JPH0739413B2 - Method for producing benzylphthalazinone derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an improved process for producing a benzylphthalazinone derivative or a salt thereof which is useful as a medicine in a high yield.

More specifically, the present invention has the general formula (3)

[0003]

[Chemical 6]

(Wherein X represents a halogen atom and R ¹ represents a lower alkyl group)

The present invention relates to a method for producing a benzylphthalazinone derivative represented by (so-called benzylphthalazone derivative) and a salt thereof.

[0006]

2. Description of the Related Art Japanese Patent Publication No. 55-31154 discloses that a compound represented by the general formula (3) is useful as an antihistamine and a production method (Example 10) utilizing the cycle ammonium rearrangement of the compound. Has been done. According to this production method, the crude final product is said to be obtained in a yield of 90% or more, but it contains a large amount of by-products, and the target product is isolated by crystallization. The yield is 30% or less.

[0007]

As described above, since the conventional method has a very low yield, it is desired to establish a production method with a higher yield.

[0008]

As a result of earnest research, the present inventor has established a high-yield production method.

That is, the present invention has the general formula (1)

[0010]

[Chemical 7]

The compound represented by the formula (wherein X represents a halogen atom) or a salt thereof is represented by the general formula (2):

[0012]

[Chemical 8]

The compound represented by the formula (wherein R ¹ represents a lower alkyl group) or a salt thereof is reacted in the presence of a dehydration condensing agent, and the compound is represented by the general formula (3).

[0014]

[Chemical 9]

A process for producing a benzylphthalazinone derivative represented by the formula (wherein X and R ¹ are as defined above) and salts thereof.

Examples of the halogen atom in the general formula (3) include chlorine atom, bromine atom and iodine atom, and examples of the lower alkyl group of R ¹ include methyl group, ethyl group and propyl group.

Examples of the salt of the compound represented by the general formula (3) include inorganic acid salts such as hydrochloride, sulfate, carbonate, bicarbonate, hydrobromide and hydroiodide, acetate and maleic acid. Examples thereof include salts, organic carboxylates such as fumarates, lactates and tartrates, and acid addition salts such as methanesulfonates, benzenesulfonates and toluenesulfonates.

Examples of the salt of the compound of the general formula (1) include the same salts as the salt of the compound of the general formula (3). In addition to the acid addition salt in the compound of the general formula (3), the salt of the compound of the general formula (2) includes alkali metal salts such as sodium salt and potassium salt.

As the dehydrating condensing agent, for example, a combination of an azocarboxylic acid ester and a phosphine derivative can be preferably used. Specifically, the general formula (4)

[0020]

[Chemical 10]

An azodicarboxylic acid ester represented by the formula (wherein R ² represents a lower alkyl group);

[0022]

Embedded image (R ³ ) ₃ P (5)

A phosphine derivative represented by the formula (wherein R ³ represents an aryl group or a lower alkyl group) can be used.

Examples of the lower alkyl group for R ² include a methyl group, an ethyl group and an isopropyl group. R ³
Examples of the aryl group include a phenyl group, and examples of the lower alkyl group of R ³ include an n-butyl group.
The most preferable dehydration condensing agent is a combination of diethyl azodicarboxylate and triphenylphosphine, or a combination of diisopropyl azodicarboxylate and triphenylphosphine.

The procedure for carrying out the present invention can be changed over a wide range.

The amount of raw material used in the reaction of the present invention is not strictly critical. The molar ratio of the compound represented by general formula (1) to the compound represented by general formula (2) can range, for example, from about 1: 1 or less to about 0.5: 1 or more. Preferably, a range of about 1: 1 to about 0.8: 1 can be used without departing from the scope of the invention.

The reaction temperature when carrying out the reaction of the present invention is not strictly critical and is from about -80 ° C to about 10 ° C.
It can be carried out at 0 ° C. In order to suppress the production of by-products, it is desirable to carry out the reaction at a temperature of -20 ° C or lower.

The reaction of the present invention can be carried out under atmospheric pressure. However, higher or lower pressure may be used depending on other reaction conditions, components used, reaction rate, etc. in order to effectively carry out the reaction.

The reaction of the present invention can be carried out in an inert solvent.

Any reaction solvent may be used as long as it does not inhibit the reaction, and the reaction raw materials may not be completely dissolved. For example, aromatic hydrocarbons such as benzene, mesitylene, toluol, and xylol; heterocyclic compounds such as pyridine; ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether; sulfoxides such as dimethyl sulfoxide; dimethylformamide, dimethylacetamide , Hexamethylphosphoric acid triamide, N-methylpyrrolidone and other amides; tetramethylurea and the like. These solvents can be used alone or in the form of a mixture thereof.

The amount of solvent used in the reaction of the present invention is not strictly critical and is, for example, from about 5% by weight or less to about 30% by weight or more, based on the total weight of the starting materials. The above can be extended.

The target product produced by the method of the present invention can be isolated by a crystallization method. For example, the crude reaction product is concentrated under atmospheric pressure or reduced pressure, and then a lower alcohol such as methanol, ethanol, isopropanol, amyl alcohol, butanol, t-butanol, or acetone is added and dissolved. An inorganic acid or an organic acid is added to the solution thus obtained to precipitate the desired product as crystals. These crystallization acids are not particularly limited, but hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid are particularly desirable.

[0033]

【Example】

Next, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1 4- (p-chlorobenzyl) -2- [N-methyl-perhydroazepinyl- (4)]-1- (2H) -phthalazinone hydrochloride

[0036]

[Chemical 12]

After dissolving 236.1 g of triphenylphosphine in 1 liter of tetrahydrofuran, it was cooled to -30 ° C., and diethyl azodicarboxylate 156.8 was added thereto.
g was added dropwise. Furthermore, 4- (p-chlorobenzyl) -1
After adding 81.2 g of-(2H) -phthalazinone, N-
A solution prepared by dissolving 38.9 g of methyl-4-homopiperidinol in 100 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -30 ° C for 16 hours and then at 20 ° C for 5 hours, and then the reaction solution was concentrated under reduced pressure at 50 ° C. The residue was dissolved in 1 liter of isopropyl alcohol, and concentrated hydrochloric acid was added. The precipitated crystals were suction filtered and washed with isopropyl alcohol. This was dried to obtain 106.7 g (yield 85%) of the desired product as white powdery crystals.

Melting point: 225 ° C.

Mass spectrum (m / e): 381
(M ⁺ )

Elemental analysis value: C H N theoretical value (%) 63.16 6.02 10.04 measured value (%) 63.05 6.07 10.08

Infrared absorption spectrum (cm ^-1 , Nudijol): 3050, 2930, 1655, 1590, 14
90,690

¹ H-NMR spectrum (δ, D ₂ O):
2.1-2.4 (b, 6H), 2.9 (s, 3H),
3.3-3.6 (b, 4H), 4.6 (s, 2H),
5.4 (m, 1H), 7.5 (m, 4H), 8.1
(M, 3H), 8.5 (m, 1H)

Example 2 4- (p-chlorobenzyl) -2- [N-methyl-perhydroazepinyl- (4)]-1- (2H) -phthalazinone hydrochloride

[0044]

[Chemical 13]

After dissolving 23.6 g of triphenylphosphine in 200 ml of tetrahydrofuran, it was cooled to -30 ° C., and 15.7 g of diethylazodicarboxylate was added thereto.
Was dripped. After further adding 8.1 g of 4- (p-chlorobenzyl) -1- (2H) -phthalazinone at the same temperature, a solution of 3.9 g of N-methyl-4-homopiperidinol dissolved in 10 ml of tetrahydrofuran was added dropwise. did.
This was stirred at -30 ° C for 16 hours and then at 20 ° C for 5 hours, and then concentrated hydrochloric acid (4.8 g) was added. Then acetone 40
0 ml was added, filtered and dried to obtain 10.7 g (yield 85%) of the desired product as white powdery crystals.

The physical properties were in agreement with those of Example 1.

Example 3 4- (p-chlorobenzyl) -2- [N-methyl-perhydroazepinyl- (4)]-1- (2H) -phthalazinone hydrochloride

[0048]

[Chemical 14]

After dissolving 118.0 g of triphenylphosphine in 500 ml of tetrahydrofuran, it was cooled to -30 ° C., and diisopropylazodicarboxylate 9 was added thereto.
1.0g was dripped. After adding 40.5 g of 4- (p-chlorobenzyl) -1- (2H) -phthalazinone at the same temperature, N-methyl-4-homopiperidinol 19.
A solution prepared by dissolving 5 g in 50 ml of tetrahydrofuran was added dropwise. After stirring at −30 ° C. for 16 hours and then at 20 ° C. for 5 hours, 24 g of concentrated hydrochloric acid was added. Subsequently, 2 liters of acetone was added, filtered and dried to obtain 53.5 g (yield 85%) of the desired product as white powdery crystals.

The physical properties were in agreement with those of Example 1.

Example 4 4- (p-chlorobenzyl) -2- [N-methyl-perhydroazepinyl- (4)]-1- (2H) -phthalazinone hydrochloride

[0052]

[Chemical 15]

After dissolving 23.6 g of triphenylphosphine in 200 ml of tetrahydrofuran, it was cooled to -30 ° C., and 15.7 g of diethylazodicarboxylate was added thereto.
Was dripped. After further adding 8.1 g of 4- (p-chlorobenzyl) -1- (2H) -phthalazinone at the same temperature, a solution of 3.9 g of N-methyl-4-homopiperidinol dissolved in 10 ml of tetrahydrofuran was added dropwise. did.
This was sequentially stirred at -30 ° C for 5 hours, 0 ° C for 5 hours, and 20 ° C for 5 hours, and then 4.8 g of concentrated hydrochloric acid was added. Subsequently, 400 ml of acetone was added, filtered, and dried to obtain 10.7 g (yield 85%) of the desired product as white powdery crystals.

The physical properties were in agreement with those of Example 1.

[Chemical 16]

[Chemical 17]

[Chemical 18]

Claims (6)

[Claims] 1. A compound represented by the general formula (1): The compound represented by the formula (wherein X represents a halogen atom) or a salt thereof is represented by the following general formula (2): (Wherein R ¹ represents a lower alkyl group) or a salt thereof is reacted in the presence of a dehydration condensing agent, and the compound represented by the general formula (3): (Wherein X and R ¹ are the same as defined above), and a method for producing a benzylphthalazinone derivative and a salt thereof. 2. A process for producing a benzylphthalazinone derivative or a salt thereof according to claim ¹ , wherein X is a chlorine atom and R ¹ is a methyl group. 3. A dehydration-condensation agent represented by the general formula (4): An azodicarboxylic acid ester represented by the following formula and a phosphine derivative represented by the general formula (5): (R ³ ) ₃ P (5) (wherein R ³ represents an aryl group or a lower alkyl group). Claim 1 to be used
A method for producing a benzylphthalazinone derivative and a salt thereof. 4. The benzyl as claimed in claim 3, wherein the dehydration condensing agent is a combination of diethylazodicarboxylate and triphenylphosphine, or a combination of diisopropylazodicarboxylate and triphenylphosphine. Process for producing phthalazinone derivative and its salt. 5. The method for producing the benzylphthalazinone derivative according to claim 1, wherein the salt is a hydrochloride. 6. A compound represented by the general formula (1) is combined with a compound represented by the general formula (2) at −80 ° C. to 10 ° C.
The method for producing a benzylphthalazinone derivative or a salt thereof according to claim 1, wherein the reaction is carried out at a temperature of 0 ° C.