CH620897A5 - Process for the preparation of o-(N-monosubstituted amino)-benzyl alcohols or of the corresponding secondary alcohols - Google Patents

Description

The present invention relates to a new process for the preparation of o- (N-monosubstituted amino) -benzylalcohols or of the corresponding secondary alcohols, specifically by introducing a group -CHOH d. H. through the selective introduction to the ortho position

R

of N-monosubstituted anilines.

There is known an o-hydroxyalkylation of anilines, for which acylation of a p-substituted aniline in the o-position by means of the Friedel-Crafts reaction and then a reduction of the resulting o-acyl-p-substituted aniline comprises, wherein a p-substituted-o-aminobenzyl alcohol is obtained. However, this method requires reaction conditions which are difficult to carry out, such as heating at a temperature above 200 ° C for two to three hours, and moreover, this method gives an unsatisfactory yield. An economical process for the production of o-aminobenzyl alcohols, which also has a wide range of applications, is not yet known.

A variety of starting compounds in the chemical industry as well as many synthetic intermediates with valuable medicinal properties are based on the use of o- (N-monosubstituted amino) benzyl alcohols, which is why it was desirable to find a new process which was able to produce benzyl alcohols economically , with a wide range of applications.

The invention therefore relates to a process for the preparation of o- (N-monosubstituted amino) benzyl alcohol or the corresponding secondary alcohols, which is characterized in that an N-monosubstituted aniline which may have one or more substituents which, however, is unsubstituted in at least one o-position to the amino group, is reacted with a boron trihalide and the N-boron dihalide substitute obtained in this way is substituted

Compound with an aldehyde of the formula RCHO, in which R is hydrogen, optionally substituted alkyl, aralkenyl, aralkyl, aryl or 2-furyl, in the presence of a base at a temperature below 100 ° C, with region-specific the residue -CHOH in the ortho position

R

of the aniline mentioned and at the same time the boron halide group is split off.

One of the great advantages of this method according to the invention is an extremely wide range of applications. Starting from methylaniline, this process is now set out using the following reaction scheme, for example.

NHCH.

BX.

RCHO

25th

base

NHCH. CHOH

wherein R is hydrogen, alkyl, aralkenyl, aralkyl or aryl 30 and X is halogen. The hydrocarbon groups represented by R are optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, alkoxycarbonyl, nitro and cyano.

One embodiment of the process according to the invention mentioned for the production of the same products is based on reacting an N-monosubstituted aniline optionally substituted with one or more substituents with a boron trihalide in the presence of an aldehyde and a base at a temperature below 100 ° C. , the region-specific 1-hydroxyalkyl or 1-hydroxy-substituted alkyl being introduced into the aniline mentioned in the o-position and at the same time the bordihalide group being split off.

An N-monosubstituted aniline, which optionally contains one or more substituents, is thus used as the starting material, it being possible for the N-substituent to be an alkyl, alkenyl, alkynyl, aralkyl or aryl which may be substituted by one or more further substituents, selected from halogens, alkyl, cycloalkyl, alkoxy, nitro, cyano and also kylsulfonyl, and wherein the substituent of the benzene ring called aniline is a halogen, alkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, nitro, cyano, alkoxycarbonyl or can be acyloxy. The definition of said substituents can be supplemented by the following examples: The 55 alkyl group includes methyl, ethyl, propyl, butyl and amyl. The alkenyl group includes allyl, butenyl, pentenyl and hexenyl, the alkynyl group propynyl, butynyl, pentynyl and hexynyl, the aralkyl group benzyl, phenethyl and phenylpropyl, the aralkenyl group includes cinnamyl and phenylbutenyl, the 60 aryl group phenyl, tolyl, xylyl, naphthyl , Pyridyl, thienyl and furyl, the alkoxy group methoxy, ethoxy, propoxy and butoxy, the aryloxy group phenoxy, naphthoxy and pyridyl-oxy, the aralkyloxy group benzyloxy, phenethyloxy and phenylpropyloxy, the alkoxycarbonyl group methoxycarbo-65 nyl, ethoxycarbonyl, propoxycarbonyl, acoxyoxyoxy and butoxy includes acetoxy, propionyloxy, butyryloxy and pentanoyloxy, the cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the alkylsulfonyl

3rd

620 897

group includes methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl and the halogen is chlorine, fluorine and bromine.

Boron trichloride and boron tribromide, for example, can be used as the boron trihalide.

The other starting material, the aldehyde, is an aliphatic or aromatic aldehyde and includes, for example, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, phenylacetaldehyde, cinnamaldehyde, and furfural. These aldehydes are optionally substituted with one or more inert substituents selected from halogens, alkyl, alkoxy, alkoxycarbonyl, nitro and cyano and can be used in a polymeric form such as paraldehyde.

The base added to the reaction system acts as a kind of catalyst, and for this purpose, for example, an organic amine, preferably an organic tertiary amine such as triethylamine, tri-n-butylamine, dimethylaniline, pyridine, etc., can be used.

The process defined above, which is now based on allowing an optionally substituted N-monosubstituted aniline boron trihalide to act and treating a boron compound obtained in a second step with an aldehyde in the presence of a base, can be practically with or without isolation of those which occur as intermediate substances Boron compound, d. H. of the N-monosubstituted aniline boron dihalide.

The first step of this process can be carried out by reacting the N-monosubstituted aniline with a boron trihalide in a suitable inert solvent such as methylene chloride, dichloroethane, benzene, toluene or xylene, if necessary in the presence of an organic amine such as triethylamine. Tri-n-butylamine or dimethylaniline, treated with cooling or heating.

The second stage is best carried out by reacting the boron compound thus obtained with an aldehyde in the presence of a base in an inert solvent such as methylene chloride, dichloroethane, benzene, toluene or xylene. The reaction can be accomplished at room temperature or with cooling or mild heating, preferably at a temperature below about 100 ° C. The present process according to the invention proceeds smoothly and selectively in both stages, the o- (N-mono-substituted amino) benzyl alcohols being able to be obtained in a good yield.

According to one embodiment, the process according to the invention can be carried out in a single step in such a way that the starting monosubstituted aniline, which optionally has one or more substituents, with a boron trihalide in the presence of an aldehyde of the formula RCHO and a base at a temperature of below about 100 ° C, treated. In this case too, the implementation goes smoothly.

The o- (N-monosubstituted amino) benzyl alcohols or the corresponding secondary alcohols thus obtained are useful as starting materials in the chemical industry or as synthetic intermediate substances in the production of medicinal active substances.

The above method is illustrated in the following examples using currently preferred and practical embodiments.

example 1

A solution of 100 mg of methylaniline in 1 ml of methylene chloride is added to a solution of 110 mg of boron trichloride in 5 ml of methylene chloride with ice cooling, and the mixture thus obtained is then stirred with ice cooling for one hour. A solution of 95 mg of triethylamine in 1 ml of methylene chloride is then added to the ice-cooled mixture and the mixture is then refluxed for two hours. Then a solution of 100 mg of benzaldehyde and 208 mg of tri-n-butylamine in 2 ml of methylene chloride is added to the mixture while cooling with ice, which mixture is then stirred at room temperature for 2 hours. The reaction mixture is mixed with pieces of ice and shaken with methylene chloride. The methylene chloride-15 layer is then washed with aqueous sodium carbonate and then with a saturated brine and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a silica gel column and the product is recrystallized from 20-chloroform-petroleum ether, and 148 mg of 2-methylaminobenzhydrol are obtained as crystals with F from 124 to 126 ° C. The yield is 74.4%. [E. Testa et al., Chemical Abstracts, 60, 6848b (1964)].

IR v "ax '\ cm1: 3590 (OH), 3432 (NH). 25 NMR (CDC13) ó: 2.73 (3H, s., N-CH3), 3.52 (2H, broad m., NH + OH), 5.78 (IH, s., = CH-OHi.

Example 2

A solution of 100 mg of boron trichloride in 5 ml of dry benzene is mixed with a solution of 100 mg of p-chloro-N-methyl-aniline in 2 ml of dry benzene with cooling at 7 to 10 ° C with ice water and the resulting mixture is then treated for two hours at reflux. A solution of 99 mg of o-chlorobenzaldehyde and 131 mg of tri-n-butylamine in 2 ml of dry benzene is then added with ice-water cooling, and the mixture is then stirred at room temperature for one hour. The reaction mixture thus obtained is mixed with pieces of ice and shaken with ether. The ether layer is washed with aqueous sodium carbonate and then with a saturated brine, dried over potassium carbonate and evaporated under reduced pressure. The residue is chromatographed on a column of silica gel and the product is recrystallized from chloroform-petroleum ether and 174 mg of 2-methylamino-5,2'-dichlorobenzhydrol are obtained, as crystals with F from 106 to 108 ° C and in a 87 4% yield.

Analysis for Ci4H, 30NCl2:

see above: C 59.58 H 4.65 N 4.97 Cl 25.13 found: C 59.50 H 4.47 N 5.20 Cl 24.83 IR, v ™ C \ cm "1: 3586 (OH), 3427 (NH).

NMR (CDCI3) ò: 2.84 (3H, s., N-CH3), 3.30 (2H, broad, s "NH + OH), 6.12 (1H, s., = CH-OH).

Examples 3 to 5 Using the starting compounds I and II, each of the reactions is carried out as in Example 2, the corresponding products III being obtained.

35

40

NHCH_ „_TT /. > -NHCH,

3 RCHO (II) R »_1_ M 3

^

«

R

(I) (III)

620 897

4th

Example 1 II III

No. R'R Yield F (° C) IR

(%) (CHCI3, cm'1}

3 H o -N02-Ph 96.8 93-95 3586.3436

4 H p-N02-Ph 79.3 127-128 3604.3434

5 p-Cl Ph 84.0 88.5-89 3430 (film)

Note: Ph means phenyl

Example 6

Using 100 mg of p-chloro-N-methylaniline and 90 mg of benzaldehyde as starting materials, the reaction is carried out as described in Example 2, except that 195 mg of boron tribromide was used instead of boron trichloride, with 118 mg of 2-methylamino-r-chlorobenzhydrol as crystals F from 88.5 to 89 ° C and were obtained in a 67.5% yield.

Example 7

A solution of 13.5 g of methylaniline in 30 ml of toluene was added dropwise to a solution of 14.77 g of boron trichloride in 60 ml of toluene at -20 ° C. with stirring. A solution of 12.8 g of triethylamine in 20 ml of toluene is then added to the above mixture, which mixture was then stirred at room temperature overnight. The precipitate formed is filtered off under nitrogen and washed with toluene. The filtrate and washings are combined, evaporated under reduced pressure to remove the toluene, and the residue is distilled to give 10.5 g of N-methylaniline borane dichloride as an oil at 60-65 ° C at 3 mm Hg result. [Niedenzu, J. Am. Chem. Soc., 81, 5553 (1959)].

15 To a solution of 100 mg of N-methylaniline borane dichloride in 5 ml of methylene chloride is added a solution of 56 mg of benzaldehyde and 99 mg of tri-n-butylamine in 2 ml of methylene chloride while cooling with ice, and the resulting mixture is stirred at room temperature for one hour Hour stirred.

The reaction mixture is then mixed with pieces of ice and shaken with methylene chloride. The methylene chloride layer is then washed with aqueous sodium carbonate and then with a saturated brine and evaporated under reduced pressure to remove the solvent. The back

25 was then chromatographed on a column with silica gel and the product was recrystallized from chloroform-petroleum ether and 85 mg of 2-methylaminobenzohydrol were obtained as crystals with F from 124 to 126 ° C. and in a 75.0% yield .

30th

Examples 8 to 12 Using the starting substances I and II, the reactions are carried out as described in Example 7, the corresponding product III being obtained.

example

I.

II

III

No.

R '

R

yield

F (° C)

IR

(%)

(CHCI3, cm "1)

8th

H

m-NOa-Ph

83.3

125-126

3605, 3445

9

H

P-CH3O-Ph

83.5

189-191 *

3588, 3428

(Dec.)

10th

H

PhCH = CH—

49.6

154-156 *

1727, 1644,

1529, 1349 *

11

H

2-furyl

'62.0

184-186 *

1730, 1645,

1528, 1349 *

12

H

Pr

38.3

131-133 *

3595, 3425

Note: Pr means propyl; * means that the measurement was carried out on 0, N-di-p-nitrobenzoate.

Example 13

A solution of 4.5 g of boron trichloride in 3 ml of methylene chloride is mixed with a solution of 6.5 g of diphenylamine in 12 ml of methylene chloride with cooling at -70 ° C. and the mixture thus obtained is stirred for one hour. The precipitated crystals are filtered at room temperature, washed with benzene, then mixed with 10 ml of benzene and treated at reflux for two hours.

65 After cooling, the reaction mixture is filtered to remove insoluble material and evaporated under reduced pressure to remove the solvent. The residue is then distilled under reduced pressure, which

5

620 897

1.34 g of diphenylaminoborane dichloride as an oil which distills at 117 to 120 ° C at 0.9 mm Hg and has an F of 65 to 69.

[Gerrard and co-workers, J. Chem. Soc., 5168 (I960)]. Using 200 mg of diphenylaminoborane dichloride, 85 mg of benzaldehyde and 147 mg of tri-n-butylamine, the reaction is carried out as described in Example 7 and 49 mg of 2-phenylaminobenzhydrol are obtained. This substance is recrystallized from benzene-hexane and crystals with F of 111 to 112 ° C. are obtained.

Analysis for C19Hi7ON:

calc .: C 82.88 H 6.62 N 5.09 found: C_ 82.67 H 6.28 N 5.03 IR, î ^ SP, 3597, 3405, 1594 cm "" 1,

NMR, ó (CDC13): 5.89 (IH, s.), 6.62-7.47 (14H, m., Ar.

H).

Example 14

A solution of 129 mg is added to a solution of 179 mg of p-ethoxycarbonyl-N-methyl aniline in 2 ml of dry benzene

Boron trichloride in 2 ml of dry benzene is added while cooling with ice. A solution of 0.1 ml of benzaldehyde and 222 mg of triethylamine in 3 ml of dry benzene is then added, after which the mixture thus obtained is stirred at room temperature for 3 hours. The reaction mixture is then mixed with water and shaken with ether. The organic layer is washed with water, dried and evaporated to remove the solvents. The residue is washed with petroleum ether and there are io 196 mg of 2-methylamino-5-ethoxycarbonylbenzhydrol as crystals with F from 132 to 135 ° C. and in a 69% yield.

Analysis for C17Hit, N03:

calc .: C 71.56 H 6.71 N 4.91 15 found: C 71.45 H 6.87 N 4.97 1R, v ™ cU 3417, 3357, 1666 cnT1.

NMR, Ó (CDC13): 1.3 (3H, t., J = 7 Hz, OCHzÇHs), 2.75 (3 H, s., N-CH3), 4.25 (2 H, q "J = 7 Hz, OCH, -CHA 5.75 (1H, s., -CH-OH), 6.4-7.9 (8H, m.).

Claims (4)

620 897 1. A process for the preparation of o- (N-monosubstituted amino) benzyl alcohols or of the corresponding secondary alcohols, characterized in that an N-monosubstituted aniline which optionally has one or more substituents, but which is present in at least one o- Position to the amino group is unsubstituted, reacted with a boron trihalide and the N-boron dihalide-substituted compound thus obtained is reacted with an aldehyde of the formula RCHO, where R is hydrogen, optionally substituted alkyl, aralkenyl, aralkyl, aryl or 2-furyl, react in the presence of a base at a temperature below 100 ° C., the region -CHOH being in the or- R The tho position of the aniline mentioned is introduced and at the same time the boron halide group is split off. 2. The method according to claim 1, characterized in that the radical -ÇHOH is a corresponding 1-hydroxyalkyl- R or substituted 1-hydroxyalkyl. 2nd PATENT CLAIMS 3. The method according to claim 1, characterized in that the boron trihalide is boron trichloride. 4. The method according to claims 1 to 3, characterized in that the reactions are carried out in an inert solvent.