KR790001482B1 - Process for preparing phenothiazin derivatives - Google Patents

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Description

Method for preparing phenothiazine derivatives

The present invention relates to a new and advanced process for the preparation of phenothiazine derivatives represented by general formula (I).

Where A is 2-dimethylaminopropyl group, 3-dimethylaminopropyl group, 2- (N-methylpiperidino) methyl group, 2- (1-methyl-2-piperidyl) ethyl group, 3- (1-methyl -4-piperazinyl) -propyl group, N'-acetoxyethylpiperazinyl-N-propyl group, 3-dimethylamino-2-methylpropyl group and N'-heptanoyloxy ethylpiperazinyl-N- It is a profile machine. Y represents hydrogen, methyl, ethyl, chlorine, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfinyl, ethylsulfonyl, dimethylaminosulfonamide, acetyl, propionyl and Butanoyl group. Some of these derivatives are known compounds and are used in medicines such as painkillers, antiangiogenic agents, antihistamines, and neurostabilizers.

More specifically, the present invention relates to a method of combining the haloamine side chain represented by the general formula (II) with the phenothiazine nucleus of the structural formula (III).

Wherein A and Y are as described above, X is halogen, and their preparation is described in the following patents and documents.

U.S. Pat. 2,645,640 (July 14, 1953)

U.S. Pat. 2,837,518 (June 3, 1958)

U.S. Pat. 2,902,484 (1959)

Helv. Chim. Acta. 41, 1,072 (1958)

According to these known methods, the method for producing a phenothiazine derivative (I) includes (1) a cyclization reaction of diphenylamine derivative (IV) and sulfur by heating under an iodine catalyst, (2) diphenyl sulfur derivative (V) Cyclization reaction by condensation of (3) It is due to the coupling | bonding of the haloamine (II) which is a side chain, and the phenothiazine nucleus (III).

In the reaction (2), sodium amide, lithium hydride, normal-butyllithium, phenyl lithium, and the like were used as the condensing agent. However, these condensers are not only expensive in terms of price, they are difficult to handle, and also have an uneconomical disadvantage due to the long reaction time when linking phenothiazine nuclei and side chains.

The present invention seeks to provide a new and advanced process for the preparation of phenothiazine derivatives of formula (I) which can eliminate the above drawbacks. In this method, the alkali metal hydroxide (IV) and the phenothiazine nucleus (III) are put in an inert solvent, and distillation is carried out to remove the water produced, obtaining a metal salt of phenothiazine of the structural formula (II). ) And the phenothiazine derivative of formula (I) is obtained in high yield in a short reaction time (2-6 hours). Here, the alkali metal hydroxide of the formula (VI) refers to lithium hydroxide, potassium hydroxide, sodium hydroxide and the like, and preferred compounds are potassium hydroxide or sodium hydroxide.

Y in the phenothiazine nucleus of formula (III) is hydrogen, methyl group, ethyl group, chlorine, trifluoromethyl group, methoxy group, ethoxy group, methylthio group, ethylthio group, methylsulfinyl group, ethylsulfonyl group, dimethylaminosulfonamide Group, acetyl group, propionyl group, or butanoyl group.

Inert solvents refer to inert aromatic organic solvents and include benzene, toluene, ethylbenzene, xylene and the like.

Of the metal salt compounds of the formula (Y), Y is the same as Y of the above-described formula (III), M is lithium, potassium, or sodium, but preferred metals are potassium and sodium.

In Ax of Structural Formula (II), A is 2-dimethylaminopropyl group, 3-dimethylaminopropyl group, 2- (1-methyl-2-piperidyl) ethyl group, 3- (1-methyl-4-pipera Genyl) propyl group, 2- (N-methylpiperidino) methyl group, 3-dimethylamino-2-methylpropyl group, N'-acetoxyethyl piperazinyl-N-propyl group, N'-heptanoyloxyethyl This corresponds to a piperazinyl-N-propyl group, where x represents chloride or bromide, such as when combined Ax results in 2-dimethylaminopropylchloride or 2-dimethylaminopropylbromide.

In structural formula (I) which is a product, A is the same as A of structural formula (II), and Y is also the same as Y of structural formula (III).

The reaction temperature is not limited because the boiling point of the solvent, that is, the reflux temperature of each solvent is different, but the preferred reaction temperature is 70-150 ℃.

In order to assist in understanding the reaction progress, a schematic reaction mechanism is as follows.

As a further example for further understanding of the manufacturing process, the reaction of 2-methoxyphenothiazine and methyl chloride in the presence of sodium hydroxide solution in accordance with the reaction mechanism is as follows. A azine can be prepared.

The following examples illustrate the invention in more detail but are not intended to limit the scope thereof.

Example 1

Preparation of 10- (3-dimethylamino-2-methylpropyl) phenothiazine

2.4 g (0.012 mole) of phenothiazine and 0.95 g (0.017 mole) of potassium hydroxide were added to 35 ml of xylene and refluxed using a Dean-Stark water separator until the theoretical 0.22 ml of water was separated. 1.86 g (0.0137 mol) of 1-dimethylamino-2-methyl-3-chloropropane and 22.5 ml of xylene mixture are slowly added dropwise during reflux for 50 minutes, followed by further reflux for 4 hours. The reaction solution was cooled to room temperature and then extracted with 30 ml of 0.7N hydrochloric acid. The aqueous solution was washed with ether, added with 2 ml of 40% sodium hydroxide aqueous solution to make basic, and extracted four times with ether. The ether solution was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 3.53 g (98.2%) of oily 10- (3dimethylamino-2-methylpropyl) phenothiazine.

This was confirmed by thin layer chromatography. The R _f value was 0.45 (benzene: ethyl acetate = 7.3), and the δ value of the NMR spectrum (CDCl ₃ , 100 MHz) was as follows.

0.96 (d, 2H), 1.98-2.36 (m, 3H), 2.18 (s, 6H) 3.40-4.15 (m, 2H) and 6.62-7.22 (m, 8H)

As a result of confirming the melting point, the present invention coincides with the known melting point of 67 ℃, in addition to the melting point of known hydrochloride (217 ℃) 214-216 ℃, the melting point of known tartarate (160 ℃) It was 157 159 ° C., almost identical to).

Example 2

Preparation of 10- (3-dimethylamino-2-methylpropyl) phenothiazine

4.8 g (0.024 mole) of phenothiazine and 1.41 g (0.035 mole) of sodium hydroxide were added to 35 ml of benzene and refluxed using a Dean-Stark water separator until the theoretical 0.44 ml of water was separated. 3.72 g (0.0274 mol) of 1-dimethylamino-2-methyl-3-chloropropane and 30 ml of benzene mixture were slowly added dropwise during reflux for 50 minutes, followed by further reflux for 6 hours. The reaction solution was cooled to room temperature and extracted with 30 ml of 0.7N hydrochloric acid. The aqueous solution was washed with ether, basicized with 2 ml of 40% sodium hydroxide aqueous solution, and extracted four times with ether. The ether solution was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield 6.56 g (91.3%) of oily 10- (3-dimethylamino-2-methylpropyl) phenothiazine.

Confirmation of the product was carried out in the same manner as in Example 1, the results of confirmation, such as δ value and melting point of the NMR was also the same as in Example 1.

Example 3

Preparation of 10- (3-dimethylaminopropyl) phenothiazine

4.8 g (0.024 mole) of phenothiazine and 1.89 g (0.034 mole) of potassium hydroxide are placed in 50 ml of xylene and refluxed using a Dean-Stark water separator until the theoretical 0.43 ml of water is separated. A solution of g (0.0275 moles) of 1-dimethylamino-3-chloropropane in 27.5 ml of xylene was slowly added dropwise at reflux for 50 minutes, followed by further reflux for 4 hours. The reaction solution was cooled to room temperature and extracted with 55 ml of 0.7N hydrochloric acid. The aqueous solution was washed with ether, added with 4 ml of 40% sodium hydroxide aqueous solution to make basic and then extracted four times with ether. The ether solution was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 6.52 g (97.6%) of 10- (3-dimethylaminopropyl) phenothiazine as an oily phase. As a hydrochloride, it was confirmed to be compared with a known decomposition temperature and found to be 179 ° C, which was almost identical to a known decomposition temperature of 181 ° C. In addition, it was confirmed by NMR spectrum and thin layer chromatography to confirm that it was the same as a known substance.

Example 4

Preparation of 10- (3-dimethylaminopropyl) phenothiazine

4.8 g (0.024 mole) of phenothiazine and 1.41 g (0.035 mole) of sodium hydroxide were added to 35 ml of toluene and refluxed using a Dean-Stark water separator until the theoretical 0.43 ml of water was separated. 3.44 g (0.0275 mol) of 1-dimethylamino-3-chloropropane and 22.5 ml of toluene mixture were slowly added dropwise during reflux for 50 minutes, followed by further reflux for 5 hours. The reaction solution was cooled to room temperature and extracted with 55 ml of 0.7N hydrochloric acid. The aqueous solution was washed with ether, added with 4 ml of 40% sodium hydroxide aqueous solution to make basic and then extracted four times with ether. The ether solution was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield 6.18 g (92.5%) of oily 10- (3-dimethylaminopropyl) phenothiazine. Confirmation of the product was carried out in the same manner as in Example 3, and as a result, δ value and melting point of NMR were consistent with Example 3.

Example 5

Preparation of 10- [2- (1-methyl-2-piperidyl) ethyl] -2-methylthiophenothiazine

2.95 g (0.012 mole) of 2-methylthiophenothiazine and 0.90 g (0.016 mole) of potassium hydroxide are mixed with 50 ml of xylene, and the theoretical 0.22 ml of water is completely separated using Dean-Stark water separator. After refluxing, 2.04 g (0.0132 mol) of 2- (1-methyl-2-piperidyl) ethyl chloride and 22.5 ml of xylene mixed solution were slowly added dropwise to reflux for 50 minutes, followed by 4 hours. More reflux. The reaction solution is cooled to room temperature, extracted with 30 ml of 0.7N hydrochloric acid, and the aqueous solution is washed with ether. 2 ml of 40% aqueous sodium hydroxide solution was added to the acidic washing solution to make it basic and then extracted four times with ether.

The ether solution was dried over anhydrous magnesium sulfate for 24 hours, and then distilled under reduced pressure to obtain 4.12 g (92.5%) of oily 10- [2- (1-methyl-2-piperidyl) ethyl] -2-methylthiophenothi. Get azine.

As a result of checking the melting point thereof, the melting point was 72 ° C in accord with the known melting point 72-74 ° C, and in addition, the NMR spectrum and thin layer chromatography confirmed the same as the known material.

Example 6

Preparation of 10- [2- (1-methyl-2-piperidyl) ethyl] -2-methylthiophenothiazine

2.95 g (0.012 mole) of 2-methylthiophenothiazine and 0.57 g (0.017 mole) of sodium hydroxide are added to 40 ml of ethylbenzene until the theoretical 0.22 ml of water is separated using a Dean-Stark water separator. After refluxing, a mixture of 2.04 g (0.0132 mol) of 2- (1-methyl-2-piperidyl) ethyl chloride and 25.0 ml of ethylbenzene was slowly added dropwise at reflux for 50 minutes, followed by further reflux for 4 hours. do. The reaction solution was cooled to room temperature and extracted with 30 ml of 0.7N hydrochloric acid. The aqueous solution was washed with ether, basicized with 2 ml of 40% sodium hydroxide aqueous solution, and extracted four times with ether. The ether solution was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 3.78 g (84.8%) of oily 10- [2- (1-methyl-2-piperidyl) ethyl] -2-methylthiophenothiazine. Get

Acknowledgment of the product was carried out in the same manner as in Example 5, and as a result, the δ value and melting point of NMR were consistent with those in Example 5.

Example 7

Preparation of 10- (2-dimethylaminopropyl) phenothiazine

과 27.5ml의 크실렌 혼합액을 환류중에 1시간동안 서서히 적가하고 계속하여 4시간 더 환류한다. 반응액을 실온으로 냉각하여 55ml의 0.7N 염산으로 추출하고 이 수용액을 에테르로 세척한다.4.8 g (0.024 mole) of phenothiazine and 1.41 g (0.035 mole) of sodium hydroxide are mixed in 50 ml of xylene and refluxed using a Dean-Stark water separator until the theoretical 0.43 ml of water is completely separated. 3.34 g (0.027 mole) of 1-N, N-dimethyl-1-methyl-2-chloroethane in a refluxed organic solution

And 27.5 ml of xylene mixture are slowly added dropwise for 1 hour while refluxing, followed by further reflux for 4 hours. The reaction solution is cooled to room temperature, extracted with 55 ml of 0.7N hydrochloric acid, and the aqueous solution is washed with ether.

4 ml of 40% aqueous sodium hydroxide solution was added to the acidic washing solution to make it basic, and then extracted four times with ether.

The ether solution was dried over anhydrous magnesium sulfate for 24 hours and then distilled under reduced pressure to obtain 5.38 g (78.5%) of oily 10- (2-dimethylaminopropyl) phenothiazine.

As a result of confirming the melting point, the melting point was 58 ° C, which was almost identical to the known melting point of 60 ° C. In addition, reconfirmation by NMR spectrum and thin layer chromatography confirmed the same as the known material.

Example 8

Preparation of 10- [3- (1-methyl-4-piperazinyl) propyl] -2-trifluoromethylphenothiazine

3.2 g (0.012 mole) of 2-trifluoromethylphenothiazine and 0.71 g (0.018 mole) of sodium hydroxide were mixed in 50 ml of xylene and the theoretical 0.22 ml of water was completely separated using a Dean-Stark water separator. Reflux until

2.38 g (0.013 mol) of 3- (1-methyl-4-piperazinyl) propylchloride in refluxed organic solution

And 22.5 ml of xylene mixture were slowly added dropwise for 1 hour during reflux, followed by further reflux for 4 hours. The reaction solution is cooled to room temperature, extracted with 30 ml of 0.7N hydrochloric acid, and the aqueous solution is washed with ether.

2 ml of 40% aqueous sodium hydroxide solution was added to the acidic washing solution to make it basic, and then extracted four times with ether.

The ether solution was dried over anhydrous magnesium sulfate for 24 hours, and then distilled under reduced pressure to give 3.90 g (80.0%) of oily 10- [3- (1-methyl-4-piperazinyl) propyl] -2-trifluoromethylfe. Get nottiazine.

As a result of comparing this with the well-known melting point (its hydrochloride), it was 242 degreeC matching the well-known melting point 242-243 degreeC.

In addition, reconfirmed by NMR spectrum, thin layer chromatography, it was confirmed that the same as the known material.

Example 9

Preparation of 10- (3-dimethylamino-2-methylpropyl) -2-methoxyphenothiazine

When 5.5 g (0.024 mole) of 2-methoxyphenothiazine and 1.42 g (0.036 mole) of sodium hydroxide are mixed with 50 ml of xylene and the theoretical 0.43 ml of water is completely separated using the Dean-Stark water separator. Reflux until

3.66 g (0.027 mole) of N, N-dimethyl-2-methyl-3-chloropropane in refluxed organic solution

과 22.5ml의 크실렌 혼합액을 환류중에 1시간동안 서서히 적가한 후 계속하여 4시간 더 환류한다.

And 22.5 ml of xylene mixture are slowly added dropwise for 1 hour during reflux, followed by further reflux for 4 hours.

The reaction solution is cooled to room temperature, extracted with 55 ml of 0.7N hydrochloric acid, and the aqueous solution is washed with ether.

4 ml of 40% aqueous sodium hydroxide solution is added to the acidic washing solution to make it basic and then extracted four times with ether.

The ether solution was dried over anhydrous magnesium sulfate for 24 hours and then distilled under reduced pressure to yield 6.38 g (81.0%) of oily 10- (3-dimethylamino-2-methylpropyl) -2-methoxyphenothiazine.

As a result of comparing this with the well-known melting point, it was 45 degreeC matching the well-known melting point 44-48 degreeC. In addition, it was confirmed by NMR spectrum and thin layer chromatography to confirm that it is the same as a known material.

Claims (1)

Phenothiazine nucleus of formula (III) and alkali metal hydroxides of formula (VI) are removed by boiling distillation together in an inert organic solvent such as benzene, toluene, xylene, ethylbenzene, etc. A method for preparing a phenothiazine derivative of formula (I), characterized in that the haloamine side chain of

Wherein Y in structural formula (III) represents hydrogen, methylthio group, trifluoromethyl group, and methoxy group, x in structural formula (II) represents chloride A is 2-dimethylaminopropyl group, 3-dimethylamino-2-methylpropyl group, 3-dimethylaminopropyl group, 2- (1-methyl-2-piperidyl) ethyl group, 3- (1-methyl-4-piperazinyl) propyl group, and the metal hydroxide of formula (VI) is potassium oxide, Represents sodium hydroxide, where A in structural formula (I) is the same as A in structural formula (II), and Y is the same as Y in structural formula (III).