JP2835413B2 - Phenothiazine derivative and method for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel phenothiazine derivative useful as an intermediate and a method for producing the same, and further relates to a method for producing mequitazine and a derivative thereof which are easily obtained thereby.

[Problems to be solved by conventional technologies and inventions]

Mequitadine and its derivatives are pharmaceutically useful substances having antihistamine, cholinergic action, antiadrenergic, sedation, tranquilization, antispasmodic action and the like.

Conventionally, methods for producing mequitazine and its derivatives have been described in US Pat.
-Through various processes using quinuclidinone as a starting material,
A method of obtaining quinuclidine-3-methanol as an intermediate product (Grob, Helb, Chim, Acta 37 (1954), 1689-1698), and then condensing the quinuclidine derivative with phenokiazine or a phenoxyazine derivative (particularly, Kosho 47
No. 16311) is known.

However, the conventional method using quinuclidine-3-methanol as an intermediate product requires a long number of steps and a low yield, and requires an use of cyanide or lithium aluminum hydride as an industrial production method. Was pointed out as a problem that was not advantageous.

Therefore, through a simple reaction step and in high yield,
Moreover, the development of an economical method for producing quinuclidine-3-methanol that minimizes the problem of waste disposal has been attempted. For example, Japanese Patent Publication No. 2-91071, Japanese Patent Publication No. Hei 2-33716.
And other publications have been reported.

However, even in the method using quinuclidine-3-methanol, there are problems such as the use of lithium aluminum hydride.In the production of metaquinidine and its derivatives, the use of quinuclidine-3-methanol as an intermediate is industrially difficult. Not a satisfactory method. For this reason, the development of a method for producing mequitazine and its derivatives using quinuclidine-3-methanol and other intermediates without using quinuclidine-3-methanol is expected in the art, but no satisfactory product has yet been found. It is.

Accordingly, an object of the present invention is to provide a novel intermediate useful in the production of mequitazine and its derivatives.

Another object of the present invention is to provide a novel method for producing mequitazine and its derivatives using the intermediate.

[Means for solving the problem]

The present inventors have made intensive studies to solve the above-mentioned problems. As a result, when the novel phenothiazine derivatives represented by the general formulas (I) and (II) are used as intermediates, the number of steps is small. It has been found that mequitazine and its derivatives can be produced easily and without the problem of waste disposal, and further studies have led to the completion of the present invention.

That is, the gist of the present invention is as follows: (1) General formula (I) Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom,
It represents a halogen atom, an alkyl group, an alkoxy group or an alkylthio group. ] The phenothiazine derivative represented by these.

(2) General formula (II) Wherein R ¹ and R ² are the same as above. A phenothiazine derivative represented by the general formula (III): Wherein R ¹ and R ² are the same as above. A method for producing a phenothiazine derivative represented by the general formula (I), which comprises reacting a compound represented by the formula with 3-methylenequinuclidine oxide in a solvent in the presence of a condensing agent; A method for producing a phenothiazine derivative represented by the general formula (II), which comprises reacting a phenothiazine derivative represented by the formula (I) with a chlorinating agent in a solvent; and (5) a method represented by the general formula (II) A phenothiazine derivative reduced in a solvent using a reducing agent or in the presence of a hydrogenation catalyst, and then, optionally, heated in the presence of an acid, wherein the formula (IV) Wherein R ¹ and R ² are the same as above. ] The manufacturing method of the phenothiazine derivative represented by these.

In the general formulas (I), (II), (III) and (IV), R ¹ and R ² represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group. Here, the halogen atom represents fluorine, chlorine, bromine or iodine, preferably a chlorine atom. The alkyl group may usually be linear or branched, having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, and amyl. As the alkoxy group, methoxy, ethoxy,
Those having 1 to 5 carbon atoms such as propoxy, isopropoxy and n-butoxy are usually used, and preferably 1 to 4 carbon atoms.
belongs to. As the alkylthio group, those having the same alkyl moiety as the above-mentioned alkyl group are used.

The phenothiazine derivative represented by the general formula (I) is
General formula (III) Wherein R ¹ and R ² are the same as above. And 3- as shown in the following reaction formula.
It is produced by reacting methylenequinuclidine oxide.

The compound represented by the general formula (III) is a compound known per se, and can be produced by a known synthesis method.

3-Methylenequinuclidine oxide is also a compound known per se, and can be easily synthesized from 3-quinuclidinone by a known synthesis method or a method analogous thereto (US Pat. Nos. 3,725,410 and 3,792,053). JP-A-61-280497, JP-A-2-62883).

The phenothiazine derivative represented by the general formula (I) is
It can be produced by reacting both of these compounds in a solvent in the presence of a condensing agent. This reaction is usually
An inert solvent such as toluene, xylene, hexane, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, chlorobenzene, dichlorobenzene, dichloromethane, or dichloroethane is used as a solvent under a nitrogen stream, and these are used alone or in combination. You may. The solvent may be any solvent as long as it is an inert solvent, and is not particularly limited, but toluene is preferably used from the viewpoint of reaction and post-treatment.

The amount of the solvent used is an amount sufficient to dissolve all of the raw material compounds usually used and all of the phenothiazine derivative represented by the general formula (I), which is a reaction product.

As the condensing agent, an alkali metal derivative is generally used, and examples thereof include hydroxides, hydrides, and amides of alkali metals. Specifically, at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride and sodium amide is exemplified, and potassium hydroxide, sodium hydride and the like are preferable. The condensing agent used in the present invention is used alone or as a mixture of the above condensing agents, and the amount of the condensing agent is usually 1 to 10 times mol, preferably 2 to 5 times mol.

The 3-methylenequinuclidine oxide used in this reaction may be in the form of a base, or may be in the form of a salt. Examples of the acid for forming such a salt include hydrochloric acid, hydrobromic acid and the like.

This reaction is usually carried out at room temperature to 150 ° C., and the reaction time is 30 minutes to 20 hours. Since the higher the reaction temperature, the higher the reaction rate, the reaction is preferably carried out at 90 to 110 ° C, but the reaction is preferably carried out at 80 to 110 ° C at the beginning of the reaction because of the generation of heat.

After completion of the reaction, the product can be isolated and purified by appropriately using ordinary organic chemical means such as concentration, extraction, chromatography, reprecipitation, and recrystallization. For example, after completion of the reaction, the mixture is cooled to room temperature, water is added, and crystals precipitated from a solvent layer such as toluene are collected by filtration, washed with water to obtain a phenothiazine derivative represented by the general formula (I) which is a target compound. It can be purified.

In the purification, it is desirable to extract and remove unreacted raw materials in the reaction solution to a solvent layer by adding a solvent such as toluene.

The phenothiazine derivative represented by the general formula (II) can be produced by reacting the phenothiazine derivative represented by the general formula (I) with a chlorinating agent in a solvent.

The chlorinating agent used in this reaction is not particularly limited as long as the object of the present invention can be achieved, and examples thereof include phosphorus oxychloride, thionyl chloride, and phosphorus pentachloride. These are used alone or in combination, but phosphorus oxychloride is preferred from the viewpoint of the reaction temperature.

The amount of the chlorinating agent to be used is generally 3 to 10 times the molar amount of the phenothiazine derivative represented by the general formula (I). If it is less than 3 moles, the reaction rate is slow and the chlorination effect is not sufficient, and if it exceeds 10 moles, the reaction rate is high, but the post-treatment process becomes complicated and there is also a problem in economics. Not preferred.

The reaction solvent used in this reaction is not particularly limited as long as it is an inert solvent, and may be the same as the above-mentioned inert solvent used in the production of the phenothiazine derivative represented by the general formula (I). When phosphorus oxychloride is used as the chlorinating agent, it is particularly preferable to use a halogen-based solvent such as monochlorobenzene, dichloroethane, and dichloromethane.

The amount of the solvent used is sufficient to dissolve all of the raw material compounds usually used and all of the phenothiazine derivative represented by the general formula (II), which is a reaction product.

The reaction is usually carried out at room temperature to 150 ° C., preferably 100 ° C.
It is good to carry out at ~ 200 ° C.

After the completion of the reaction, the product can be isolated and purified by a usual organic chemistry technique as in the case of the phenothiazine derivative represented by the general formula (I). For example, after completion of the reaction, the reaction mixture is cooled to room temperature, dropped into water to decompose excess chlorinating agent, then a solvent such as dichloromethane is added, the solvent layer is concentrated under reduced pressure, and crystals to be crystallized are collected by filtration. By doing so, the phenothiazine derivative represented by the general formula (II), which is the target compound, can be purified. In the purification, since the solubility of the target compound in acetonitrile is relatively low, the crystals can be efficiently purified by adding acetonitrile to the crystals to be crystallized and collecting the crystals by filtration.

The phenothiazine derivative represented by the general formula (IV) is reduced by reducing the phenothiazine derivative represented by the general formula (II) in a solvent using a reducing agent or in the presence of a hydrogenation catalyst, and then optionally And by heating in the presence of an acid.

The solvent used in this reaction is not particularly limited as long as the purpose of the reaction can be achieved, and examples thereof include alcohols such as methanol and ethanol, THF, and ether. In these solvents, it is preferable to use ethanol from the viewpoint of the reaction and the yield.

The amount of the solvent to be used is an amount sufficient to dissolve or sufficiently uniformly stir all of the usually used starting compounds and all of the phenothiazine derivative represented by the general formula (IV), which is a reaction product.

Examples of the reducing agent include a borohydride compound or a hydride compound, for example, sodium borohydride, potassium borohydride, lithium borohydride, aluminum borohydride, lithium hydride, sodium hydride, potassium hydride, hydrogen At least one selected from the group consisting of lithium aluminum chloride and diborane is exemplified, and these may be used alone or as a mixture.

In the present reaction, when the phenothiazine derivative represented by the general formula (II) is reduced with a reducing agent to produce the phenothiazine derivative represented by the general formula (IV), a catalyst is not required, and the reaction is carried out in the reactor by the general formula ( The phenothiazine derivative represented by II) and the reducing agent are charged in a molar ratio of 1 to 15 times, preferably 5 to 10 times, respectively, and reacted in the solvent under heating and reflux for usually 1 to 20 hours.

After completion of the reaction, the mixture is extracted by adding a solvent such as water, dichloromethane, dichloroethane, etc., the solvent layer is separated, and the solvent is concentrated under reduced pressure.If necessary, the mixture is heated in the presence of an acid such as acetic acid or propionic acid. By doing so, the derivative represented by the general formula (IV), which is the target compound, can be obtained. The reaction temperature is usually from room temperature to 150 ° C. for 1 to 20 hours.

In the heat treatment in the presence of such an acid, when a borohydride compound or a boron compound such as diborane is used as a reducing agent, a phenothiazine derivative represented by the general formula (IV) and an adduct of boron are mixed. Therefore, it is necessary to decompose the adduct by the heat treatment.

The phenothiazine derivative represented by the general formula (IV) is extracted with a solvent in the same manner as in the purification of the phenothiazine derivative represented by the general formula (II), the solvent layer is separated, concentrated under reduced pressure, and crystallized. The crystals can be purified by a method in which acetonitrile is added to the precipitated crystals and the crystals are collected by filtration.

The reduction reaction in this reaction can also be carried out by a usual hydrogenation reaction. Examples of the hydrogenation catalyst include noble metals such as palladium, platinum, ruthenium, and rhodium or oxides thereof, and at least one of them is used. Usually, carbon, silica, alumina, silica-alumina, calcium carbonate, strontium carbonate, barium sulfate, diatomaceous earth or clay is used as a carrier supported on the carrier. Alternatively, a nickel-based fresh medium such as Raney nickel may be used. Among these, at least one selected from the group consisting of palladium carbon, platinum carbon, ruthenium carbon and Raney nickel is preferable.

The hydrogenation reaction is desirably carried out in an inert solution such as benzene, toluene, hexane, methanol, ethanol, ether, tetrahydrofuran, dioxane, ethyl acetate, aqueous hydrochloric acid and aqueous acetic acid.
This reaction proceeds under normal temperature and normal pressure conditions, but the reaction can be promoted by heating and pressurization, and may be performed under cooling in some cases.

In the hydrogenation reaction, the amount of the hydrogenation catalyst used is usually 1 to 100%, preferably 5 to 10% with respect to the phenothiazine derivative represented by the general formula (II). The amount is usually 1 to 1.5 moles, preferably 1 mole, per 1 mole of the phenothiazine derivative represented by the general formula (II).

After the completion of the reduction reaction by the hydrogenation reaction, the phenothiazine derivative represented by the general formula (IV), which is the target compound, can be purified in the same manner as in the case of the above-described reduction using an agent.

The phenothiazine derivative represented by the general formula (IV) thus obtained is mequitazine and its derivative, and is used for applications such as an antihistamine.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not controlled at all by these Examples.

Example 1 Synthesis of 10- (3-hydroxy-1-azabicyclo [2,2,2] oct-3-ylmethyl) phenothiazine 59.8 g (0.36 mol) of phenothiazine and 97.9 g of potassium hydroxide (85%) under a nitrogen stream. (1.50 mol) in toluene 500
The mixture was heated, and stirred at 100 ° C. for 1 hour. Then USP3,
41.2 g (0.3 mol) of 3-methylenequinuclidine oxide produced by the method described in 725, 410 was added, and the mixture was stirred at 110 ° C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, 200 ml of water was added, and the precipitated crystals were collected by filtration and washed with 100 ml of water. Next, 200 g of a 10% acetic acid solution was dissolved in the obtained crystals, and toluene was dissolved.
200 ml was added and extracted with stirring, and the aqueous layer was separated. Further, 50 g of a 30% sodium hydroxide solution was added dropwise to the aqueous layer, and white crystals to be crystallized were collected by filtration to obtain 49.8 g (0.15 mol) of the target compound (yield: 50%).

Mp: 127 to 130 ° C. Elemental analysis: Calculated C: 70.97 H: 6.55 N: 8.28 Found C: 71.09 H: 6.70 N: 8.15 1 H-NMR (CDCl 3) δ: 6.60~7.30 (8H, m) 4.00 (1H, d, 15Hz) 4.25 (1H, d, 15Hz) 2.37 ~ 3.01 (6H, m) 2.25 (1H, s) 0.70 ~ 2.03 (5H, m) MS: 338 (M ⁺ ), 212,198,180,140,122 Example 23 10 Synthesis of-(3-chloro-1-azabicyclo [2,2,2] oct-3-ylmethyl) phenothiazine 10- (3-hydroxy-1-azabicyclo [2,2,2] oct obtained in Example 1 -3-ylmethyl) phenothiazine 16.9 g (0.05 mol), phosphorus oxychloride 23.0 g (0.15 g)
Mol) was added to 50 ml of monochlorobenzene and heated to 110-1
Stirred at 20 ° C. for 13 hours.

After the completion of the reaction, the mixture was cooled to room temperature, and added dropwise to 100 ml of water to decompose excess phosphorus oxychloride.
The aqueous layer was made strongly alkaline by adding 0 ml and 150 g of a 20% sodium hydroxide solution, and the dichloromethane layer was separated. The solvent was concentrated under reduced pressure, acetonitrile (50 ml) was added to the crystals to be crystallized, and white crystals were collected by filtration to obtain 7.8 g (0.022 mol) of the desired compound (44% yield).

Melting point: 156-160 ° C. (decomposition) Elemental analysis: Calculated value C: 67.30 H: 5.93 N: 7.85 Cl: 9.93 Actual value C: 67.43 H: 6.00 N: 7.79 Cl: 10.05 ¹ H-NMR (CDCl ₃ ) δ: 6.53 to 7.52 (8H, m) 4.58 (1H, d, 15Hz) 4.36 (1H, d, 15Hz) 0.92 to 3.51 (11H, m) MS: 356 (M ⁺ ), 320,212,198,158,122 Example 3 Synthesis of mequitazine Example 2 7.3 g (0.02 mol) of 10- (3-chloro-1-azabicyclo [2,2,2] oct-3-ylmethyl) phenothiazine obtained in the above, sodium borohydride 8.7 g (0.
23 mol) was added to 100 ml of ethanol, and the mixture was stirred for 10 hours while heating under reflux. After completion of the reaction, 200 ml of water and 100 ml of dichloromethane were added. After stirring and extracting, the dichromeltane layer is separated, the solvent is concentrated under reduced pressure, 25 ml of acetic acid is added, and the mixture is heated at 110 to 120 ° C.
Stir for 10 hours.

After completion of the reaction, 100 ml of water and 50 ml of toluene were added, neutralized with 88 g of 40% sodium hydroxide, the toluene layer was separated, and the solvent was concentrated under reduced pressure. Acetonitrile 30
The white crystals were collected by filtration, and 4.4 g of the target compound (0.014
Mol) was obtained (yield 67%). The obtained mequitazine is NM
The R, IR and mask spectra agreed with those of the standard.

〔The invention's effect〕

According to the present invention, general formulas (I) and (II) as intermediates
By way of a novel phenothiazine derivative represented by the following formula, mequitazine and its derivative, a phenothiazine derivative represented by the general formula (IV), can be easily produced.

When the method of the present invention is used, mequitazine and its derivatives can be produced industrially advantageously because the number of steps is small and the use of cyanide and lithium aluminum hydride is unnecessary.

──────────────────────────────────────────────────続 き Continuation of front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 453/02 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. The compound of the general formula (I) Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom,
It represents a halogen atom, an alkyl group, an alkoxy group or an alkylthio group. ] The phenothiazine derivative represented by these. 2. A compound of the general formula (II) Wherein R ¹ and R ² are the same as above. ] The phenothiazine derivative represented by these. 3. The method according to claim 1, wherein R ¹ and R ² are hydrogen atoms.
Or the phenothiazine derivative according to (2). 4. A compound of the general formula (III) Wherein R ¹ and R ² are the same as above. A method for producing a phenothiazine derivative represented by the general formula (I), comprising reacting a compound represented by the formula with 3-methylenequinuclidine oxide in a solvent in the presence of a condensing agent. 5. The process according to claim 4, wherein the condensing agent according to claim (4) is a hydroxide, hydride or amide of an alkali metal. 6. The hydroxide, hydride or amide of an alkali metal according to claim (5) is selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride and sodium amide. At least one
The production method according to claim 5, which is a seed. 7. A process for producing a phenothiazine derivative represented by the general formula (II), comprising reacting the phenothiazine derivative represented by the general formula (I) with a chlorinating agent in a solvent. 8. The process according to claim 7, wherein the chlorinating agent according to claim (7) is phosphorus oxychloride, naonyl chloride or phosphorus pentachloride. 9. A method for reducing a phenothiazine derivative represented by the general formula (II) in a solvent using a reducing agent or in the presence of a hydrogenation catalyst, and then heating in the presence of an acid, if necessary. General formula (IV) characterized by the following: Wherein R ¹ and R ² are the same as above. ] The manufacturing method of the phenothiazine derivative represented by these. 10. The method according to claim 9, wherein the reducing agent according to claim 9 is a borohydride compound or a hydride. 11. The borohydride compound or hydride according to claim 10, wherein the compound is sodium borohydride, potassium borohydride, lithium borohydride, aluminum borohydride, lithium hydride, sodium hydride, hydrogen The method according to claim 10, wherein the method is at least one selected from the group consisting of potassium halide, lithium aluminum hydride, and diborane. 12. The hydrogenation catalyst according to claim 9, wherein
The method according to claim 9, wherein the method is at least one selected from the group consisting of palladium carbon, platinum carbon, ruthenium carbon and Raney nickel.