CH634819A5 - Process for the preparation of 2-[N-(2-hydroxyethyl)-N-lower alkyl-amino methyl]-benzhydrols. - Google Patents

Description

The invention relates to a process for the preparation of 2- [N- (2-hydroxyethyl) -N-lower alkylaminomethyl] benzhydroles (I). The benzhydrol products of this process can be converted directly into the corresponding phenylbenz (f) -2,5-oxazo-cines, which are valuable physiologically active substances (see US Pat. No. 3,830,803, US Pat. No. 3,978,085, British Pat. No. 1 148 717 and CA-PS 863 349).

The direct process for the preparation of compounds of formula I, as specified later, from compounds of formula II is known. This reaction is carried out by treating the starting compound with a reducing agent in the form of a metal hydride such as lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran or ether (see e.g. GB-PS 1 148 717). However, reduction with lithium aluminum hydride is not a practical synthetic method for large-scale reactions that are commercially required. The solvents that have to be used are very flammable, and lithium aluminum hydride itself is extremely dangerous and the cost is so high that its use on a large scale is not justified.

In contrast, the method according to the invention can be carried out in a commercially advantageous manner. It uses less hazardous solvents, can be carried out relatively cheaply and can lead to high product yields with high purity.

The process according to the invention is used to produce a 2- [N- (2-hydroxyethyl) -N-lower alkylaminomethyl} benzhydrol of the formula

R

in which R is a methyl or ethyl group, X is a fluorine, chlorine or bromine atom or a methyl group, Y is a fluorine or chlorine atom or a methyl or methoxy

group and m and n each represent 0, 1 or 2. In the process, a compound of formula

0 R

in which D is a halogen atom, reduced in an inert solvent with sodium borohydride in the presence of an alkanoic acid. The compound of formula III is obtained by treating a compound of formula c-n (ch

0 r with a halogenating agent in an inert solvent.

The reduction of certain amides to amines with sodium borohydride in the presence of an alkanoic acid is given in "Sodium Acyloxyborohydride as New Reducing Agents", Tetrahedron Letters No. 10, pp. 763-766 and "Reduction of Amides with Sodium Borohydride", Ventron Alembic, Issue No. 9, pp. 6 and 7. However, these reactions seem to differ from the reduction according to the invention of the halogenated compound of the formula III. The known reactions require a large excess of sodium borohydride with loss of effectiveness due to hydrogen evolution and probably formation of amine borane, the reduction presumably taking place via the alkyloxyborohydride. The reduction according to the invention, on the other hand, proceeds easily in many different solvents using a much smaller excess of sodium borohydride. The presence of halogen D is essential and the reaction does not proceed in its absence, and in the preferred procedure in which the compound of formula III and the alkanoic acid are gradually added to the reaction mixture containing all of the sodium borohydride, no evolution of hydrogen occurs after the first slight addition of acid.

The product I is usually obtained from the reaction mixture by aqueous working up in solution in the inert solvent. It can be obtained as a pure substance by removing the solvent by conventional methods, or the solution can be used as such, e.g. B. in the production of the physiologically active phenylbenz (f) -2,5-oxazocine.

The starting substances II for the process according to the invention are generally known (GB-PS and CA-PS as mentioned above). The first stage (halogenation) of the process is carried out in an inert solvent such as a chlorinated hydrocarbon, e.g. B. dichloromethane or di-chloroethane, or an aromatic hydrocarbon,

634 819

such as toluene, benzene or the like. The preferred solvent is dichloroethane. Suitable halogenating agents include Phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and thionyl chloride.

Phosphorus trichloride is preferred because of its low cost. In general, an equivalent amount or a slight excess of up to about 10% of the halogenating agent is used.

The required temperature is moderate and is e.g. B. at 20 to 90 ° C depending on the time requirements. At 55 to 80 ° C the reaction is complete in about 1 to about 4 hours. Too high reaction temperatures and too long reaction times should be avoided in order to keep the possibility of side reactions low. The completeness of the reaction is generally monitored by chromatography. The reaction mixture is preferably cooled, neutralized with an aqueous base, then separated and dried.

The reduction reaction can be carried out easily and economically and can lead to high yields (e.g. 80 to 100% of the theoretical amount). In contrast to the known methods in which the strong reducing agent lithium aluminum hydride and difficult and dangerous reaction conditions are used, the reaction according to the invention can be easily controlled if it is carried out on a large scale.

The reaction is carried out in the presence of an alkanoic acid, preferably a lower alkanoic acid having no more than 4 carbon atoms, such as acetic acid. If the acid is omitted, little or no desired product is obtained. The amount of alkanoic acid used can e.g. about 0.1 to about 1.0 mole / mole sodium borohydride. The reduction is conveniently carried out in an inert aliphatic chlorinated hydrocarbon solvent which has a reflux temperature of more than 60 ° C, preferably dichloroethane. The reaction temperature is preferably the reflux temperature of the reaction mixture. Starting the reaction below 60 ° C can be dangerous.

The reduction can be carried out by adding acetic acid to a mixture of sodium borohydride and the starting material N- (2-halogenoethyl) -N-lower alkyl-o-benzoylbenzamide (III) in dichloroethane. This reaction is usually fairly exothermic, although controllable. Optionally (and preferably for reactions on a larger scale) the reaction is started on a relatively small scale, with all reaction components being present. This initial reaction mixture, which contains the entire amount of sodium borohydride to be used for the reaction on a large scale, is expediently kept at the reflux temperature in this procedure. The remaining compound III in dichloroethane is gradually added together with the alkanoic acid in this embodiment of the process. This process requires less alkanoic acid (e.g. less than 0.2 mol / mol sodium borohydride). In addition, less sodium borohydride can be used. For example, it is preferred to use about 1.5 moles / mole of Compound III compared to 2.0 moles / mole of Compound III unless this preferred procedure is used. The reaction can be carried out under an inert atmosphere (e.g. nitrogen) as a safety measure and also to reduce the risk of side reactions, although this is generally not necessary.

After complete reduction (which is conveniently shown by chromatography) the reaction mixture

3rd

5

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30th

35

40

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50

55

60

65

634819

gradually (initially carefully) added to water and then made alkaline and heated to reflux temperature (to destroy residual sodium borohydride and neutralize the alkanoic acid). The product can then be isolated or, optionally, the organic layer containing the product can be separated and used for another reaction to produce the pharmaceutically active phenylbenz (f) -2,5-oxazocine.

The invention is illustrated by the following examples. Example 2 shows the preparation of the starting compound III.

example 1

The example shows a complete five-step synthesis sequence, starting from commercially available substances and ending with a pharmaceutically active phenyl-benz (f) -2,5-oxazocin.

Stages 3 and 4 of this example show a preferred process according to the invention as part of this reaction sequence.

Stage 1: Acid chloride production

To a slurry of 222.2 g (1.0 mol) of o-benzoylbenzoic acid in 230 ml of dichloroethane, 35.4 ml (0.46 mol) of phosphorus trichloride were added all at once. After stirring for 1 hour the temperature had reached a maximum of 39 ° C. Stirring was continued overnight at room temperature whereupon thin layer chromatography showed complete conversion to the acid chloride. The layer containing the product was decanted off.

Level 2: amide formation

The acid chloride-dichloroethane solution from stage 1 was added to a solution of 111.39 g (1.1 mol) of triethylamine and 82.62 g (1.1 mol) of N-methylethanolamine in 400 ml of dichloroethane in the course of 1 h at 5 to 12 ° C added dropwise. After the addition was complete, the reaction mixture was stirred for an additional hour after which thin layer chromatography showed complete conversion to N- (2-hydroxyethyl) -N-methyl-o-benzoylbenzamide.

Stage 3: Production of N- (2-chloroethyl) -N-methyl-o-ben-zoylbenzamide (III)

35.4 ml (0.406 mol) of phosphorus trichloride were added to a slurry of the product of stage 2 at room temperature within 5 minutes. This caused the temperature to rise by 20 ° C and the slurry became much thinner. When heated to 55-60 ° C and maintained at that temperature for 1 hour, thin layer chromatography showed complete conversion to the desired product. The reaction mixture was cooled to 0 ° C. and diluted with 500 ml of water within 5 minutes, the temperature being kept below 5 ° C. The two-phase mixture was stirred for 5 min and the layers were then able to separate. The lower organic layer was washed with an additional 500 ml of water and sufficient base (sodium hydroxide) at a temperature below 10 ° C to raise the pH to about 7, and then dried over 90 g of anhydrous sodium sulfate.

Level 4: Reduction

To a slurry of a portion of the solution obtained in Step 3 (108 ml) and 28.4 g (0.75 mol) of sodium borohydride was added dropwise 3.5 ml of acetic acid. After foaming and heat had ceased, the temperature was raised to the reflux temperature and held at this value for 15 minutes. The remainder of the solution of the product from stage 3, containing 9 ml of acetic acid, was added dropwise to the refluxing slurry with stirring over the course of 2 hours. The temperature was maintained at reflux by gently warming the flask, the addition itself being quite exothermic. After the addition was complete, the reaction mixture was stirred for another hour at the reflux temperature, after which the thin layer chromatography showed complete conversion to the desired product. The entire procedure was carried out under a nitrogen atmosphere.

To the slurry obtained above was added 200 ml of water at room temperature over 1 hour (initially very slowly). The addition resulted in a fairly strong foaming and the temperature rose to 45 ° C. 75 ml of 40% aqueous sodium hydroxide solution were added to the reaction mixture thus diluted. The temperature was raised to the reflux temperature and kept at this value for 3/4 h. The mixture was then cooled and the layers separated to give a solution of 2- [N- (2-hydroxyethyl) -N-methylaminomethyl] benzhydrol in dichloroethane.

Stage 5: cyclization

The benzhydrol obtained in stage 4 (still in dichloroethane solution) was cyclized with aqueous hydrobromic acid by the process of US Pat. No. 3,978,085. The reaction gave 131.5 g of 5-methyl-l-phenyl-l, 3,4,6-tetrahydro-5H-benz (f) -2,5-oxazocin hydrobromide, mp. 259-261 ° C. The melting point, thin layer chromatography and the infrared spectrum indicated a pure product.

The overall yield over the 5 stages (starting with o-benzoylbenzoic acid) was 60 to 65% of theory.

Example 2

A mixture of 56.66 kg (200 moles) of N- (2-hydroxyethyl) -N-methyl-o-benzoylbenzamide, 101 toluene and 10.07 kg (10% excess) of phosphorus trichloride was warmed slightly until an exothermic reaction began to form a hot melt at 77 ° C. After 0.5 h at 75 to 77 ° C, the thin layer chromatography showed complete formation of the N- (2-chloroethyl) -N-methyl-o-benzoyI-benzamide. 901 isopropanol were added quickly and the mixture was rapidly cooled, inoculated and cooled to below 0 ° C. The product was collected, washed with 2x101 cold isopropanol and dried. This gave 50.6 kg (83.3%) of the product, mp. 85.5 to 86.2 ° C.

Example 3

A solution of 144 kg (481 mol) of N- (2-chloroethyl) -N-methyl-o-benzoylbenzamide in 378 kg of dichloroethane was prepared. A mixture of 50 kg of this solution, 273 kg (721.5 mol, 1.5 eq.) Sodium borohydride and 1201 dichloroethane was treated at 46 ° C with 0.5 kg acetic acid. The temperature rose steadily to the reflux temperature of 86 ° C. The remaining dichloroethane solution was added slowly, the exothermic heat keeping the mixture at reflux temperature without heating during the addition and 2 hours after the addition was complete. The reaction was monitored by thin layer chromatography (if the reaction is not yet complete, a small additional amount of sodium borohydride can be added). The complex was then decomposed by carefully adding 1001 water at reflux temperature and then 50140% (wt) aqueous sodium hydroxide solution. 2- [N- (2-Hydroxyethyl) -N-methylaminomethylj-benzhydrol was formed in dichloroethane. The benzhydrol in dichloroethane was washed with water to a pH of 8 and then as follows4

s io

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5

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Cyclized to 5-methyl-l-phenyl-l, 3,4,6-tetrahydro-5H-benz (f) -2,5-oxazocin:

The organic phase was separated and cooled to 20 ° C. 48 to 50% (224 kg, 149.21) hydrobromic acid were added with stirring within V2 h with cooling to keep the temperature below 50 ° C. The mixture was gently warmed to reflux, held at reflux for 2.5 hours, cooled to room temperature, and then cooled to 0 ° C. The product was centrifuged off, dried with rotation (spun dry), washed with a total of 1101 acetone and dried again with rotation. The moist product was again placed in a cleaning kettle in which 242.81 toluene, 110.41 water and 20.4 kg of sodium hydroxide beads had previously been added and the mixture was heated to 60 ° C. with stirring, for a further 0.5 h at 60 ° C stirred and left to separate for 0.5 h. The lower aqueous alkaline layer was drained off and the toluene layer was washed with 2 × 561 tap water at 60 to 70 ° C. to a pH of 7. The toluene was evaporated under reduced pressure and the remaining oil was cooled to room temperature and then diluted with 2201 acetone. The solution was

5 de clarified by passing through a cartridge filter into a cleaning tank. To the stirred, water-cooled, clear acetone solution, 38.02 kg (31.881) of hydrochloric acid were slowly added (to a pH of 1) over the course of 0.5 to 1 h. The resulting slurry was stirred, cooled to room temperature and then to 0 ° C. The product was centrifuged off, washed well with acetone (1101 in total) and sucked dry and then dried overnight in a vacuum oven at 50 to 60 ° C.

15 Other substituted 2- [N- (2-hydroxyethyl) -N-lower alkylaminomethyl] benzhydroles were prepared according to the previous examples:

Example No. Starting substance

table

product

\

nch2ch2oh

CH2nch2CH2OH ch.,

gh.

Cl

Cl o ch.

ch2nch2ch2oh ch.

Cl c = 0

c-nch2ch2oh

Cl height eH2NCH2C! I2nn o .'ch.

ch.

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6

Table (continued)

Example No. Starting substance

product

c = o c-nch-ch-oh

II I

o ch-.

choh

CH2nch2CH2OH CH ^

ch.

ch.

c = 0

c-nch2ch2oh ch.

-CH.

CHOH

CH2NCH2CH20n o ch, '• 3

ch.

10th

c = 0

c-nch2ch2oh ch2nch2ch2gh o ch.

ch.

Claims (7)

634 819 2. The method according to claim 1, characterized in that acetic acid is used as the alkanoic acid, s 3. The method according to claim 1 or 2, characterized in that m and n are 0. . 2nd PATENT CLAIMS 1. Process for the preparation of 2- [N- (2-hydroxyethyl) -N-lower alkylaminomethyl] benzhydroles of the formula CH2N (CH2) 2OH R in which R is a methyl or ethyl group, X is a fluorine, chlorine or bromine atom or a methyl group, Y is a fluorine or chlorine atom or a methyl or methoxy group and m and n are each 0.1 or 2, characterized that you have a compound of formula C-N (CH2) 2D Alkanoic acid reduced with sodium borohydride in an inert solvent. 4. The method according to any one of claims 1 to 3, characterized in that D is a chlorine atom. 5. The method according to any one of claims 1 to 4, characterized io that one carries out the reduction by Mix the sodium borohydride with part of the alkanoic acid and the compound of the formula III and then gradually add the rest of the alkanoic acid and the compound of the formula III to the reaction mixture. * 15 6. Application of the method according to claim 1 to compounds of formula III, which by reacting a compound of formula: III ii C-N (CH _) _ OH left 1 22 0 R 30th 0 R be prepared with a halogenating agent in an inert solvent. 7. Application according to claim 6 of the method according to ei-in which D is a halogen atom and R, X, Y, m and nem of claims 2 to 5. have the meaning given above, in the presence of a 35th