DE2321080A1 - PROCESS FOR THE PRODUCTION OF PHARMACOLOGICALLY ACTIVE AMINA ETHERS OF BENZOPHENONE - Google Patents

Description

8 Munich 19
Romanstrasse 64-17.26 2§

A 1392

ARISTOCHIMICA SpA, Trezzano sul Naviglio, Italy

Process for the production of pharmacologically active amine

ether of benzophenone

The present invention relates to a method of manufacture , of ether derivatives of benzophenone, which have interesting pharmaco-: dynamic properties and by the following formula

-O (CH ₂ ) _n -N Ο (I)

can be represented in which R 1 and Rp represent alkyl groups with a low number of carbon atoms and _{R 1 represents a halogen atom.}

In particular, the invention relates to a process for the preparation of 3> 5-dimethoxy-4- (ß-morpholinoethoxy) -4'-chlorobenzophenone (whose technical name is diineclophenone, which is used below, and for which R ₁ and R “= CH ..-, R, = Cl and η = 2), which has proven to be the most pharmacologically effective derivative. This compound shows marked effectiveness against cough in the following pharmacological tests:

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ORIGINAL JNSPECTiD

a) Experimental ammonia-induced cough (on cats)

\ ■

j b) cough experimentally induced by sulfuric acid (am j dog) ■

j '

; c) cough experimentally induced by citric acid (am j guinea pigs).

i In some of these tests in comparison tests with the conventional lent remedies for coughing, dimeclophenone has shown a greater effect against coughing than codeine, chlophedianol and silicon ! mat, without triggering a depressive effect on the respiratory center. .

• It is also not very toxic, and its hydrochloride is in ; stable in the presence of water. It is used as an active ingredient in therapeutic applications Preparations in the form of syrup and coated tablets for oral administration in question, and in the form of suppositories for rectal administration To be administered together with one or more carriers or pharmacologically inert diluents.

j The invention also relates to the therapeutic compositions in particular against cough, which occurs according to the method according to the invention received products.

The inventive method for the preparation of the ether derivatives of benzophenone of the formula I given above consists in that a 3, ^, 5-trialkoxy-4'-halogen-benzophenone is produced, by doing

a) a reaction of a Grignard compound of a p-dihalogen

benzene obtained with 3,4,5-trialkoxybenzaldehyde, 3,4 ₃ 5-tri- '■ alkoxy-V-halodiphenylcarbinol is oxidized or

; b) the conversion of a Grignard compound of a p-dihalobenzene is carried out with 3,4,5-trialkoxybenzonitrile,

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- ** ζ -.

and the 3,4,5-TrIaIkOXy- ¹ I '-halogenobenzophenone obtained is selectively hydrolyzed and reacted with chloroalkylmorpholine.

' The inventive method can be carried out by the following reaction

tion scheme are illustrated. . :

a) (B) (C)

Shark

(CH) 0. -Hal + Mg-Hal-

-MgHaI

HIGH

(D)

, Shark

OHC

- ^ shark-

-OH + NaOH

DMP

-) 2 η

(H)

-N 0

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(D-

■ »Hai- / C Ϊ NC- / Τ ϊ VO (CH ₂ J _n -N

where Hal is a halogen atom and R., Rp and Rj. are lower ι represent alkyl groups.

. The invention also relates to the use of the 3j4,5-trialkoxy-4'-halo-benzophenone and in particular of 3 _s 4-, ^{5-trimethoxy-4!} - chlorobenzophenons for the production of the ether derivatives of benzo-

; phenones of the general formula I given above. The invention also relates to 3,4,5-trimethoxy-4 ^f -chlorobenzophenone as a new product, which is used commercially, in particular as an intermediate

[ product for the process according to the invention can be used.

'According to a preferred embodiment of the invention In the process, the dimeclophenone is made by means of oxidation of the carbinol j (A) obtained by implementing the Grignard compound of a

p-Dihalobenzene (B) was obtained with 3j4,5-trimethoxybenzaldehyde (C) or, alternatively, by preparing the benzophenone by reacting the Grignard compound of a p-dihalobenzene (D) with 3 _a 4,5-tri-methoxybenzonitrile (E) ; the trimethoxy ether of chlorobenzophenone (F) obtained in this way is then selectively hydrolyzed, and the phenol product (G) obtained is reacted, as the sodium salt, with β-chloroethylmorpholine (H) in an aprotic dipolar solvent, the desired product (I) being obtained . The aforementioned reactions are shown in the above reaction scheme, with two alternative routes indicated by a and b, which can be followed and both to obtain the intermediate; chemical product (F), the trimethoxy ether of chlorobenzophenone.

ι.

. The following examples serve to further explain the finding.

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example 1

Under a nitrogen atmosphere, the Grignard reagent is made from 37 »1 g (about 0.20 moles) p-chlorobromobenzene and 4.69 S (about 0.20 gatom) Magnesium prepared in shavings in 400 ml of anhydrous ethyl ether. The ethereal solution of the organomagnesium compound is slowly under Stirring and external cooling a solution of 35 »3 g (0.19 mol) 3,4,5-trimethoxybenzaldehyde added in anhydrous ethyl ether. When the addition of the aldehyde has ended, the reaction of the reaction mixture is completed with heating under reflux for 30 minutes. The compound is then saturated with ammonium chloride with stirring and external cooling and slow addition of Hydrolyzed water. Then the ethereal phase is separated from the aqueous phase and the latter is extracted twice with ethyl ether. The combined ethereal extracts are washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. Of the. obtained raw oily The residue slowly solidifies. The 3,4,5-trimethoxy-4'- · Chlor-diphenylcarbinol has a melting point of 99 ~ 101 C.

Example 2

30.8 g (0.1 mole) of 3,4,5-trimethoxy-4-chloro ^{t-diphenyl-carbinol} are dissolved in 200 ml acetone resistant / permanganate. With external cooling and stirring, a solution of 12 g of chromic anhydride in 50 ml of 35% sulfuric acid is gradually added to the carbinol solution, taking care that the temperature does not exceed 30 ° C. The acetone is evaporated and the remaining mixture is diluted with water and extracted repeatedly with ethyl ether. The combined ether extracts are washed with dilute sodium carbonate solution, then washed with water and dried over anhydrous sodium sulfate, filtered and then evaporated to dryness in vacuo. The solid residue obtained in this way is crystallized from benzene. It is (4'-chloro) benzophenone as 3 _5-trimethoxy 4.5 P = 100 - 102 ⁰ C obtained.

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! Example 3

i. ■ - '■■ -'

i Under a nitrogen atmosphere, the Grignard reagent becomes 10 g

! (0.055 mol) p-chlorobromobenzene and 1.34 g (0.055 gAtom) magnesium shavings in 100 ml of anhydrous ethyl ether. A solution of 9.66 g (0.050 mol) 3 _S 4 * 5 ~ i trimethoxybenzonitrile in anhydrous ethyl ether is gradually added to the ether solution of the organomagnesium compound, while stirring and external cooling. After ^; When the addition of the nitrile has ended, the reaction is allowed to proceed to the end while heating the reaction mixture under reflux for 30 minutes. The Grignard compound is hydrolyzed with stirring and external cooling by gradually adding a 10% HCl solution. The mixture is filtered on a Buchner funnel and the yellow solid residue is washed on the filter with ethyl ether. The yellow plague substance is introduced into a 500 ml reaction vessel and treated with the aqueous phase of the nitrate. The ether layer of the filtrate is extracted with 100 ml ι 10 iiger HCl, and the acidic washing liquid is added to the 'yellow precipitate. The mixture is heated for several hours' · under reflux, and the resulting oily liquid extracted with [chloroform. The chloroform extracts. v / earth washed gel-washed with water, dried over anhydrous sodium sulfate and filtered,. and the filtrate is evaporated to complete dryness in vacuo. The oily residue obtained crystallizes on cooling. It crystallized from benzene and has a melting point of 100-102 ⁰ C. It is thus obtained the 3,4,5-trimethoxy (4'-chloro) benzophenone, which is identical to that obtained according to the preceding sample product. Its melting point is not lowered when mixed with the product obtained by oxidation of the corresponding carbinol (Example 1), and the infrared spectra of the two products agree exactly.

Example 4

30 g (0.1 mol) of 3i4,5-trimethoxy- ⁱ l'-chloro) .- benzophenone are dissolved in 130 to 150 ml of concentrated sulfuric acid, and the solution is kept at kO - 60 ° C. for 5 hours while stirring. the

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Reaction liquid is added dropwise to 1.5 l of ice water, and the brown precipitate formed is filtered off by suction, washed several times with water, dried in vacuo and recrystallized from ethanol. It becomes 3,5-dimethoxy-lJ-hy- ■ Droxy- (4'-chloro) -benzophenone obtained from P = 156-160 ° C.

Example 5 "

A mixture of 29.2 g (0.1 mol) 3, ^/ * -Dimethoxy-4-hydroxy- (i | '-chlor) -benzophenone and 18.6 g (0.1 mol) ß-chloroethylmorpholine hydrochloride in anhydrous warm Methanol is gradually added with stirring to a methanolic solution of 8.2 g (0.205 mol) NaOH. The sodium salt of phenol precipitates as a yellow plague substance. The methanol is evaporated in vacuo, 300 ml of dimethylformamide are added to the residue and the mixture is refluxed for several hours. The solvent is evaporated in vacuo and the residue is taken up in water and extracted repeatedly with ethyl ether. The combined ether extracts are first washed with dilute sodium hydroxide solution, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The one that solidifies on cooling; The residue is recrystallized from acetone or benzene. 3,5-Dimethoxy-4- (ß-morpholinoethoxy) -4'-chlorobenzopehone with a melting point of 97-99 ° C. (dimeclophenone base) is obtained.

10 g (0.025 mol) of dimeclophenone are dissolved in Xt hylather, and the solution is an anhydrous HCl ether solution in the required Amount added. The dimeclophenone hydrochloride precipitates; P = 185-189 ° C.

The dimeclophenone hydrochloride possesses spectro- _; photometric absorption maxima at 261 to 262 and 288 ΐημ. ;

The titer of the product determined by potentiometric titration with! a 0.1n solution of HClOj. in ice-AcOH in the presence of mercury \ silver acetate was 99.9 %

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Claims (4)

Claims .Process for the production of 3,5-dimethoxy-4- (ß-morpholino- • ethoxy) -4'-chlorobenzophenone (its technical name DimecΙοί phenone), characterized in that the trimethoxy ether; of chlorobenzophenone (P), which by a) Oxidation of the one by means of implementation of the Grignard compound p-dihalobenzene (B) with 3 »4,5-trimethoxybenzaldehyde (C) obtained carbinol (A) or b). by converting the Grignard compound of a p-dihalobenzene (D) with 3,4,5-trimethoxybenzonitrile (E) is obtained, selectively hydrolyzed, with ß-chloroethylmorpholine (H) is implemented. 2. The method according to claim 1, characterized in that the trimethoxy ether of chlorobenzophenone obtained according to a) or b) (F) is selectively hydrolyzed and the phenol product thus obtained ■ (G) in the form of the sodium salt with the ß-chloroethylmorpholine (H) ■ is implemented. 3. The method according to claim 2, characterized in that the reaction is carried out in an aprotic dipolar solvent. 4. Chlorobenzophenone (F) trimethoxy ether. 409827/10 64