FI61303B - FOERFARANDE FOER FRAMSTAELLNING AV ETT BENZHYDROLDERIVAT - Google Patents

Description

61303

Method for preparing a benzhydrol derivative - Preparation of a benzhydrol derivative

The invention relates to a new process for the preparation of 2 - ([N- (2-hydroxyethyl) -N-methyl] amino] methylbenzhydrol of formula I.

CIL-OH

ch3

The compound of formula 1 of the present invention is used as an intermediate in the preparation of a pharmacologically valuable 3,4,5,6, -Tetrahydro-5-methyl-1-phenyl-1H-2,5-benz8oxazole-nl-hydrochloride, i.e. nefopam, which is used as a muscle relaxant, analgesic and as an antidepressant drug.

The preparation of a compound of formula 1 is already known. Eg Ger.Pat. 1620198, phthalaldehyde is used as a starting material in the preparation of this compound. According to a German patent, phthalaldehyde is grignarded with phenylmagnesium bromide and coupled with an N-substituted amino alcohol to give compound 11.

(O) (6117

CH 3 N- (CH 2) 2 -OH

'2' 61303 This compound 11 is catalytically hydrogenated with Pd / C, Pt or Raney-Ni to give compound 1.

Get. Pat. The second process according to 1620198 uses as starting material o-benzoylbenzoic acid, which is converted to the acid chloride by means of thionyl chloride. It is then coupled with methylethanolamine to give the intermediate N- (2-hydroxyethyl) -N-methyl-o-benzoylbenzamide, which is reduced with LiAlH 2 J to give the final compound of formula I.

U.S. Pat. 3,487,153 discloses the use of o-benzoyl-benzoic acid amide as a starting material in the preparation of the nefopam intermediate. Thionyl chloride is used to form the corresponding acid chloride, which is reacted with N-methyl-2-aminoethanol. The resulting N- (2-hydrocelethyl) -N-methyl-o-benzoylbenzeamide is reduced with LiAlH 2 Z to 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzhydrol.

Ger.Offen. 2834312 uses o-benzoyl-benzoic acid as the starting material, which is reacted with phosphorus trichloride in dichloroethane. The resulting acid chloride is reacted with triethylamine and N-methyl-2-hydroxyethylamine to form N- (2-hydroxyethyl) -N-methyl-o-benzoyl-benzamide.

This compound is treated with phosphorus trichloride (pH - 7.0) to give N- (2-chloroethyl) -N-methyl-o-benzoylbenzamide, which is then reduced with NaBH 4 in acid.

There is thus obtained 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzhydrol.

_3_ 61303 FI · Pat. 54793 (corresponding to Can. Pat. 982608) uses a compound of formula III as a starting material, which is reduced with NaBH 4 to give the corresponding benzhydrol derivative of formula IV, which is reacted with an alkylamine to give a substituted 2-aminomethylbenzyl alcohol of formula V. The above patent does not cover the preparation of nefopam or its intermediates.

R, R.

I1 I 1 CH-Hal. ^ V ^ CH-Hal (θχ (O. '

^ --- C - 0 III CH-OH IV

Hai = Cl, Br R1 - H, CH3 R! R 2 - H, OH, NH 2, (C 1 -C 4 -alkyl. -N-CH-NH-R 2

R3 - Cl, F

CH-OH V

Looking at the above patents, Ger.Pat. 1620198 and U.S. Pat. Pat. 3487153, they note the disadvantage that in the reduction of the starting materials it is necessary to use either catalytic hydrogenation with palladium-coated carbon, platinum or Raney nickel as catalyst, or reduction with lithium aluminum snow hydride. The latter reagent is expensive and reacts very strongly with water, so that even a small amount of moisture in the work environment or in the Liu intake can cause an open flame.

-4- 61303

The reaction also generates explosive hydrogen. Technically, grignardization and catalytic hydrogenation are difficult to perform on a large scale. In addition, the price of o-phthalaldehyde is high.

Ger. Offen. In the process of 2834312, reduction of the amide carbonyl with sodium borohydride in acetic acid requires large excesses, i.e. about 2-3 equivalents of sodium borohydride. The reaction is rather low in yield (about 50-55%) and the reaction time is long, so the manufacturing cost becomes high. In addition, the number of synthesis steps is large and the use of phosphorus trichloride is difficult, especially on a production scale.

EN. Pat. 54793 (corresponding to Can. Pat. 982608), the benzophenone derivative (formula 111) is reduced with NaBH 4 to the corresponding benzhydrol derivative (formula IV). However, this compound is unstable due to the methylene halogen in the o-position, especially in cases where R 1 of formula IV is hydrogen, so it decomposes even in short storage, releasing hydrogen chloride gas, forming a very stable 5-ring ether which is unusable for further reaction. For this reason, it is almost impossible to use the method on a large scale, because the intermediate cannot then be isolated quickly enough, even to obtain a reasonable amount of the final product.

The process of this invention for the preparation of 2 - [[N- (2-hydroxyethyl) -N-methylethyl] amino] methylbenzhydrol seeks to eliminate the above-mentioned disadvantages. The method according to the invention is more economical and easier to carry out, especially on a technical scale, than the methods mentioned above. The process of the invention has only two synthetic steps, the first intermediate being a stable compound, and the reduction is performed using half the equivalent of sodium borohydride. It is cheaper and easier to use than lithium aluminum hydride or catalytic hydrogenation.

-5- 61303

In addition, the formation of Schiff bases between the amine and the carbonyl group of the benzophenone derivative has not been observed by the process according to the invention, which would be possible if F1 Pat were used. Primary amines of 54793. The yield of the process according to the invention is 95-96%.

The process according to the invention is characterized in that 2-chloromethylbenzophenone is reacted with methylethanolamine in the presence of sodium carbonate to give 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzophenone.

This compound is reduced with sodium borohydride to 2- [1N- (2-hydroxyethyl) -N-methyl] amino] methylbenzhydrol.

t§)

N CH2C1 VI

CH3-NH-CH2-CH2-OH

Na 2 CO 3 'r' 6 '61303 <§>

C = 0 VII

(oT

Nv / N CH2N (CH3) CH2CH2OH NaBH4 Ψ (6)

CH-OH VIII

(of

CH2N (CH3) -CH2-CH2-OH

The starting material, 2-chloromethylbenzophenone, can be prepared in a known manner by halogenating the corresponding 2-methylbenzophenone (Monatshefte fur Chemie 99, 1990-2003, 1968) or 2-hydroxymethylbenzophenone, the former being commercially available and the latter can be prepared in a known manner from phthalate (Brit. Pat. 1526331). Compound VII is new.

6130 3

Example 1 8.50 g (0.037 mol) of 2-chloromethylbenzophenone are dissolved in 40 ml of ethyl alcohol, 4.0 g of sodium carbonate and 2.80 g (0.037 mol) of 2-methylaminoethanol are added. The mixture is boiled for 3 hours and the salts are filtered off from the cooled solution. The pure reaction product is obtained by evaporating the ethanol from the solution and crystallizing the product as the hydrochloride salt from a mixture of diethyl ether and ethyl alcohol. The yield is 10.7 g (95%) of a crystalline powder, 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] -raethylbenzophenone hydrochloride, m.p. 135-136 ° C.

Example 2 10.0 g (0.033 mol) of the hydrochloride salt prepared in Example 1 are dissolved in a mixture of 15 ml of water, 60 ml of methanol and 3.5 g of sodium hydroxide. 0.65 g of sodium borohydride is added to the mixture and stirred at room temperature for 0.5 hours.

The solution is acidified with concentrated hydrochloric acid and the methanol is evaporated off under vacuum. 40 ml of water are added, the pH of the aqueous solution is adjusted to basic with dilute sodium hydroxide and the product is extracted into chloroform. The chloroform extracts are washed well with water, dried over sodium sulfate and the solvent is evaporated off. The product is isolated by precipitation as a hydrochloride from a mixture of diethyl ether and ethyl alcohol. The yield is 9.8 g (96%) of a crystalline powder, 2 [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzhydrol hydrochloride, m.p. 128-133 ° C.

Claims (2)

Process for the preparation of 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] -methyl-benzhydrol (I), (?) CH-OH I rar CH2-N-CH2-CH2OH ch3 characterized in that reacting 2-chloromethylbenzophenone in a suitable solvent with 2-methylaminoethanol at elevated temperature to give 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzophenone as a reaction product, which is isolated and reacted in a second step with a suitable solvent in a suitable solvent. preferably using at least 0.065 parts by weight of sodium borohydride per part by weight of 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] methylbenzophenone hydrochloride to give the final product 2 - [[N- (2-hydroxyethyl) -N-methyl] amino] -metyylibentshydrolia. A compound for use as an intermediate in the process according to claim 1, 2 - [[N- (2-hydroxyethyl) -N-methyl] -amino] -raethylbenzophenone, characterized in that it has the formula (O] oo (O) f CH 2 N (CH 3 ) CH2CH2OH