DD288602A5 - PROCESS FOR PREPARING NEW 2-SUBSTITUTED 1H-BENZ [E] [1,4] OXAZEPINE-5-ONE - Google Patents

Abstract

The process for the preparation of new 2-substituted * of the general formula I has the object to provide a selective, technically and economically advantageous synthesis route, according to which these compounds, which can serve as organic intermediates for further syntheses and for the production of biologically active preparations, can be produced are. The object is achieved in a two-step synthesis by suitable 2-Nitrobenzoesaeureacylester be reduced by catalytic hydrogenation under defined mild conditions chemoselectively to the corresponding 2-Aminobenzoesaeureacylestern isolated and in a Polyphosphorsaeureschmelze at temperatures in the range of 80C to 230C to the inventive Heterocyclen the Formula I are cyclized. Formula I {heterocycle; 2-substituted * organic intermediate; biological activity; Two-step synthesis; 2-Nitrobenzoesaeureacylester; catalytic hydrogenation; Reduction; 2-Aminobenzoesaeureacylester; Polyphosphorsaeureschmelze; cyclization}

Description

Il

wherein R has the above meaning, by chemoselective reduction in 2-aminobenzoesäureacylester of the general formula III,

o 9

Il ^{! L}

OC-O-CH ₀ -CR ² III

NH ₂

wherein R has the above meaning, which are cyclized to the target compounds of formula I.

2. The method according to claim 1, characterized in that the chemoselective reduction of the 2-Nitrobenzoesäureacylester.der general formula II is carried out by catalytic hydrogenation.

3. The method according to claim 1 and 2, characterized in that a reusable hydrogenation catalyst, such as preferably platinum black or palladium / activated carbon, is used.

4. The method according to claim 1,2 and 3, characterized in that the catalytic hydrogenation of the nitro compounds II is preferably carried out at room temperature and atmospheric pressure in a lower alcohol as a solvent.

5. The method according to claim 1 to 4, characterized in that the hydrogenation reaction is carried out under measurement of hydrogen uptake to a point at which the maximum possible amount of the respective 2-Aminobenzoesäureacylesters of the general formula III is present in the hydrogenation solution.

6. The method according to claim 1 to 5, characterized in that the amino compounds of general formula III are isolated before their cyclization in pure form.

7. The method according to claim 1 to 6, characterized in that the cyclization of the amino compounds III by heating in a Polyphosphorsäureschmelze to a temperature in the range of 8O ⁰ C to 230 ⁰ C.

<t Field of the invention

The invention relates to a process for the preparation of novel 2-substituted 1 H-benz [e] [1,4] oxazepine-5-ones, which are used as organic intermediates for further syntheses and for the preparation of biologically active compounds, such. As drugs, are used. The invention can be used in the chemical industry.

Characteristic of the known technical solutions

No examples of the synthesis of 2-substituted 1H-benz [el [1,4] oxazepine-5-ones are known from the chemical patent and technical literature.

As a known, chemically similar class of substances, the dor 2,3-dihydro-1H-benz [e] [1,4] oxazepin-5-one can be considered. In addition to papers describing compounds without substituents in 2-position (JL Everett, J.Robert, WCJ Ross, J. Chom. Soc. 1953, 2391, E.Uhlig, D.Weither, Chem. Ber.99 [1966] 3910 AASantilli, TSOsdene, J. Org. Chem. 31 (1966) 4268; AASantilli.TSOsdene, US Patent 3522274 [07/28/1970]; D.Walther, E.Uhlig, Z. Anorg., Allg. Chem 400 (1973) 189;

D. Rousselle, J. Gilbert, P. Rumpf, Bull. Soc. Chim. Fr. 1975 Pt. 2,283; J. Gilbert, D. Rousselle, P. Rumpf, Eur. J. Med. Chem. Chim. Ther. 10 [1975] 607; J. Lehmann, Arch. Pharm. [Weinheim] 316 [1983] 339), there are some that have derivatives with a 2-substituent such as COOR (R = H, CH ₃ ) (F. Michael, W.Busse, Chem. Ber. 91 [1958] 985, F. Micheel, O.Eickenscheidt, I.Zeidler, Chem. Ber. 98 [1965] 3520) or one or two alkyl radicals in this position (CGWood, A.Geertsema, L.Freeburg,

E.J. Reardon, H.R. Jürgens, L.B. Clapp, J. Heterocyclic Chem. 2 [1965] 414).

All work has in common that the ring closure reaction to the Siebenring-I leterocyclus a '<s lactonization of a (sometimes only intermediate) 2- (N-hydroxyethyl) amino-benzoic acid derivative takes place, which may be several times, namely at the core, N-atom and ethyl radical, may be substituted. Synthetic-chemical access to this central ring precursor is diverse and involves additions of anthranilic acid derivatives to ethylene oxide (J. L Everett et al., AA Santilli et al., J. Lehmann, supra), S _N Ar reactions of active 2-halobenzoic acid derivatives .beta.-amino alcohols (F.Micheel et al .; LBClapp et al.), S _N reaction of methyl anthranilate with ß-chloro alcohols (D. Rouselle et a ^1.) and synthesis for 2,5-bis | bis- (ßhydroxyethyl) amino] terephthalate (E. Uhlig et al.). This substance class of the 2,3-dihydro-iH-benz [e] [1,4] oxazepine-5-ones similar to the compounds according to the invention is special? with regard to their pharmacological properties (analgesics and diuretics in the US patent to AA Santilli et al.), their comparison of activity with heteroanalogs (Gilbert J., Eur. Med. Chem. Chim. Ther. 10 [1975] 607) and the applicability al ? Pharmaconvorstufe (J.Lehmann, cited above) of interest. None of this work, however, involves the oxine-ring ring ainOau by methods of reduction and intramolecular cyclization of nitro compounds.

Object of the invention

The object of the invention is to provide a process by which 2-substituted 1H-benz [e] [1,4] oxazepine-5-ones can be prepared in a technically uncomplicated and economically advantageous manner in good yield.

Explanation of the essence of the invention

The invention has for its object to provide an effective method for the preparation of new 2-substituted 1 H-Benz [e] [1,4] oxazepin-5-one, which can be used as organic intermediates for further syntheses and for the preparation of biologically active preparations are.

The object is achieved according to the invention in that a 2-Nitrobenzoesäureacylester of the general formula II,

0'0

Il

CO-CH ₀ -CR

wherein R represents an alkyl radical or an aryl radical, optionally substituted, is first reduced to one point by catalytic hydrogenation with a reusable catalyst such as, preferably, platinum black or palladium / charcoal in a lower alcohol solvent at room temperature and normal pressure while measuring hydrogen uptake, on the maximum possible amount of the corresponding 2-aminobenzoic acid acyl ester of the general formula III in the hydrogenation solution,

0 0

Il

C-O-C-R-CHp

wherein R has the above meaning, whereupon the formed amino compound III is isolated from the hydrogenation solution in pure form and by heating in a Polyphosphorsäureschmelze at oine temperature in the range of 80 "C to 230 ° C, which is dependent on the nature of the radical R. acid catalyzed to a 2-substituted 1H-benz [e] [1,4] oxazepin-5-one of general formula I,

R in which R has the above meaning, is cyclized.

It is used to solve the problem so a method of reduction and cyclization of nitro compounds. The synthesis of 2-Nitrobenzoesäureacylester of formula II used as starting materials can according to known rules (Organikum, author collective, VEB German Publishing of Science, Berlin 1986,16th edition, page 200) success. In the reduction of the 2-nitrobenzoic acid acyl ester II by catalytic hydrogenation, a surprising effect occurs. It is that, initially, it does not work as described by numerous syntheses for condensed 1,4-oxazine derivatives (e.g., BRT Coutts, D. Noble, DGWibberley, J. Pharm. Pharmacol., 16 [1964] 773, RTCoutts, KWHindmarsh, Can J. Pharm. Sci. 1 [1966] 11; J. LJernow, P. Rosen, US Patent 3862180 [21.1.1975]; D.Heilmann, I.Siehr, G.Kempter, M.KIepel, GDR Patent 235262 (Apr. 30, 1986); D. Heilmann, I-Siehr, H.-D. Beerbalk, G. Kempter, Z. Chem. 26 [1986] 99; D. Sicker, B. Pretorius, G. Mann, L. Meyer, Synthesis 1989, 211) or quinoline derivatives (D.Sicker, G. Mann, Z. Chem. 25 [1985] 365) by methods of the reductive cyclization of nitro compounds , to a spontaneous intramolecular cyclization of the resulting reduction products to heterocycles already comes in the hydrogenation.

The reason for this is considered to be that the steric conditions for the intramolecular cyclization of 2-aminobenzoic acid acyl ester to the seven-membered 2-substituted 1H-8enz [e] [1,4-oxazepin-5-ones are far more demanding and not so favorable that already among the mild conditions of hydrogenation can be a spontaneous ring closure, as is typical for the emergence of the above-cited running under sterically very favorable Edukt cyclization conditions syntheses for six-membered heterocycles typical. The synthesis method according to the invention takes this fact into account by first isolating the 2-aminobenzoic acid esters in pure form and subsequently cyclizing them under drastic conditions.

In some cases, it has been observed that in the hydrogenation solution another subsequent reaction can be carried out with the 2-aminobenzoic acid III formed by reduction. It consists in the fact that this ester can be split hydrogenolytically into anthranilic acid and the corresponding methyl ketone R-CO-CH ₃ . This unexpected reaction behavior is apparently in analogy to the known hydrogenolytic cleavability of the -O-CHj grouping in benzyl ethers RO-CHr-CeH ₆ to the alcohol R-OH and ToluenlW.H.Härtung, R. Simonoff, Org. Reactions7 [1953] 263; S.Hilbig.T. Andries, W.Steglich, T. Anke, Angew. Chem. 97 [1985] 1063).

In the present case, it is important for the yield of the desired amino compound III in which ratio the rates of hydrogenation of the nitro compound II and of the hydrogenolysis of the amino compound III are. It has been found that the rate of the hydrogenolysis reaction is strongly dependent on the nature of the R radical. Except for one example (R = CgH ₅ ), however, it was always significantly lower than that of the nitro group reduction.

However, the competing hydrogenolysis effect observable in some cases can be easily minimized by suitably performing the hydrogenation. The hydrogen consumption is to be measured. In particular, the hydrogenation must not be conducted until the end of the hydrogen uptake, because then, in addition to the necessary reduction of the nitro compound II, subsequent undesired hydrogenolysis of the amino compound III could also be the consequence. The hydrogenation is therefore, if hydrogenolysis occurs, to break off in the presence of a maximum ratio of product III to anthranilic acid as a cleavage product in the hydrogenation solution. The ratio is dependent on the nature of the radical R and in optimizing the synthesis of a particular compound III, e.g. ascertained by thin-layer chromatographic analysis of the hydrogenation solution. The amount of hydrogen to be consumed until this ratio is reached is usually close to the value calculated for the nitro group reduction for the uptake of three molar equivalents of hydrogen for a usually slower than the nitro group reduction in the hydrogenolysis reaction.

The 2-aminobenzoesäureacylester III isolated in pure form can be converted into the 2-substituted 1H-benz [e] [1,4] oxazepin-5-ones according to the invention by acid-catalyzed intramolecular cyclization in a hot polyphosphoric acid melt. The nature of the radical R determines the height of the Cyclisierungstemperatur lying in the interval from 8O ⁰ C to 230 ° C. For the heterocycles prepared according to the invention, there is the possibility of a tautomeric equilibrium with the constitutionally isomeric 2-substituted 3H-benz [e] [1,4] oxazepin-5-ones.

embodiments The invention will be explained below with reference to exemplary embodiments.

2-nitrobenzoic acid acyl ester (general formula II)

According to the literature cited above, these starting materials were prepared from 2-nitrobenzoic acid and α-bromomethyl ketones Br-CH ₇ -CO-R

in which R has the meaning given to formula II.

2-Nitrobenzoesäureac6tonylester1

Kp. "P, = Kp. ₀ , o5Toir 150-153 ⁰ C, n ° ° 1.5378

2-Nitrobenzoesäurephenacylester2

Mp. 124-126 ⁰ C (methanol)

2-Nitrobenzoesäure- (4-methylphenacylester) 3

(R = 4-CH ₃ -C ₆ H ₄ -)

Mp. 98-99 ⁰ C (methanol)

2-Nitrobenzoesäure- (4-methoxyphenacylester) 4

(R = 4-CH ₃ OC ₆ H ₄ -)

Mp 109-110.5 ° C (methanol)

2-nitrobenzoic acid (4-hydroxyphenacyl ester) 5 (R = 4-HO-C ₈ H ₄ -)

Mp 192-194 ⁰ C (methanol)

2-N-trobenzoic acid (4-phenylphenol: yl ester) 6 (R = 4-C ₆ Hs-C ₈ H ₄ -) m.p. 137.5-139 ⁰ C (acetone) 2-nitrobenzoic acid (4-bromophenacyl ester) 7 (R = 4-Br-C ₆ H ₄ -)

Mp. 107-108 ⁰ C (methanol)

2-nitro-benzoic acid (3,4-di-chloro-morphacyl ester) (R = 3,4-CI ₂ -C ₆ Hr-)

M.p. 138-139 ⁰ C (methanol)

2-nitrobenzoic acid (β-naphthacyl ester) 9 (R = β-naphthyl)

Mp 135.5-137 ° C (methanol)

2-Aminobenzoic acid acyl ester (general formula III)

Production Example 1

2-aminobenzoic acid acetonyl ester 10 (R = CH ₃ in formula III)

2.23 g (0.01 mol) of 2-nitrobenzoic acid acetonyl ester 1 are dissolved in OQmI ethanol and hydrogenated after addition of 50 mg of platinum black at room temperature and normal pressure until the intake of 672 ml of water. The catalyst is filtered off and the

Solvent from the filtrate i. Vak. distilled off. The solid residue is recrystallized from a little methanol. Yield: 1.74 g (90% of theory) of colorless needles In an analogous manner, the following compounds were prepared:

2-aminobenzoic acid phenacyl ester (R = C ₆ H ₅ in formula III)

From compound 2 in 44% yield. Mp 122.5-124 ⁰ C (methanol)

2-aminobenzoic acid (4-methylphenacyl ester) 12 (R = 4-CH ₃ -C ₆ H ₄ - in formula III)

From compound 3 in 61% yield. Mp. 112-113 ⁰ C (methanol)

2-aminobonoic acid (4-methylthoxy-phenyl) ester (R = 4-CH ₃ OC ₆ H ₄ - in formula III)

From variant 4 in 75% yield. M.p. 114-115 ⁰ C (methanol)

2-aminobenzoic acid (4-hydfoxyphenacyleste; ') (R = 4-HO-C ₆ H ₄ - in formula III)

From compound 5 in 85% yield. Mp 203-205 ⁰ C (methanol)

2-aminobenzoic acid (4-phenylphenacyl ether) (R = 4-C ₆ H ₅ -C ₁ H ₄ - in formula III)

From compound β in 72% yield. Mp 169-171 ° C (methanol / acetone)

2-aminobenzoic acid (4-bromophenacyl ester) 16 (R = 4-Br-C ₆ H ₄ - in formula III)

From compound 7 in 51% yield. Mp. 133 to 134.5 ⁰ C (methanol)

2-aminobenzoic acid (3,4-dichlorophenacyl ester) 17 (R = 3,4-CI ₂ -C ₆ H ₃ -In formula III)

From compound 8 in 75% yield. Mp. 137-139 ⁰ C (methanol / acetone)

2-aminobenzoic acid (β-naphthacyl ester) (R = β-naphthyl in formula III)

AiT's compound 9 in 56% yield. Mp 148-15O ⁰ C (methanol)

2-Substituted 1H-Benz [e] [1,4] oxazepln-5-one (general formula I)

Manufacturing Bills 2

2-Methyl-IH-benz [e] [1,4] oxazepine-5-one 19 (R = CH ₃ in formula I) 1,93 g (0,01 mc) of acetoacetyl 2-aminobenzoate 10 are dissolved in 10 g of polyphosphoric acid at 200 ° C heated. After 2 min, 150 ml of cold water are poured in and mixed with dilute sodium hydroxide solution until pH 8 is added. The resulting

Precipitate is filtered off and recrystallized from much acetone or glacial acetic acid. Yield 1.58 g (90% of theory) of cream-colored crystals Mp 290-310 ⁰ C subl. (Fischer-cuvette) Production Example 3

2- (4-methylphenyl) -1 H-benz | e] [1,4) oxazüpin-5one 20 (R = 4-CH ₃ -C ₆ H ₄ - in formula I) 2,69g (0,01 mol) 2-Aminobenzoic acid (4-methylphenacyl ester) 12 is heated in 10 g of polyphosphoric acid for 2 h at 1 OA ⁰ C and then poured into 150 ml of cold water. The precipitate is filtered off, 30min with 100ml saturated

Sodium hydrogen carbonate solution stirred, filtered off, washed neutral, dried and recrystallized from ethanol. Yield: 2.33 g (93% of theory) of yellow crystals

Mp 263-266.5 ⁰ C

In an analogous manner, the following compounds were prepared:

2-phenyl-1H-benz [e] [1,4] oxazepine-5-on21 (R = C ₆ Hs-In Formula I)

From compound 11 in 77% yield. Mp. 271-275 ⁰ C (ethanol)

2- (4-methoxyphenyl) -1H-benz [e] [1,4] oxazepine-5-on22 (R = 4-CH ₃ OC ₆ H ₄ -In formula I)

From compound 13 in 75% yield. Mp. 281-284 ⁰ C (ethanol)

2- (4-hydroxyphenyl) -1H-benz [e] [1,4] oxazepine-5-one (R = 4-HO-C ₆ H ₄ - in formula I)

From compound 14 in 64% yield.

M.p. 306-309 ° C (acetone) 2- (4-phenylphenyl) -1H-benz [e] (1,4) oxazepin-5-one 24 (R = 4-C ₆ KC ₆ H ₄ - in formula I)

From precursor 15 in 77% yield. Mp 298-305 ° C (ethanol)

2- (4-bromophenyl) -1H-benz (e) H, 4-oxazepin-5-one 25 {R = 4-Br-C ₆ H ₄ - in formula I)

From compound 16 in 75% yield. Mp 297-300 ° C (ethanol)

2- (3,4-dichlorophenyl) -1H-benz [e] [1,4] oxazepine-5on26 (R = 3,4-CIR-C ₆ H ₃ - In formula I)

From compound 17 in 72% yield. Mp 265-270 ⁰ C (ethanol)

2- (β-naphthyl) -1H-benz [e] [1,4] oxazepine-5-one27 (R = p-naphthyl in formula I)

From compound 18 in 69% yield. Mp. 263-267 ⁰ C (ethanol)

Claims (2)

1. A process for preparing novel 2-substituted-1H-benz [e] [1,4] oxazepine-E-on of the general formula I, O. MR wherein R is an alkyl radical or an aryl radical, optionally substituted, characterized in that 2-Nitrobenzoesäureacylester of the general formula II, OO 'Q' G-O-CHp-C-R