DE2315258A1 - PROCESS FOR THE PREPARATION OF PHENOTHIAZINYL ACETONITRILE - Google Patents

Description

2315238

Tue *. Γ. 7 ■ • r -'.- Jn ? Cn, - D ^r . E. Asr.nuir- ;:
Dr.F: .Kc; iv. ..-.- he - D ^. Pir / aR Hit-.au3r

Γ-, P. Zua.-3lsin jun.

Patent attorneys

8 Munich 2, ßräuhausstraie 4 / ill

14 / ge
SC. 4056

RHONE-POUEENC S.A., Paris / France

Process for the preparation of phenothiazinylacetonitriles

The present invention relates to a new method of manufacture of phenothiazines of the general formula

(D

in which R is a hydrogen atom or the methyl radical, R ^ denotes a hydrogen atom or a methyl or ethyl radical, and Y is a hydrogen atom or an alkyl, alkyloxy or Denotes alkylthio radical having 1 to 4 carbon atoms.

The products of general formula I are intermediate products in the synthesis of derivatives of phenothiazine of the general formula

309841/1160

231525

(ID

in which R, R ^ and T have the meaning given above, which have remarkable anti-inflammatory properties and are the subject of British Patent Specification 1,04-8,680.

The products of the general formula II can by hydrolysis of Nitriles of the general formula I are obtained.

According to British patent specification 1 048 680, the nitriles of the general formula I can be obtained by one of the following processes:

a) If- R denotes a hydrogen atom, 'by performing the reaction sequence shown schematically below,

+ Hal-

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(IV)

or by carrying out the following sequence of reactions

-CH-CN

(PO

• t ») when R is a diethyl radical", by adding a reactive Esters of the general formula

CH-, - Z
5

(V)

in the Z the reactive ester radical, such as a halogen atom, or '"a Residue of a sulfuric acid ester, such as the methoxysulfonyloxy residue, or the remainder of a sulfonic acid ester, such as the methanesulfonyloxy or p-toluenesulfonyloxy radical, means with a product of the general Formula IV implements,

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c) if E is a methyl radical and IL is a hydrogen atom, by doing . the following reaction sequence is carried out:

-COOIL

-GH ₂ -HaI

wherein Y has the meaning given above, Hal is a halogen atom and Ep is an alkyl radical having 1 to 4 carbon atoms

According to the invention it has now been found that the products of the general Formula I by reacting a nitrile of the general Formula.

E "- CH ₀ - CN (VI)

I C.

in the Ey, has the meaning given above with a derivative of 3-chloro-phenothiazine (nomenclature from Beilstein) of the general formula:

(VII)

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in which Ϊ and E have the meaning given above "are obtained can be.

In general, the reaction is carried out in anhydrous liquid ammonia carried out in the presence of sodium amide and at a temperature around -3O ° C.

The products of the general formula VII, in which R is hydrogen Atom means can be prepared according to the procedures described in British Patent 716,205 or by P. K. Kadaba and S.P. Massie, J. Org. Chem., 24, 986 (1959).

The products of the general formula VII in which R is a methyl radical can be prepared by alkylating a product of the general formula VII in which R is a hydrogen atom will.

The following examples explain the process according to the invention. example 1

Is added to a suspension of 145 g of sodium amide in liquid ammonia I25O cm at a temperature of -30 ⁰ C 127.5 g of acetonitrile, and 75 g 3-Chloro-IO-methyl-phenothiazine.

After 4 hours at -30 ⁰ C, the dark solution is einsedairiOft

3 - ⁷ I ^w

and then taken up in 600 cm of ether and 200 cm of water. The ethereal layer is decanted and then down to neutral

did six times with 200 cm of water and then four times with 200 cm ^ 'IT t'ethanesulfonic acid and then again up to

■ z

Ileutrality washed twice with 200 cm of water. The essential Layer is dried over sodium sulfate, filtered and then under reduced pressure (20 mm mercury)

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"at 50 ⁰ C concentrated to dryness.

The remaining varnish is absorbed with 120 cnr carbon tetrachloride. The product which crystallizes is filtered. Are thus obtained 27 g (10-methyl-phenothiazinyl-3) acetonitrile having a melting point of 86 ⁰ C.

Example 2

5.1 g of propionitrile and then 3 g of 3-chloro-10-methyl-phenothiazine are added to a suspension of 3.4-5 g of sodium amide in 50 cm ^{5 of liquid ammonia.}

After 4 hours at -30 ⁰ C, the. dark solution evaporated and then taken up with 20 cm of water and 20 cnr of ether.

The ethereal layer is decanted, washed four times with 20 cm of water until neutral, dried and then
under reduced pressure (20 mm mercury) at 50 ⁰ C and concentrated to dryness.

The remaining oil is over an aluminum oxide column of 2 cm in diameter and 40 cm in height, using a Cyclohexane-ethyl acetate mixture (99-1 by volume) eluted.

The eluates are concentrated to dryness and the obtained Product is recrystallized from 10 cnr ethanol.

0.2 g of 2- (10-methyl-phenothiazinyl-3) -propionitrile with a melting point of 99 ° C. is obtained in this way.

Example 3

One adds to a suspension of 128.7 g of sodium amide in I300 cm liquid ammonia for 20 minutes, 165.3 g propionitrile;

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10 minutes after this addition has ended, 83.3 g of 3-chloro-7-methoxy-10-methyl-phenothiazine are added added.

After 4 hours at -30 ⁰ C, the dark solution was evaporated

7 7

and the residue obtained is with 500 cur ether and 200 cnr Water absorbed. The beige-colored product present in suspension is separated off by filtration. This gives 15 6 3-amino-7-methoxy-10-methyl-phenothiazine.

The ethereal layer of the filtrate is separated by decantation, washed successively four times with 500 cnr water, three times with 250 cm N methanesulfonic acid and then four times with 100 cm water until neutral, dried over sodium sulphate and under reduced pressure (0.5 mm. Mercury) concentrated to dryness at 8O ^{0 C.}

The residue obtained (57 g) is taken up with 200 cnr ethanol. The product which crystallizes is separated off by filtration. 24 g of 2- (7-methoxy-10-methyl-phenothiazinyl-

3) propionitrile with a melting point of 75 ° C. After recrystallization from methanol, the product melts at 94.degree.

Concentration of the aqueous mother liquors of the above product gives a residue which weighs 29 g and which

7th

one over 926 g of Siliciutidioxyd in a column of 5.5 car diameter and a height of 1, ^ - 5 m, where one with 15 l of a methylene chloride-carbon tetrachloride mixture (1-1 by volume) eluted. By focusing the Eluates are obtained 7 g of 2- (7-mothoxy-10-methyl-phenol-3-nyl-3) propionitrile. > ■>

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Claims (1)

231525; Claim Process for the preparation of ines phenothiazines of the general formula in which E is a hydrogen atom or the methyl radical "means Ey, represents a hydrogen atom or a methyl or ethyl radical and Y is a hydrogen atom or an alkyl, alkyl oxy or alkylthio radical means with 1 to 4 carbon atoms, characterized in that that one is a nitrile of the general formula E ₁ - CH ₂ - CN in which E ^ a hydrogen atom or a methyl or ethyl radical means with a phenothiazine of the general formula in which Y and E are as defined above. 309841/116