DD204917A1 - METHOD FOR PRODUCING PHENYL SUBSTITUTED AND BENZ-CONDENSED CYCLOALKYLAMINOACETANILIDES - Google Patents

Abstract

The invention relates to a novel process for the preparation of cycloalkylaminoacetanilides which are useful as potential intermediates for the preparation of biologically active preparations. The process allows a simple synthesis of the specified compounds in very good yields, wherein the economic use of the cyclic secondary amines, which are only required as reactants, whereas the acid acceptors used as recoverable Hils bases, is to be particularly emphasized.

Description

Title of invention:

Process for the preparation of plieny! Substituted and benzene-fused cycloalkylaminoacetanilides *

The invention relates to a novel process for the preparation of phenyl-substituted and benzo-fused cycloalkylaminoacetanilides, which are useful as potential intermediates for the preparation of biologically active preparations.

Characteristic of the known methods;

For the preparation of cyeloalkylaminoacetanilides of the formula I, two methods have hitherto become known,

R ¹ -EB-CO-CH-R ³

namely a two-stage synthesis or the preparation in a one-pot process.

In the two-step syntheses, a substituted aniline is reacted with a t-halocarboxylic acid halide in the first stage using various acid scavengers, and the haloacylanilide is isolated, the further reaction with a secondary cyclic amine giving a compound of formula 1. According to this method, N. LOS ¹ GRBIi, Arkiv Kemi Min. Geol. 22A, .H: o 18 (1946), LS POSDICZ and GW RAPP, J. Am. Chem. Soc. 65> (1943) 2.307, S. GUPTA, MK SHAH and E. TS. GAIID, J. Indian Chem, Soc., 3 (1954) 845, R FRAME and A. BARTH, Biochem. Physiol. Plants 163 (1972) 257, Γ. ' HAMADA, M. STJGIURA and ϊ. SUZUKI,

c7 ^J , o

Li

Λ ^ f / f

&*> ύ UHC

- ² -

97 (10) (1977) 1137 and F, HEYMMS, L, LeTHEBIZIlH, J.-J. GOOS ¹ ROIDJ Journal Med. Chem. 23 (1980) 134 Various cycloalkylaminoacetanilides of the formula I prepared "The reaction of the Halogenacylanilids carried out with a double or triple molar excess of secondary amine.

The one-pot procedure allows the synthesis of acylaminoheterocycles of formula II without isolation of the haloacylaminoheterocycles «

B cyol. Amin

E '= H, alkyl radical

G. EEIVIPTEE, W. EHBLICHMAM, S. SCHULDES, J. SCHWIEGEE, A. BAETH and A. JUMAB, DDE-Wirtschaftspatent C 07 D / 219 052 synthesize acylaminoheterocycles, in their acyl group in the above-mentioned position a hydrogen atom through a secondary cyclic base is substituted by an aminoheterocycle with a c6-Halogencarbon ~ acid halide and then brought to Beafetion with 3 moles of the secondary cyclic amine. In a variant of the method is formed in the reaction of the oc-Halogencarbonsäurehalogenids with the heterocyclic amine hydrogen halide. Addition of an auxiliary base bound as a salt, the salt removed from the Beaiction, then continued with 2 moles of secondary cyclic amine synthesis and a compound of formula II isolated.

With regard to the Cycloallvylaminoacetanilide mentioned in the title:

- The shortcomings of the two-stage procedure are not applicable in this case «

- Our yields are higher than in the single-step process «

R Λ S η 6 " ³ "

U Μ · ^ ^ ^w

- The uneconomically high consumption of cyclic secondary amines is avoided; the auxiliary bases used are quantitatively recovered »

Object of the invention:

The aim of the invention is a process for the synthesis of pheny! Substituted and benzocondensed cycloalkylaminoacetanilides of the formula III from haloacylanilide and secondary cyclic amine tonter use of auxiliary bases in very good yields.

Aryl-NH-CO-CH-R *

1 III

cycl. lake. Amin

Explanation of the essence of the invention:

The invention relates to a process for the preparation of Cycloalkylaminoacetaniliden of formula III, which are applicable as potential intermediates for the preparation of biologically active preparations. In formula III, the following groups are for aryl: the biphen-3-yl and the haphth-2-yl group _f H ^{1 is} hydrogen or the methyl radical. Cyclic secondary amine in formula III denotes the pyrrolidin-1-yl, piperid-1-yl, hexamethylenimine, morpholin-4-yl, piperazine-1,4-yl-y T, 2,3,4-tetrahydroquinoline -1-yl, 1 ^^^ - tetra-dihydro-iso-chloro-L-1 -yl, 2,3-dihydro-indol-1-yl-rest.

It has been found that haloacylanilides of general formula IV in which R ^! and aryl for the corresponding ones

Aryl-NH-CO-CH-R '

IV

Residues5 are as indicated in formula j11, and

< h h η ^κ Π ζ OUH ν + j U - 4 -

and J = chlorine or bromine, with secondary cyclic amines in a solvent like benzene? Toluene _s tetrahydrofuran ", DiO2: on _? Chloroform and acetone using the auxiliary bases triethylamine or 1,4-diazabicyclo [2 * 2j2joctan (triethylenediamine) for 3-6 hours in boiling solvent to give the title compounds in good yields, the resulting hydrogen halide by the auxiliary bases triethylamine or 1,4- Diazabicyclo [2 "2" 2] octane as a salt bound and can be easily removed from the reaction mixture.

The salts of the abovementioned auxiliary bases permit, in contrast to those of the cyclic secondary amines, the quantitative recovery of the auxiliary bases themselves and thus make possible a very economical process. "

The Halogenacylanilide required as starting materials were obtained according to the already cited information.

Ausfülirung_sbeispj.elg ^:

Example 1:

4-phenyl-piperid-1-yl-acet-m-phenylanilide

To o, o2 mol of chloroacetyl-m-phenyl-anilide in 100 ml of dry benzene are added 0.02 mol of 4-phenyl-piperidine and 0.02 mol of triethylamine. »It is refluxed for 5 hours under reflux. The precipitated triethylammonium chloride is filtered off, the benzene phase is washed with water and dried. The PiItrat is in vacuo from. Solvent was removed and the residue was recrystallized from n-hexane.

Melting point: 70-74 ⁰ C. Yield: 94 ^ of

theory

< η £ λ γ ^λ 1 U

Example 2: 4-phenyl-piperid-1-yl-acet-naphthylamide

Chloroacetyl-1-naphthylamide is refluxed in 100 ml of dry benzene with 0.02 mol of 4-phenyl-piperidine and 0.02 mol of triethylamine for β hours. The precipitated hydrochloride is separated, the benzene phase is washed with water and dried. The solvent is removed in vacuo and the residue from n-heptane. recrystallized

Melting point 109-110 ⁰ C Yield: 94 $ of theory

Example 3 '

2- (4-Phenyl-piperid ~ 1-yl) -propionic acid m-phenyl-anilide

0j02 mol ö6-bromopropionyl-m-phenyl-anilide are refluxed in 100 ml of dry toluene with 0.02 mol of 4-phenyl-piperidine and 0.02 mol of triethylamine for 4 hours »The precipitated E; / drobromid is filtered off with suction, the solvent removed in a vacuum. The residue is recrystallized from n-heptane

 Melting point: 101-105 ° C Yield: $ 90 of theory

Example 4: 2- (4-Phenyl-piperid-1-yl) -propionic acid _/ 2 _"na p} ithylaiaid 0.02 mol U- bromopropionyl - ^ - naphthylamide be in 100 mL dry benzene with 0.02 mole of 4- Phenyl-piperidine and 0.01 mol of 1 _? 4 ~ Diazabicoclo £ 2 _e 2,2joctane heated at reflux for 5 hours. "The resulting hydrobromide is removed. The filtrate is washed with water, dried and freed from the solvent in vacuo. The residue is recrystallized from n-heptane, "Melting point: 78-82 ⁰ C. Yield: 95 $ of theory

Example 5 σ Eyrrolidin-i-yl-aeet-m-phenyl-anilide

0.02 mol of chloroacetyl-m-phenylanilide are refluxed in 100 ml of dry benzene with 0.02 mol of pyrrolidine and 0.02 mol of triethylamine for 6 hours. The hydrochloride is filtered off with suction. The filtrate is washed with water and dried. The solvent is distilled off in vacuo »The residue is recrystallized from gasoline 60/85, melting point: 88-91 ⁰ C yield; SOfo of the theory

Example 6:

2- (pyrrolidin-1-yl) -propionic acid m-phenyl ~ anilide

0.02 mol of e ^ -bromopropionyl-m-phenyl-anilide and 0.02 mol of pyrrolidine are refluxed in 100 ml of tetrahydrofuran with 0.02 mol of triethylamine for 6 hours. The hydrobromide is filtered off. The filtrate is freed from the solvent in vacuo. The residue is recrystallized from petroleum ether 30/50. Melting point: 35-39 C Yield: -95 $ of theory

Example 7:

1,2,3 '4-tetrahydro-isoquinol-2-yl ~ acet-m-phenyl-anilide

To 0.02 mol of chlorooroethyl-m-phenylanilide in 100 ml of dry benzene are added 0.02 mol of 1,2,3,4-tetrahydroisoquinoline and 0.01 mol of 1,4-diazabicyclo-2,2,22-octane. The mixture is heated for 5 hours at reflux * The precipitated hydrochloride is filtered off. The solvent is removed in vacuo. The residue is recrystallized from n-heptane

Melting point: 99-101 ⁰ C Yield: 90 $ of theory

_ν ) U '-j

Example 8:

Indolin-1-yl-acet-ni-phenyl-anilide

0.02 mol of chloroacetyl-m-phenyl-anilide are heated with 0.02 mol of indoline and 0.02 mol of triethylamine in 100 ml of dry benzene for β hours in a Pöickfluß. The precipitated triethylammonium chloride is filtered off, the benzene phase is washed with water and dried. The filtrate is concentrated to dryness in vacuo and recrystallized from n-heptane

Melting point: 116-120 ⁰ C Yield: 89 $ of theory

Example 9:

2 ~ (indolin-1-YLJ-propionic acid-in-phenyl-anilide

To 0.02 mol of (X-bromopropionyl-m-phenylanilide in 100 ml of dry toluene, 0.02 mol of indoline and 0.02 mol of triethylamine are added, the reaction mixture is refluxed for 4 hours, and after filtering off the hydrobromide, the reaction mixture is filtered Distilled solvent in vacuo and the residue recrystallized from n-heptane Melting point: 68-72 ⁰ C Yield: 82 $ of theory

In an analogous V / else the Halogencarbonsäureanilide with secondary cyclic amines using triethylamine and 1,4-diazabicyclo [2 are _t 2 _t 2j by reacting octane obtain the following additional compounds:

1,2,3j4-tetrahydro-quinol-1-yl-acet-m-phenyl-anilide mp: 52-59 ⁰ C (from petrol 60/85) Yield: 90 $ of theory

2- {1,2,3s> 4-Tetrahydro-quinol-1-yl) -propionic acid-m-phenyl-anilide

Melting point: 99-104 ⁰ C (from n-heptane) goal for ': $ 85' of theory

O " ⁸ "

, 2, 3,4-tetra-iso-isoquinol-2-yl) -propionic-m =

, Melting point 153-155 ° C (from ethanol) Yield: $ 80 of theory

Piperid-1-yl-acet-m-phenyl-anilide Melting point: 79-82 ° C (from gasoline 60/85) Yield: 93 $ of theory

Hydrochloride of hexamethyleneimino-acetyl-m-phenylanilide

The reaction was carried out according to Example 1. The reaction product was taken up in ether and hydrogen chloride introduced. The hydrochloride precipitated as a white salt.

Melting point: 158-161 ⁰ C (from ethanol) yield: 82 $ of theory

Morpholin-4-yl-acet-m-phenyl-anilide Melting point: 58-61 C (from n-hexane) Yield: 81 $ of theory

Piperazine-1,4-di-yl (acet-m-phenyl-anilide) Melting point: 195-201 ⁰ C (from ethanol) yield: 83 $ of theory

2- (Piperid-1-yl) -propionic acid m-phenyl-anilide Melting point: 7O-73 ° C (from n-heptane) Yield: $ 95 of theory

oi-hexamethyleneimino-propionyl-m-phenyl-anilide mp: 55-58 ⁰ C (from petroleum ether 30/50) Yield: 88 $ of theory

2- (morpholin-4-yl) -prop ionsäure-m-phenyl-anilide mp: 74-76 ⁰ C (from petroleum ether 30/50) Yield: 95 $ of theory

2- (piperazin-1,4-yl) -di (proρionsäure-m-phenyl-anilide) Melting point: 199-201 ⁰ C (from ethanol) yield: 80 $ of theory

1,2,3,4-Tetrahydro-quinol-1-yl-aceto-naphthylamine Melting point: 149-152 ° C (from n-heptane) yield: $ 95 of theory

1,2,3,4-tetrahydroisoquinol-2-yl-aceto-naphthylamide Melting point: 129 ~ 134 ° C (from ethanol) Yield; $ 90 theory

Indolin-i-yl-acet-1-naphthylamide Melting point: 154-158 ⁰ G (from ethanol) Yield: 85 ^ of theory

2- (i, 2,3,4-tetrahydro-quinol-1-yl) -propionic acid-naphthylamide

Sehmelzpuiilrfc: 1O6-1O9 ° C (from n-heptane) Yield: 87 ^ of theory

2 ~ (1, 2, 3, 4-tetrahydro-isoc-nol-2-.yl) -propionic acid- _y -naphthylamine

Melting point: 78-81 ⁰ C (from petrol 60/85) Yield: 81 $ of theory

2- (indolin-1-yl) propionic acid - ^ - naphthylainid Schmelzpunlrt: 118-120 ⁰ C (from ethanol) yield: 92 $ of theory

2- (pyrrolidin-1-yl) -propionic acid / naphthylamide; 70-72 ⁰ C. (from n-heptane) yield; $ 80 of theory

2- (piperid-1-yl) propionic acid-A-naphthylamide Melting point: 92-94 ⁰ C (from n-heptane) Yield: 82 $ of theory

o & -Hexamethyleniminopropionyl-j3-naphthylamide Melting point: 41-45 ⁰ G (from n-heptane) Yield: 90 $ of theory

2- (morpholin-4-yl) propionic acid - ^ - naphthylamide Melting point: 98-101 ⁰ C (from n-hexane) Yield: $ 83rd the theory

2- (piperazin-1,4-yl) -di (propionic acid naphthylamide) Melting point: 229-239 ° C (from ethylene glycol) Yield: $ 81 of theory

Claims (4)

Addressed by: 1) A process for the preparation of cycloalkylaminoacetanilides, characterized in that halogenoylanilides of the formula IY ₇ in which R '= H or the methyl radical ₃ X = chlorine or bromine "and aryl for the biphen-3-yl or iTaphth ~ 2 yl-rest stands, with secondary cyclic amines to compounds of the Pormel III, in which for cycliseiies secundares YcL he pyrrolidin-1-yl, piperid-1-yl, hexamethylene imino «, morpholin-4-yl, piperazine-1,4-yl-? 1,2,3,4-tetrahydro-quinol-i-yl, 1,2,3,4-tetrahydrosoquinol-2-yl, 2,3-dihydro-indol-i-yl and 4-bienylpiperide-1 -yl residue, react using auxiliary bases. 2) Process according to item 1, characterized in that for the reaction the auxiliary bases triethylamine and 1,4-diazabicyclo [2.2.2] octane are used, which are recovered quantitatively, 3) Process according to item 1 and 2 _S characterized in that the reaction is carried out in an inert solvent such as benzene, toluene, tetrahydrofuran, dioxane, chloroform and acetone in the heated. 4) Process according to Ptmkt 1-3, characterized in that molar amounts of Halogenacylaniliden and cyclic secondary amines are used in the use of auxiliary bases.