DD158237A1 - METHOD FOR THE PRODUCTION OF SUBSTITUTED [2- (AMINOMETHYL) -HENYL] PHENYLMETHANOES - Google Patents

Abstract

Substituted (2- (aminomethyl) -phenyl) -phenylmethanones can be prepared easily and in good yields in a two-step process by reacting (2-methylphenyl) -phenylmethanones in an inert organic solvent with a halogenating agent in the presence of a radical generator and reacting the obtained (2- (halomethyl) -phenyl) -phenylmethanones with a secondary amine.

Description

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Title of the invention:

Process for the preparation of substituted / 2- (amino-methyl) phenyl_7-phenylmethanones

Field of application of the invention:

The invention relates to a process for the preparation of substituted (2-aminomethyl) -phenyl-7-phenylmethanones of the general formula

E.

in which E 1 is a hydrogen or halogen atom, E _{2 is} a hydrogen or halogen atom or a nitro group, R 1 is a alkyl alcohol, hydroxyalkyl, aralkyl or cycloalkyl radical and E 1 is a hydroxyalkyl or lower alkyl radical;

2W ^ $ && ξ mtm

alkyl radical or IU and BL together with the N atom to which they are attached ₉ a heterocyclic ring, den »Β the piperidine«, Met hy piperazine, hydrosilylpiperazine »or morpholine ring, _e

Some of the compounds have anti-inflammatory properties and, above all, are valuable drugs for the synthesis of pharmaceuticals. »

Characteristic of the known technical solutionsί

The compounds of general formula I are partially known

According to FR-PS 1 549-342, ÜS-PS 3 86? 381 3497508, 3635 96? "3 6? 8111, R. Coombs, W · J" Houlihan u _e a _e, J »med * Ohem..14 (1971) _t 1072? Po Aeberli and 'W · J ₆ Houlihan, J _e Orge Chem "^ 4 (1969), 2715 is also known that £" 3 ° ~ and 4 ~ (aminomethyl) -?' Phenylj ~ phenylmethanone in a two step process by bromination of (3- and 4-methylphenyl) -phenylmethanones and subsequent reaction of the monobromination products thus obtained with secondary amines can be prepared _e

In particular, when studying the bromination conditions, with the bromination of the methanones with bromine in a molar ratio of 1 s 1.1, the authors found that the (2-methylphenyl) phenylmethanones under the same conditions gave only unsatisfactory yields for each o-ch , '

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According to R · Coombs, WJ Houlihan and co-workers, a mixture of non-brominated starting material, / ~ 2- (monobromomethyl) -phenyl_7-, is formed during the 'bromination of (2-methylphenyl) -phenylmethanones (according to MR spectra and bromine determination). pbenylmethanone and ^ "2- (di- or tribromomethyl) -phenyl_7-phenyl-methanone in the ratio 1: 0.6: 0.3, which corresponds to a yield of only 31-5 mole percent of monobromo compound The further reaction of this bromination mixture with secondary amines have The authors did not investigate, as one can obviously expect only very inconsistent end products.

However, when (2-methylphenyl) -phenylmethanones are converted to 1,3-dioxolane derivatives before bromination, the yield being 70 % , satisfactory yields of both the monobromo derivative and the further reaction with secondary amines are obtained.

These results must lead to the conclusion that the synthesis of / ~ 2- (aminomethyl) -phenylJ7-phenylmethanone can be carried out in good yields only on ^ "" 2- (halomethyl) -phenylJ / '- phenylmethanone, if the carbonyl group before the halogenation is protected ·

In the literature mentioned above, the reaction of (2-methylphenyl) -phenylmethanones with Ä'thylenglykol to 2- (2-methylphenyl) -2-phe.nyl-1,3-dioxolanen described by bromination to the 2- ₍ / ~ 2- (bromomethyl) -phenyl ^^ - phenyl-i, 3-dioxolanes are reacted with the corresponding secondary amines from which the substituted 2- ^ ~ 2- (aminomethyl) -phenyl phenyl-7-phenyl-1,3 -dioxolanes and, after removal of the protective group, to give the substituted ^ ~ 2-aminomethyl) ·

- Zf. -

phenylj ^ -phenylmethanones "Thus, the synthesis proceeds via 4 steps.

E ₉ Faragher, Th "L. Gilchrist (J. Chem. Soc. 1_2Z§" Part, I, 336, CA, 86 (1977) »5392) the bromination of (2 ~ methylphenyl) have ~ phenylmethanonen re-examined, taking in contrast to E. Coombs and co-workers, (2 ~ methylphenyl) phenylmethanone brominated well with bromine in the presence of UY ~ light in the side chain (yields up to -80 % of theory). "

The product formed is, however, described as thermally very unstable * If the solution for a short time is set aside _s begins the product by itself with evolution of hydrogen bromide to decompose _c emerge Isobenzofuranderivate that were not isolated, their formation but indirectly Y / ege proved * Implementation with amines is not described «

In addition to these technically possible methods, synthetic routes are described in the literature, which can not be realized on an industrial scale.

J · Te Barnish and Ch.R. Hauser (J _e org · Chem «, (1968), 1372; O ₈ Ao 68, (1968), 105128) describe the reaction of ΪΓ, Ν-dimethylbenzylamine with benzonitrile and n-butyl ! lithium and / ~ "2 ~ dimethyl aminomethyl) -phenyl_7 ~ phenylmethanone _e

I. Ehee u _e a, (Bull · Chenu-Soco Jap * 4J $ (1970), 947-950, G. A "21 O970)., 3620), publish the

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Synthesis of / 2- (dimethylaminomethyl) -phenyl J7-pheny1-methanone from 2-dimethylaminomethylphenyl-lithium with benzyl bromide in the presence of iron pentacarbonyl.

Ch · Ivanov u. A. Draganov (Monatsh. Chem. 99 »(1968), 1990, C.A. 22 (1969) ι 3719) lead to a direct chlorination of (2 ~ methylphenyl) -phenylmethanone with chlorine, wherein neither yields nor other concrete results are reported.

Object of the invention:

The invention makes it possible to produce the compounds of general formula I in a two-step process from the compounds of general formula II in good yields in a technically simple manner.

The success of the method according to the invention was not. On the basis of the prior art set forth, there was a prejudice that the compounds of the general formula I were obtained by direct halogenation of (2-methylphenyl) -phenylmethanones of the general formula II and subsequent amination of the thus-obtained 2- (halomethyl) phenyl_7-phenylmethanones of the general formula III in a 2-step process, ie without incorporation of a protective group on the carbonyl group of the compounds of general formula II could be prepared in good yields, since either the monobromination of (2-methylphenyl) -phenylmethanone without Protective group only with 31.sup.-5 % (R.Coombs) or in the other case (E. Faragher, TL Gilchrist) the resulting monobromine compound of the general formula III decomposes readily to form isobenzofuran.

- 6 - £ £ Ό Q 3 L f

Because of this fact, one must consider the intended implementation between the. £ ~ 2- ( bromomethyl) -phenyl-7-phenyl-methanone and secondary amines for the preparation of the compounds of the general formula I as questionable, since the addition of organic and inorganic bases is rather a molecular HBr-cleavage in ^ f * 2 ~ ( Bromomethyl) -phenylj ^ -phenylmethanone and thus the formation of 1-phenyl · isobenzofuran (Ro Faragher) should favor, as to allow the course of the reaction in terms of the desired substitution of the halogen by the amino group of the added base.

In addition, ₉ that with respect to the chlorinability of, · (2-methylphenyl) -phenylmethanonen the general formula II in the side chain and the reactivity of the available chlorination products of the literature exact information can not be found »

Explanation of the nature of the invention

The invention is based on the problem of preparing compounds of the general formula I in a technically simple manner in a 2-stage process from the compounds of the general formula II in good yields.

According to the invention, this is achieved by reacting a (2-methylphenyl) -phenylmethanone of the general formula

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II

wherein E ,, and E _{2 have} the abovementioned meaning, halogenated in an inert organic solvent and in the presence of a Eadikalbildners with a halogenating agent and the resulting compound of the general formula

CH ₂ -HaI

III

CO

in which Hal denotes a halogen atom and E 1 and E _{2 have} the abovementioned meaning, with an amine of the general formula

common formula

HH

E ₄

in which R ~ and E ₂ , which have the abovementioned meaning, are aminated «

As inert organic solvents z. Be benzene, chloroform, or preferably carbon tetrachloride verwend- · bar "Suitable halogenating agents are suitable, for example, Brom'oder sulfuryl chloride * The reaction may proceed at temperatures between room temperature and the boiling temperature of the reaction mixture, preferably at reflux temperature, ζ * B _e to the removal of the resulting Cxases from the reaction mixture and to keep away atmospheric oxygen in the halogenation, ·

As the radical peroxides, _e z are ₀ B benzoyl peroxide or, preferably, diisopropyl peroxydicarbonate suitable.

Y / hile the I-Ialogenierungsmittel are employed in approximately equivalent amounts, the addition of these free radical generator is preferably carried out in catalytic amounts of _β To satisfy about 0.01 to 0.05 moles of peroxide used pro.Mol compound of general formula II '

Since hydrogen halide is formed in the reaction of the compounds of the general formula III with amines of the general formula IV, it is expedient either 2 mol of amine per mole of the compound of the general formula III

- 9- 229352 7

of the general formula IV or at least 1 mol, preferably 1 to 1.3 mol of amine of the general formula IV and at least 1 mol, preferably 1 to 1.5 mol, of an inorganic base.

The reaction is expediently carried out in such a way that a (2-methylphenyl) -phenylmethanone of the general formula II is initially charged in an indifferent solvent, the total amount of the sulfonium chloride is added and the reaction mixture is heated to reflux. Then the catalyst is dissolved in indifferent organic solvent. dissolved, slowly added dropwise and left to react for some time.

The sulfuryl chloride as a chlorinating agent has the advantage that almost no higher chlorination occur at the methyl group, MR measurements in the reaction solution provided chlorination degrees of 65 to 75 % of Mqnochlormethylverbindung the general formula III.

In the bromination, bromine and catalyst are expediently dripped in parallel in order to avoid an excessively vigorous reaction of the bromine and overbrominating. Otherwise, the reaction can be carried out as in the chlorination «

The (2-halomethylphenyl) -phenylmethanones of general formula III need not be isolated but can be reacted in the form of this solution with the secondary amines. It is advantageous to carry out in the presence of alkali solutions, the Aminumsetzung, .um not to catch the liberated hydrogen halide with excess amine.

The mixture is subsequently stirred with water in order to remove excess alkali or amine and salts from the organic phase

The compounds of the general formula I which are contained in the organic phase can be removed to a large extent. transferred by stirring with dilute acids in the corresponding salts and then re-absorbed by leaching with alkali in an organic phase. This achieves extensive cleaning, which can be repeated as needed. "

Since in the halogenation of the compounds of general formula II with sulfuryl chloride or, with bromine only a maximum of 65 to 75 % of monohalogenomethyl compounds which can be aminated to compounds of general formula I, 20 to 25 % of the starting material from the reaction solution can be recovered if after stirring with dilute acid and separation of the phases, the organic phase containing the starting product is distilled,

Since the yields are without consideration of the recoverable starting product over 2 stages on average at 50 to 65 % of theory, this means a yield of 62 to 81 % of theory based on reacted (2-methylphenyl) -phenylmethanone of the general formula II, what good for a two-step reaction »

Exemplary embodiments: Example 1:. '

20 g (0.102 mol) of (2-methylphenyl) phenylmethanone are stirred in 50 ml of tetrachloromethane, 10 ml of sulfuryl chloride are added, the mixture is heated to lively reflux and the mixture is treated with 2.5 ml of a 1 molar solution of diisopropyl peroxydicarbonate in tetrachloromethane in 0.5

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Hours offset. Then allowed to react at the same temperature for 1 hour under reflux, so that the catalyst is destroyed. The solution of / ~ 2- (chloromethyl) phenyl_7-pbenylmethanone, which contains about 70 % monochloromethyl product and about 2.0 to 25 % unreacted starting material, is used for subsequent reaction. , , ,

The tetrachloromethane solution is mixed with 10 g of potassium hydroxide dissolved in 25 ml of water or with 18 g of 45% sodium hydroxide solution and 8 ml of water, then 13 ml (0.16 mol) of methylaminoethanol are added with stirring and the mixture is stirred. Mixture heated under slight reflux for 6 hours. Then, after cooling, 25 ml of water are added, stirred and the phases separated. The aqueous phase is still stirred with 25 ml of carbon tetrachloride and separated. The combined tetrachloromethane solutions are stirred with 30 ml of water and 15 ml of concentrated hydrochloric acid, the tetrachloromethane layer is stirred with 30 ml of water, the aqueous layers are combined and made alkaline with about 15 ml of concentrated sodium hydroxide solution (Evaporation of the tetrachloromethane of this phase gives a oily residue (about 6 to 10 g), from which can be recovered by vacuum distillation 4-5 S (2-methylphenyl) -phenylmethanone.) The alkaline solution is extracted twice with 75 ml of chloroform. Both chloroform phases are stirred together with 30 ml of water. The chloroform solution is treated with hydrogen chloride in propanol-2 until the reaction of dimethylaminoazobenzene, the solution is concentrated and the oily residue is taken up in 25 ml of acetone. Crystallization occurs. After filtration with suction, the mixture is washed with 75 ml of acetone, the yield of ^ "* 2 ~ / E- (2-hydroxyethyl) -N-methyl-aminomethyl_7 ^ phenylJ7-phenylmethanonhydrochlorid is 20.2 g = 65.4 % of theory, calculated to 0.102 mol of (2-methylphenyl) phenylmethanone, P 159

163 ⁰ * Taking into account the recovered (2-methylphenyl) -phenylmethanone (4 g), the yield is 81.5%.

Example 2s

40 g (0.204 mol) of (2-methylphenyl) phenylmethanone are initially charged with 150 ml of tetrachloromethane, heated with stirring and reflux (heating with an IR lamp). Then 10 ml of a 1 molar solution of diisopropyl peroxide dicarbonate in carbon tetrachloride and 33 g of bromine dissolved in 40 ml _s of carbon tetrachloride are added dropwise in about 30 minutes, 1 hour-reaction, further work-up as example

Yield of "2-" ^ K = (2-hydroxyethyl) -IT '= "methyl" aminomethyl _> _7-phenyl-7-phylmethanone hydrochloride is 31 * 5 S = 50.5 % of theory, calculated to 0.204 mol (2-methylphenyl) phenylmethanone, F 159-163 °.

example

20 g (0.102 mol) of (2-methylphenyl) -phenylmethanone are dissolved in 75NO-tetrachloromethane with stirring, 10 ml of sulfuryl chloride are added and brought to reflux. 2.5 ml of a 1 molar solution of diisopropyl peroxydicarbonate in carbon tetrachloride are dissolved within The mixture is then refluxed for 1 hour while stirring. The resulting ~~~ (chloromethyl) phenyl-phenylmethanone is left in carbon tetrachloride and, after cooling, 19 × 8 ml (0.2 mol) are added. Piperidine added. The reaction mixture is heated at 60 ° with stirring for 6 hours. After cooling, 50 ml of water and 10 ml of concentrated hydrochloric acid are added, the layers are separated. The acidic aqueous layer is made alkaline and stirred twice with 50 ml of chloroform each time. The combined chloroforms are added

_ ₁₃ . 229352 7

The reaction mixture is stirred with water (50 ml) and the equivalent amount of hydrogen chloride in propanol 2 is evaporated to dryness, taken up in 25 ml of acetone and left to crystallize. phenyl-7-phenyl-methanone hydrochloride is 16.2 g = 50.3% of theory, calculated on 0.102 mol of (2-methylphenyl) -phenyl-methanone F 173-175 °

Example 4 ·:

The preparation of ^ 2- (chloromethyl) -phenyl-7-phenyl-methanone is carried out from 0.102 mol of (2-methylphenyl) -phenylmethanone as in Example 3. Instead of piperidine, 18.9 g of morpholine (0.2 mol) are added and the reaction mixture is worked up analogously. The yield of (2-morpholinylmethyl) -phenyl-7-phenylmethanone hydrochloride is 21.5 g = 66.3 % of theory, calculated on 0.102 mol of (2-methylphenyl) -phenylmethanone, F 181-182 °.

Example 5 *

20 g (0.102 mol) of (2-methylphenyl) -phenylmethanone v / earth submitted with 10 ml of sulfuryl chloride in 50 ml of carbon tetrachloride. The mixture is heated with stirring to reflux and within one hour, 3 | 0 g of benzoyl peroxide dissolved in 25 ml of carbon tetrachloride, added dropwise. The mixture is then heated under reflux for 1 hour.

After cooling, 10 'g of potassium hydroxide dissolved in 25 ml of water are added, followed by the addition of 12.5 ml of methylaminoethanol. The mixture is heated at 50 to 60 ° for 7 hours. The work-up is carried out as in Example 1.

- u - L LD O DZ ./

Ausbeate on / * 2 - "iT (2-aydroxyätliyl ^) - K-BIetliyl-aminomethyl ^ yl" / 7 * snylraethiänon "P ^ yl ^len" 7 '° P ⁿ ~ liydrocnlorid is 17.0 g £ $ 56 of the theory calculated on - (2-methylphenyl) <phenylmethanone »

Analogously as described in Example 3, the following compounds of general formula I were obtained:

Example for the reaction product obtained with II (R ^ f of the general E ₂ - H) use "formula I (as dete Aminkom hydrochloride) component

Yield / mp.

Methyl-

- CH,

diethanolamine

2 ~ Be nz y 1 amino ethanol

70 io

208-213 ° C (from isopropanol)

CH ₂ - CH ₂ --OH 58 io - N. 182 j 5 - 184 ⁰ C

CH ₂ - CH ₂ - OH (from ethanol)

CH,

- / Λ

CH ₂ --OH

65 io.

83-102 ° C (from water) The product crystallizes with 1 mol of water of crystallization

The temperatures were all in ⁰ C.

Claims (6)

Invention claim: 1 · Process for the preparation of substituted (aminomethyl) -phenyl-7-phenylmethanones of the general formula wherein IL is a hydrogen or halogen atom, R _{2 is} a hydrogen or halogen atom or a nitro group, IU is a lower alkyl, hydroxyalkyl, aralkyl or cycloalkyl radical and R 1 is a hydroxyalkyl or lower alkyl radical or R 1 and R ₂ together with the N Atom to which they are attached, a heterocyclic. see ring, ζ. Be the piperidine, methylpiperazine, Hydroxyäthylpiperazin- or morpholine, mean, characterized in that a (2-methylphenyl) · phenylmethanone the general formula II wherein IL and Rp are as defined above, halogenated in an inert organic solvent and in the presence of a radical generator with a halogenating agent and the resulting compound of the general formula - Shark III wherein IL and Rp have the abovementioned meaning and Hai represents a halogen atom, - with an amine of the general formula IV R wherein R-, and R ^ have the abovementioned meaning, aminated. 2.A method according to item 1, characterized in that benzene, chloroform or carbon tetrachloride is used as the inert organic solvent » 3.The method according to items 1 and 2, characterized in that used as the halogenating agent is bromine or sulfuryl chloride , ₁₇ . , 22 93 5 2 7 4-. Method according to points 1 to 3, characterized in that peroxides are used as the Kadikai image-forming agent « 5. Process according to items 1 to 4, characterized in that benzoyl peroxide or diisopropyl peroxide dicarbonate are used as peroxides Process according to items 1 to 5, characterized in that the radical generator is used in amounts of from 0.01 to 0.05 mol per mole of compound of the general formula II used. 7 · Method according to points 1 to 6, characterized in that. that the reaction is carried out at temperatures between room temperature and the boiling point of the reaction mixture. Process according to "Points 1 to 7", characterized in that per mole of the compound of general formula III used, at least 1 mol, preferably 1 to 1.3 mol, of amine of general formula IV and at least 1 mol, preferably 1 to 1.5 mol , an acid acceptor. 9. The method according to points 1 to 8, characterized in that is used as Säureacceptor alkali or an alkali carbonate solution. 10. The method according to items 1 to 7, characterized in that per mole of the compound of the general formula III at least 2 moles of amine of the general formula IV are used. 11 * Procedure according to points 1 to 10, characterized. characterized in that the compounds of general formula I are isolated as acid addition salts.