DE2328972A1 - N-alkyl-benzoyl aminobenzylamines - by direct alkylation antitussives - Google Patents

Abstract

Title cpds. of formula (I): (where R1 = 1-3C alkyl; R2 = PriNH or morpholino and X = Cl or Br); are prepd. by alkylating analogues where R1 = H, with HCO2H-HCHO (for R1 = Me) or with R1Z/base, where Z = Cl, Br, I, or SO3R3, where R3 is pref. Me or 4-methylphenyl. (I) and its salts are known antitussives.

Description

Case 5/597 Dr. Fl./Kp/

DR.KARL THOMAE GMEH., BIBERACH AN DER RISS

New method for the production of 2 - A cy lami no- ben ?, Y I r. r ι '\ η e η

British patent 1 98140 describes, inter alia, P-acylamine-bensylamine of the general formula I,

Hal Tl | V - ^ CH ₂ - CO - R _{2 (I)}

in the

Shark a chlorine or bromine atom, R is a lower alkyl radical with 1 to 3 carbon atoms and

R denotes the morpholino or isopropylamino radical, their physiologically tolerable salts with inorganic and organic acids and processes for their preparation.

The compounds of the above general formula I have valuable pharmacological properties, in particular antitussive and breath-stimulating effects. Surprisingly it was now

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found that the compounds of the above general formula I can also be prepared by the following process:

Implementation of a compound of the general formula ITj

^ H

CIL,
Hal _JT 7Γ ^ ™ _"Coe ._ K _{2 (ΙΪ}}

MtT Γ '

KH - CO

in the

R and Kai are as defined at the outset, riding a compound of the general formula III,

R ₁ -X (III)

in the

R is as defined at the outset and

X is a chlorine, bromine or iodine atom or a radical of the formula -0-SOpR ,, where R., expediently represents the methyl or M-methylphenyl group.

The reaction is preferably carried out in an inert solvent such as acetone, methanol, dioxane or tetrahydrofuran, optionally in the presence of a base such as sodium hydroxide, potassium hydroxide or potassium tert. butoxide, expediently carried out at temperatures between 0 ° C and the boiling point of the solvent used, for example at temperatures between 20 and 80 ° C.

Methylation can also be carried out by heating, for example to temperatures between 80 and 100 ° C, with formaldehyde and formic acid .

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leads to be.

The process of the present application could not have been foreseen since it is known from the literature that a uniform reaction product is not obtained in the alkylation of amines. For example, in the alkylation of secondary aninones using an excess of the corresponding alkylating agent, a mixture of the corresponding tertiary amine and the corresponding quaternary ammonium compound is always obtained (see, for example, Fieser and Fieser in Organic Chemistry. Page 229, Verlag Reinhold Publishing Corporation 1956 and Houben-V.'eyl V \ _ / l , page 2'O. When o-acylaniino-benzylamines are heated with acids, normally 3, ⁱ <-dihydro-chiriazolines are obtained and when reacting with formaldehyde 1, 2, 3, ^ - Tetrahydro-chir.uzoli ne (ε-iehe for example A. V / eisseriberger in Chemistry of Heterocyclic Compounds 2j [/ I,. Pages 395 and MO] (1967)),

The compounds of general formula 1 obtained can, if desired then converted into their physiologically compatible salts with inorganic or organic acids. The acids here have proven to be hydrochloric acid> Hrov-A.-asteroic acid, Sulfuric acid, phosphoric acid, lactic acid, citric acid or maleic acid proved suitable.

The compounds used as starting materials of the general Formula II is obtained, for example, by reacting the corresponding benzyl halide with the corresponding glycine derivative (see e.g. British patent 1 098 1 * JO).

The following examples are intended to explain the invention in more detail:

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BATHROOM QRiGiMAL

example 1

2-Benzoylamino-6-chloro-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine

0.42 g (0.001 mol) of 2-benzoylamino-6-chloro-N- (morpholino-carbonylmethyl) -benzylamine hydrochloride and 0.11 g (0.002 mol) of potassium hydroxide are dissolved in 20 ml of acetone and 0.28 g at room temperature (0.002 mol) methyl iodide added. The reaction mixture is left to stand for 15 hours at room temperature, then the precipitated salts are filtered off with suction and washed with acetone. The acetone solution is evaporated, the evaporation residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. After crystallization from ether, the residue yields 0.25 g (62.2 % of theory) of 2-benzoylamino-6-chloro-N-methyl-N- (morpholino-carbonyl-! 7iethyl) -benzylamine with a melting point of 122.5-123 ° C.

Example 2

2-Benzoylamino-6-chloro-N-isopropyl-N- (morpholino-carbonyl-methyl) -benzylamine

Melting point: 125-127 ° C

Made from 2-benzoylamino-6-chloro-N- (morpholino-carbonyltnethyU-benzylamine hydrochloride, Isopropyl iodide and potassium hydroxide analogous to Example 1.

Example 3

2-Benzoylamino-4-chloro-N-methyl-N- (isopropylamino-carbonyl-methyl) benzylamine

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Melting point of the hydrochloride: 189-193 ° C (decomp.). Made from 2-benzoylamino-4-chloro-N- (isopropy1amino-carbonylmethyl) -benzylamine, Methyl iodide and potassium hydroxide as in Example 1.

example

2-Benzoylamino-6-chloro-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine

2.12 g (0.0055 mol) of 2-benzoylamino-6-chloro-N- (morpholino-carbonylmethyl-benzylamine (melting point: 16-163 ° C), 5 ml (0.012 mol) of 98% formic acid and 0.55 ml (0.0055 mol) of 30% strength aqueous formaldehyde solution are heated on the steam bath for 6 hours, brought to dryness in vacuo, the residue dissolved in water and evaporated again with 2N ammonia to pH 9 and the precipitated oil is extracted with ethyl acetate. The organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized with ether, filtered off with suction and washed with ether. 1> 50 g ( 67 % of theory) of the abovementioned compound with a melting point of 122.5-123 ° C.

Example 5

2-Benzoylamino-6-chloro-N-methyl-N- (morpholino-carbonyl-methyl) -benzylamine

1.25 g (0.0032 moles) of 2-benzoylamino-6-chloro-N- (morpholino-carbonylmethyl-benzylamine (Melting point: 160-163 ° C.) and 0.6 g (0.00322 mol) of methyl p-toluenesulfonate are dissolved in 30 ml of methanol 6 Boiled under reflux for hours. After evaporation of the methanol in vacuo, the residue is taken up in ethyl acetate, and the resulting Solution is washed with water and 2N ammonia. The dried solution (magnesium sulfate) is brought to dryness in a vacuum.

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narrowed. The remaining residue is purified by chromatography on a silica gel column with ethyl acetate. The desired fractions are concentrated in vacuo and the oil obtained is crystallized with ether. 0.42 g (31 % of theory) of the abovementioned substance with a melting point of 122.5-123 ° C. is obtained.

example 6th

2-Benzoylamino-6-bromo-N-methyl-N- (morpholine-carbonyl-methyl) -benzylamine

Melting point: 159-161 ° C.

Made from 2-benzoylamino-6-bromo-N- (morpholino-carbonylmethyD-benzylamine and formaldehyde / formic acid analogous to the example

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Claims (5)

Claims New process for the preparation of 2-acylamino-benzylamines of the general formula I, - ', * Kai Κ. CH ₂ - N KH - CO -CH ₂ - CO (D in the Shark a chlorine or bromine atom, R. a lower alkyl radical with 1 to 3 carbon atoms and Rp denotes the morpholino or isopropylamino radical, as well as their physiologically compatible salts with inorganic or organic acids, characterized in that a compound of the general formula II, Hal CIL - N - CO - (II) NH-CO 409881/1251 originally inspected in the Rp and Hal are as defined at the outset, with a connection of the general formula IIIι R ₁ -X (IH) in the R as defined at the beginning, X is a chlorine, bromine or iodine atom or a radical of the formula -0-50 R, where R, expediently the methyl or Ί-methylphenyl group represents, means, is optionally reacted in the presence of a base and, if desired, one obtained Compound of general formula I converted into its physiologically acceptable salt of an inorganic or organic acid will. 2. The method p.t'ir-'iß claim 1, characterized in that the reaction is carried out in a solvent and at temperatures between 0 ⁰ C and the boiling point de :: solvent used v / ird. 3. The method according to claim 1 and 2, characterized in that in the reaction as the base sodium hydroxide, potassium hydroxide or potassium tert-butoxide is used. Ί. Method according to claim 1 and 2, characterized in that methylation is carried out by heating with formaldehyde and formic acid. 5. The method of claim Ί, characterized in that the reaction is carried out at temperatures between 80 and 100 ⁰ C. BATH 409881/1251