DE2237073C2 - Process for the preparation of pyrido [3,4-e] -as-triazines and their salts - Google Patents

Description

optionally in the presence of an acid as catalyst, converts the resulting N- [3-nitropyridyl- (4) -aminol-iminoether of the general formula]

40

MR

NN = COC ₂ H ₅

45

50

reduced with catalytically excited hydrogen, wherein at the same time ring closure takes place, and optionally subsequent to the oxidation of the thus obtained, 1,2-hydrochloride of the general formula IV, optionally isolated as Hydrochlorld, the compound of the general formula I obtained in a salt Oberfuhrt,

NO ₂

wherein R stands for a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a phenyl radical, he follows. The imino ethers of the general formula III, which are new compounds, can surprisingly in a clear reaction in high yields are produced and also surprisingly have a strong tendency to reductlven ring closure. No side reactions leading to hydrazldine type byproducts occur during their formation and In the reduction of the aforementioned instant ether derivatives, not only does the conversion of the o-position nitro group into an amino group take place, but this occurs at the same time in situ reacting with the very reactive tmlnoether group, creating an intramolecular Cyclization to Dlhydropyrido [3,4-e] -as-trlazinen occurs.

The invention is therefore a method for Preparation of pyrldo [3,4-e] -as-tralzines of the general formula

The invention relates to a new method for the production of. optionally in the 3-position of the Trlazlnrlngcs by an alkyl radical with 1 to 6 carbon

65 wherein R represents a hydrogen atom, an alkyl radical with 1 up to 6 carbon atoms or a phenyl radical, as well as their salts from 4-Hvdrazlno-3-nitroovrldin

and. Oxidation of the J, 2-PlhydrapyTldPi3,4-e] -as-t! Iaz | ns obtained therefrom the general formula

IV,

10

which is characterized in that the 4-hydrazino-3-nitropyrldIn with a triethyl orthocarboxylate of the general formula

RCOC ₂ H ₅ 0-C ₂ H ₅

H,

20th

(produced, for example, according to Aliphatic Orthoester, Reinhold, H. Y., 1943 or Chem. Rv. 45 [1949], p. 463).

optionally in the presence of an acid as a catalyst, converts the obtained N- [3-Nitn ?? yrldyl- (4) -amino] -iminoether of the general formula

- N = C - O - C ₂ H ₅

ra

30th

35

NO ₂

reduced with catalytically excited hydrogen, with ring closure taking place at the same time, and optionally following the oxidation of the 1,2-dihydro compound of the general formula IV obtained in this way, optionally isolated as the hydrochloride, the obtained compound of the general formula I is converted into a salt.

To implement the 4th hydrazino-3-nitropyridine with the orthocarboxylic acid triethyl ester is used as a catalyst p-toluenesulfonic acid is preferably used.

For the reduction and associated cyclization of the N- [3-NItropyrIdyl- (4) -aminoJ-lminoethers of the general formula III are noble metal catalysts, especially palladium on carbon, are preferred.

For the oxidation of the 1,2-dihydropyrido [3,4-e] -astriazlne of the general formula IV it can be advantageous Serve atmospheric oxygen.

The oxidation sensitivity of 1,2-dihydropyrldo [3,4-eI-ss-trlazine of the general formula IV is generally so large that it is sufficient to dissolve it to evaporate following the reduction, the 1,2-Dlhydroverblindungen under the action of the bo Atmospheric oxygen In the corresponding aromatic compounds [Pyrldo (3,1-e) -as-trlazlne] of the general Formula I are transferred.

However, the solution can also be used after the reduction Filter in an oxygen-free inert gas atmosphere and add hydrochloric acid to the filtrate in order to obtain the 1,2-hydrochloric acid of the general formula IV as Isolate hydrochloride.

One advantage of the invention is that the aromatic compounds of the general formula I can be prepared in fewer reaction steps (2 instead of 4 steps). Another advantage is that the yield of the compounds of the general formula I is increased to about 2 times when all reaction stages are taken into account (60 to 70 * instead of the 30 to 35 * according to the state of the art). Another advantage lies in this that, in contrast to the products of the prior art containing high amounts of impurities, according to the invention, due to the clear formation and cyclization of the compounds of the general formula III, an end product of high purity (uniform due to layer chromatography) is obtained in the high yields mentioned.

The invention is illustrated by the following examples explained in more detail

example 1 Pyrtdo [3,4-e] -as-trtazine

a) N- [3-Nitropyridyl- (4) -amIno] -formiminoethyl ether

18.5 g (0.12 mol) of 4-hydrazino-3-nitropyridine were heated to boiling with 300 cm ^{1 of} triethyl orthoformate in the presence of 0.1 g of p-toluenesulfonic acid for 3 hours with stirring. The mixture was then cooled with ice water and the orange-colored precipitate was filtered off; Yield: 20.4 g (81.0 * of theory) N- [3-nitropyridyl- (4) -amino] -formiminoethyl ether, melting point: 108 to 109 ° C. Analysis: For CsHj ₀ N ₄ O ₃ (molecular weight: 210.2):

calculated: C = 45.70%, H = 4.76 *, N = 26.65 *; found: C = 45.41 *, H = 7.78 *, N = 26.45 *.

b) pyrido [3,4-e] -as-triazine

There were 21.02 g (0.1 mol) obtained as described in the previous section a) N- [3-NitropyridyI- (4) -amino] -formlmlnoäthyläther in 800 cm ^J ethanol in the presence of 1.5 g of Pa ' ladiuiu / charcoal catalyst on a shaker. Shaken in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. After the catalyst had been filtered off, the solution was ^{concentrated in vacuo at a temperature of at most 50 °} C. to about V _{20 of} its volume. The precipitate was filtered off and recrystallized from heptane; Yield: 11.2 g (85% of theory) of pyrido [3,4-e] -as-triazine; Melting point: 91 ° C (with decomposition). Analysis: For C ₆ H ₄ N ₄ (molecular weight: 132.13):

calculated: found:

C = 54.51%, C = 54.60 *,

H = 3.05%, H = 3.10 *,

N = 42.45%; N = 42.45 *.

Example 2

3-Phenylpyrido [3,4-e] -as-triazine a) N- [3-NitropyrldyH4) -amlno] -benzylmlnoethyether

There were 15.4 g (0.1 mol) of 4-hydrazine-3-nltropyridln with 50 cm ^{1 of} trlethyl orthobenzoate in the presence of a little p-toluenesulfonic acid heated to boiling with stirring, the ethanol formed in the reaction and then a large part of the Orthoesters were removed. The residue was triturated in gasoline and then recrystallized from methanol; Yield: 25.5 g (89% of theory) of N- [3-Nltropyrldyl- (4) -amlno] -benzlmlnoethyl ether; Melting point: 109 to 110 ⁰ C.

FQ; c _h h _h na (Mpiaccular weighted; 286.29);

calculated; G = 58.70%, H = 4.93%, N = 19.55%;
found; C = 58.80 », H-4.99», N = 19.6Q%,

There were 28.62 g (0.1 mol) as (m above section β) described obtained NP-Nltropyridyl- (4) -amInö] -benzimfrioäthyiather in 1300 cm ^{1 of} ethanol in the presence of 1.5 g of a Palladlurn / Knocbenkoble- Catalyst hydrogenated until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and the solution was evaporated in vacuo. The residue was recrystallized from ethanol. Red shiny plate-shaped crystals were obtained; Yield: 18.3 g (88% of theory) 3-phenylpyrido- [3,4-e] -as-triazIn; Melting point: 127 to 127.5 ° C.
Analysis: For CuH ₁ N ₄ (molecular weight: 208.23):

calculated: C = 69.20 ", H = 3.87", N = 26.85 *;
found: C = 69.14%, H = 3.86%, N = 26.99%.

Example 3

3-Methylpyrtdo [3,4-e] -as-triazine
a) N- [3-NitropyridyI- (4) -amino] -acetiminoethyl ether

55 g (0.357 mol) of 4-hydrazino-3-nitropyridine and 0.1 g of p-toluene-sulfonic acid were heated to boiling with 472 g of ethyl orthoacetate for 2 hours with stirring. After the mixture had cooled, an orange-colored precipitate of N- [3-nitropyridyl- (4) -amino] -acetiminoethyl ether separated out, the weight of which after filtration and drying was 67.65 g (84.3% of theory); Melting point: 120 to 122 ° C (after recrystallization from 1/1 times the amount of benzene). Analysis: For CH ₁₂ N ₄ O ₃ (molecular weight: 224.2):

calculated: C = 48.20%, H = 5.38%, N = 24.90%;
found: C = 47.90%, H = 5.40%, N = 24.78%.

b) 3-MethyI-1,2-dihydropyrldo [3,4-e] -as-triazine dihydrochloride

There were 3.36 g (15 mol) as described in the previous section a) obtained N- [3-Nitropyridyl- (4) -aminoJ-acet! Mlnoäthyläther in 400 cm ¹ ethanol in the presence of 0.5 g of palladium / animal charcoal -Catalyst hydrogenated until the theoretical amount of hydrogen was consumed. The catalyst was then filtered off from the solution in an inert (oxygen-free) atmosphere and the filtrate was poured into hydrochloric isopropanol. The precipitate which separated out after the solution had been concentrated to about 1/2 of its volume was filtered off. This was recrystallized from a mixture of ethanol and isopropanol, precipitating with ether; Yield: 2.32 g (70% of theory) of 3-methyl-1,2-dlhydropyrldo [3,4-e] -astrlazln-dihydrochloride; Melting point: 220 to 221 ° C.
Analysis: For C ₇ H ₁₀ CIjN ₄ (molecular weight: 221.10):

calculated:

C = 38.05%, H = 4.56%, Cl = 32.10%, N = 25.35%;

found:

C = 38.00%, H = 4.50%, Cl = 32.54%, N = 25.45%.

c) 3-methylpyrido [3,4-e] -as-triazln
2.21 g (0.01 mol) of 3 ^ Methy! -L, 2'dlhydrppyridoP ^ J-ss-trtazin-dihydrochlorfd, obtained as described in section W, were dissolved in 30 cnV of water and a solution of 6, 6 g (0.02 mol) of potassium cyanide in 25 cm ^{4 of} water were added. The mixture was then made alkaline with potassium hydroxide solution. After stirring for hour, the product was extracted with ether and, after evaporation of the solvent, 1.31 g (90% of theory) of 3-methylpyrido [3,4-el-as- triazIn received;

ίο Melting point: 112 to 113 "C (after recrystallization from benzene),
Analysis: For C ₇ H ₆ N ₄ (molecular weight: 146.16):

calculated: C = 57.60%, H = 4.14%, N = 38.35%;
found: C = 57.06%, H = 4.47%, N = 37.98%.

Example 4
3-ethylpyrido [3,4-e] -as-ti1azine

a) N- [3-Nitropyridy! - (4) -am! no] -propionImIno-

äthyiäthe -

7.7 g (0.05 mol) of 4-hyraazino-3-nitropyrldine were ^{heated to boiling for 3 hours in the presence of 0.1 cm 1 of} hydrochloric acid ethanol with 25 cm 'of triethyl orthopropionate. The axiianol formed during the reaction was distilled off and the precipitate which separated out on cooling was filtered off; Yield: 9.6 g (80% of theory) of N- {3-nitropyridyl- (4) -amino] propioniminoethyl ether; Melting point: 98 to 100 ° C.

Analysis: For C, oH, ₄ N ₄ Oi (molecular weight: 238.2):

calculated: C = 50.40%, H = 5.92%, N = 23.52%;
found: C = 50.46%, H = 6.00%, N = 23.42%.

b) 3-ethyl-1,2-ditiydropyrido [3,4-e] -as-triazine dihydrochloride

There were 1.8 g (7.55 mol) v / Ie of N- [3-N'ftropyridyl- (4) -amino] -propioniminoethyl ether described in section a) above in 250 cm ^{3 of} ethanol in the presence of 0.5 g of a palladium / bone carbon catalyst shaken in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. After filtering off the catalyst, the solution was evaporated in a nitrogen atmosphere and when the residue was mixed with hydrochloric acid ethyl alcohol, light brown crystals resulted; Yield: 0.85 g (47.8% of theory); Melting point: 253 to 254 ° C (after recrystallization from methanol).
Analysis: For C ₁ H ₁₂ CI ₂ N ₄ (molecular weight: 235.13):

calculated:

C = 40.80%, H = 5.14%, Ci = 30.25%, N = 23.85%;

found:

C = 40.60%, H = 5.05%, Cl = 30.72%, N = 23.34%.

c) 3-Ethylpyrldo [3,4-e] -as-trlazln

There were 2.35 g (0.01 mol) of 3-ethyl-1,2-dlhydropyrldo [3,4-e] -as-trlazln-dlhydrochlorld obtained as described in section b) above In the example 3, section c) described catfish oxidized, whereby 3-Ethylpyrldo [3,4-e] -as-triazln in a yield of 92% of theory with a melting point of 113 to 119 ° C (from benzene) was obtained.

Claims (1)

Claim; Process for the preparation of pyrido [3,4-e] -as-trfazinen the general form) wherein R represents a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or a phenyl radical, as well as their salts from 4-hydrazino-3-nitropyridine and oxidation of the resulting therefrom 1,2-Dihydropyrido [3,4-e] -as-triazole of the general formula IV, atoms or a phenyl radical substituted pyrido-P, 4-e] -8s-trla?! nen _and their salts, these compounds are known antimicrobial agents or agents for inhibiting the growth of microorganisms, It is known that 3-alkyl-pyrldo [3,4-e] -as-trJ3Zfne by reacting 4-chloro-3-nitropyridine with an acid hydrazide, catalytic reduction of the 4-acylhydrazino-3-nitropyridine obtained and subjecting the so obtained compounds of a ring closure reaction can be prepared (French patent 1449 778). With repeated reproduction of this synthesis, however, 3-MethyI-pyrido [3,4-e] -as-trlazln could only be obtained in a yield of 1596 and this is crude product was heavily contaminated. A product of acceptable purity could only be obtained after several recrystallization operations. According to another known Vei ^ pWen pyrido [3,4-e] -as-triazln and its 3-methyl derivative of A- Hydrazino-3-nitropyridine starting with a 4-stage Synthesis (reduction, formylation or acctylation, cyclization and oxidation) in 30 to 35% yield produced (J. Heterocycl. Chem. 8, 1971.47). The invention is based on the finding that pyrido [3,4-eJ-as-triazine in high yield and with high purity can be produced if their production via imino ethers of the general formula characterized in that the 4-hydrazino-3-nitropyridine with a triethyl orthocarboxylate of the general formula 0-C ₂ H ₅ RCOC ₂ H ₅ 0-C ₂ H ₃ 35 Π, = C-O-C ₂ H ₅