JPH02289569A - New production of pyrido(1,2-a)pyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound by making, from 3-cyano-4-imino- pyrido[1,2-a]pyrimidine derivative as starting material, a new intermediate either through another new intermediate or by direct tetrazole-cyclization of the nitrile group of said derivative and by hydrolysis of the resulting new intermediate. CONSTITUTION:A compound of formula I [R<1> and R<3> are each H or alkyl; R<2> and R<4> are each H, halogen, alkyl, phenyl or of formula II (R<5> is H or OH; R<6> is H or acyl; R<7> is H, alkyl or allyl)] is reacted with hydrazoic acid or its salt to effect tetrazole-cyclization of the nitrile group of said compound into a new compound of formula III followed by acting an acid or base on this compound to prepare a second new compound of formula IV, which is then hydrolyzed to obtain the objective compound, a pyrido[1,2-a]pyrimidine derivative of formula V. Alternatively, the compound of the formula I is, without through the new compound of the formula III, directly converted into the new compound of the formula IV, which is then hydrolyzed to obtain the objective compound of the formula V. The above process is excellent in terms of yield, safety, operability, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides pyrido [1.2-
a] Novel method for producing pyrimidine derivatives represents an atom or a hydroxyl group, R6 represents a hydrogen atom or an acyl group, R7
represents a hydrogen atom, a lower alkyl group, or an allyl group. )
represents. ] pyrido [1. 2-a
] Virimidine derivative (hereinafter abbreviated as compound (I)).
) and their salts are known as drugs having anti-allergic effects, and various anti-allergic drugs containing these as active ingredients are generally widely used.

Conventionally, as a method for producing this kind of compound, for example, JP-A-5
As described in JP-A No. 4-36294, JP-A-63-18351, JP-A-63-246374, etc., the general formula [V] 1{' ``In the formula, 81 to R4 are the same as in H. 》 or general formula [VI] R1 (wherein, R represents a methyl group or an ethyl group, Rl, [
4 is the same as above. The most common method is to react the compounds shown in ) with various hydrogen azide salts to form tetrazole cyclization, and aluminum azide or ammonium azide is used as the hydrogen azide salt. . That is, J. Am. Cheffi. Soc. , 80.
3908-3911 (1985), in general, in the method of forming a tetrazole ring from a nitrile group, using sodium azide alone requires a high temperature and long reaction time, and the yield is low. It is said to be effective to convert sodium azide into ammonium azide, aluminum azide, etc. using ammonium chloride, aluminum chloride, etc. in combination to carry out the tetrazole cyclization reaction, and the above-mentioned publications also describe this method. The method is being adopted.

However, even when ammonium chloride, aluminum chloride, etc. are used in combination, the yield is only max.
The content is just over 0%, which is by no means high, and the combined use of these compounds causes some adverse effects. That is, for example, when used together with ammonium chloride, sodium azide acts as ammonium azide,
This ammonium azide has a very high sublimation property, and if reacted at high temperature for a long time, it escapes from the system, so it has to be used in large excess, which is extremely inefficient.

In addition, when aluminum chloride, etc. is used together, sodium azide acts as a polyvalent metal salt of hydrazoic acid such as aluminum azide in the system; Since valent metal salts are extremely dangerous compounds with explosive properties, strict care and skill are required when handling them. In addition, when these polyvalent metal salts are used in the reaction, a large amount of azide groups that do not participate in the tetrazole cyclization reaction remain after the reaction, resulting in the generation of a large amount of hydrogen azide, which causes air pollution, etc. In addition to the problems that arise, it becomes necessary to dispose of metal waste caused by aluminum and the like.

Therefore, when attempting to put these methods into practical use (commercialization), there are problems in addition to low yields, problems in ensuring the safety of the working environment and workers, problems with equipment for preventing air pollution, and problems with the industry. Problems such as the time and labor required for waste treatment had to be taken into consideration, and improvements in these issues were desperately desired.

(Objective of the Invention) The present invention was developed in view of the current situation as described above. I] is obtained,
The purpose of the present invention is to provide a new and effective method for producing compound [I].

(Structure of the Invention) The invention relates to the general formula [II1] [wherein 81 and B3 each independently represent a hydrogen atom or a lower alkyl group, and R2 and R4 each independently represent a hydrogen atom, a halogen atom, a lower represents an alkyl group, atom or hydroxyl group, R6 represents a hydrogen atom or an acyl group, R7
represents a hydrogen atom, a lower alkyl group, or an allyl group. 》
represents. The compound represented by J is reacted with (it hydrazidic acid or (i) a salt of hydrazidic acid to form the general formula [IV]).
] (In the formula, Rl to R4 are the same as above.) By reacting this with an acid or a base,
General formula [111] H4 (wherein, R1 to R4 are the same as below) is reacted with hydroacetic acid. is the same as above.), and then hydrolyzed, it is characterized by the general formula [I] H' (wherein R1 to R4 are the same as 6 as above). This is an invention of a method for producing a compound.

Further, the present invention is a method for producing a compound represented by the general formula [I[[]κ9 (wherein 81 to R4 are the same as above).

It is characterized by reacting a compound represented by H′ (wherein Rl and R4 are the same as above) with a salt of hydrazidic acid,
General 2 [rV] <<In the formula, Rl~R4 are the same as in the navigation. ) is an invention of a method for producing a compound represented by

Additionally, the present invention is an invention of a method for producing a compound represented by the general formula [rV] (wherein, l{ +, R4 are the same as in Moeki).

Historically, the present invention is an invention of a compound represented by the general formula [IV] (wherein R1 to R4 are the same as in Ichiki 1).

The present invention also provides a compound of the general formula [11] (wherein 1 {1 to R4 are the same as above), which is characterized by reacting an acid or a base with a compound represented by the general formula [11 H4 (in the formula) , R'-R' is the same as below.

That is, the present invention provides a compound represented by the general formula [II1] (
Hereinafter, it will be abbreviated as compound [I[1]. ) is used as a starting material, and its nitrile group is cyclized with tetrazole to form the general formula [
rV] (hereinafter abbreviated as compound [IV]) or without via the compound represented by general formula [11] (hereinafter abbreviated as compound [111).
This is then hydrolyzed to form compound [I], which is an extremely superior production method compared to conventional methods in terms of yield, safety, and workability. The present invention provides a method.

In the compounds represented by formulas [I] to [rV] according to the present invention, 11' and l{J are each independently a hydrogen atom, or, for example, a methyl group, an ethyl group, a proyl group. It represents a lower alkyl group such as a butyl group or an amyl group (both straight and branched), and R2 and R4 are each independently a hydrogen atom,
For example, halogen atoms such as chlorine, bromine, fluorine, and iodine, lower alkyl groups (either straight or branched) such as methyl, ethyl, probyl, butyl, and 9-amyl groups, such as methoxy Base. Ethoxy group. R5 represents a hydrogen atom or a hydroxyl group, a lower alkoxy group such as a proboxyl group, a butoxy group, or an amyloxy group (either straight or branched), a phenyl group, and R6 represents a hydrogen atom, Or for example acetyl group, bro and λnyl group. It represents an acyl group such as a butyryl group, and 1{7 is a hydrogen atom, such as a methyl group or an ethyl group. It represents a lower alkyl group (either straight or branched) such as a probyl group, a butyl group, or an amyl group, or an allyl group.

The production method of the present invention consists of approximately two steps, namely, compound [I1
The nitrile group of [1] is tetrazole cyclized to form compound [1].
11, and a step of hydrolyzing compound [I1] to convert an imino group into a ketone group.

Each step will be explained in detail below.

A chemical compound [1
As a method for producing compound [I1] from 111, (
A method for directly producing a compound [nl by reacting the it compound [II1] with hydrazoic acid to form a tetrazole cyclization of the nitrile group; There is a method of producing compound [111] by cyclizing a nitrile group with tetrazole to form compound [rV], and then reacting this with an acid or a base.

In the case of (i), the hydrazoic acid used in the tetrazole cyclization reaction may be used as a free acid or in a solution such as an aqueous solution.Usually, to avoid dangers such as explosion and poisoning,
A method is adopted in which the salts of hydrazidic acid are liberated by acting on them with an acid in a reactor.

Examples of the salts of hydrazidic acid used in methods 1i) and (j) include alkali metal salts such as sodium azide and potassium azide, calcium azide. Alkali group 10 metal salts such as magnesium azide, other polyvalent metal salts such as aluminum azide, zinc azide, tin azide, ammonium azide, such as trimethylammonium azide. There are various hydroazide salts such as salts of organic bases such as aniline azide, but among the commercially available hydroazide salts, it is most preferable to use sodium azide alone as it is the easiest to handle and is also inexpensive. . That is, in the production method of the present invention, the tetrazole cyclization reaction proceeds sufficiently under mild reaction conditions even with sodium azide alone, and the desired tetrazole compound can be obtained in a short time and in an extremely high yield. It is not necessary to use ammonium chloride, aluminum chloride, etc. in combination as in the case of the method, and all the problems mentioned above when using ammonium chloride, aluminum chloride, etc. in combination can be avoided.

The amount of hydrazoic acid or its salts to be used is within the normal range. ,it
Since a sufficiently high yield can be achieved with an amount slightly in excess of the amount or the theoretical amount, the generation of unnecessary hydrazoic acid is suppressed as much as possible, especially when sodium azide is used alone. Since there is almost no occurrence of air pollution, problems such as air pollution are almost eliminated.

The reaction temperature of the tetrazole cyclization reaction according to the present invention is (i
l, (i) In either case, any temperature between θ°C and the temperature of the reaction solvent can be used.If you want to shorten the reaction time, a higher temperature is preferable, but the reaction is sufficiently short even at room temperature. Progressing over time, a crystal yield is achieved. The reaction time may vary depending on the reaction temperature (it. (ii) In either case, several tens of minutes to several hours is usually sufficient.

(The reaction solvent used in the tetrazole cyclization reaction in the case of it is a solvent that does not inhibit the tetrazole cyclization reaction of the nitrile group and is not itself affected by hydrazoic acid or its salts. For example, alcohols such as methanol and ethanol,
Ketones such as acetone and methyl ethyl ketone, esters such as methyl acetate and ethyl acetate, benzene. Aromatic hydrocarbons such as toluene, chloroform. Halogenated hydrocarbons such as dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethynorephonolemamide (DMF), dimethylacetamide, dioxane, dimethylsulfoxide, hexamethylphosphoric triamide (HM
In addition to solvents such as PA), ether, various glymes, diclimes, and water, acetic acid. Examples include acidic organic solvents such as formic acid, and these may be used alone or in an appropriate mixture, but are not particularly limited to these as long as they can satisfy the above requirements.

(In the case of IT, there are no particular restrictions on the type of acid used to liberate hydrazoic acid from its salts, such as hydrochloric acid, sulfuric acid, mineral acids such as nitric acid, formic acid, etc.) , acetic acid, benzenesulfonic acid, tosic acid, and methanesulfonic acid.
It is sufficient to use an amount sufficient to liberate hydrazidic acid from the salts of hydrazidic acid, but when using an acid that may have a negative effect on the tetrazole cyclization reaction, it is sufficient to liberate hydrazidic acid. On the other hand, when using an acid such as acetic acid or formic acid, which has no adverse effect on the tetrazole cyclization reaction and which itself functions as a solvent. There are no restrictions on the amount used, and there is no need to use other solvents. After the reaction is completed, compound [111 may be isolated according to a conventional method such as adding water to the reaction solution and scraping off precipitated crystals, if necessary.

The reaction solvent used in the case of (ii) is (i)
Among the persimmon solvents exemplified in the case of , acetic acid. All solvents except acidic organic solvents such as formic acid may be mentioned.

In the case of (ii), compound [IV] is obtained by the tetrazole cyclization reaction of compound [I[1], but compound [r
All of V1 are new compounds that have not been described in any literature.

Compound [rV] may be isolated by neutralizing the reaction solution after the completion of the tetrazole cyclization reaction and taking off the precipitated crystals, but it is also possible to separate the compound [rV] by directly adding an acid or base to the reaction solution without isolating the crystals. It is also d1 ability to act and proceed to the next ring closing mechanism.

In (ii), as the acid acting on the compound]■1,
For example, hydrochloric acid, sulfuric acid. Mineral acids such as nitric acid, organic acids such as acetic acid, formic acid, benzenesulfonic acid, tosylic acid, methanesulfonic acid, various protonic acids, aluminum chloride, zinc chloride. Tin tetrachloride. Examples include Lewis acids such as hexafluorinated antimonic acid, and examples of bases include caustic alkalis such as sodium hydroxide and potassium hydroxide, sodium carbonate. Examples include alkali carbonates such as potassium carbonate, metal alkoxides such as sodium methoxide and sodium ethoxide, ammonia, and organic bases such as pyridine and triethylamine.

The step of causing compound [IV] to undergo ring closure by acting with an acid or base is usually carried out under heating, for example at 60 to 100°C, and the reaction time is usually sufficient for one to several hours. As a reaction solvent, water is usually used when the compound [TV] is separated, but of course it is not limited to water.
It goes without saying that various solvents used in the tetrazole cyclization reaction can also be used.

After the reaction is completed, water is added to the reaction solution if necessary, and then water is added, for example, with hydrochloric acid. When the reaction solution is neutralized using a mineral acid such as sulfuric acid or nitric acid or an organic acid such as acetic acid or chloric acid, Compound I] will precipitate as crystals. Just let go.

In addition, in the case of lit, if the amount of acid used is not sufficient to liberate the hydrazoic acid, and some of the hydrazoic acid is present in the form of a salt, in the same system ( method and (
Since the tetrazole cyclization reaction by method j) is performed at the same time, hydrazoic acid. Salts and compounds [II1]
By reaction with, the generated compound [IV] is converted into compound [
In order to convert to 111, it is necessary to perform the ring-closing step using an acid or a base in method (j) on the entire reaction solution.

The compound [11] thus obtained by the method (it or (j)) is a new compound that has not been described in any literature.

Δ II or 8 r ゛M=Compound [I] is compound [11] mixed with water or a water-containing organic solvent such as water-containing methanol or water-containing ethanol. Hydrous acetone. Water-containing acetonitrile, water-containing THF, water-containing DMF
It can be easily produced by hydrolysis in a conventional manner. Although the reaction proceeds at room temperature, in order to shorten the reaction time, it is usually carried out under heating, for example at 60 to 110°C. In addition, in order to similarly shorten the reaction time, for example, hydrochloric acid. The coexistence of mineral acids such as sulfuric acid and nitric acid, and organic acids such as benzenesulfonic acid, tosylic acid and methanesulfonic acid,
As usual.

Compound [■] may be used in isolation, but in the case of a method using a reaction solution (compound [IV)] obtained by the detrazole cyclization reaction of compound [I [1], compound IN] There is no problem in using the reaction solution (treated with acid or base) as it is. This means that the starting material [II
This means that the target compound [I] can be obtained in one pot without isolating the intermediate from [], and this is an embodiment that further enhances the usefulness of the present invention.

After the hydrolysis reaction is completed, compound [I] may be isolated according to a conventional method, such as cooling and collecting precipitated crystals.

In addition, in the production method of the present invention described above, compounds [I1 to [I
It goes without saying that if there is a functional group that requires protection in the substituents R 1 and H 7 related to V], a protecting group introduction step and a deprotection step should be incorporated as appropriate. C. In the present invention, the compound [Dl1] used as a starting material is described, for example, in J. Org.
Chem. , 51. 2988 -2994 (19
It can be easily obtained by reacting ethoxymethylenemalonitrile and a 2-aminopyridine derivative in a solvent such as ethanol at room temperature according to the method described in 86), etc., so use the product obtained in this way. That's enough.

In addition, this compound [I[[] is tautomerized in solution, and has both the structure shown in IIIal, in which the pyrimidine ring is closed, and the horizontal structure in which the pyrimidine ring is opened, shown in IIIbJ. It has been reported in the above-mentioned literature that this can be obtained.

[II1 al [111 bl
Therefore, the starting materials of the present invention also have the above-mentioned [II1 al,
Although it can take both forms of [IIIbl], in this specification, for convenience, the drying of L compound [II1] is explained as [II[al].

Reference examples and examples are listed below, but the present invention is not limited in any way by these reference examples and examples.

〔Example〕

Reference Example 1: To ethanol 20 (7) were added 1.8 g (97 mmol) of ethoxymethylenemalonitrile I and 0.5 g (97 mmol) of 2-amino-3-methylpyridine, and the reaction was stirred at room temperature F for 2 hours. After the reaction, the precipitated crystals were One unit was taken and 13.5 g of 3-cyano-4-imino-9-methyl-48-pyrido[1.2-a]pyrimidine was obtained. Yield: 76%.

m, p, 164-166°C.

Reference example 2. In Reference Example 1, 2-amino-3-methylpyridine was converted into 2-
3-Cyano-4-imino-8-
Methyl-4H-pyrido[1,2-al pyrimidine was obtained. Yield: 86%.

m. p. 204-206℃. Reference example 3. In Reference Example 1, 2-amino-3-methylpyridine was converted into 2-
3-Cyano-4-imino-7-
Methyl-4H-pyrido[1,2-al]rimidine was obtained. Yield 8l%0m. p. 183-185℃.

Reference example 4. In Reference Example 1, 2-amino-3-methylpyridine was converted into 2-
3-cyano-4-imino-7 was obtained by using the same method as in Reference Example 1 except for replacing amino-5-chlorpyridine with 3-cyano-4-imino-7.
-Chloro-4H-pyrido 11.2-a3 pyrimidine was obtained. Yield 72%.

m. p. 227-228℃. Reference example 5. In Reference Example 1, 2-amino-3-methylpyridine was converted into 2-
3-cyano-4-imino-4H-pyrido[
1. 2-a]pyrimidine was obtained. Yield 79%
.

I. ρ． 172-175℃.

Reference example 6. In Reference Example 1, 2-amino-3-methylpyridine was
- replaced with amino-3-phenoxymethylpyridine,
Other than that, it is completely same as Reference Example 1 and 3-Cyano 4-
imino-9-phenoxymethyl-4H-pit [1.
2-a Copyrimidine is /j4. Yield 72%.

m. p.　175℃.

Reference example 7. In Reference Example 1, 2-amino-3-methylpyridine was
-Amino-3-[(4-acetyl-3-hydroxy-2
3-cyano-4-imino-9-[(4-acetyl-3-hydroxy-
2-n-propylphenoxy)methyl]-4H-pyrito[l. 2-al pyrimidine was obtained. Yield 77%.

m. p.　174℃.

Reference example 8. In Reference Example 1, 2-amino-3-methylpyridine was
-amino-3-[(4-isobrobylphenoxy)methyl J-3-cyano-4-imino-9-((4-isobrobylphenoxy)methyl J-4H- Pirit [1.2-
al pyrimidine was obtained. Yield 42%.

m. p. 130~1:12℃.

Examples l. 3-cyano 4-imino 9 in HMPA I00ml
-Methyl-4H-pyrido [1. 2-a] Add 10.0 g (54.3 mmol) of pyrimidine and 3.53 g (54.3 mmol) of sodium azide, and
The reaction was stirred at 0° C. for 3 hours. After cooling, the reaction solution was neutralized with diluted hydrochloric acid, and the precipitated crystals were collected to give 3-(3-methyl-
2-Biridyl)amino-2-(1B-tetrazole-5
-yl)-2-propenonitrile light brown powder 9.8g
I got it. Yield 79%.

m. 9. 191℃ (decomposition).

IR(κB r): 3050c+n-', 222
0CII+-', 1630cm-''II-NMR
δppm (DMSO-d6): 10.97
(d, Ift, NH(;lI=C>, 8.
79(d, !11. 4-HJ, 7.11(dd
, Ill. 5-111, 3.18(s, Ill
, NjjN-N-N), 2.41(s, 3HJ:I
I3).

MS (m/e): 227 (M”).

Example 2. 3-cyano-4-imino-9-methyl-4H-pyrido [1. 2-a]pyrimidine 1
0.0 g (54.3 mmol) and sodium azide: l. 53 g (54.3 mmol) was added, and the mixture was stirred and reacted at 70° C. for 3 hours. After cooling, the reaction solution was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected to give a light brown color of 3-(3-methyl-2-biridyl)amino-2-(il+-tetrazol-5-yl)-2-bropenonitrile. 9.1 g of powder was obtained. Yield 73%.

Example 3. 3-cyano 4-imino 9 in methanol l00rnl
-Methyl-4H- and Lido [1. 2-a] pyrimidine IO. Og (54.3 mmol) and 3.53 g (54.3 mmol) of sodium azide were added, and the reaction was refluxed for 3 hours with stirring. After cooling, the reaction solution was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected. and 3-(3-methyl-2-
9.5 g of light brown powder of (pyridyl)amino-2-(IH-tetrasol-5-yl)-2-probenonitrile was obtained. Yield 77%0 Example 4. 3-cyano-4-imino-9-methyl-4H-pyrido[1.2-a]pyrimidine IO in 100 rnl of water. Og(
54.3 mmol) and sodium azide: l. 53g
(54.:1 mmol) was added, and the mixture was stirred and reacted at 70° C. for 6 hours. After cooling, the reaction solution was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected to obtain 3-<3-methyl-2-pyridyl>amino-2-(IH-tetrazol-5-yl)-2-probenonitrile. 7.5 g of light brown powder was obtained. Yield 60
%.

Example 5. Acetic acid 60ml! 3-cyano 4-imino 9-methyl-4H-pyrido [1.2-al pyrimidine 10.0 g
(54.3 mmol) and sodium azide: j.5
3 g (3 mmol of 5C) was added, and the reaction was stirred at 115°C for -1 hour. After cooling, water was added to the reaction solution, and the precipitated crystals were collected. -5-yl)-4H-pyrido[1.2-al
13.5 g of a dark brown powder of pyrimidine was obtained. Yield 86
%.

m. p. 233℃ (decomposition).

Summer R (κBr): 3400cm-'
, +695CD+-''II-NMR δPpm
((:F3GOOD) : 9.66(s, III
, 2-11), 9.23(d, I}I, 6-}1
), 8.22 (d. IH, 8-11), 7.
79 (L, II1, 7-111, 2.81 (s,
311, Gji3), MS (m/e): 22
7 (M”).

Example 6, 3-(3-methyl-2-biridyl)amino-2-(IH-tetrazol-5-yl)- in 20 rnl of IN hydrochloric acid
2-probenonitrile 2.0g (10.9 mmol)
was added, and the mixture was stirred and reacted at 100°C for 1 hour. After cooling,
The precipitated crystals were collected and 4-imino-9-methyl-3-
(IH-tetrazol-5-yl)-4H-pyrido [
1. 2-a] Light brown powder of pyrimidine 1.7 g
I got it. Yield: 85%.

m. l). 236℃ (decomposition).

Example 7. IN potassium hydroxide 3-(3-methyl-2-
2.0 g (10.9 mmol) of pyridyl)amino-2-(IH-tetrazol-5-yl)-2-probenonitrile was added, and the mixture was reacted with stirring at 100°C for 3.5 hours. After cooling, the reaction solution was neutralized with hydrochloric acid, and the precipitated crystals were collected to give 4-imino-9-methyl-3-(IH-tetrazol-5-yl)-411-pyrido[1.2-a1 pyrimidine] 1.78 g of light brown powder was obtained. Yield 89%0 111.1). 239℃ (decomposition.

Example 8. IN Hydrochloric acid 25- to 4-imino-9-methyl-3-(I
I+-tetrazol-5-yl)-4H-pyrido [1.
2-a] 0.95 g (4.2 mmol) of pyrimidine was added, and the reaction was stirred at 80°C for 3.5 hours. After cooling, the precipitated crystals were collected, and 9-methyl-3-(IH-tetrazole- 0.85 g of light brown powder of 5-yl)-4■-pyrido[1.2-a]virimicin-4-one was obtained. Yield: 89%.

m. p. 277°C (decomposition).

Example 9. Acetic acid 60mI! 3-cyano 4-imino 9-medyru 4H-pyrido [1. 2-a] 10.0 g (54.3 mmol) of pyrimidine and 3.53 g (54.3 mmol) of sodium azide were added, and the reaction was stirred at 115° C. for 1 hour. Next, 15 m7 of concentrated hydrochloric acid was added to this.
! was added, and the mixture was stirred and reacted again at 100°C for 2 hours. After cooling, M's crystals were taken out and 9-methyl-3-(II
+-tetrazol-5-yl)-4H-pyrido [1.2
9.1 g of light brown powder of 1-alpyrimidin-4-one was obtained. Yield 73%.

m. p. 281℃ (decomposition).

Example 10. Water 8 (lnJ! to 3-cyano 4-imino 9-methyl-4H-pyrido[1.2-a]pyrimidine 1
0.0 g (54.3 mmol), sodium azide3.
53 g (54.3 mmol) and 5.5 i of concentrated hydrochloric acid
(54 mmol) was added, and the mixture was stirred and reacted at room temperature for 3 hours, and then 5.5 g of concentrated hydrochloric acid was added, and the mixture was further stirred and reacted at 90° C. for 1 hour.

After cooling, the precipitated crystals were collected and 9-methyl-3-(I
I1-tetrazol-5-yl)-4H-birite [1.
2-a] 9.1 g of light brown powder of pyrimidin-4-one was obtained. Yield 73%.

m. p. 288℃《Decomposition》.

Actual JFI example 11. In Example 9, 3-cyano-4-imino-9-methyl-
4-day-pyrido[1.2-a]pyrimidine with 3-cyano4-imino8-methyl-4H- and lido[1.2-a]
8-Methyl-3-(IN-tetrazol-5-yl)-4H-pyrido[1.2-alpyrimidin-4-one was obtained in exactly the same manner as in Example 9 except that pyrimidine was substituted with pyrimidine. The rate is 81%.

m. 9. 299°C (decomposition).

Example 12. In Example 9, 3-cyano-4-imino-9-methyl-
4H-pyrido[1.2-alpyrimidine is converted into 3-cyano4-imino7-methyl-4■-pyrido[1.2-al
7-methyl-3-(It-1-tetrazole-7-methyl-3-(It-1-tetrazole-
5-yl)-4H-pyrido[1.2-a]pyrimidine-
4-on was obtained. Revenue: 87%.

rn. p. 305℃ (decomposition).

Actual h'h example 13. In Example 9, 3-cyano 4-imino 9 methyl-4
H-Virid [1. 2-a Copyrimidine to 3-cyano-4-imino-7-chloro-4H-pyrido[1.2-
a] 7-chloro-3-(Il1-tetrazole-
5-yl)-4H-pyrido[1.2-a]pyrimidine-
4-on was obtained. Yield 84%0m. ρ． 295°C (decomposition).

Example 14. In Example 9, 3-cyano 4-imino 9-methyl-
3-(
Il+-tetrazol-5-yl)-4H-pyrido [
1. 2-a]pyrimidine-4-one was obtained. Yield: 86%.

m. p. 307℃ (decomposition).

Example 15. In Example 5, 3-cyano-4-imino-9-methyl-4-day-1-pit[1.2-alpyrimidine was converted to 3-cyano-4-imino-9-phenoxymethyl-4H-pyrido[
1. 2-a]pyrimidine, and otherwise the same procedure as in Example 5 was carried out to prepare 4-imino-9-phenoxymethyl-3-(IH-te.trazol-5-yl)-4H-pyrido[1.2-a] Pyrimidine was obtained. Collection: 61%, m. ρ． 270℃ (decomposition). IR (κB', cm-'): 34QQ, 16!IQ
, 1600, 1320,'H-NMR
(270MHz, DMSO-di) δppm:
9.54 (1N, s. 2-11), 9.13 (I
ll, d, 6-1t). 8.26 (Ill, d,
8-old, 7.86 (III. L, 7-11), 7
．． 34 (211, t. 3°.5°-II). 7.1
0(2H, d, 2゜.6゜old, 7.00(IH
, L, 4'-11), 5.62 (211, s, C
! ! 2). MS (m/s): 129, Example 16. In Example 5, 3-cyano-4-imino-9-methyl-4H-pyrido[1.2-a]pyrimidine was converted into 3-cyano-4-imino-9-[(4-acetyl-3-hydroxy-2-n-propylene). 4-imino-9-[(4-acetyl-3-hydroxy-2-n-propylene) was prepared in exactly the same manner as in Example 5, except that 4-imino-9-[(4-acetyl-3-hydroxy-2-n-propyridine) phenoxy)
methyl]-3-(IH-tetrazol-5-yl)-4
H- and lido[1.2-a]pyrimicin were obtained.

Yield P.98%.

m. 9. 286℃ (decomposition).

IR (KBr, cm-'): 3150, 1700,
1630. ltioO, +270. ．． 'H-NMR (270MHz, C?3G
OOD) δppm: 9.91 (II, s, 2-
11). 9.1:l (Ill, d, 6-tl),
8.76 (lit, d, 8-H), 8.08 (II
I, t, 7-11), 7.92 (III.d.5
゜-I+1, 6.89 (IH. d, 6゜-H),
5.89 (211.S, OCI+2). 2.90
(211.t, (;!!21;l12G+13), 2
．． 28 (311.s.Cij3GO) . 1.69-
1.77 (211,?, (:lhGjj2CII3)
, 1.08(:III, t, c++.t),
MS (mis): 419, Example 17. In Example 5, 3-cyano-4-imino-9-methyl-4H-pyrido[1.2-a]pyrimidine was converted to 3-cyano-4-imino-9-[(4-isobrobylphenoxy]).
Methyl]-4-imino9-[(4-isobrobylphenoxy]methyl-
]-3-(IH-tetrazol-5-yl)-4H-pyrido[1.2-alpyrimidine was obtained. Yield 62%.

m. p. 277℃ (decomposition) IR (KBr, cm”): 3150,1
695, 1640, 1600, +250, 'It - N M R (27QllllHx, C
F3C (IOC) δppm: 9.8B (group, s,
2-tl). 9.07 (III, d, 6 old,
8.72 (IH, d, 8-111. 8.02 (Il
l, L, 7-}1), 7.29(2H, d, 3
゜, 5゜-1! ), 7. fl7(28, d, 2゜,
6'-H). 5.81 (211.s, (Jl■),
2. Old one 2.96 (IH, m, (Jj), 1.28
(68, s, (Jj3x 2).

MS (m/s): 361, Example +8. In Example 9, 3-cyano4-imino9-methyl-4H-pyrido[1.2-a]pyrimidine was converted to 3-cyano4-imino9-phenoxymethyl-4H-pyrido[1.2-a]pyrimidine.
9-phenoxymethyl-3-(IH
-tetrazol-5-yl)-4H-pyrido[1.2-
a] pyrimidin-4-one was obtained. Yield: 75%.

m. p. 281t: (decomposition).

Example +9. In Example 9, 3-cyano-4-imino-9-methyl-4H-pyrido[1.2-alpyrimidine was converted to 3-cyano-4-imino-9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)]. 9-((4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl)]-4H-pyrido[1.2-a]virimicin was replaced with 9-((4-acetyl-3-hydroxy-2-n-probylphenoxy)methyl) in the same manner as in Example 9 except for 13
-(IH-tetrazol-5-yl)-4H-pyrido[
1.2-a]pyrimidin-4-one was obtained.

Yield: 98%.

m. ρ． 254℃《Decomposition》.

Example 20. In Example 9, 3-cyano-4-imino-9-methyl-4H- and lido[1,2-alpyrimidine were converted into 3-cyano-4-imino-9-[(4-isobrobylphenoxy)].
9-[(
4-isopropylphenoxy)methyl]-3-(IH-
Tetrazol-5-yl]-4H-pyrido[1.2-a
1-pyrimidin-4-one was obtained. Yield: 82%.

m. p. 277°C (decomposition).

(Effects of the Invention) The present invention provides a novel and highly effective method for producing a birido[1,2-al pyrimidine derivative represented by the general formula I1, which is useful as an antiallergic agent.
According to the production method of the present invention, it is possible to easily [
11》Target pyrido in extremely high yield [1. 2-
a] Is it particularly effective in obtaining a pyrimidine derivative? In addition, when the tetrazole cyclization reaction of the nitrile group of the compound [[IIJ is carried out using sodium azide, it is highly safe and there are fewer problems such as air pollution and industrial waste, so it has a remarkable effect in history. becomes.

Further, according to the production method of the present invention, the desired viride [1.
2-a]pyrimidine derivatives can also be obtained, and the starting material itself is 6i! ! Another major advantage of the present invention is that it is easy to synthesize crab.

Patent applicant: Wako Pure Chemical Industries, Ltd. Patent applicant: Tokyo Tanabe Pharmaceutical Co., Ltd.

Claims (6)

[Claims] (1) General formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] [In the formula, R^1 and R^3 each independently represent a hydrogen atom or a lower alkyl group, and R^2 and Each R^4 is independently a hydrogen atom, halogen atom, lower alkyl group, phenyl group, or ▲a numerical formula, chemical formula, table, etc.▼(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. ). ] is reacted with (i) hydrazoic acid, or (
ii) React with salts of hydrazidic acid to form the general formula [IV]▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] (In the formula, R^1 to R^4 are the same as above.) After forming the compound, by treating it with an acid or a base, the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] A compound represented by (in the formula, R^1 to R^4 are the same as above), which is then hydrolyzed. A method for producing a compound represented by the general formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 to R^4 are the same as above.) (2) General formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] (In the formula, R^1 to R^4 are the same as above.) Reacting the compound represented by hydrazoic acid A method for producing a compound represented by the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1 to R^4 are the same as above.) (3) General formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] (In the formula, R^1 to R^4 are the same as above.) A method for producing a compound represented by the general formula [IV] ▲Mathematical formula, chemical formula, table, etc.▼[IV] (In the formula, R^1 to R^4 are the same as above.) characterized by reaction. . (4) General formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] (In the formula, R^1 to R^4 are the same as above.) The action of an acid or base on the compound represented by A method for producing a compound represented by the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1 to R^4 are the same as above.) (5) General formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] (In the formula, R^1 to R^4 are the same as above.) A compound represented by the following. (6) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1 to R^4 are the same as above.) A compound represented by the following.