DE1185619B - Process for the preparation of new pyrido [2, 3-e] [1, 3] oxazines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

German KL: 12 ρ - 10/10

Number: 1185 619

File number: G 36388IV d / 12 ρ

Filing date: November 13, 1962

Opening day: January 21, 1965

The invention relates to a process for the preparation of new pyrido [2,3-e] [l, 3] -oxazines of the general formula

in which Ri is a hydrogen atom, an alkyl radical with a maximum of 5 carbon atoms, one optionally phenyl, benzyl substituted by a maximum of 3 halogen atoms, lower alkyl or alkoxy groups or phenacyl radical or a thenyl or pyridylmethyl radical.

In addition to hydrogen, for example, radicals Ri the following into consideration: methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl or amyl radicals, phenyl or benzyl radicals, o-, m- or p-chlorophenyl radicals, the 3,4-dichlorophenyl radical, o-, m- or p-methylphenyl residues, o-, m- or p-methoxyphenyl residues, o-, m- or p-chlorobenzyl residues, 2,4- or 3,4-dichlorobenzyl radicals, o-, m- or p-fluorobenzyl radicals, o-, m- or p-methoxybenzyl radicals and 3,4-dimethoxy or 3,4,5-trimethoxybenzyl radicals.

These compounds have valuable pharmacological properties, especially analgesic, anti-pyretic, anti-inflammatory, muscle-relaxing as well as bacteriostatic and fungistatic effectiveness. They also show an inhibitory effect on monoamine oxidase. But they are also valuable Intermediates, ζ. B. for the production of other pharmacologically active substances as well of pesticides.

With regard to their analgesic or anti-inflammatory effectiveness, various products of the process were treated with the equally effective 4-oxo -2- (β- chloropropyl) -2,3-dihydro- [benzo-1,3-oxazine known from Austrian patent specification 215 993 ] compared.

I. Analgesic efficacy test according to F r i e b e 1

The analgesic effect was determined by Gross’s method, the tails by white mice with the apparatus of F r i e b e 1 and R e i c h 1 e (Arch. exp. Path. u. Pharmakol., 229, P. 400 [1956]) were irritated by thermal irradiation.

Method of making new
Pyrido [2,3-e] [1,3] oxazines

Applicant:

JR Geigy AG, Basel (Switzerland)
Representative:

j ₀ Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann
and Dipl.-Chem. Dr. R. Koenigsberger,
Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:

Niels Clauson-Kaas, Copenhagen;

Dr. Rolf Denss, Basel;

Dr. Franz Ostermayer, Riehen;

Dr. Ernst Renk, Basel (Switzerland)

Claimed priority:

Switzerland of November 14, 1961 (13 217)

The response time defined by Gross for the The above-mentioned irritation was performed on different groups of ten to twenty animals, of which each weighed 18 to 25 g, determined 30 and 15 minutes before the administration of the test substances. then All groups of animals were given a suspension of one of the test substances with gum arabic in water administered orally in doses of 400 mg / kg. 30, 45, 60, 90 and 120 minutes after the administration of the Test substances, the average reaction time of each group of animals was determined and based on it the difference between the mean reaction time after 30, 45 and 60 minutes and the mean Response time before administration of the test substances, expressed as a percentage of the latter, determined.

Hotplate test

The analgesic effect was tested using the hotplate test according to W ο ο 1 f e and McDonald (Journ. Pharmacol. Exp. Ther., 80, p. 300 [1944]).

Albino mice weighing up to 18 g were used. For each dose of the compounds to be tested at least ·; twenty animals each

409 769/423

turns. The test was conducted by placing the mice individually in a jar with a bottom temperature of 56 ° C were introduced, whereupon the time to the onset of the reaction was measured. The reaction is to lick the front paws, in rare cases jumping. The response time for each animal twice before and once each 30, 45, 60, 90 and 120 minutes after the application of the preparation. Here, too, the average was used as a measure of the intensity of the effect Extension of the reaction time, found 30, 45 and 60 minutes after the administration of the test substance as a percentage of the normal reaction time determined prior to administration.

The preparations were suspended with gum arabic and applied with a stomach tube.

toxicity

To determine the lethal dose 50 (DL50), the substances to be tested were white mice administered orally in various single doses and the results evaluated as usual.

The results are shown in the following table:

Checked connections -CH ₂ - \ _s / \ _s / Extension of the
a) Friebel test
400 mg / kg po Response time in ° / o
b) Hotplate test
400 mg / kg po DLs) mouse
mg / kg po / "V ⁰ V ⁰
| i £ - CH ₂ CO - O
R ₁ : H 4-oxo-2 - (/ 3-chloropropyl) -2,3-dihydro- [benzo-
1,3-oxazine] 49 y 100 mg: 33
200 mg: 40
400 mg: 59 1 1240 -CH ₂ -O 34 24 > 5000 - CH ₂ - ^ ^ - OCH ₃ 10 32 > 5000 21 27 > 5000 OCH ₃ - CH ₂ CO - \ __ / 21 42 > 5000 OCH ₃ 43 30th > 5000 OCH ₃ 13th 103 4530 25th 52 2400 2 28 5000

The products of the process show similar or slightly higher toxicities compared to 65. in the the well-known 4-oxo-2 - (/ J-chloropropyl) -2,3-dihydro hotplate test show process products with Toxizi- [benzo-1,3-oxazine] in the test according to F. r i e be! consistently do the same order of magnitude as the comparative ones Significantly stronger analgesic effectiveness Substance approximately the same analgesic effectiveness.

while process products with a somewhat higher toxicity also have an at least correspondingly higher toxicity have analgesic effect.

Stretch test

Checked connections

I. 2,4-Dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine,

II. S-pyridylmethyl - ^ - oxazine dioxo-S ^ -dihydro-lH-pyr ido _ro [2,3-e] [1,3]

III. 4-Oxo-2 - (/? - chloropropylene) -2,3-dihydro- [benzo-1,3-oxazine] according to Austrian patent specification 215 993.

method

the animals received 1 ecm of a 1% formaldehyde solution injected intraperitoneally. 9 hours later, the animals were sacrificed and the total amount of the Exudates formed in the peritoneum are measured. The mean inhibition of exudation achieved with each test substance is expressed as a percentage. It is obtained from the middle one in each test series Exudate amount and from the exudate amount determined in the blind test with only formaldehyde injection calculated.

Results

'5 Tested connections

Based on the method of E. Siegmund, R. Cadmus and G. Lu (Proc. Soc. Exp. Biol. Med., 95, p. 729 [1957]), twenty albino mice are used per dose of a pharmaceutical to be tested; Animal weight: 17 to 23 g. The pain is caused by intraperitoneal injection of 0.25 cm ^{3 of} a 0.025% phenylquinone suspension (phenylquinone in gum arabic), the animals responding to this pain with characteristic stretching movements. Animals that perform less than two stretching movements within 5 minutes are considered insensitive. The preparation is administered orally as a suspension with gum arabic 20 minutes before the phenylquinone injection. The number of insensitive animals is determined at the following times; 0 to 5, 5 to 10, 10 to 15, 30 to 35, 45 to 50 and 60 to 65 minutes after using phenylquinone. As a result, the following table shows the highest percentage of insensitive animals found in one of the above-mentioned time intervals.

R .:

CH ₃

-CH ₂ -4

Checked

links

Percentage
insensitive animals

dose
mg / kg

50
200
400

50
200
400

200
400
800

animals

100

100

30th
45
20 change of

Amount of exudate

in% (dose:

200mg / kg p. O.)

toxicity
DL50 mouse
mg / kg po

40 4-Oxo-2 - (/ i-chloropropyl) -2,3-dihydro- [benzoj
1.3-oxazine],

-69

-45

-53

-39

Mouse mg / kg p. O.

> 5000

> 5000

4530

> 5000

1240

3750

> 5000 The process products show in comparison to the well-known 4 - oxo - 2 - (/> '- clilorpropyl) - 2,3 - dihydro- [benzo-1,3-oxazine] with similar toxicities a significantly stronger anti-inflammatory effect.

The compounds of general formula I are prepared by being known per se Way either

a) to a compound of the general formula

Of compound I, 50 mg / kg and of compound II in any case 200 mg / kg are more effective than that Compound III in the most favorable dosage of 400 mg / kg, so that for the first two compounds despite the higher toxicity of compound I a much more favorable ratio of analgesic Efficacy to toxicity results from that of comparative compound III.

II. Anti-inflammatory effectiveness
Method (formalin peritonitis)

Each of the test substances was used as an aqueous solution for twenty male rats weighing 120 up to 140g injected subcutaneously. Immediately afterwards

CO - NH - Ri

in the presence of an inorganic or organic base, a compound of the general formula

X-C-Y

III

in which X and Y are identical or different and hydrocarbon radicals bonded via oxygen atoms, especially lower alkoxy radicals or phenoxy radicals. or halogen atoms, in particular

Chlorine atoms, or each radical X and Y represent the group

- N

means, allows to act, and a compound of the general, possibly obtained as an intermediate formula

or

OH

CO-NH-COOR
O - COOR

CO - NH - R /

IVa

IVb

in which R is a lower alkyl radical or the benzyl radical and Ri 'is a hydrogen atom, a lower alkyl radical or the phenyl radical, converted into the corresponding compound of the general formula I by heating or
b) a compound of the general formula

OH

COOR '

in which R 'is a lower alkyl radical, in particular the methyl radical, in the presence of a Base with an isocyanate of the general formula

Ri - N = C = O VI

and a compound of the general formula obtained as an intermediate if necessary

CO-NH-Ri

VII

COOR '

converted into a compound of the general formula I by heating

and optionally then a compound of the general formula I obtained in which Ri is a Means hydrogen atom, converted into a metal or ammonium salt and this with a reactive ester of a hydroxy compound of the general formula

Ri "-OH VIII

where Ri "is an alkyl radical with at most 5 carbon atoms, one optionally with at most halogen atoms, lower alkyl or alkoxy groups substituted benzyl or phenacyl radical or a thenyl or pyridylmethyl radical.

In procedure a), the choice of reaction conditions depends largely on the type of

Radicals X and Y. If these are hydrocarbon radicals bound via oxygen atoms, z. B. alkoxy radicals, the condensation is in particular by heating in the presence or absence a solvent or diluent until a compound of the general formula is released XH completed. If at least one of the above symbols is represented by a halogen atom, the condensation is preferably carried out by heating in organic bases, e.g. B. pyridine, Quinoline or quinaldine. Other suitable acid-binding agents are, for example, aqueous alkali or sodium hydride or lithium amide in an anhydrous medium.

A special embodiment of this procedure is that one is on a connection of the general formula II in aqueous alkali or in the presence of organic bases, in particular of quinoline, quinaldine, sym. collidine or 2,6-lutidine, in the presence or absence of one Solvent is a chlorocarbonic acid derivative of the general formula

Cl - CO - Y '(IHa)

in which Y 'denotes a chlorine atom or a methoxy, ethoxy or phenoxy radical, allowed to act. The reaction of a compound of the general formula II with a chlorocarbonic acid derivative is particularly preferred of the general formula IHa in acetonitrile as solvent and using of sym. collidine or 2,6-lutidine at room temperature.

As starting compounds of the general formula III, there may be mentioned in particular: phosgene, methyl chlorocarbonate, Ethyl chlorocarbonate, phenyl chlorocarbonate, benzyl chlorocarbonate, Ν, Ν'-carbonyl diimidazole, diethyl carbonate, dimethyl carbonate and diphenyl carbonate.

The starting materials of the general formula II are, for. B. starting from optionally substituted 3-Hydroxypyridine-2-carboxylic acids obtainable in a manner known per se.

A particular embodiment of procedure b) consists in that an isocyanate is used general formula

Ri '"- N = C = O VIa

in the Ri '"a lower alkyl radical or an optionally by halogen atoms or lower Alkyl radicals substituted phenyl radical means used and the reaction in the presence of triethylamine performs as a base. The implementation of reactive esters of hydroxy compounds of the general formula VIII with metal salts of compounds of general formula I in the 3-position have a hydrogen atom, for example with sodium, potassium or silver salts of such compounds, is advantageous at temperatures between 0 and about 200 ° C, preferably in a suitable inert organic solvents, e.g. B. in dimethylformamide or dimethyl sulfoxide Carried out at room temperature.

Reactive esters of hydroxy compounds of the general formula suitable as starting materials VIII are e.g. B. alkali halides, benzyl halides and phenacyl halides with optionally by Halogen atoms, alkyl or alkoxy groups substituted aromatic ring, further z. B. Aryl sulfone

acid and alkanesulfonic acid alkyl esters and dialkyl sulfates.

The following examples explain the process according to the invention. The temperatures are in Degrees Celsius.

example 1

a) 1.38 g of 3-hydroxypicolinic acid amide and 2.5 ml of quinoline are mixed in a distillation flask and cooled to 0 °. 1.92 ml of ethyl chloroformate are added in one portion and the mixture is heated to 40 to 50 ° with stirring. Their temperature now rises without any external Apply heat rapidly to about 100 °, whereby the mixture becomes a homogeneous light brown oil. It is now heated to 200 ° for 3 minutes. In doing so, it first turns green and then black. the The mixture is cooled to 150 ° and dissolved in 30 ml of 99% ethanol added at once. The dark ethanol solution is cooled to 0 ° and with a mixture of each cooled to -10 ° 10 ml of concentrated hydrochloric acid and water are added in one portion. From the clear solution obtained After cooling and, if necessary, scraping, the crude 2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] - [1,3] -oxazine hydrochloride crystallizes as a blue-green powder. It is filtered off after 15 minutes, washed with two portions of 5 ml of ethanol each and dried. Yield 58%. The base can be released using one of the following two methods:

The crude hydrochloride can be converted into the base by washing with water until the filtrate is neutral be transferred. Also dissolve the hydrochloride in 2η sodium hydroxide solution and then neutralize it with dilute hydrochloric acid lead to the base. This can be from boiling water, glacial acetic acid or pyridine are recrystallized and then melts at 280 °. The compound does not give iron chloride reaction (in Methanol) and no precipitation with a solution of 2,4-dinitrophenylhydrazine in 2η-hydrochloric acid.

2,4-Dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine can also be activated by the following ring closure reactions getting produced:

1. 8.3 g of 3-hydroxypicolinamide are dissolved in 50 ml of dry acetonitrile and 8.2 g of sym. Collidine suspended and with a solution of 11.0 g of phenyl chloroformate in 20 ml of acetonitrile Stirred at 40 ° for 20 hours. The suspension is evaporated in vacuo at 50 °, the residue 50 ml of water are added and the insolubles are filtered off with suction. The filtration residue is washed with 50 ml of water and 20 ml each of isopropanol and acetone. That which arises 2,4-Dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine has a melting point of 276 to 278 °; Yield 81%. Recrystallization from glacial acetic acid with the addition of charcoal becomes colorless Product obtained with a melting point of 280 °.

2. 3.3 g of N, N-carbonyl-diimidazole and 1.4 g of 3-hydroxypicolinamide are in 40 ml of absolute Tetrahydrofuran heated to boiling under reflux for 16 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo. There remains a gray residue, which after the Recrystallization from dioxane with the addition of decolorizing charcoal melts at 280 °; yield 46%.

b) 30 g of 2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] - [1,3] -oxazine are suspended in 80ml dimethylformamide. While stirring and cooling with ice 8.9 g of a 50% suspension of sodium hydride in mineral oil are added in portions so that that the temperature does not rise above 15 °. After the evolution of gas has ended, further Cooling, a solution of 31.4 g of benzyl bromide in 30 ml of dimethylformamide was added. After 1- to Standing for 2 days at room temperature shows a sample diluted with 5 times the volume of water, a pH of 7 to 8. When this is the case, the total reaction mixture is made up to 500 ml Poured water. The 3-benzyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine which precipitates out in crystalline form is suctioned off, washed with 50 ml of water, isopropanol and ether and made from dioxane with the addition of Recrystallized coal; Mp 174 °; Yield 75 to 80%.

c) From 30 g of 2,4-dioxo-3,4-dihydro-2H-pyrido- [2,3-e] [1,3] oxazine the sodium salt according to paragraph b) is prepared with 9 g of sodium hydride suspension (50%) in 70 ml of dimethylformamide. Under ice cooling a solution of 31.2 g of ethyl iodide in 20 ml of dimethylformamide is added, the mixture Left to stand for 16 hours at room temperature and then poured into 400 ml of water. The departed Crystals of 3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine are suctioned off, washed with 50 ml of water and off Isopropanol recrystallized; "M.p. 150 to 151 °; Yield 30%.

d) From 16.4 g of 2,4-dioxo-3,4-dihydro-2H-pyrido- [2,3-e] [I, 3] -oxazine, 4.8 g of sodium hydride suspension (50%) and 40 ml of dimethylformamide is prepared as in paragraph b) the sodium salt and a Added a solution of 13.2 g of dimethyl sulfate in 20 ml of dimethylformamide. After 2 days the mixture will poured onto 200 ml of water. The 3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrido- [2,3-e] [1,3] oxazine crystallizes out of the solution gradually off; Mp 136 ° (from isopropanol); Yield 45%.

e) 3.6 g of the ammonium salt of 2,4-dioxo-3,4-dihydro-2 H-pyrido [2,3-e] [l, 3] -oxazine are in 20 ml Suspended dimethylformamide and mixed with 3.6 g of benzyl bromide with stirring. After 20 minutes a homogeneous solution is created. This is left to stand for 16 hours and then to 100 ml of water poured. 3-Benzyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine is precipitated crystalline from; Mp 174 ° (dioxane); Yield 63%.

f) From 16.4 g of 2,4-dioxo-3,4-dihydro-2H-pyrido- [2,3-e] [1,3] oxazine, 4.8 g of sodium hydride suspension (50%) and 40 ml of dimethylformamide are prepared as in paragraph b) and the sodium salt is 16.6 g Methanesulfonic acid isoamyl ester left to stand for 7 days at room temperature. After diluting 3-Isoamyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine gradually crystallizes with 300 ml of water the end. It is filtered off and crystallized from acetone with the addition of animal charcoal; 98-100 °; Yield 25%.

g) From 30 g of 2,4-dioxo-3,4-dihydro-2 H-pyrido- [2,3-e] [1,3] oxazine, 8.9 g of sodium hydride and 80 ml of dimethylformamide are prepared as in paragraph b) and the sodium salt is prepared with 50 g of toluenesulfonic acid - η - amyl ester in 25 ml of dimethylformamide was left to stand for 78 hours at room temperature. By pouring into 500 ml of water, the 3-n-amyl-

409 769/423

2.4-dioxo-3.4-dihydro-2H-pyrido [2,3-e] [I, 3] oxazine precipitated in crystalline form. It becomes out of dioxane, then out Isopropanol recrystallized; 100 to 102 °; Yield 53%.

The following compounds of the general formula I are obtained in a manner analogous to that given in Example 1:

Ri

Recrystallized from

yield

methyl

n-propyl

η-butyl

Isoamyl

Benzyl

o-chlorobenzyl

m-chlorobenzyl

p-chlorobenzyl

m-fluorobenzyl

p-fluorobenzyl

o-methylbenzyl

m-methylbenzyl

p-methylbenzyl

3 \ 5'-dimethylbenzyl

p-tert-butylbenzyl

2 ', 4'-dichlorobenzyl

3 \ 4'-dichlorobenzyl

o-methoxybenzyl

m-methoxybenzyl

p-methoxybenzyl

3 \ 4'-dimethoxybenzyl ..
3'.4 ', 5'-trimethoxybenzyl

Thenyl (2 ')

Pyridyl (2 ') methyl

Pyridyl (4 ') methyl

136 °
until 13Γ
up to 115 °
up to 100 °
174 °
up to 158 °
137 °
up to 153 °
up to 152 °
up to 180 °
up to 165 °
up to 126 °
145 °
175 °
up to 163 °
up to 157 °
up to 179 °
up to 169 °

iir

168 °

172 °
to 146 °

175 °
122 °
195 °

Isopropanol
Isopropanol
Isopropanol
Isopropanol
Isopropanol
Isopropanol — Acetone Isopropanol — Dioxane Isopropanol — Acetone Isopropanol — Acetone Acetone — Dioxane
Dioxane
Isopropanol
Isopropanol
Acetone-dioxane
Isopropanol — Acetone Isopropanol — Acetone Acetone — Dioxane
Dioxane

Acetone-dioxane
Isopropanol
Acetone-dioxane
Acetone-dioxane
Acetone-Isopropanol Acetone-Isopropanol Isopropanol-Dioxane

54 52 60 58 63 44 59 58 39 44 64 31 54 70 45 53 80 30 72 74 37 51 40 37 42

Example 2

A solution of 2.00 g of 3-hydroxy-N-benzylpicolinamide in 3.6 ml of 2.5 η potassium hydroxide solution and 30 ml of water is mixed with 0.9 ml of ethyl chloroformate and shaken for 10 minutes. The precipitated oil is taken up in methylene chloride-ether and the organic phase extracted with 1 η-potassium hydroxide solution KOH, washed with water, dried and evaporated. After crystallization from isopropanol, the residue gives colorless crystals of 3-benzyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine; F. 174 ^: ; Yield 8%.

Example 3

A suspension of 2.8 g of 3-hydroxy-N-benzylpicolinamide in 8.0 ml of sym. Collidine, 2.5 ml of ethyl chloroformate are added. The received Reaction mixture is heated to 180 ° in an oil bath over 15 minutes and 15 minutes left at this temperature with simultaneous distillation of volatile components. The cooled reaction mixture water and ether are added, the mixture is filtered and the residue is added with animal charcoal recrystallized from isopropanol-methylene chloride. 2.00 g of 3-benzyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine are obtained in the form of colorless Crystals; Mp 174 °; Yield 64%.

3- [2'-Methyl-butyl- (4 ')] - 2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine was obtained in an analogous manner manufactured; M.p. 98 to 100 ° C (from isopropanol); Yield 62%.

Example 4

11.8 g of N-methyl-3-hydroxy-picolinamide are in 50 ml of dry acetonitrile and 10.9 g of sym. Collidine with stirring with 7.0 ml of methyl chloroformate added in 20 ml of acetonitrile. The initially homogeneous reaction mixture separates gradually a precipitate. It is stirred for 4 to 6 hours at 30 to 40 ° and left to stand overnight. After evaporation in vacuo, a residue remains to which 150 ml of water are added will. 3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2.3-e] [1,3] oxazine separates when standing; Mp 136 ° (from isopropanol); Yield 50%.

The following derivatives of 2,4-dioxo-3,4-dihydro-2 H-pyrido [2,3-e] [l, 3] -oxazins obtained:

3-isoamyl: m.p. 98 to 100 ° (acetone); yield 31%;

3-Benzyl: mp 174 ° (dioxane); Yield 72%;

3-isobutyl: mp 131 ° (isopropanol-acetone); yield 49%.

Example 5

A solution of 9.0 g of 3-hydroxy-N-phenylpicolinamide in 25 ml of sym. Collidine is 8.0 ml Ethyl chloroformate is added, a precipitate being formed on heating. That The reaction mixture is heated to 155 ° in an oil bath for 15 minutes and to 175 ° for 15 minutes simultaneous distillation of volatile components. The reaction product is cooled with water and Ether added, filtered and the remaining

violet crystals from dioxane with the addition of animal charcoal recrystallized. Colorless crystals of 3-phenyl-2,4-dioxo-3,4-dihydro-2 H-pyrido [2,3-e] [1,3] oxazine are obtained; M.p. 279 to 281 °; Yield 44%.

The following 2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazines were produced in an analogous manner manufactured:

3- (p-Methylphenyl) -: mp 253-254 ° (dioxane); Yield 61%;

3- (m-Methylphenyl) -: mp 163-165 ° (ethanol); Yield 20%;

3- (p-Methoxyphenyl) -: mp 219-221 ° (chloroform-isopropanol); Yield 48%;

3- (m-Chlorophenyl) -: mp 197-198 ° (chloroform-isopropanol); Yield 35%.

15th

Example 6

2.0 g of 3-hydroxy-N-phenyl-picolinamide are in 20 ml of absolute acetonitrile dissolved with 1.5 g of sym. Collidine and 1.0 ml of methyl chloroformate added and stirred at 20 to 30 °. After 10 to 14 hours, the resulting suspension is at evaporated to a pressure of 20 torr. The residue is triturated with 30 ml of water. The rubbery one insoluble product is triturated with alcohol (3 to 5 ml) after pouring off the water, whereby it crystallizes. The crude 3-methoxycarbonyloxy-N-phenyl-picolinamide is dissolved in a little hot acetone and the sparingly soluble residue is filtered off. By cooling and after adding the product crystallizes from ether. 1.3 g are obtained (51% yield). After two more crystallizations the compound melts at 100 to 104 °.

0.45 g of 3-methoxycarbonyloxy-N-phenyl-picolinamide are heated to 250 ° for 10 minutes with 1.5 g of diphenyl ether. After cooling, 5 ml Ether shifted. A crystalline, dark precipitate forms from which after recrystallization from dioxane (charcoal) colorless crystals of 3-phenyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] -oxazine from melting point 279 to 281 °; Yield 26%.

B e i s ρ i e 1 7

A solution of 2.5 g of 3-hydroxy-picolinic acid methyl ester, 1.8 g of phenyl isocyanate and six drops of triethylamine in 20 ml of absolute ether was Left to stand at room temperature for 30 hours. The solvent is excreted from the large crystals are decanted, and these are redissolved from methylene chloride-ether. Colorless ones are obtained Crystals; M.p. 72 to 74 °; Yield 58%.

When heated to about 200 °, the product converts into the with elimination of methanol 3-phenyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] - [1,3] -oxazine um; F. 279 to 281 °.

Example 8

A solution of 2.5 g of 3-hydroxy-picolinic acid methyl ester, 1.8 g of phenyl isocyanate and six drops of triethylamine in 20 ml of dry acetonitrile was Left to stand at room temperature for 30 hours. The reaction mixture is evaporated in vacuo and the crystalline residue digested with ether, filtered and recrystallized from dioxane. You get colorless crystals of 3-phenyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine; M.p. 279 to 281 °; Yield 45%.

The following 2,4-dioxo-3,4 - dihydro - 2 H - pyrido [2,3 - e] [1,3] - oxazines were prepared in an analogous manner:

3- (p-Methylphenyl) -: mp 253-254 ° (dioxane);

Yield 47%;
3- (p-Chlorophenyl) -: mp 258 to 260 ° (dioxane); Yield 32%;

3- (3 ', 4'-dichlorophenyl) -: mp. 263 to 264 ° (dioxane); Yield 21%.

Example 9

3.0 g of 3-hydroxy-picolinic acid methyl ester, dissolved in 10 ml of anhydrous acetonitrile are mixed with 4.0 g of n-butyl isocyanate and five drops of triethylamine about Left in a closed jar for 3 days at room temperature. After evaporation of the solvent in vacuo, a crystalline residue remains, which melts at 111 to 112 °. By Recrystallization from a little methanol increases the melting point of the 3-n-butyl-2,4-dioxo-3,4-dihydro-2H-pyrido [2,3-e] [1,3] oxazine obtained to 115 °; Yield 57%.

Claims (1)

Claim: Process for the preparation of new pyrido- [2,3-e] [l, 3] -oxazines of the general formula in which Ri is a hydrogen atom, an alkyl radical with a maximum of 5 carbon atoms, one optionally substituted by a maximum of 3 halogen atoms, lower alkyl or alkoxy groups Phenyl, benzyl or phenacyl radical or a thenyl or pyridylmethyl radical, characterized in that one in on known way either a) to a compound of the general formula OH CO - NH - optionally in the presence of an inorganic or organic base, a compound the general formula X-C-Y III in which X and Y are identical or different and are hydrocarbon radicals bonded via oxygen atoms or represent halogen atoms or each radical X and Y represent the group means, lets act and one at most Compound of the general formulas obtained as an intermediate IVa or NH - COOR COOR NH - Ri ' IVb in which R is a lower alkyl radical or the benzyl radical and Ri 'is a hydrogen atom, a lower alkyl radical or the phenyl radical, converted into the corresponding compound of the general formula I by heating or
b) a compound of the general formula OH COOR ' in which R 'denotes a lower alkyl radical, in the presence of a base with an isocyanate the general formula Ri-N = C = reacts and a compound of the general, possibly obtained as an intermediate formula O - CO - NH - Ri COOR ' converted into a compound of the general formula I by heating and optionally then a compound of the general formula I obtained in which Ri means a hydrogen atom, converted into a metal or ammonium salt and this with a reactive ester of a hydroxy compound of the general formula Ri "- OH VIII where Ri "is an alkyl radical with at most 5 carbon atoms, one optionally with a maximum of 3 halogen atoms, lower alkyl or alkoxy groups substituted benzyl or phenacyl radical or a thenyl or pyridylmethyl radical means, implements. Considered publications:
German Patent No. 906 934;
Austrian patent specification No. 215 993. 409 769/423 1.65 © Bundesdruckerei Berlin