SU464998A3 - Method for producing 3-amino-pyrazoline derivatives - Google Patents

Description

and their salts, which consists in the fact that the dinene of the general formula

RI Kg I I R-NH-dR-tiH-C-NH III)

N-OK4

where: R, Ri and R2 are as defined, and R4 is hydrogen or an adyl radical,

or its salt is reacted with an acylating agent and, if it is desired, the compound of formula 1 (where Ks is a hydrogen atom) is subjected to adylation or, if it is desirable, the compound of formula 1 (where Rs is an acyl radical) is converted by disadylation into the corresponding compound of the same formula (where R4 is hydrogen); if desired, the resulting compound is converted into salt or released from the salt.

As characteristic values for R-Rs and when they denote an alkyl group, there may be mentioned straight and branched alkyl groups having preferably 1 to 7 carbon atoms (for example methyl, ethyl, propyl, isopropyl, isobutyl). Alkyl groups may have one or more substituents selected from the group consisting of halogen atoms (for example, chlorine or bromine), amino, alkylamino, dialkylamino, nitro, oxy, and aryl (for example, phenyl) groups. Particularly suitable substituted alkyl groups of R are diphenylalkyl groups.

The aryl group is monodiclic or polydiclic aromatic. radical (phenyl or naphthyl). The aryl coldo may have one or more substituents selected from the group consisting of halogen (for example, chlorine or bromine), nitro, alkyl (for example methyl or ethyl), alkoxy (for example methoxy or ethoxy), amino, alkylamino and dialkylamino. This group also includes heteroaryl radicals, for example pyridyl.

Cycloalkyl group - groups containing preferably carbon atoms, such as diclopentyl or diclohexyl.

Aralkyl group - alkyl groups having 1-5 carbon atoms, substituted by an aromatic ring (for example, benzyl or R-PSNILEHTIL). The aryl part of the aralkyl group may have one or more substituents indicated in the definition of aryl groups.

Particularly useful compounds of formula 1 are those derivatives in which the R-alkyl group has 1-4 carbon atoms, the dicloalkyl group has 5-6 carbon atoms, nitrophenyl, methylphenyl, benzyl or dimethoxyphenethyl or phenyl group; Ri and Rs are hydrogen; Rs is adylel, iropionyl, hydroxyosoyl, or p-piperidinopronionyl group.

as a suitable value of Ra, when it means an adil radical of an organic carboxylic acid, there may be mentioned adyl radicals derived from aliphatic carboxylic acids having L-10 carbon atoms, and substituted derivatives thereof (e.g. adethyl, propionyl,

hydroxyenoyl, ozozoyl or (i-piperidino-propionyl groups). Adil radicals can also occur from heterodiclic acids, such as nicotinic or isonicotinic acid.

(oly compounds of formula 1 can be additive salts of acids, orazuyutsya inorganic acids (. for example, hydrochloric, hydromic, sulfuric, nitric acid, etc.; or organic acids

(eg, p, acetic, lactic, tartaric, maleic, fumaric, nicotinic acids, etc.).

The compounds of formula 1 are the following derivatives: 1- (-nitrophenyl) -3-amino-β-pyrazoline; 1 - (/ g-tolyl) -3-amino-D-pyrazoline; 1- (3,3-diphenyl-propyl) -3-amino-A-pyrazoline; 1-benzyl-3-amino-A-pyrazoline; -12 (a, 4- (dimethoxyphenyl) - - amino-A-pyrazoline; 1-diclohexyl-3-amino-A-pyrazoline; 1-n-butyl-3-amino - A-pyrazoline; adetyl derivatives 1 - (3 , 3-diphenyl-propyl) -3-aminoD-pyrazoline; p-piperidino-propionyl arbitrary 1- (3,3-diphenyl-propyl) -3-amino-A-pyrazoline; a derivative of salidyl acid and 1- (3.3) -diphenyl) -propyl-3-amino-A of pyrazole; atetil derivative of 1-benzyl-3-amino-A-pyrazoline; atetil derivative of (3,4-dimethoxy-phenyl) ethyl-3-amino-A-pyrazoline, 1-diclohexyl -Z-aminoA -2-pyrazolin-adethyl derivative of 1-kbutyl-Z-amino-A-pyrazo lina and their salts.

The compounds of formula 1 thus obtained, in which Rs is hydrogen, can be converted to the corresponding adyl derivatives, N-ad-dated can not be carried out using known methods of adylation, preferably using acid halides, especially acid chlorides or anhydrides.

Compounds of formula 1 in which Rs is adyl can be converted to the corresponding compounds of the same formula in which Ra is

hydrogen. Reakdi can be carried out using known methods of disadilation. It can proceed preferentially when treating an adil derivative with a base. For this purpose, preferably can

alkali metal hydroxides, such as sodium hydroxide, are used. Reakdy can be performed preferably in the presence of an organic solvent. Suitable organic solvents are aliphatic alcohols, for example ethanol.

Amidoxime starting materials of the formula II can be obtained in good yields by the interaction of the nitrile of the formula III

EI Co.

Г I (Н-С11- («1Ш)

where R is R2 have the indicated meanings,

with hydroxylamine. Nitriles of the formula III are obtained by unknown methods, for example by the interaction of the corresponding amine with acrylonitrile or (3-haloethylnitrile with an amine.

Compounds of formula I, prepared in such a way that Cs is hydrogen, can be N-apylated. The reaction is carried out according to known methods, preferably using acid halides. Thus, compounds of formula I are prepared in which the RS is an acyl radical of an organic carboxylic acid.

The compounds of the formula I thus obtained can be converted into their salts formed with inorganic or organic acids. Salt formation may be carried out by known methods, preferably by reacting a compound of formula I in the presence of an organic solvent with an equivalent amount of the appropriate acid.

Example 1. 1.79 g (0.01 mol) of p-phenyl-amino-propionic acid amino-acid amine rasp Example

Nitrile Formula 1I

H- (p-Nitro-anilino) propionitrile

3- (p-Methyl-an: 1Lino) propionitrile

steep in 10 ml of pyridine, after which, with stirring and cooling, 2.1 g of α-toluenesulfonic acid chloride are added so that the temperature does not exceed 20 ° C. The reaction mixture is heated on a water bath for 3 hours, after which pyridine is evaporated in vacuo. The residue is shifted from 4 ml of an aqueous solution of sodium hydroxide and 5 ml of 96% ethanol. Precipitated crystalline

0 the product is filtered with suction and washed until neutral with water. After recrystallization from ethanol, 1.06 g of 1-phenyl-E-amino-A2-pyrazoline is obtained. Yield 66%, so pl. 168-169 ° C.

five

Example 2. 26.5 g (0.182 mol) of p-phenylamino-propionitrile was dissolved in 150 ml of ethanol, after which a solution of 28.6 g of hydroxylamine hydrochloride, 30.4 g of sodium hydrogencarbonate and 50 ml of water was added. Reactionary

The mixture was heated under reflux for 8 hours, after which the alcohol was distilled off and 200 ml of water was added to the residue. Upon gentle stirring, an oily product is formed, which soon becomes crystalline. Thus, 26.2 g of p-phenylamino-propanoic acid amidoxime are obtained. Yield 90%, so pl. 88-92 ° C, which does not change after recrystallization from a mixture (1: 1) of ethyl acetate to patrol ether.

Calculated,%: C 60.3; H 7.32; N 23.45.

CflHisNsO.

Found,%: C 60.6; H 7.43; N 23.7.

Examples 3-4. The compounds obtained analogously to Example 2 are listed in Table. one.

Table

T. pl., C

Amidoxnm formula II

Amidoxime 3- (l-nitroanilino) -propioiovon

acids

Amidoxime 3- (l-methylanilino) -propionic acid

Example 5. A mixture of 1.99 g (0,0062 mol) - (3,3-diphenyl-propyl) - 3-amino - A-pyrazoline-acetyl derivative, 20 million n. an aqueous solution of sodium hydroxide and 20 ml of 96% ethanol is heated to boiling for 3 hours. The clear yellow solution is cooled, after which the needle-like crystals precipitated are filtered by suction, washed with water and dried under an IR lamp. Thus, 1.61 g of 1- (3,3-diphenyl-propyl) -3-amino-A-parazoline is obtained. Output 92%, so pl. 159-16GS. After recrystallization, the melting point rises to 163-165 ° C.

Calculated,%: C 7.37; H 7.50; N 15.13.

Cl8H2lN3.

Found,%: C 77.17; H 7.42; N 15.34.

The base is converted to the dihydrochloride with ethanol containing hydrochloric acid. T. pl. 160 ° C, which remains unchanged after recrystallization from ethanol containing hydrochloric acid.

Calculated,%: C1 20.1; C, 61.40; H 6.58; N 11.92. SiNgszs.

Found,%; C1 20.33; C, 61.5; H 6.50; N 11.86.

Examples 6-10. The compounds prepared analogously to Example 5 are listed in Table. 2,

Amino-piercer formula 1

Acyl Derivative of Formula 1

Example

1- (3,3-Difen11l-propyl) -3-amino-D pyrazoline

1-Benzyl-3-Amine-D-n: Fazolin

(3,4-Dimethoxyphenyl) -eth 1L -3amino-D-pyrazoln

1-Cyclohexyl-3-amino-D-pyrazoline

1 st Butyl-3-amio-D2-pyrazoline

Acetyl-derivative 1-n. butyl 310 amino-D-pyrazoline

Example II 26.44 g (0.1 mol) of p- (3,3-diphenyl-propylamino) propionitrile is dissolved in 100 ml of ethanol, after which a solution of 14 g of hydroxylamine hydrochloride, 16.8 g of sodium carbonate hydrochloride and 50 ml of water. The reaction mixture was boiled in a water bath for 4 hours. The alcohol is then distilled off in vacuo, the aqueous residue is mixed with 200 ml of water, the precipitated product is filtered, washed with water and dried. Get 29G of the crude amidoxime. P- (3,3-diphenyl - propylamino) - propionic acid. Yield 97%; m.p. 155-158 ° C. The crude product can be used for further reaction without purification. After recrystallization

Received amidoxime formula II

The original nitrile of formula III

Example

Amidoxime (3,4-dimethoxyfere-3- 2- (3,4-Dimethoxyphenyl-) -ethyl-aminotropionic aminopropionitrile acid

Amidoxime 3-benzylaminopropio3-benzylaminopropionitrile new acid

Amidoxime 3-cyclohexylamino3-Cyclohexylaminopropnonitrile propionic acid

Amidoxime 3-n-butylaminopropio3-m-Butylaminopropionitrile nova acid

Example 16: To 211.3 g (1.0 mol) of 3,3-diphenyl-propylamine, 53.1 g (1.0 mol) of acrylonitrile was added with stirring and cooling with water for about an hour. The solution is heated in a water bath for about 8 hours. The resulting thick solution (264 g) is cooled. -When being gently stirred, p- (3,3-diphenylpropylmino) propylnitrile is obtained with a good yield; m.p. 54 ° C; m.p. 195-197 °. Crude nitrile

table 2

M.p.

163-165 (of

nego ethanol)

73-80 (from cyclohexane), gpdrochloride 238 (from anhydrous ethanol)

158-160 (from ethyl acetate hydrochloride 182-185 (from 96% ethanol)

86-88 (from cyclohexane), hydrochloride 233 (from anhydrous ethanol)

65-70 (from petroleum ether), hydrochloride 147 (from anhydrous ethanol)

from ethanol, the melting point rises to 158-160 ° C.

Calculated .N 14.13%.

CisnocNsO.

Found N, 13.97%.

The base can be converted to the dihydrochloride with ethanol containing hydrochloric acid, m.p. 209-211 ° C.

Calculated,%: C 58.40; H 6.81; N 11.3-5; C1 19.15.

CisHssCI NsO.

Paydeno,%: C 58.42; H 7.00; N 11.17; C1 19.02.

Examples 12-15. The compounds obtained in Example 11 are listed in Table. 3. Table 3

M.p.

108-110 (from ethyl acetate)

Hydrochloride 167 (from 96% ethanol)

119 (out of water)

82-85 (from ethyl acetate and petroleum eff | pa)

can be used for further reaction without purification. Calculated,%: C 82.10; P 7.67; N 10.64.

Cl8n2oN2 Found,%: C 81.96; H 7.44; N 10.56.

Example 17. 2.79 g (0.01 mol) of amidoxime p- (3,3-diphenyl-propylamino) -propionic acid are dissolved in 15 ml of anhydrous pyridine, after which 2.1 g (0.011 mol

acid chloride l-toluene sulfonic acid with

room temperature with stirring and cooling (dropwise). After the addition, the reaction mixture is heated in a water bath for 3 hours and the pyridine is distilled off in vacuo. The residue is mixed with a mixture of 10 ml n. a solution of sodium hydroxide and 5 ml of 96% ethanol. The precipitated crystals are filtered, washed with water and dried. 2.0 g of 1- (3,3-diphenyl-propyl) 3-amino-D2-pyrazoline are obtained. Yield 72%; m.p. 159-16GS.

Example 18. From 3- (p-chloroaniline) propionitrile, amidoxime of 3- (para-chloroaniline) propionic acid is obtained to obtain amidoxime 3- (para-chloroaniline) propionic acid by the method described in Example 2.

Example 19. A solution of 20.8 g of hydroxyl hydrochloride, ina and 25.2 g of sodium bicarbonate in 60 ml of water are added to a solution of 34.3 g (0.144 mol) of n-dodacylamyopropionitrile in 120 ml of 96% ethanol. The mixture is heated under reflux for 6 hours. The precipitated tipfi cooled crystals are filtered under vacuum, washed with water and dried. Obtain 28 g (ODOZ mol) amidoxime Z- (n-dodecylamine) -propionic acid, so pl. 85-88 ° C.

Example 20. 86.7 (0.45 mol) 3- (p-naphthylamine) propionitrile was dissolved in 400 ml of 96% ethanol and a solution of 65 g of hydroxylamine hydrochloride and 80 g of sodium bicarbonate in 200 ml was added to the solution water. The mixture is heated under reflux for 8 hours. The crystals precipitated upon cooling are filtered off under vacuum and washed with water. After recrystallization, 94.2 g (0.41 mol) of amiodoxime H- (p-naphthylamine) -propionic acid are obtained. Colorless product has so pl. 148-150 ° C; yield 92%.

Example 21. A solution of 4.6 g (0.02 mol) of amidoxime-3- (p-naphthylamine) propionic acid and 5.03 g (0.06 mol) of ethyl acetate in 40 ml of anhydrous ethanol is added to solution 0, 46 g of sodium in 15 ml of anhydrous ethanol. The mixture is boiled for 8 hours, after which the booster is distilled off in vacuo, 50 ml of water are added to the residue and the resulting crystals are filtered, washed with water and dried. 3.25 g (0.0128 mole) of colorless crystals are obtained. T. pl. 10-8-112 ° C; yield 64%. After recrystallization from 96% ethanol, (. P-naphthyllmine) -ethyl-5-methyl-1,2.4-oxadiazole is obtained with m.p. . 10-112 ° C.

Example 22. 2.54 g (0.01 mol) of 3-2-OP-naphthylamine) ethyl-5-methyl-1,2,4-oxadiazole is boiled for 6 hours in 20 ml of 20% -, sodium nitrate solution. The solid is dissolved, filtered off under vacuum, washed with water until neutral, and dried. . :. Obtain 1.8 g (0,0075 mol) of colored crystals 1- (8-naphtha; l) 3-amine-.M., Pip olina. Yield 85%; m.p. 185-190 SGS from recrystallization from methanol The melting temperature decreases to 173 ° C.

Example 23. From 3- (para-chloro-anilinoethyl) -5-methyl, g 1,2,4-.oxadiazole a - by the method,

Described in Example 1, 1- (succinophenyl) -3-ami-no-D-pyrazoline is obtained. T. pl. 144-146 ° C; yield 73%.

Example 24. 2.79 g (0.01 mol) of the amidoxime of P- (3,3-diphenylpropylamin6) -propionium

Acids are dissolved in 15 ml of formless pyridine and added with water cooling to room temperature, 55 g of benzoyl chloride (OJ011 mol). Then the reaction mixture is heated on water for

2 hours and in vacuum bend the pyridine. The residue after adding 10 ml of 2N. The sodium hydroxide solution heats / reflux for 20 hours and then crystals are filtered off in vacuo. After washing and drying, 1.5 g (0.054 mol) of 1- (3,3-diphenylpropyl) -3-amino-A -pyrazoline are obtained. Mp: 157-160 ° C; yield 54%.

Example 25. 2,79 g (0.01 mol) amidoxime ip- (3,3-diphenylpropylamino) -propionic

acids are dissolved in 15 ml of anhydrous pyridine and to the solution, while cooling with water to room temperature, Г, 19 g (0.011 mol) of chlorogolic acid ester is added. The reaction mixture was incubated for

24 hours and then pyridine is distilled off in vacuum. To the residue was added 10 ml of 2N. sodium hydroxide solution and boiled for 8 hours. The resulting crystals are filtered under vacuum, washed and dried. Get

1.7 g (0.068 mol) of 1- (3,3-diphenylpropyl) -3-amino-D2-pyrazoline. T. pl. 158-160 ° C; yield 68%.

(Example 26. 2.95 g (0.01 mol) of an acetyl derivative of 1N dodecyl-3-a1 Mino-D2-pyrazoline is boiled for 3 hours with a mixture of 20 ml of n. Sodium hydroxide solution and 20 ml of 96% - ethanol. After the ethanol is distilled off, the crystals formed are filtered off in vacuo, washed with a small amount of

water and dry. 2.00 g (0.007 mol) of 1-n is obtained. dodecyl-3-a.mino-D2-pyrazoline. T. pl. 74-78 ° C; yield 70%.

Example 27. 0.5 g (0.002 mol) (3.4. 1methoxyphenyl) ethyl 3-amino-D-pyrazoline is dissolved in 20 ml of benzene and 0.24 g (0.002 mol) of acetic anhydride is added to the solution. The mixture is heated in a water bath for 30 minutes and then benzene is distilled off.

After recrystallization from ethyl acetate, 0.4 g (0.00137 mol) of an acetyl derivative (3,4-dimethoxyphenyl) ethyl ethyl-3-amino-D-pyrazoline is obtained; yield 68%.

60

Subject invention

 .-one. The method of obtaining derivatives of I-amino D-pyrazols of the general formula I, which. can be; -11c in the following tautomeric 65 forms:

II

B-iT-g-Bi

TSfx., X-K2

Rg-tj

II

KK

where R is a glkyl, cycloalkyl, aralkyl or aryl group, which may be substituted under certain conditions;

RI and R2 are a hydrogen atom or, under certain conditions, a substituted alkyl or aryl group;

Ra is a hydrogen atom or an acyl radical of an organic carboxylic acid,

or salts thereof, characterized in that the compound of the general formula

KI Rg

Claims (4)

I G R-UH-OH-m-ti-NHg III) : N-OR, where R, RI and R2 are as defined; R4 is hydrogen or an acyl radical, or its salts are reacted with an acylating agent and, if desired. 12 R-iTg-B, (P or K uh-s 2 KN-EZ the compound of formula I (where Rs is a hydrogen atom) is subjected to acylation or, if Rs is an acyl radical, is transferred by deacylation into the corresponding compound of the same formula (where R4 is hydrogen) and, if desired, the resulting compound of formula I is salified in a known manner. 2. A method according to claim 1, wherein the compound of formula P is reacted with an acylating agent, preferably in the presence of an organic solvent. 3. A method according to claim 2, characterized in that the compound of formula II is reacted with an acid anhydride or acyl halide with heating. 4. A method according to claim 3, characterized in that the compound of formula II is reacted with acetic anhydride, benzoyl chloride, ethyl chloroformate or l-toluene sulfonic acid chloride.