DE1139123B - Process for the preparation of heterocyclic compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT DOCUMENT 1139

INTERNAT. KL. C 07 d

REGISTRATION DATE: NOVEMBER 10, 1960

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL:

NOVEMBER 8, 1962

ISSUE OF

PATENT WRITING: 16. M 41 1963

MATCHES WITH EDITORIAL

1139 123 (F 32514 IV d / 12 p)

The subject of the patent 1 120 455 is a process for the production of heterocyclic compounds, which is characterized in that one / i-oxocarboxylic acid ester of the general formula

R ₂
R ₄ - O - CO - CH - OC - Ri

wherein Rj is a hydrogen atom, one optionally alkyl group substituted by carbalkoxy groups, an aryl, carboxy or carbalkoxy group, R2 Hydrogen atom or an alkyl, cycloalkyl, araikyl or aryl radical and R4 is an alkyl, cycloalkyl, Aralkyl or phenyl group means in an acidic, neutral or basic medium with an aromatic o-aminocarboxylic acid hydrazide of the general formula

R3

i NH

Process for the preparation of heterocyclic compounds

Addition to patent 1 120 455 The main patent started on September 6, 1959

Patented for:

Paint factories Bayer Aktiengesellschaft, Leverkusen

Dr. Rolf Pütter, Düsseldorf,

Dr. Gerhard Wolfrum, Opladen,

and Dr. Karl-Heinz Menzel, Leverkusen,

have been named as inventors

It has now been found that 2-methylpyrazolo [5, l-b] quinazolone derivatives the general

Ar

formula

CO - NH - NH ₂

converts, in which R3 is a hydrogen atom or an alkyl, cycloalkyl or aryl radical and Ar a mononuclear or polynuclear, optionally by halogen atoms, alkyl, alkoxy, aryl, phenoxy, Substituted amino, alkylamino, acylamino, nitro, carboxy, sulfonic acid or sulfamyl group, represents aromatic ring system, and then the obtained pyrazolo [5, l-b] quinazolone derivatives of general formula

Ar

CH

2 C - CH ₃

wherein Ar is an optionally substituted, o-condensed with the heterocyclic ring, one or polynuclear aromatic radical is obtained in a particularly simple manner when acetonyloxazinone the general formula

45

CH ₂ CO - CH ₃

Ar

C.
O

Il

wherein Ri, R ₂ , R ₃ and Ax have the abovementioned loading in the presence of water and / or organic

have meaning and the remainder Ar still another 50 solvents in neutral or weakly acidic

Pyrazolo [5, l-b] quinazolone groups contain medium with hydrazine or its salts,

can, isolated. The reaction proceeds according to the following scheme:

309 576/210

3 _H 4

N CH ₂ CO-CH ₃ N CH

c / c

Ar I + H ₂ N -NH ₂ -> Ar | C-CH ₃ + 2H ₂ O

0 \ N

The reaction is exothermic and generally succeeds without external heat input. It recommends however, to warm the reaction mixture for some time after the components have been combined, to achieve full implementation.

When the acetonyloxazinones are reacted with hydrazine or its salts, the reactants are preferably in an equimolecular ratio used. As a solvent, for. B. glacial acetic acid, dimethylformamide or acetonitrile in Ask. In most cases there is even no need to isolate the acetonyloxazinones beforehand; man arrives in the simplest way and with good yields to the 2-methyl-pyrazolo [5, l-b] quinazolones by an aromatic o-aminocarboxylic acid is first converted into the o-acetoacetylaminocarboxylic acid with diketene transferred, then to the reaction mixture a dehydrating agent, for. B. acetic anhydride, there, whereby the cyclization to Acetonyloxazinon is effected, and finally hydrazine or adding a hydrazine salt.

The 2-methyl-pyrazolo [5, l-b] quinazolones are filtered off from the aqueous reaction medium isolated. When working in an organic medium, the reaction product is first precipitated completely by adding water and filtering it off.

According to the new process, the 2-methylpyrazolo [5, l-b] quinazolones are the formula given above is particularly easily accessible, since the acetonyloxazinones used as starting compounds from aromatic o-aminocarboxylic acids, diketene and a dehydrating agent in smooth Reaction can be produced.

The acetonyloxazinones suitable for the implementation as starting materials can, for. B. off Anthranilic acid, o-aminonaphthoic acids or o-amino-anthraquinone-carboxylic acid and their Core substitution products are produced. Examples of possible substituents include Halogen atoms, nitro, amino, sulfo, sulfonamido, methyl or carboxy groups.

For the process for the production of the acetonyloxazinone required as starting materials here no protection claimed.

example 1
101.5 parts of acetonylbenzoxazinone of the formula

V \

C - CH ₂ - CO - CH ₃
O

are mixed into a mixture of

C N

ίο entered 30 parts of hydrazine hydrate in 300 parts of glacial acetic acid. Then for 2 hours is stirred at 45 to 5O ⁰ C. After this time, 500 parts of water are added and the reaction product is filtered off. It is thoroughly washed with water and dried. 85 parts of 2-methylpyrazolo- [5.1b] quinazolone with a decomposition point of 360 ° C. are obtained

the formula _TT

H H

N C

C-CH ₃

25 is prepared from 5-chloroanthranilic Acetonyloxazinon (F. 159 ° C) and in the same manner from 2-naphthylamine-3-carboxylic acid prepared Acetonyloxazinon (F. 150 ⁰ C) to 2-methyl-6-chloropyrazolo [5, lb ] quinazolone (F. 355 to 361 ⁰ C with decomposition) or 2-methyl-6,7-benzo-pyrazolo [5, Ib] -quinazolone (M. 340 ⁰ C with decomposition) implemented.

The acetonylbenzoxazinone of the formula given above is used as the starting material obtained in the following way:

The mixture is heated 137 parts of anthranilic acid in 600 parts of carbon tetrachloride at reflux to 70 ⁰ C. and allowed to accrue within 30 minutes 84 parts of diketene. The initially clear solution solidifies to form a thick crystal paste. The mixture is kept at boiling temperature for a further 20 minutes and then 110 parts of acetic anhydride are added within a few minutes. After a clear solution has formed again, this is heated to the boil for a further hour, then cooled to 5 ° C. and the compound which precipitates out in crystalline form is filtered off. The reaction product is washed on the filter with ligroin and then dried. There are 145 parts Acetonylbenzoxazinon of melting point 121 to 122 ⁰ C.
The acetonylbenzoxazinone from 5-chloroanthranilic acid is obtained by dropping 168 parts of diketene into a solution of 342 parts of 5-chloro-2-aminobenzoic acid in 1400 parts of water and 80 parts of sodium hydroxide, filtering off the 2 - (acetoacetyl - amino) - 5 - chlorobenzoic acid (470 parts; mp 152 to 153 ° C) and reacting 255 parts of this compound in 780 parts of o-dichlorobenzene with 110 parts of acetic anhydride.

This gives 210 parts Acetonyloxazinon, F. 159 ⁰ C.

Acetonyloxazinone prepared from 2-aminonaphthalene-3-carboxylic acid was obtained as follows :

187 parts of 2-aminonaphthalene-3-carboxylic acid are in a solution of 40 parts of sodium hydroxide

dissolved in 900 parts of water and added slowly with cooling at 3O ⁰ C with 84 parts of diketene. When the reaction has ended, the reaction product is precipitated by adding 107 parts of hydrochloric acid (d = 1.19), filtered off with suction and washed with water. After recrystallization from methanol-water, 210 parts of 2- (acetoacetyl-amino) be -naphthalene-3-carboxylic acid of melting point 186-187 ⁰ C obtained. 135 parts of this compound are heated to 100 ° C. in 780 parts of o-dichlorobenzene and 55 parts of acetic anhydride are added over the course of 10 minutes. The mixture is stirred for a further 3 hours at 100 ^° C., a clear solution being obtained. After cooling to 5 ° C, the oxazinone crystallizes out in yellow crystals. After filtering off and drying, 105 parts with a melting point of 150 ^° C. are obtained.

Example 2

A mixture of 30 parts of hydrazine hydrate and 300 parts of water is adjusted to pH 7 with hydrochloric acid. 100 parts of acetonylbenzoxazinone of the formula given in Example 1 are then entered. After adding 1 to 2 parts of a commercially available dispersant, the mixture is stirred at room temperature. The pH of the reaction mixture is kept at 7 by continuously adding sodium carbonate solution. If the pH remains at 7 even without the addition of sodium carbonate, the reaction is essentially complete. The mixture is then stirred for a further 1 hour at about 50 ^° C., then cooled and the reaction product is isolated by filtering off. After washing with water and, after drying, 80 parts of 2-methyl-pyrazolo [5, lb] quinazolone by the decomposition point of 36O ⁰ C.

Example 3
247 parts of the acetonyloxazinone of the formula

CH ₂ -CO -CH ₃

are added to a mixture of 1000 parts of water, 165 parts of glacial acetic acid and 55 parts of hydrazine hydrate, and then heated with stirring for 3 hours at 6O ⁰ C. After cooling, the reaction product is isolated by filtration, washed repeatedly with water and dried. 209 parts of 2-methyl-5-carboxy-pyrazolo [5.1b] -quinazolone of the formula are obtained

HOOC

CH

C-CH ₃

C.
O

The product does not melt up to 380 ° C.
Similarly, the Acetonyloxazinon obtained from 2-aminoterephthalic acid to give 2-methyl-6-carboxy-pyrazolo is [5, lb] reacted quinazolone (F.> 38O ⁰ C).

The acetonyloxazinone of 2-amino-benzene-l, 5-dicarboxylic acid can be prepared as follows:

181 parts of 2-aminoisophthalic acid are used in a solution of 700 parts of water and 80 parts

ίο Dissolved sodium hydroxide and mixed with 84 parts of diketene ^{with cooling at 30 0 C.} After the reaction has ended, the reaction product is precipitated by adding 220 parts of hydrochloric acid (D = 1.19), filtered off with suction and washed. 220 parts of 2- (acetoacetylamino) benzene-1,3-dicarboxylic acid are obtained. 133 parts of this compound are dissolved in a solution of 600 parts of water and 40 parts of sodium hydroxide. Phosgene is then passed in at 5 to 10 ^{° C. with cooling.} A pH of 8 is maintained by adding sodium carbonate solution dropwise. After 2 hours, the acetonyloxazinone which has precipitated in the form of the sodium salt is filtered off with suction and dried.

The acetonyloxazinone from 2-aminoterephthalic acid was produced in the following way:

181 parts of 2-aminoterephthalic acid are dissolved in a solution of 80 parts of sodium hydroxide in 1100 parts of water, and under cooling at 30 ⁰ C with 84 parts of diketene. After the reaction has ended, the reaction product is precipitated by adding 220 parts of hydrochloric acid (D = 1.19), filtered off with suction and washed thoroughly with water. 208 parts of 2- (acetoacetylamino) benzene-1,4-dicarboxylic acid are obtained. 133 parts of this connec tion are heated ^{to 100 °} C. in 400 parts of acetic anhydride for 1.5 hours. It is then cooled to 5 ° C. and the yellow acetonyloxazinone formed is filtered off with suction. After drying, 115 parts with a melting point above 330 ^° C. are obtained.

Example 4

68.5 parts anthranilic acid are dissolved in 200 parts of glacial acetic acid at 7O ⁰ C and gradually added at this temperature with 45 parts of diketene. After the addition has ended, the mixture is kept at 70 ^° C. for a further hour and then 65 parts of acetic anhydride are added all at once. The batch is then ^{heated to 75 °} C. for 5 hours. After cooling to 25 ^° C., the mixture, prepared in the cold, of 35 parts of hydrazine hydrate and 120 parts of glacial acetic acid is added. The temperature rises rapidly to 75 ° C; after one minute the deposition of the reaction product begins. The viscous crystal pulp is heated for a further hour on the water bath and then filtered off with suction, the residue is washed on the suction filter several times with glacial acetic acid and dried. 73 g of 2-methylpyrazolo [5.1b] quinazolone are obtained; F. 360 ° C (decomposition).

Similarly, 4-nitro-anthranilic acid, 5-sulfo anthranilic acid and 5-sulfonamido-anthranilic acid to give the corresponding Acetonyloxazinonen and that to 2-methyl-7-nitro-pyrazolo [5, lb] quinazolone (F.> 35O ⁰ C , decomposition), 2-methyl-6-sulfopyrazolo-5, lb] quinazolone (F. 380 ⁰ C) and 2-methyl-6-sulfonamido-pyrazolo [5, lb] quinazolone (F.> 380 ° C) are reacted.

Claims (1)

PATENT CLAIM: Further training of the process for the production of heterocyclic compounds according to Patent 1120 455. characterized in that acetonyloxazinones of the general formula N CH.CO - CH ₃ / C
O wherein Ar is an optionally substituted, o-condensed with the heterocyclic ring one Ar or polynuclear aromatic radical, in the presence of water and / or organic Solvents in neutral or weakly acidic medium with hydrazine or its Reacts salts and then the 2-Methy! -Pyrazolo [5, l-b] quinazolone derivatives obtained general formula CH ₃ isolated.