CH562195A5 - Alpha substd 2-aminomethyl-benzylalcohols prepn - anorexics with no cns side effects - Google Patents

Abstract

Title cpds. (I): (where R1 is H or lower alkyl, R2 is H, OH, NH2 or lower alkyl, R3 is F, Cl or methylmercapto) are prepd. by reacting corresp. cpds. (I; R2 = Cl or Br, CHOH replaced by C=O) with an alkali metal borohydride and conversion of inter to (I) by reaction with R2NH2.

Description

  

  
 



   The present invention relates to a new process for the preparation of α-substituted 2-aminomethylbenzyl alcohols of the formula I.
EMI1.1
 where Rl is hydrogen or a lower alkyl group, R2 is hydrogen, the hydroxyl or amino group or a lower alkyl group and R3 is a fluorine or chlorine atom or the methyl mercapto group, as well as of their physiologically acceptable acid addition salts.



   There are already various processes for the preparation of a-substituted 2-aminomethyl-benzyl alcohols known ge been z. B. by Belgian patent specification No. 725 839.



  These compounds are then prepared either by ring opening of an appropriately substituted phthalide and subsequent reduction of the amide formed using lithium aluminum hydride or by ring opening of an isoindoline with an acid anhydride and deacylation of the acyl compound that forms. Another possibility given in the Belgian patent is the reduction of a 2-cyanobenzophenone with lithium aluminum hydride and, if appropriate, subsequent alkylation of the amino group.



   In contrast, the process according to the invention is characterized in that a compound of the formula II
EMI1.2
 where Hal denotes a chlorine or bromine atom, reduced by means of an alkali borohydride, for example sodium borohydride, and then the α-substituted 2-halomethylbenzyl alcohol of the formula III formed
EMI2.1
 with an amine of the formula IV R2-NH2 (IV).



   This implementation is based on a solution or



  a suspension of the haloketone of the formula II in a suitable organic solvent, preferably a lower alcohol, into which the alkali borohydride is introduced at room temperature or with moderate cooling. After the usual work-up, either the isolated 2-halomethylbenzyl alcohol or the extraction residue can be used directly for the amination.



   For this purpose, the 2-halomethylbenzyl alcohol obtained is dissolved, for. B. in a lower alcohol and adds it - preferably with cooling - to a solution of the desired amine. Working up is carried out in the customary manner.



   The end products of the formula I obtained by the process described above can, if desired, be converted into their acid addition salts in the customary manner.



  Acids suitable for salt formation are, for example, inorganic acids such as hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid or perchloric acid, and also organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, tartaric acid, citric acid, malonic acid, ascorbic acid, salicylic acid, methanesulfonic acid or toluenesulfonic acid.



   The course of this reaction is surprising insofar as the elimination of halogen from the vinylogous α-haloketone had to be expected in the reduction with an alkali borohydride (cf. Foerst, Newer Methods of Preparative Organic Chemistry Volume IV, page 196).



   The process described above also shows clear advantages over the already known processes: For example, the handling of an alkali borohydride is much more convenient and does not require the protective measures which are unavoidable when handling lithium aluminum hydride. In addition, the process gives significantly higher yields than are obtained in the reactions according to the Belgian patent; While the yields there are on average 45% and only a few yields of 70% can be obtained, the yield in the process according to the invention is consistently over 80%.



   The 2-halomethylbenzophenone used as starting material can be prepared, for example, by halogenation of the correspondingly substituted 2-methylbenzophenone.



   The compounds obtainable by the new process have a pronounced appetite-suppressing effect in which the undesirable, but in the case of many appetite suppressants, usually very strong stimulating effect on the central nervous system is only weakly pronounced.



   example 1
2-methylaminomethyl-a- (4-chlorophenyl) benzyl alcohol HCI
48.6 g of sodium borohydride are added in portions at 100 ° C. over the course of 4 hours to a stirred suspension of 396 g of 2-bromomethyl4'-chlorobenzophenone in 3 liters of methanol. The reaction mixture is kept at 10 ° C. for a further 3 hours and then diluted with 5 liters of water, acidified with 100 ml of concentrated hydrochloric acid and extracted three times with 1 liter of chloroform each time. The combined chloroform extracts are dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is dissolved in methanol and added over the course of 2 hours at a temperature of 10 ° C. to a solution of methylamine in 2 liters of methanol.



  The reaction mixture is left at room temperature overnight and the solvent is then removed in vacuo.



  After 3 liters of water have been added, the mixture is extracted three times with chloroform, the combined chloroform solutions are dried and evaporated to dryness. The residue is taken up in 1 liter of ethanol and brought to a pH of 2 to 3 by introducing hydrogen chloride gas. The end product crystallizes immediately and is recrystallized from methanol / ether.



  Yield: 256.9 g = 86.2% of the melting point 227.0-227.5 C.



   Example 2
2 methylaminomethylz - (4-fluorophenyl) benzyl alcohol HCI
In a solution of 295 g of 2-bromomethyl-4'-fluorobenzophenone in 3 liters of methanol, 75.6 g of sodium borohydride are introduced in portions at a temperature of 10 ° C. over the course of 4 hours. After the reaction mixture has been left to stand for three hours at 10 ° C., it is diluted with 5 liters of water, acidified with 100 ml of concentrated hydrochloric acid and extracted three times with 1 liter of chloroform each time. The combined chloroform extracts are dried over anhydrous sodium sulfate and the solvent is removed in vacuo. A solution of the residue in methanol is added to 3 liters of a solution of methylamine in methanol at a temperature of 10 ° C. in the course of 2 hours.

  The reaction mixture is left at room temperature overnight and then concentrated in vacuo. 2 liters of water are added to the residue, the mixture is extracted three times with chloroform, the chloroform extracts are dried and the solvent is evaporated to dryness. The residue is taken up in one liter of ethanol and brought to a pH of 2 to 3 by introducing hydrogen chloride gas. The end product that fails immediately becomes out
Recrystallized methanol / ether.



   Yield: 246 g = 83.4% of melting point 221-222 C.



   Example 3
2- [1 - (methylamino) ethyl <t- (4-chlorophenyl) benzyl alcohol HCI
3.8 g of sodium borohydride are added in portions to a stirred solution of 32.5 g of 2- (1-bromoethyl) -4'-chlorobenzophenone in 150 ml of methanol within 11/2 hours at a temperature of 10 C. After another
Hour at 10 C, the reaction mixture is diluted with 1 liter of water, acidified with 10 ml of 4N hydrochloric acid and extracted three times with 100 ml of chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and the solvent is removed in vacuo. Of the
The residue is taken up in methanol and im at 10 C
Added in the course of 2 hours to 0.25 liters of a saturated solution of methylamine in methanol.

  The reaction mixture is left at room temperature overnight and then concentrated in vacuo. After adding 0.5 Ltr.



   Water, the mixture is extracted three times with chloroform, the chloroform extracts are dried and evaporated to dryness. The residue is taken up in ethanol and brought to a pH of 2 to 3 by passing in hydrogen chloride gas. The end product crystallizes as the hydrochloride and is recrystallized from methanol / ether.

 

   Yield: 25.5 g (81.7%), m.p. 198.0-200.0 C.



   The following compounds were also obtained by the process given in Examples 1-3: R1 R2 R3 mp. C Yield (HC1 salts)% HH 4 - C1 191-193 88.3 H n-C3-H7 4-C1 129-132 82.6 H NH2 4-Cl 138-140 91.5 H OH 4-Cl 172-173 80.0 H CH3 4SICH, 184 83.9 H n-C4H9 4-C1 102-105 83.2 H iso-C4Hg 4-C1 154 78.5 H C2H5 4-C1 209 87.3 H CH3 3-Cl 174 75.0

 

Claims (1)

PATENT CLAIM Process for the preparation of α-substituted 2-aminomethylbenzyl alcohols of the formula I. EMI3.1 where R is hydrogen or a lower alkyl group, R2 is hydrogen, the hydroxyl or amino group or a lower alkyl group and R3 is a fluorine or chlorine atom or the methyl mercapto group, as well as their physiologically acceptable acid addition salts, characterized in that a compound of the formula II EMI3.2 wherein Hal denotes a chlorine or bromine atom, reduced with an alkali borohydride and the a -substituted 2-halomethylbenzyl alcohol of the formula III obtained in this way EMI3.3 with an amine of the formula IV R2-NH2 (IV). SUBCLAIMS 1. The method according to claim, characterized in that the alkali borohydride used is sodium borohydride. 2. The method according to claim, characterized in that the compounds obtained are converted into their physiologically acceptable acid addition salts.