SU488415A3 - The method of obtaining derivatives of tetrazole - Google Patents

Description

Kie azides, such as aluminum or azides based on nitrogen-containing bases, such as MONO-, tri-, tetramethylammonium, aniline, morpholine and piperidium azides, can also be used. In the case of using a non-alkali metal azide, it can be obtained in the reaction mixture of the main reaction. The reaction can be carried out in the presence of an electron acceptor, for example aluminum chloride, boron trifluoride, ethyl sulfo or benzenesulfonic acid. Under these conditions, the reaction can also proceed with the use of a nitrogen-containing acid at 20-150 ° C in a suitable solvent under elevated pressure. When a different azide is used, for example, sodium azide, the reaction product is the corresponding tetrazole salt. This salt can be converted into the free acid in the usual manner by treatment with a strong acid, for example hydrochloric.

According to the proposed method, a compound of the formula R-CN3 NH is formed as an intermediate product. The lightly split group Z may be an alkoxy, thio or alkylthio group, for example, lower alkoxy or lower alkylthiol.

Compounds of formula IT wherein Y is CN-rpynny can be obtained by dehydrogenating the corresponding compound of formula

R-CONH2 IV.

where R has the indicated meanings. As a dehydrating agent, for example, Phosphorus oxychloride is used. The reaction is preferably carried out in the presence of at least 1 mole of dehydrating agent per 1 mole of compound IV. The reaction is carried out in the presence of an acid binding agent, for example, triethylamine, a solvent, for example N, N-dimethylformamide, dimethyl sulfoxide, pyridine, benzene, hexamethylphosphoramide or an excess of dehydrating agent, which can be used as a reaction medium. The reaction is carried out at O-100 ° C, depending on the dehydrating agent used. When phosphorus oxychloride is used, the preferred temperature is O-100 ° C.

Compounds IV can be obtained by reacting compounds of the formula

R-COOR V,

where R has the indicated meaning, and R is a lower alkyl group, with ammonia, using the usual reaction of forming amides from ethers in the presence of alcohol as a solvent at O-120 ° C.

Compounds II, where Y is a group - CZ NH, can be obtained in a known manner from compounds II, where Y is GN, for example by reaction with an alcohol, thiol or H2S in the presence of HCF.

The compounds of formula V are known compounds or may be prepared in a known manner.

Compounds of formula I and intermediates may be isolated from the reaction mixture in a known manner.

The proposed method results in compounds I or their derivatives. This method also provides for the treatment of some tetrazole derivatives in order to obtain free compounds of the formula I or to convert one derivative to another.

Pharmaceutically active derivatives of the compounds of formula I include pharmaceutically active salts. Such salts include water-soluble salts, for example ammonium salts, alkali metal salts (sodium, potassium,

lithium). and alkaline earth metals (calcium, magnesium) and salts of suitable organic bases, for example lower alkylamines, such as methylamine or ethylamine, or substituted lower alkylamines, for example

oxy-substituted alkylamines, or simple nitrogen-containing heterocyclic compounds, for example, piperidine or morpholine.

Rs, Re, R and Rs are hydrogen, branched alkyl radicals containing

I-5 carbon atoms, chlorine, bromine, alkenyl radicals with 2-5 carbon atoms, such as allyl, phenyl, benzyl, acetyloxy, straight and branched alkoxy radicals containing 1-6 carbon atoms, such as alkoxy - alkoxy groups, in which each of the groups contains 1-5 carbon atoms, or alkoxy groups containing 1-4 carbon atoms and substituted with five or six membered oxygen-containing heterocyclic rings, for example tetrahydrofurfuryl oxyl.

In this specification, in the claims, the term "lower means that alkyl or alkoxy radicals contain up to 6 carbon atoms.

Example 1. 5- (6-Chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-yl) -tetrazol.

A mixture of 23.4 wt. including b-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, 7.8 weight. h

sodium azide, 6.4 wt. including ammonium chloride and 200 wt. Part K, 1H-dimethylformamide is transferred and heated on the steam bath for 18 hours. Most of the solvent is distilled off in vacuo. 400 wt. Was added to the solution.

including water acidified with 20% hydrochloric acid. The precipitate which separates is filtered off, washed with water and recrystallized from dioxane. Get 15.5 weight. including 5- (6-chloro5, 7-dimethyl-4-oxo-4H-Lbepzopyran-2-yl) tetrazole as a colorless precipitate with mp. 246-247 ° C (decomposition).

Found,%: C 52.3; H 3.39; CI 12.6.

CisHgClNiOs.

Calculated,%: C 52.1; H 3.28; N 20.24; C1 12.81.

Spectral analysis.

Mass spectrometrically determined molecular weight is 276-278.

IR spectroscopy in zone 1660 defines a carbonyl benzopyran ring. Obtaining the sodium salt of 5- (6-chloro-5,7 dimethyl-4-oxo-4H-1-benzopyran-2-yl) -tetrazol. A mixture of 5.01 wt. including 5- (6-chloro-5,7-dimethyl-4oxo-4H-1-benzopyran-2-yl) tetrazole and 1.52 wt. including sodium bicarbonate dissolved in 50 wt. h of water. The precipitate is filtered off and dried and 5.20 weight is obtained. including sodium salt of 5- (6-chloro-5,7-dimethyl-4-oxo4H-1-benzopyran-2-yl) -tetrazol. The resulting salt is purified; ayut, separated from ethanol by the addition of ether. Spectral analysis. The carbonyl of the beisioiraic ring gives a wide infrared band in the zone of 1645 cm. The NMR spectrum shows a singlet in a 4.2v 3-yrotone benzoranyl ring (solvent is deuterium oxide). Preparation of the starting compound 6-chloro 5, 7-dimethyl-4-oxo-4P-1-biezonn-1-2-carboiitrile. To 400 weight. including N, Ndimethylformamid slowly add 21 wt. including phosphorus oxychloride with stirring and cooling. Then 33.9 wt. including 6-chloro-5,7-dimethyl-4oxo-4H-1-benzopyra-2-carboxamide was added to the solution. The resulting reaction mixture is stirred at room temperature for 18 hours. The dark solution is poured onto 1500 wt. h. ice water. The precipitate was filtered off and recrystallized from ethanol. Get 30.5 weight. including 6-chloro-5,7-dimethyl-4-oxo-4-H-1-benzopyran-2carbonitrile with t. pl. 142-143 ° C. Example 2. 5- (8-ALLYL-5-) -3-methylbutoxy- (4-oxo-4H-1-benzopyran-2-yl) -tetrazolkali salt. 5 wt. including 5- (8-allyl-5 -) - 3-methylbutox - (4oxo-4H-1-benzoiran-2-yl) -tetrazole and 1.4 weight. including potassium bicarbonate dissolved in 75 wt. h. The mixture is dried and receive 5.2 weight. including the potassium salt monohydrate of 5- (8allyl-5- (8-methylbutoxy-) -4-oxo-4P-1-benzopyran-2-yl) -tetrazole as a white powder. Found,%: C 54.02; P 5.53; N 13.92. C18H19KN40zP20. Calculated,%: C 54.02; P 5.39; N 14.00. The NMR spectrum in a hexadeuterodimethylsulfoxide reveals a 3-proton of a beisopyran ring in the 3.57v zone. The UV spectrum shows a laser of 261 nm (e, 19.821). Example 3. 5- (8-ALLNL-5-) -3-methylbutoxy- (4-oxo-4H-1-benzopyran-2-yl) -tetrazolcalcium salt. 5 wt. including 5- (8-allyl-5-) -3-methylbutoxy (4-oxo-4H -1-benzopyra-2-yl) tetrazole and 1.29 wt. including sodium bicarbonate dissolved in 200 wt. h of water. The resulting solution is stirred and 1.25 wt. including calcium nitrate in 100 weight. h of water. The product in the form of a powder is treated with boiling water, isolated and dried under vacuum. Get 4.8 weight. including 5- (8-allyl-5-) -3-methylbutoxy- (4-oxo-4H-1benzopyran-2-yl) -tetrazol in the form of the calcium salt of pentahydrate. Found,%: C 52.97; H 6.01; N 14.02. CseHssCaNsOe ONSO. Calculated,%: C, 52.97; H 6.02; N 14.07. The NMR spectrum in hexadeuterodimethylsuloxide shows the 3-proton of the benzopyran ring in the 3.35v zone, the UV-spectrum shows Vmax 264 nm (e „51,700). Example 4. 5- (8-All-5-5) -3-methylbutosi- (4-oxo-4H-1-benzopyran-2-yl) -tetrazol, salt of morpholine. 4.05 weight. including 5- (8-Allyl-5 -) - 3-methylbutoxy (4-oxo-4H-1-benzoiran-2-nl) -tetrazol and 1.03 weight. including morpholine dissolved in 50 wt. h of water. The resulting solution is dried and get 4.8 weight. including 5- (8-allyl-5-) -3-methylbutoxy (4-oxo-4H -1-benzopyran-2-yl) -tetrazol - morpholine salts - monohydrate. Found,%: C 59.23; H 6.96; N 15.8. C22H29N5O4 H2O. Vychnseno,%: C 59.31; H 7.01; N 15.72. The NMR spectrum in hexadeuterodimethylsulfoxide detects 3-ortho-and benzopyrano rings in the zone of 3.55, the UV spectrum shows 264 nm (e, 25000). Example 5. 5- (8-ALLYL-5-) -3-methylbutoxy- (4-oxo-4H-1-benzoiran-2-yl) -tetrazol, ethylamine salt. 4.7 weight. including 5- (8-allyl-5) -3-methylbutoxy (4-oxo-4H-1-benzonran-2-yl) tetrazole and 0.973 vol. including 70% ethylamine solution in water is dissolved in 50 wt. h of water. The resulting solution is dried and get 5.3 weight. including 5- (8-allyl-5) -3-methylbutoxy- (4-oxo-4H-1-benzoyiran-2-yl) -tetrazol ethylamine salt, sesquihydrate as a yellow powder. Found,%: C 58.49; H 7.48; N 17.09. C2H27N5O3-1.5H20. Calculated,%: C 58.49; P 7.31; N 17.31, 17.05. The UV spectrum shows a laser of 261 nm (e. ,, 28,153). Example 6. 5- (8-ALLYL-5-) -3-methylbutoxy- (4-oxo-4H-1-benzopyran-2-yl) -tetrazol salt of tris (hydroxymethyl) methylammonium. 5 wt. including 5- (8-allyl-5) -3-methylbutoxy (4-oxo-4H-1-benzoiran-2-yl) -tetrazole and 1.76 weight. including tris- (oxmethyl) -methylamine is dissolved in ethanol and heated. The resulting solution is cooled, diluted with ether and the resulting crystalline precipitate is collected, washed with ether and dried in vacuo. Get 5.6 weight. including 5- (8-allyl-5-) -3methylbutoxn- (4 oxo-4H-1-benzopyran-2-nl) tetrazole — salt (oxymethyl) methmethylamine salt, nolhydrate. Found,%: C 55.86; H 6.66; N 15.13. C22H3iN506 0.5NoO. Calculated,%: C 56.16; H 6.86: N 14.893. The NMR spectrum in hexadeuterodimethylsulfoxide surrounds the 3-channels of the benzopyran ring in the 3.25v zone, and the UV spectrum shows the first peak at 261 nm (е ™ 22.934). Example 7. Nitriles listed in table. 1 is obtained from the corresponding amides used in the method of example 1.

Table 1

488415

ten

And about the same II and et a l. 2

Example 8. Tetrazole listed in table. 2, is obtained from the corresponding nitriles used in the method of Example 1.

Subject invention

Claims (3)

1. A process for the preparation of tetrazole derivatives of the general formula I -B ® H where Rg, Re, R, Rs may be the same or different and mean hydrogen, alkyl, halogen, hydroxy, alkenyl, phenyl, alkenyloxy, aralkyl, acyloxy or alkoxy, alkoxy, substituted with alkoXG, hydroxy, or pyroxy; , a six-membered heterocyclic ring containing carbon and oxygen, and alkyl, alkenyl or alkoxy groups contain 1-6 carbon atoms, and V is oxygen (1d poly sulfur, or their salts, characterized in that the compounds of general formula II R y in which R is a group of the formula where Rs, Kb, RT, Rs and W have the indicated meanings, Y-groups — CN or — CZ NH, where Z is an easily detachable group, are treated with azide in an inert medium solvent. 2. Method for and. 1, characterized in that ammonium azide or alkali metal azide is used as the azide. 3. The method according to claim 1 or 2, which is different. in that the reaction is carried out in the presence of an electron acceptor.