DD287032A5 - PROCESS FOR PREPARING 3-CARBAMOYL-4-ARYL-1,2-DI-HYDRO-ISOCHINOLIN-1H-ONEN - Google Patents

Abstract

The invention relates to a process for the preparation of * the general formula I by cyclocondensation of * to * and saponification of the ring-closed nitriles. Such compounds have an anticonvulsive effect in the MES test. Formula I {* Cyclocondensation; sodium; * Saponification; *}

Description

wherein R ¹ , R ² and R ^{3 have} the abovementioned meaning, are isolated and cyclocondensed to compounds of general formula IV.

3. The method according to claim 1 and 2, characterized in that the hydrogen chloride formed by bases, preferably triethylamine, is neutralized in a preferably aprotic solvent.

4. The method according to claim 1 and 2, characterized in that the cyclization is preferably carried out by alkoxide with the addition of a solvent, preferably alkanol.

5. The method according to claim 1, characterized in that the cyano group is saponified in the presence of alkalis.

6. The method according to claim 1 and 5, characterized in that preferably KOH / isopropanol is used.

Field of application of the invention

The invention relates to a process for the preparation of G-carbamoyl-aryl-i-dihydro-isoquinoline-IH-ones of the general formula I. Such compounds have an anticonvulsant effect in the MES test.

CONH ₂

Characteristic of the known state of the art

Compounds of general formula I are described neither in the patent nor in the chemical literature. F.Duro, N.A.Santagati and F. Vittorio are working in Il Farmaco, Ed. Sc. 36,400 (1981) reported the synthesis of 2-methyl-3-alkoxycarbonyl-4-phenyl-i-dihydro-isoquinoline-IH-one from the corresponding isocoumarin. The accessible from the acid chloride 2-methyl-3- (N-alkylcarbamido) -4-phenyl-1,2-dihydro-isoquinoline-1H-one act locally anesthetics.

Object of the invention

The aim of the invention is to produce such compounds from relatively easily accessible starting materials in a simple manner and with high yields.

Explanation of the essence of the invention

The object of the invention is to find a technically applicable synthesis route for the preparation of 3-carbamoyl-4-aryl-1,2-dihydroisoquinolin-1H-ones of the general formula! According to the invention, the object of preparing the compound of general formula I,

CONH ₂

where R ^{1 is} alkyl, akaryl

R ¹ = H, alkyl, amine, F, Cl, Br and

R '= H, F, Cl, Br, NO, in which aminoacetonitriles of the general formula II

,1

HN --- CN

where R * has the abovementioned meaning and 2-benzoyl-benzoic acid chlorides of the general formula III,

where R ² and R ^{3 have} the abovementioned meaning, and are converted to 3-cyano-4-aryl-1,2-dihydroisoquinolin-1H-ones of the general formula IV,

IV

wherein R ¹ , R ² and R ^{1 have} the abovementioned meaning, are cyclized in the presence of bases and the

Cyanogen group is then saponified. The (N-alkyl-N-cyanomethyl) - (2-benzoyl) -benzamides of the general formula V formed from II and III,

where R ⁽ , R 'and R ^{5 have} the abovementioned meaning, can be isolated and etched by cyclization to IV.

Ausführungsbelsplele

The invention will be explained in more detail below in nine embodiments. 3-carbamoyl-4-aryl-1,2-dihydro-isoquinoline-1H-one

example 1

2-isopropyl-3-carbamoyl-4-phenyl-1,2-dihydru-isoquinolin-1H-one I;

R ¹ = CH (CHj) ₁ , R ¹ = R ³ = H

16 g (55 mmol) 2-isopropyl-3-cyano-4-phenyl-1,2-dihydro-isoquinolin-1H-one (IV; R ¹ = CH (CHj), R ² = R ³ H), 9, 5g (27OmMoI)

KOH, 5ml H] O and 160ml isopropanol are 2h. heated to reflux. After cooling, 500 ml H ₂ O are added and

the solid is sucked off. I6.2g (96%) I is obtained. The compound melts at 219-22TC.

Example 2

2 · ΐ5ορΓορνΙ · 3 · € 3Γ03ηιονΙ · (4 · (4-ίΙυοΓρΙιβηνΙ)) - 1 ₁ 2- (ϋΙιναΓθ-ΐ5 (κ: ΜΙηοΜη-1Η-οη I; R ¹ = CH (CH ₃ ) ,, R ² = 4-F, R ³ = H

The procedure is as in Example I ₁ From 30.7 g (0.1 mol) of 2-isopropyl-3-cyano- (4- (4-fluorophenyl)) - 1,2-dihydro-isoquinolin-1H-one (IV; R ¹ = CH (CH ₃ I ₂ , R ² = 4-F, R ³ = H),

will receive 30g (92%) I. The compound melts at 209-210 ⁰ C.

Example 3

2-Benzyl-3-carbamoyl-4-phenyl-1,2-dihydro-isoquinolin-1H-one I; R ¹ = benzyl, R ² = R ³ = H

The procedure is as in Example 1. From 35.5 g (0.1 mole of 2-benzyl-3-cyano-4-phenyl-1,2-dihydro-isoquinolin-1H-one (IV; R ¹ = benzyl, R ² = R ³ = H), 33 g (88.5%) of I are obtained. The compound melts at 235 ⁰ C.

3-Cyano-4-aryl-1,2-dihydro-isoquinoline-1H-one

Example 4

2-isopropyl-3-cyano-4-phenyl-1,2-dihydroisoquinolin-1H-one IV; R ¹ = CH (CH ₃ ) ,, R ¹ = R ² = H In the 1 liter three-necked flask equipped with stirrer and reflux condenser, add 90.4 g (0.4 mol) of 2-benzoylbenzoic acid (III; R ² = R ³ = H) with 150 ml SOCI, and 0.5 hr. at room temperature and 1 h. stirred at a bath temperature of 50 ° C. The excess SOCI, is distilled off under a slight vacuum, the residue taken up in 24OmI CH ₂ CI ₂ and 39.2 g (0,4MoI) N-isopropyl-aminoacetonitrile (II; R '= CH (CH _3), and 44,4g ( 0.41 mol) Triethylamine, dissolved in 160 ml of CH ₂ Cl ₂ , is added dropwise at room temperature, followed by refluxing for 2 hours After cooling, 200 ml of water are stirred in and the phases are separated. The solvent is distilled off, the residue is taken up in 800 ml of CH ₃ OH, 22 g (0.4 mol) of NaOCH _{3 are} added and the mixture is refluxed for 1 hour, after cooling with 800 ml of H ₂ O. diluted, and the solid collected and recrystallized from isopropanol. There are obtained 51,8g (45%) IV. the compound melts at 172-173 ⁰ C.

Example 5

2-isopropyl-3-cyano- (4- (4-fluorophenol; vl)) - 1,2-dihydro-isoquinolin-1H-one IV; R ¹ = CH (CH ₃ I ₂ , R ² = 4-F, R ³ = H

The procedure is as in Example 4. From 97.6 g (0.4 mol) of 2- (4-fluorobenzoyl) benzoic acid (III, R ² = 4-F, R ³ = H) and 39.2 g (0.4 mol) of N-isopropyl-aminoacetonitrile (! !; R '= CH (CHj) ₂ ), 62.4 g (51%) of IV are obtained. The compound melts at 179-18O ⁰ C. Example 6

2-Benzyl-3-cyano-4-phenyl-1,2-dihydroisoquinolin-1H-one IV; R ¹ = benzyl, R ² = R '= H

In a 2-L one-necked flask, 142 g (0.4 mol) of (N-benzyl-N-cyanomethyl) - (2-benzoyl) -benzamide (V; R ¹ = benzyl, R '= R ³ β H) and 22 g (0.4 mol) of sodium methylate in 800 ml of methanol under reflux for one hour. After a cooling is

the product was precipitated with 800 ml of water, filtered off, dried and recrystallized from isopropanol. There are 97g (72%) I received. The compound melts at 196-198 ° C.

Example 7

2-isopropyl-3-cyano-4-phenyl-6-chloro-1,2-dihydro-isoquinolin-1H-one IV; R '= CH (CH ₃ I ₂ , R ² = H, R ³ = 6-CI

The procedure is as in Example 1. Aus66g (0.4 mol) (N-cyanomethyl-N-isopropyl) - (2-benzoyl) -4-chloroben ^ amidlV; R ¹ = CH (CH ₃ ) ,, R ² = H, R ³ = 4-Cl) be 81g

(63%) I received. The compound melts at 209-210 ⁰ C.

(N-cyanomethyl-N-alkyl) - (2-benzoyl) benzamide

Example 8

(N-cyanomethyl-N-isopropyl) - (2-benzoyl) -benzamide V; R ¹ = CH (CHj) ₂ , R ² = R ³ = H

In the 1 l three-necked flask equipped with stirrer and reflux condenser, 90.4 g (0.4 mol) of 2-benzoylbenzoic acid (III, R '"fl' = H]

with 150ml thionyl chloride and 0.5Sld. at room temperature and 1 hr. At a bath temperature of 50 ⁰ C stirred. The excess thionyl chloride is distilled off under slight vacuum, the residue taken up in 240 ml of methylene chloride and 39.2 g (0.4 mol) of N-isopropyl-aminoacetcnitrile (II; R ¹ -CH (CH ₃ ),) and 44.4 g (0.44 mol ) Triethylamine, dissolved in 160ml

Methylene chloride, added dropwise at room temperature. The mixture is then refluxed for 2 hours. After cooling, be

200ml of water eingei 'irt and the phases separated. The organic phase is successively with 100ml Verd. HCI, NaHCO ₃ -LSg.

washed with water and washed with CaCl 2. The solvent is distilled off and the residue taken up in 250 ml of methanol. After some time, V crystallizes out. It will receive 75.5g (62%). The compound melts at 104-106'C.

Example 9

(N-cyanomethyl-N-isopropyl) - (2- (4-bromobenzoyl)) - benzamide V; P. '' = CH (CH ₃ ) ,, R ² = 4-bromo, R ³ = H

The procedure is as in Example 8. From 122 g (0.4 mol) 2- (4-bromobenzoyl) benzoic acid (III, R ² = 4-Br, R ³ = H) and 44.4 g (0.4 mol) N-isopropyl-aminoacetonitrile (II; R ¹ = CH (CH ₃ ),), 95 g (62%) of I are obtained. The compound melts at 204-206 ⁰ C.

Claims (2)

Claim: 1. Process for the preparation of 3-carbamoyl-4-aryl-1,2-dihydro-isoquinoline-1H-ones of the general formula I, CONH ₂ where R ¹ = alkyl, alkaryl R ² = H.Alkyl.Amin, F, Cl, Br and R ³ = H, F, Cl, Br, NO ₂
, characterized in that substituted amino-lactonitriles of the general formula II, where R ^{1 has} the abovementioned meaning and 2-benzoyl-benzoic acid chlorides of the general formula III, COCI where R ^? and R ^{3 have} the abovementioned meaning, to 3-cyano-4-aryl-1,2-dihydroisoquinoline-1 H-onen of the general formula IV, R ¹ IV wherein R ¹ , R ² and R ^{3 have} the abovementioned meaning, are cyclized in the presence of bases and the cyano group is p.iischließend saponified. 2. The method according to claim Ί, characterized in that formed from II and III as intermediates (N-alkyl-N-cyanomethyl) - (2-benzoyl) -benzamide of the general formula V,