DE2152232A1 - Benzoheterocyclic compounds and their manufacturing process - Google Patents

Description

UGB. S ₀ A ₀

Saint Gilles-lez-Bruxelles / Belgium, 4, Chaussee de Gharleroi

BarEoheterocyclic compounds and their manufacturing process

Priority: October 22, 1970, Great Britain, No. 50 214/70

The invention relates to a process for the preparation of benzoheterocyclic Compounds according to the general formula

(D

where mean:

K ₁ , R ₂ , R ^, R ^ and R ^ hydrogen, an alkyl, hydroxyalkyl,

Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl group, where these alkyl groups

Containing 1 to 4 carbon atoms, one

from
Alkenyl group / Cg-C ^, an aryl or a

Aralkyl group,

R ₆ hydrogen, an alkyl group from Cj-G ,, an alkoxy group from G ₁ -G., Halogen or the trifluoromethyl radical,

and also applies to the connections made in this way »

With regard to the chemical nomenclature, compounds according to the invention are 1,4-Mhydro-i ^ -iitheno-isoquinolin ^ - (2Ii) -ones, which are also b, 6-benzo-2-azabicyclo- (2,2,2) - oct-7-en-J5-ones may be mentioned; ec are new compounds with the exception of g-Hethyl-SO-benzo-g.-eizabicyolo-U ^^ joct ^ -en ^ -on ^and

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BATH ORIGINAL

its methylated derivatives in positions 1, 4, 7 and 8, which already by E.B.SHEININ, G.E. WRIGHT, C.L. AT find L.BAUER, J.Heter.Chem. 5,, (1968), 859, Das For example, the method used by these authors to prepare these compounds consists in the benzyne with a N-methylpyridone, substituted or not, according to the following To have the scheme implemented:

But the yields obtained with this process are only 4 to 13% of the theoretical yield. On the other hand is only possible to obtain N-alkylated derivatives. If you can Reacts benzyne with the 2-pyridone (unsubstituted on the nitrogen), an O-alkylation and an M-alkylation takes place, which lead to the formation of 2-phenoxypyridine or 1-phenyl-2-pyridone to lead.

If, on the other hand, one tries to obtain the compound unsubstituted on the nitrogen, try the corresponding is-benzylated one -derivative to debenzylate, a rearrangement of the occurs Molecule increases to form 1,4-dihydronaphthalene-1-carbobenzylamide (as a result of reduction by the sodium in the ammonia), or of naphthalene-1-earbobenzylamide (as a result of hydrolysis of the hethanesulfonic acid):

CO-WH-CH ₂ Cg H5

JVH ₃

CH ₃ SO ₃ H

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The structures of the products obtained were determined by infrared, ultraviolet spectrometry and learning magnetic resonance certainly.

The invention therefore aims to provide a much more advantageous process in terms of the yields obtained and more general scope, since it enables the synthesis of derivatives of 1,4-dihydro-1,4-etheno-isoquinolin-3- (2H) -one which are or are not substituted on the ötiekstoff. This process consists in reacting, according to a Diels-Alder reaction, an R ^, R ^ -substituted maleic anhydride with an R ₁ ^ »^» Rg-substituted isoquinolin-3-one, the carbonyl groups of the intermediates thus obtained; To hydrolyze compound to two carboxyl groups and to subject the hydrolyzed product to an oxidizing decarboxylation in order to obtain the compounds of JJOrnel (I) according to the invention, in which the symbols R ₁ , R _21, R ₃ , R ₄ , R ₁₅ and ^R 6 have the same meanings as above own:

reaction

COOH oxidizing

Decarboxylation

COOH

The yields of the reaction are in the order of magnitude of 30 to 405 * of the theoretical.

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-A-

It was unpredictable that this oxidative decarboxylation reaction would deliver the product you are looking for. In fact, it is well known that amides and lactams are easily mixed can oxidize.

In analogy with the known processes in the isocyclic series, to the neighboring dicarboxylic acids with the formation of To oxidize olefins, the oxidizing decarboxylation according to the invention can be effected:

a) by means of lead tetraacetate in the presence of pyridine and benzene (GAGROB et al., Helv.Ghim.Acta, A ±, (1958), 1191);

b) by anodic oxidation with electrodes made of polished platinum (P.RADLIGK et al., Tetrahedron Letters, 1968 , 5117? HHWESTBERG and HJDAUBEN, IbJd ₀ 1968 , 5125);

c) by converting the 1,2-dicarboxylic acids into their corresponding acid chlorides, which are then converted into their t-butyl peresters, which in turn are thermally or photochemically decomposed into the corresponding alkenes (EN-GAIN et al., Ohem. Commun. 1969 , 98) .

If R ^ is hydrogen, the compound according to the invention can be alkylated on the nitrogen atom by customary methods. However, it is preferred to accomplish the alkylation in a non-polar medium such as xylene. If, for example, Heth ^ yljodid with a sodium derivative of 1,4-dihydro-1 _T 4-ethene-p-isoquinolin- (2H.) - one (obtained by the action of sodium hydride) in dimethylformamide, one observes a decomposition and a The molecule is aromatized to form haphthalene.

The compounds prepared according to the invention show activities on the central nervous system.

The following examples illustrate the invention without illustrating it restrict.

example 1

The mixture is heated to reflux for 90 minutes and in a nitrogen atmosphere a mixture of 10 g (0.690 mol) 3-hydroxy

Γ "haπ"

Y * P * Τ? Ητηη ττη-η Τοηοίτί ππ1 λ -r \ ¹ X ( OT

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INSPECTED

70 ml of benzene, 14 g (0.1428 mol) of maleic anhydride and 7 ml of dimethylformamide (as an auxiliary solvent) to obtain the corresponding Diels-Alder addition product, that is the anhydride of 5,6-benzo-2-azabicyclo- (2 , 2,2) ockn-3-one-7,8-dicarboxylic acid, in the form of. Crystals, which are filtered off and washed with ether. Are thus obtained 12 g (yield about 70%) of melting with decomposition "at 296 ⁰ G product.

Analysis for G ₁₅ H ₉ NO ₄ (molecular weight: 243)

Calculated: f ° G 64.2 Found: 64.7 % E 3.71 3.95

# N 5.70 5.72

The mentioned anhydride is then hydrolyzed by dissolving in dimethylformamide and adding water Ms for crystallization ,, The acid thus obtained is characterized by infrared spectrometry and centisimal analysis.

However, it is not necessary to isolate the acid in order to effect the final decarboxylation, and one can work as follows:

10 g (0.041 mol) of the anhydride in suspension (with partial solubilization) in 80 ml of water containing 7.5 g of triethylamine are introduced into a 1000 ml beaker and the pyridine is gradually added until it is completely solubilized to (about 600 ml of pyridine). Then bringing the beaker in a thermostat, which is adjusted to 2O ⁰ G by cooling and bringing to a mechanical agitator to stir the mixture to thoroughly today. Two circular electrodes made of shiny platinum sheet are then attached to the liquid mixture, the anode being 5 cm high and 5 cm in diameter and the cathode 5 cm high and 2.5 cm in diameter. The electrolysis is started with a current of 0.8 amperes and a voltage of 50 to 80 V. After 35 to 50 hours the current drops below 0.2 A.

At this moment the electrolysis is stopped and the solvents are evaporated off under vacuum. You take the back

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■ " * '

got up in 600 ml of benzene, what ent .. him. with acidified water, then with water and then with a / solution of sodium carbonate, finally again with water, dried and evaporated. The residue is then left to crystallize in ethanol.

This gives 2.2 g of the desired product, namely 1,4-dihydro-1,4-ethene-isoquinolin-3 (2H) -one, in one yield from $ 31.2 of theory,

Melting point: 228-229 ° C

Analysis for O ₁₁ HqNO (molecular weight: 171)

Calculated: ^c ß> G 77.2 found: 76.14 % H 5.26 5.30

$ N 8.19 8.13

Example 2

Working as in Example 1, but starting from N-methyl-isoquinolin-3- (2H) -one and maleic anhydride for the purpose of forming the Diels-Alder addition product (MRUE and H. TIEOKEIMANN, Tetrahedron Letters, 1970 , 1209) is obtained by anodic oxidation with a yield of 35% & the N-methyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one, melting point 100-101 ⁰ OEBSHEININ et al. (J.Heterocycl.Chem. ^ , (1968), 859) give a melting point of 98-100 ⁰ O for the same compound.

Analysis for C ₁₂ H ₁₁ NO (molecular weight / 185J

Calculated: $> C 77.84 Found: 76.9 % H 5.94 5.88

% N 7.57 7.30

Example 3

By methylation with methyl iodide of 1,4-dihydro-1,4-äthenisoquinolin-3- (2H) -one, obtained in Example 1, in an alkaline medium, the compound is obtained with a yield of 80% of Example 2, the N-Methy1-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one.

To a warm suspension of 2 g of the 1,4-dihydro-1,4-ethene

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isocMnolin-3- (2H) -oib in 100 ml of troclaiem toluene 0.30 g of sodium hydride is added and the mixture is heated under reflux for 10 minutes.

Kan cools down and adds 3 g of methyl iodide «. One stirs during i 1/4 hour at ordinary temperature, then gradually heated to reflux, which is maintained for 1 hour maintains.

I-ian cools, washes in water and evaporates to dryness. Of the The residue is then recrystallized from ether.

The N-methyl-1,4-dihydro 1,4-ethene-isoquinolin-3- (2H) -one, melting point 100-101 ⁰ G, is obtained with a yield of 80?

In the same way, starting from the compound of Example 1, the following is obtained: N-ethyl-1,4-dihydro-1,4-ethenisoquinolin-3- (2H) -one, Melting point 66-67 ° C.

Analysis for G ₁₅ H ₁₅ NO (molecular weight: 199)

Calculated: $ C 78.4 Found: 78.9 £ H 6.53 6.52

# N 7.04 6.85

The N-allyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one.

Boiling point: 135-136 ° C / 11 mm Hg.

Analysis for C ₁ -H ₁₅ KO (molecular weight / 211)

Calculated: 36 G 79.6 Found: 78.3 # H 6.16 6.05

$> H 6.63 6.50

The N = benzyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one. Melting point 86 ⁰ G.

Analysis for G ₁₈ H ₁₅ NO (molecular weight: 261)

Calculated: $> G 82.7 Found: 82.1% H 5.74 5.68

% N 5.36 5.38

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The N- (2-hydroxyethyl) -1,4-dihydro-1 ^ -ethene-isoquinoline - ^ - (2H) -one.

Boiling point 160 ° C / 0.100 mm, melting point 83 ° C (benzene). Analysis for C ₁₅ H ₁₅ NO ₂ (molecular weight: 215) Calculated: ^ G 72.5 Found: 72.6

# H. 6.51 6.52% Hl 6.04 6.17

The N- (2-diethylamino-ethyl) -1,4-dihydro-1,4-athen-isoquinolin-3- (2H) -one, which is purified by chromatography on silica eluting with benzene; this product will characterized by its mass spectrum and its breakdown products.

Example 4

If one works as in Example 2, but using the Diels-Alder addition product of N-methyl-isoquinolin-3- (2H) -one with phenymaleic acid, 2-methyl-8-phenyl-5,6 is obtained -benzo-2-azabicyclo (2,2,2) oct-7-en-3-one, m.p. 148-149 ⁰ C.

Analysis for C ₁₈ H ₁₅ KO (molecular weight: 261)

Calculated: / » C 82.7 Found: $ 82.6> H 5.74 5.83

* Η 5.36 5.34

Example 5

a) 24 g of the anhydride of 1,4-dihydro-1,4-etheno-isoquinoline-3- (2K) -one-9,10-dicarboxylic acid, prepared as in Example 1, are heated for 1/2 hour while boiling. with 100 ml of water. The product dissolves, then the diacid precipitates. The mixture is cooled, filtered and washed with water, I-ian dried at 70 C in a vacuum, because the diacid crystallized in aqueous milia with 1 i-iol water, Juan 22 g of acid with melting point 162-163 ⁰ C of the formula

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BATH ORIGINAL

COOH COOH

"b) 17.3 g of the above acid are dissolved in 125 ml of benzene and brought 125 ml of pyridine. 36 g of lead tetraacetate are added at normal temperature and the mixture is stirred 3 xagen.

It is then treated with a solution of nitric acid with an excess of 10% and then extracted with chloroform. The chloroform extract is filtered through Hyflocel and washed with a dilute solution of sodium carbonate, then three times with water, dried and evaporated. The residue is evaporated . amount of 1,4-dihydro-1,4-ethene-isoquinoline-3- (2H) -one obtained crystallizes in ethanol. 0.9 g of melting point 227 ⁰ C.

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Claims (2)

Claims Process for the preparation of benzoheterocyclic compounds according to the general formula (I) (D where mean: RJ, R ₂ , R ,, R, and R ₁ - hydrogen, an alkyl, hydroxyalkyl, Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl groups, these alkyl groups containing 1 to 4 carbon atoms, an alkenyl group of C ₉ -G . , an aryl or an aryl group » Rg hydrogen, an alkyl group of C ^ -O ,, an alkoxy group of G-j-C ,, halogen or the irifluoromethyl radical characterized in that, according to a Diels-Alder reaction, a maleic anhydride R-, R ₅ -substituier1 can be reacted with an isoquinolin-3-one R .., R ₂ JR ^, Rg-substituted, the carbonyl groups of the intermediate addition compound thus obtained ( -hydrolyzed to two carboxyl groups and subjecting the hydrolysis product to oxidative decarboxylation to obtain the compounds of the above formula (1). 2. New compounds of the general formula of claim 1: 1,4-dihydro-1,4-ethene-isoquinolin-5- (2H) -one N-ethyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one N-allyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one 209818/1213 ORIGiNAL INSPECTED N-Benzyl-1,4-dihydro-1,4-ethene-isoquinolin-3- (2H) -one N- (2-diethylaminoethyl) -1,4-dihydro-1,4-ethene-isoquinoline-3 (2H) -one N-I'iethyl-9-rphenyl-1 _f 4-dihydro-1,4-ethene-isoquinoline-3- (2H) -one N- (2-hydroxyethyl) -1,4-dihydro- 1,4-ethene-isoquinolin-3- (2H) -one. 209818/1213