JP3118875B2 - Novel method for producing pyrido [1,2-a] pyrimidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel process for producing pyrido [1,2-a] pyrimidine derivatives useful as anti-allergic agents.

[0002]

BACKGROUND OF THE INVENTION Pyrido [1,2-a] pyrimidine derivatives and salts thereof are known as drugs having an antiallergic effect, and various allergic agents containing the same as an active ingredient are widely used. Conventionally, methods for producing this type of compound include, for example, JP-A-63-183581 and JP-A-63-2463.
A pyrimidine derivative or a pyridine derivative having a cyano group is synthesized from a commercially available compound as described in JP-A No. 74-246, JP-A-63-246375, etc., and then this is combined with hydrazoic acid or a salt thereof. In general, a target compound is obtained by a multi-step synthesis in which a reaction is performed to form a tetrazole ring. U.S. Patent No.
In the specification of 4,474,953, 2-aminopyridine derivative, tetrazol-5-yl acetate and orthoformate are reacted in the presence of a Lewis acid to obtain 3- [N- (2-
A method is described in which a pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylate derivative is heated to 100 to 150 ° C. in polyphosphoric acid and the ring is closed to obtain a target compound. However, this method is also a two-step reaction, and furthermore, a catalyst is used in both steps, and the operation is complicated.

[0003] As described above, complex compounds such as pyrido [1,2-a] pyrimidine derivatives cannot usually be constructed in a complex structure other than by a multi-step synthesis method. This leads to an increase in manufacturing time, manufacturing personnel and manufacturing equipment,
This has led to higher manufacturing costs.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above situation, and uses a commercially available raw material to produce the desired pyrido [1,2-a] pyrimidine derivative in one pot and substantially in one step. A new and extremely effective pyrido [1,2
[a] An object of the present invention is to provide a method for producing a pyrimidine derivative.

[0005]

In order to achieve the above object, the present invention has the following constitution. "(1) Change 1

Wherein R ¹ and R ³ each independently represent a hydrogen atom or lower alkyl, and R ² and R ⁴ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group or 7

Wherein R ⁵ represents a hydrogen atom or a hydroxyl group, R ⁶ represents a hydrogen atom or an acyl group, and R ⁷ represents a hydrogen atom, a lower alkyl group or an allyl group. A compound represented by the formula:

Wherein R ⁸ represents a lower alkoxycarbonyl group or a cyano group. And an alkyl orthoformate in the absence of a catalyst to give

Wherein R ^{1 to} R ⁴ and R ⁸ are as defined above. Wherein the compound is subjected to a ring-closing reaction as it is without isolation.

Embedded image wherein, R ⁹ represents an oxygen atom or an imino group, R ¹
To R ⁴ are as defined above. ] The manufacturing method of the compound shown by these.

(2) Conversion 1

Wherein R ^{1 to} R ⁴ are as defined above. A hydrazide of a compound of the formula

Wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group, and R ⁸ is as defined above. With no compound in the presence of a catalyst.

Wherein R ^{1 to} R ⁴ and R ⁸ are as defined above. And then subjecting it to a ring closure reaction without isolation,

Wherein R ^{1 to} R ⁴ and R ⁹ are as defined above. ] The manufacturing method of the compound shown by these.

(3) Chemical 1

Wherein R ^{1 to} R ⁴ are as defined above. A hydrazide of a compound represented by the formula:

Wherein R ⁸ is as defined above. And an alkyl orthoformate in the absence of a catalyst to give

Wherein R ^{1 to} R ⁴ and R ⁸ are as defined above. Wherein the compound is subjected to a ring-closing reaction as it is without isolation.

Wherein R ^{1 to} R ⁴ and R ⁹ are as defined above. ] The manufacturing method of the compound shown by these. "

That is, the present inventors have conducted intensive studies in search of a more efficient method for producing a pyrido [1,2-a] pyrimidine derivative, and as a result, (i)

(Wherein, R ^{1 to} R ⁴ are the same as described above) (hereinafter abbreviated as compound (1)).

Wherein R ⁸ is as defined above (hereinafter abbreviated as compound (2)) and alkyl orthoformate in the absence of a catalyst or (ii) Of the hydrazide of formula 5

(Wherein R ⁸ and R ¹⁰ are the same as described above) (hereinafter abbreviated as compound (5)) in the absence of a catalyst, or (iii) The hydrazide of compound (1) is converted to

(Wherein R ⁸ is the same as described above) (hereinafter abbreviated as compound (6)) and alkyl orthoformate in the absence of a catalyst.

(Wherein, R ^{1 to} R ⁴ and R ⁸ are the same as described above) (hereinafter abbreviated as compound (3)) in good yield. If the ring-opening reaction is directly performed without isolation, the compound is converted into a single pot and substantially in one step.

(Wherein, R ^{1 to} R ⁴ and R ⁹ are the same as described above) (hereinafter, abbreviated as compound (4)). It has been completed.

In the present invention, R ¹ and R ³ of compound (1), compound (3) and compound (4) each independently represent a hydrogen atom or a methyl group, an ethyl group, a propyl group, Butyl group,
Represents a lower alkyl group such as an amyl group (which may be linear or branched), and R ² and R ⁴ are each independently a hydrogen atom, for example, a halogen atom such as chlorine, bromine, fluorine, iodine, etc. For example, lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group and amyl group (which may be linear or branched) such as methoxy group, ethoxy group, propoxy group, butoxy group, A lower alkoxy group such as an amyloxy group (which may be linear or branched), a phenyl group or

Wherein R ⁵ represents a hydrogen atom or a hydroxyl group, and R ⁶ represents a hydrogen atom or an acyl group such as an acetyl group, a propionyl group, a butyryl group, a benzoyl group,
R ⁷ represents a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and an amyl group (which may be linear or branched). ].

In the present invention, R ⁸ of compound (2), compound (3), compound (5) and compound (6) is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, And a lower alkoxycarbonyl group such as an amyloxycarbonyl group (which may be linear or branched) or a cyano group, and is a compound (4)
R ⁹ represents an oxygen atom or an imino group; R ¹⁰ of the compound (5) represents a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and an amyl group (linear,
Can be branched. ).

The alkyl group of the alkyl orthoformate used in the present invention includes, for example, a methyl group, an ethyl group,
And lower alkyl groups such as propyl group, butyl group and amyl group (which may be linear or branched).

The production method of the present invention includes the following three methods. (A) A method in which a compound (1), a compound (2) and an alkyl orthoformate are reacted in the absence of a catalyst, and a ring-closing reaction is performed without isolating the formed compound (3). (B) A method in which the hydrazide of compound (1) is reacted with compound (5) in the absence of a catalyst, and a ring-closing reaction is performed without isolating the formed compound (3). (C) Compound produced by reacting compound (1) with hydrazide, compound (6) and alkyl orthoformate in the absence of a catalyst
A method in which a ring closure reaction is performed without isolating (3).

In the production method of the present invention, the compound (1) used as a starting material may be a commercially available product, which may be used as it is or may be appropriately purified as necessary.
For those without commercial products, see, for example, Org. React., Vol. 1, 9
These may be synthesized and used according to the method described in 1 to 104 (1942). Compound (2), compound (5), compound
As for (6) and alkyl orthoformate, most of them are available as commercial products, and these may be used.

The hydrazide of the compound (1) is
Can be easily produced by salt exchange between an acid adduct of, for example, and a hydroazide such as sodium azide;
Further, for example, an acid such as hydrochloric acid or sulfuric acid may be added to a mixture of the compound (1) and a hydroazide such as sodium azide to produce the mixture. Incidentally, all of these operations can be performed in a reaction vessel in which the compound (3) is to be synthesized.

Hereinafter, the three methods of the present invention will be described in order. First, in the method (A), the compound (1) and the compound (2) are mixed at a predetermined temperature in the presence of an alkyl orthoformate and the compound (3) produced by the reaction is reacted with an acid or a base. This is a method of synthesizing compound (4) by carrying out a ring closure reaction in the presence or simply by carrying out a heat ring closure reaction. Compound
The formation reaction of (3) is usually performed in an organic solvent, but may be performed without a solvent when the alkyl orthoformate is a liquid. When an organic solvent is used, any solvent which does not inhibit the reaction and does not react by itself may be used. For example, alcohols such as methanol, ethanol and isopropyl alcohol, acetone, methyl ethyl ketone Ketones, etc., esters such as methyl acetate, ethyl acetate, etc., aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, acetonitrile, propionitrile, etc. Nitriles, diethyl ether, tetrahydrofuran (THF), dioxane, ethers such as ethylene glycol dimethyl ether, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC)
Amides, sulfoxides such as dimethyl sulfoxide, and the like.Alcohols, nitriles, amides, and sulfoxides are particularly preferable.These solvents may be used alone or in combination of two or more. May be used in combination. The amount of the solvent used is not particularly limited as long as it can dissolve the raw materials and does not significantly reduce the reaction rate. The proportions of the compound (1), the compound (2) and the alkyl orthoformate are not particularly limited, but usually the compound (1) and the compound (2) are equimolar and the alkyl orthoformate is used in excess with respect to both. You. Reaction temperature is usually 0 ° C
Any temperature up to the reflux temperature of the reaction solvent or the alkyl orthoformate may be used, but it is preferable to perform the reaction under heating because the reaction time can be shortened.

The formation of compound (3) can be confirmed by a method such as TLC. If it is confirmed that the reaction for forming compound (3) is completed, the reaction may be shifted to a ring closing reaction. The ring closure reaction proceeds by simply heating without using a catalyst,
Performing the ring closure reaction by adding an acid or base as a catalyst is more efficient and preferable in terms of yield and time. Further, when R ⁸ is a cyano group, the use of an acid catalyst is preferable for the ring closure reaction of compound (3) with a better yield, but when R ⁸ is a lower alkoxycarbonyl group, the reaction is performed with a base catalyst. It is preferable that the yield is much better than when the reaction is performed with an acid catalyst.

The ring-opening reaction is usually carried out by adding an acid or a base as a catalyst, if necessary, to the reaction solution for the formation reaction of the compound (3). However, if necessary, an acidic organic solvent such as acetic acid or formic acid, hexamethylphosphoramide (HMPA), or water may be added to these solvents.

Examples of the acid catalyst used for the ring closure reaction include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphorus oxychloride and polyphosphoric acid, acetic acid, formic acid, benzenesulfonic acid, and the like.
organic acids such as p-toluenesulfonic acid and methanesulfonic acid,
Alternatively, for example, a Lewis acid such as aluminum chloride, zinc chloride, tin tetrachloride, boron trifluoride, antimony hexafluoride, or the like may be used, provided that the amount is such that the acidity can be maintained throughout the entire process of the reaction. Good. When an acidic organic solvent such as acetic acid or formic acid is additionally used as the reaction solvent, it goes without saying that it is not necessary to add these acid catalysts.

Examples of the base catalyst used in the present ring closure reaction include, for example, hydroxides of caustic alkalis such as sodium hydroxide and potassium hydroxide, and alkaline earth metals such as magnesium hydroxide, calcium hydroxide and barium hydroxide. Stuff,
Alkali carbonates such as sodium carbonate and potassium carbonate; metal alkoxides such as sodium methoxide and sodium ethoxide; for example, pyridine, triethylamine, n-propylamine, benzylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, N Organic bases such as 1-methylpyrrolidine, benzyltrimethylammonium hydroxide, and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and ammonia, and the amount thereof is basic throughout the reaction. Any amount that can keep

When a base is used as a catalyst, the above reason, ie, it is necessary to maintain the basicity throughout the entire process of the reaction, so that usually a base equivalent to the produced compound (3) or more is necessary. . Therefore, to obtain compound (4),
Then, it is necessary to neutralize with an acid or the like. On the other hand, when isolated without neutralization, a salt of compound (4) can be obtained.
When a salt of compound (4) is required as a pharmaceutical, a salt-forming step is not required again, and the process is shortened.
This is a more advantageous method. This ring closure reaction can be carried out at a wide range of reaction temperature from room temperature to the reflux temperature of the reaction solvent, but the higher the reaction temperature, the faster the reaction can be completed. It is carried out between the reflux temperature of the solvent.

After completion of the reaction, an aqueous solution of a strong acid such as hydrochloric acid, sulfuric acid or the like is added to adjust the liquid property of the reaction solution to a strong acid, so that crystals of the compound (4) are precipitated. Can be isolated by Due to the solubility of the reaction solvent used, if crystals do not precipitate even if adjusted to a strongly acidic compound (4)
It can be crystallized by diluting with a solvent in which is not dissolved, for example, water, or can be isolated by concentrating, re-dissolving or extracting the reaction solution. Compound obtained in this way
Further purification of (4) as necessary is optional.

When compound (4) is isolated as a physiologically acceptable salt, a sufficient amount of a basic compound for salt formation should be added during the ring closure reaction, and neutralized after completion of the reaction. If the compound (4) is neutralized to the extent that the compound (4) is not released and the salt of the compound (4) is isolated by a conventional method, the compound (4)
As described above, it is particularly significant from the viewpoint of simplification of the process, since the salt-forming step can be omitted as compared with the case where is once isolated as a free form.

Next, the method (B) is a method in which an acid is allowed to act on a mixture of the compound (1) and a hydroazide, or an acid adduct of the compound (1) is reacted with an azide. The hydrazide of compound (1), which is produced by reacting with a hydrochloride, is reacted with compound (5) to produce compound (3). Thereafter, the ring closure reaction is carried out according to the method (A). How to do it. Therefore, this method includes a tetrazole cyclization step, unlike the method (A).

Examples of the hydrazide used herein include commercially available azides such as sodium azide and lithium azide. Any acid may be used as long as it is stronger than hydrazoic acid, and examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. These azides and acids can be used in an equimolar amount or more with respect to compound (1) .However, if a large amount of azide and acid is used, excessive generation of hydrogen azide inevitably increases, making it difficult to handle. Therefore, usually about 1.0 to 2.0 times mol is used. The reaction temperature may be generally from 0 ° C. to the reflux temperature of the reaction solvent, but is usually performed at about room temperature. As the reaction solvent, the reaction solvents shown in the method (A) can be used as they are. The hydrazide of compound (1) thus produced is allowed to act on compound (5) without isolation, and is converted to compound (3). The amount of compound (5) used is
(1) may be at least equimolar, but usually 1.0 to 2.0
About twice the molar amount is preferably used. Compound (5) is a compound
It may be added after the hydrazide of (1) is formed, or may be added from the beginning. The reaction between the hydrazide of compound (1) and compound (5) is usually performed at any temperature between 0 ° C. and the reflux temperature of the reaction solvent, but a higher reaction temperature can shorten the reaction time. preferable. Compound (3)
And the subsequent operations, such as the ring closure reaction of compound (3) and the post-treatment method, may be carried out in accordance with the method (A) described above.

The method (C) is the same as the method (B), except that the compound
This is a method using compound (6) and alkyl orthoformate instead of (5). As the alkyl orthoformate, it is sufficient to use ethyl orthoformate, methyl orthoformate or the like described in the method (A). The amounts of the compound (6) and the alkyl orthoformate to be used may be at least equimolar to the compound (1), and are usually used in an amount of about 1.0 to 2.0 moles. Other reaction conditions (reaction solvent, reaction temperature, etc.) and post-treatment methods may be performed according to the method (B).

As described above, the methods (B) and (C) correspond to the method (A)
Unlike the method described in the above, the series of reaction steps includes a tetrazole cyclization reaction. In the tetrazole cyclization reaction, ammonium chloride or aluminum chloride is usually added to increase the reactivity of sodium azide or the like, and the reaction is performed as ammonium azide or aluminum azide.

However, even when ammonium chloride, aluminum chloride and the like are used in combination as described above, the yield is not as high as a little over 50% of Max, and some harm is caused by using these compounds in combination. . That is, for example, when ammonium chloride is used in combination, sodium azide acts as ammonium azide, but this ammonium azide has a very high sublimability,
If the reaction is carried out at a high temperature for a long time, it escapes out of the system, so that it is necessary to use it in a large excess, and the efficiency is extremely poor. Also,
When aluminum chloride or the like is used in combination, sodium azide acts as a polyvalent metal salt of hydrazoic acid such as aluminum azide in the system. Salts are extremely dangerous compounds with explosive properties and require strict care and skill in handling.
In addition, when these polyvalent metal salts are used in the reaction, a large amount of azide groups not involved in the tetrazole cyclization reaction remain after the reaction, so that a large amount of hydrogen azide is generated, and air pollution and the like are generated. In addition to the problem, it is necessary to dispose of metal waste caused by aluminum and the like.

Therefore, these methods are put to practical use (commercialization).
If they try to do so, they will not only have a low yield, but also have problems in securing the working environment and worker safety, problems in facilities to prevent air pollution, problems in time and labor required for industrial waste disposal, etc. Must be taken into account.

However, in the present invention, the compound (1) as a raw material
However, ammonium chloride, aluminum chloride, and the like are unnecessary because they also have a catalytic action. Therefore, according to the method of the present invention, the above-mentioned problems when a tetrazole cyclization reaction is carried out using conventional ammonium chloride or aluminum chloride are completely eliminated. In addition, the fact that the amount of additives to the reaction system is small (no use of a catalyst) leads to less contamination of the product without any improvement.
This means that the present invention is a more preferable form as a method for synthesizing a drug.

In the above-mentioned production methods (A) to (C) of the present invention, the substituents R ¹ to R ¹⁰ of the compounds (1) to (6) require protection during the reaction. When there is a functional group, it goes without saying that a step of introducing a protective group and a step of deprotecting should be appropriately incorporated.

Further, some of the compounds (1) to (6) of the present invention have tautomers, and there is substantially no problem in either form. Only the type is shown. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0032]

【Example】

Example 1. 5.4 g (50 mmol) of 2-amino-3-methylpyridine,
7.8 g (50 mmol) of ethyl 1H-tetrazol-5-ylacetate and 8.2 g (55 mmol) of ethyl orthoformate were dissolved in 20 ml of DMF, and heated and stirred at 90 ° C. for 1 hour. After the reaction, 55 ml of a 1N aqueous solution of potassium hydroxide was added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling, the reaction solution was acidified with 10% hydrochloric acid, and the precipitated crystals were collected by filtration to give 9-methyl-3-H-tetrazol-5-yl-4H-.
9.4 g of white needles of pyrido [1,2-a] pyrimidin-4-one were obtained. 82% yield.

Example 2. 2-amino-3-methylpyridine 5.
4 g (50 mmol), ethyl 1H-tetrazol-5-ylacetate 7.8 g
(50 mmol) and 8.2 g (55 mmol) of ethyl orthoformate in THF
It was dissolved in 20 ml and stirred and refluxed for 6 hours. After cooling, 13.3 g (100 mmol) of anhydrous aluminum chloride was added to the reaction solution, and the mixture was stirred and refluxed for 6 hours. After cooling, water was poured into the reaction solution, and the precipitated crystals were collected by filtration and white needles of 9-methyl-3-1H-tetrazol-5-yl-4H-pyrido [1,2-a] pyrimidin-4-one were obtained. 3.7 g of crystals were obtained. Yield 32%.

Embodiment 3 FIG. Embodiment 1 FIG. 2-amino-3 in
Example 1 was repeated except that 5.4 g (50 mmol) of 1-methylpyridine was replaced with 15.0 g (50 mmol) of 2-amino-3- (4-acetyl-3-hydroxy-2-n-propylphenoxymethyl) pyridine. 9- (4-acetyl-3-hydroxy-2-n-propylphenoxymethyl) -3-1H-tetrazol-5-yl-4H-pyrido [1,2
19.7 g of white crystals of [-a] pyrimidin-4-one were obtained. Yield 94
%.

Example 4. 7.3 g (50 mmol) of 2-amino-3-methylpyridine hydrochloride and 3.8 g (50 mmol) of sodium azide were suspended in 20 ml of DMF, and the suspension was stirred at room temperature for 1 hour. 8.5 g (50 mmol) of ethyl acetate was added, and 9
The mixture was heated and stirred at 0 ° C. for 6 hours. After the reaction, 55 ml of a 1N aqueous solution of potassium hydroxide was added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hour. After cooling, the reaction solution was acidified with 10% hydrochloric acid, and the precipitated crystals were collected by filtration to give 9-methyl-3-H-tetrazol-5-yl-4H-pyrido.
7.0 g of white needles of [1,2-a] pyrimidin-4-one were obtained. Yield 62%.

Example 5. 7.3 g (50 mmol) of 2-amino-3-methylpyridine hydrochloride and 3.8 g (50 mmol) of sodium azide were suspended in 20 ml of DMF, and the suspension was stirred at room temperature for 1 hour. 8.5 g (50 mmol) of ethyl acetate was added, and 9
The mixture was heated and stirred at 0 ° C. for 6 hours. After cooling, 10 ml of phosphorus oxychloride was added to the reaction solution, and the mixture was stirred at 90 ° C for 5 hours. After cooling, water was poured into the reaction solution, and the precipitated crystals were collected by filtration and 9-methyl-3-1H-
Tetrazol-5-yl-4H-pyrido [1,2-a] pyrimidine-4-
2.9 g of on white needles were obtained. Yield 26%.

Example 6. 7.3 g (50 mmol) of 2-amino-3-methylpyridine hydrochloride and 3.8 g (50 mmol) of sodium azide were suspended in 20 ml of DMF and stirred at room temperature for 1 hour. 6.1 g (50 mmol) and ethyl orthoformate 11.2 g (7
5 mmol), and the mixture was heated and stirred at 90 ° C. for 12 hours. After the reaction, 55 ml of a 1N aqueous solution of potassium hydroxide was added to the reaction solution, and the mixture was added at 50 ° C.
Stirred for hours. After cooling, the reaction was acidified with 10% hydrochloric acid,
The precipitated crystals were collected by filtration and 9-methyl-3-H-tetrazole
6.5 g of white needle crystals of -5-yl-4H-pyrido [1,2-a] pyrimidin-4-one were obtained. Yield 57%.

Example 7. 2-Amino-3-methylpyridine 5.
4 g (50 mmol) and 3.8 g (50 mmol) of sodium azide in DMF
Suspend in 20 ml, add 4.9 g (50 mmol) of sulfuric acid, and add
Stirred for hours. To this, 8.5 g (50 mmol) of ethyl ethoxymethylene cyanoacetate was added, and the mixture was stirred while heating at 90 ° C. for 6 hours, and 55 ml of a 1N aqueous potassium hydroxide solution was added.
Stirred for hours. After cooling, the reaction was acidified with 10% hydrochloric acid,
The precipitated crystals were collected by filtration and 9-methyl-3-1H-tetrazole-5
6.0 g of white needle crystals of -yl-4H-pyrido [1,2-a] pyrimidin-4-one were obtained. Yield 53%.

Example 8 7.3 g (50 mmol) of 2-amino-3-methylpyridine hydrochloride and 3.8 g (50 mmol) of sodium azide were suspended in 20 ml of DMF, and the suspension was stirred at room temperature for 1 hour. 6.1 g (50 mmol) of nitrile were added, and 90
The mixture was heated and stirred at ℃ for 6 hours. After the reaction, concentrated hydrochloric acid 150m
was added and heated at 110 ° C. for 4 hours. After cooling, the precipitated crystals were collected by filtration, and 9-methyl-3-1H-tetrazol-5-yl-4H-
6.7 g of white needles of pyrido [1,2-a] pyrimidin-4-one were obtained. Yield 59%.

Example 9. 7.3 g (50 mmol) of 2-amino-3-methylpyridine hydrochloride and 3.8 g (50 mmol) of sodium azide were suspended in 20 ml of DMF and stirred at room temperature for 1 hour. g (50 mmol) and ethyl orthoformate 11.2 g (75
mmol), and the mixture was heated and stirred at 90 ° C. for 12 hours. After the reaction, 150 ml of concentrated hydrochloric acid was added to the reaction solution, and the mixture was heated at 110 ° C. for 4 hours. After cooling, the precipitated crystals were collected by filtration to obtain 5.8 g of 9-methyl-3-1H-tetrazol-5-yl-4H-pyrido [1,2-a] pyrimidin-4-one white needles. . Yield 51%.

[0041]

Industrial Applicability The present invention provides a method for synthesizing a pyrido [1,2-a] pyrimidine derivative having a complicated structure from a commercially available simple compound in one pot with a high yield. Various pyridos [1,2 useful as allergic agents
The effect is remarkable in that it is possible to produce the [-a] pyrimidine derivative at a much lower cost than in the conventional method and in a short time, and the effect of the present invention is great.

──────────────────────────────────────────────────続 き Continuation of the front page Examiner Yutaka Shindome (56) References JP-A-63-246374 (JP, A) US Patent 4,474,953 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB Name) C07D 471/04 A61K 31/519 C07D 401/12 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) Chemical formula (1) [Wherein, R ¹ and R ³ each independently represent a hydrogen atom or lower alkyl, and R ² and R ⁴ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group or ] (However, R ⁵ represents a hydrogen atom or a hydroxyl group, R ⁶ represents a hydrogen atom or an acyl group, and R ⁷ represents a hydrogen atom, a lower alkyl group or an allyl group.) A compound represented by the following formula: [In the formula, R ⁸ represents a lower alkoxycarbonyl group or a cyano group. And an alkyl orthoformate in the absence of a catalyst to give a compound of the formula [Wherein, R ^{1 to} R ⁴ and R ⁸ are the same as above. Wherein the compound is subjected to a ring-closing reaction without isolation. [In the formula, R ⁹ represents an oxygen atom or an imino group, and R ^{1 to} R ⁴ are the same as described above. ] The manufacturing method of the compound shown by these. ## STR1 ## wherein R ^{1 to} R ⁴ are as defined above. And a hydrazide of a compound represented by the formula: Wherein, R ¹⁰ represents a hydrogen atom or a lower alkyl group, R ⁸
Is the same as above. Wherein R ^{1 to} R ⁴ and R ⁸ are the same as those described above. Wherein the compound is subjected to a ring closure reaction without isolation, wherein R ^{1 to} R ⁴ and R ⁹ are the same as described above. ] The manufacturing method of the compound shown by these. ## STR1 ## wherein R ^{1 to} R ⁴ are as defined above. Hydrazide of a compound represented by the formula: [Wherein, R ⁸ is as defined above. Wherein R ^{1 to} R ⁴ and R ⁸ are the same as those described above by reacting the compound of formula (I) with an alkyl orthoformate in the absence of a catalyst. Wherein the compound is subjected to a ring closure reaction without isolation, wherein R ^{1 to} R ⁴ and R ⁹ are the same as described above. ] The manufacturing method of the compound shown by these.