selectivity of 97%.

Examples 2 to 11 KL as in Example 1, except that the copper catalyst shown in the table below,
The reaction was carried out using a solvent under the reaction conditions shown in the same table.

The results are shown in the table below together with Example 1.

Claims (1)

[Claims] 1. The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...... [I] [However, in the formula, R_1 represents a hydrogen atom or a lower alkyl group, R_2 represents a hydrogen atom, an alkyl group having 8 or less carbon atoms, an aralkyl group, an alkenyl group, or an allyl group, indicates a chlorine atom, bromine atom or iodine atom. ] The triazolopyrimidine halogen derivative represented by the following general formula [II] is reacted with ammonia in the presence of a steel catalyst at a temperature in the range of 100 to 300°C and at a partial pressure of ammonia of at least 1 atm. ] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...[II] [However, in the formula, the definitions of R_1 and R_2 are the same as above. ] A method for producing a triazolopyrimidine amino derivative represented by: 2. The production method according to item 1, wherein the reaction is carried out in a 5-membered ring or 6-membered ring nitrogen-containing compound solvent.