CS225004B1 - The production of the derivate of 3-amine-delta raised to the square-pyrasoline - Google Patents

Abstract

The various tautomeric forms of (I):- (where R is alkyl, cycloalkyl, aralkyl or aryl, all opt. substd. but excluding unsubstd. phenyl; R1 and R2 are H or opt. substs. alkyl or aryl and R4 is H or the acid radical of an organic carboxyacid, are preped. by methods usual for such structures. Partic., R is 1-4C alkyl, 5-6C cycloalkyl, diphenylalyl, nitrophenyl-, methylphenyl- benzyl- or dimethoxyphenethyl, R1 and R2 are H and R4 acetyl. propionyl, hydroxybenzolyl or beta-piperidino-propionyl.

Description

The present invention relates to a process for the preparation of 3-amino-2-pyrazoline derivatives of the general formula

-R-N — CHo

I ² i _and NHR ⁴ where R is an alkyl radical having 1-7 carbon atoms, optionally substituted by halogen, after case phenyl or alkyl or naphthyl group, a cycloalkyl residue with 3 to 6 ring carbon atoms, optionally substituted by halogen, alkyl or alkoxy or nitro.

R ⁴ represents hydrogen, acetyl, piperidinopropionový benzoyl or salicylic residue.

The preparation takes place between the compounds of the general formula r-nh-ch _o -ch-c-nh _q

2 n 2

N л ⁴ OR ⁴ wherein R and R ⁴ are as defined above with an anhydride or acid chloride or ester acid benzyl ester of Formula ₅ R ⁵ -OR ⁶ wherein R ² is an alkanoyl group optionally substituted, and R5 is an alkyl group of 8 from 1 to 6 carbon atoms.

22500 $

The present invention provides a process for the manufacture of substituted 3-amino- ^{2 2} -pyrazoline derivatives. Most of the compounds produced by the process of the invention are novel.

Of the 3-amino-1-pyrazoline derivatives, it is known to be advantageously used in the photographic and pharmaceutical industries. These compounds have hitherto been obtained by a single method with several variations, such that the beta-cyanoethylhrt-hydrazines have been subjected to intaamoleCular ring closure.

This known method described in many pubbikací and patents, e.g. in US patent ^{2,726 2} 48 briselých patent ISEC with ^p and ^H 776 ³²² 679 <78 Zurn. obichee * chim. 26, page 3 132 (1956), 29 page 498 (1959), Ann. Chim. (Rome), 56, p. 332 (1966),

C. A. 6ž, page 2 244b, Cham. Ber. £ 8, p.3377 (1965), Chem. Soc. (London), 1954, p.

408, 1955 pp. 3,470.

A common feature of the above methods is that the N-N2 bond of the pyridine ring is formed prior to the last step of the synthesis. However, this method is not entirely clear. In the reactions where arylhydrazines and alkylnitriles or derivatives thereof are used, both nitrogen atoms of the hydrazino group are reactive and therefore can simultaneously form two reactions. This may be the desired 1-lгyl-3-вmino Δ ^{£ í} -pyrezoinnové. compounds contaminated with 1-lryl-5-aminopyridine. The ratio of the two isomers may be influenced by the pH (Helv. Chim. Acta 41: 306 (1958); Ber. 98: 3 357. (1965)).

In order to dissipate the possibility of a double reaction, in some cases a hydrazno group was formed by nitration and reduction of the aryl- (methylmethyl) amine obtained by reaction of the aromatic amine with the alkylnitrle (U.S. Patent Nos. 757,840 and 776,322).

The present invention relates to a process for the preparation of 3-amino-A-pyrazoline derivatives of the general formula I

_RN-CH3

I I

In ^CH 2

I _Δ

NHR ⁴ (I) wherein

R represents an alkyl radical of 1 to 7 carbon atoms, optionally tubstituted by at least one halogen atom, one or two phenyl groups, optionally substituted C1-C2 alkyl, or naphthyl, a C3-C6 cycloalkyl radical in the ring, or a phenyl or naphthyl radical, optionally a tubstituted asylum group having 1 to 2 carbon atoms, an alkoxy group having 1 to 2 carbon atoms. up to 2 Uulium atoms, a nitro group or a halogen atom, and

R ⁴ represents ^and atoms in ^: ^ík u ^lcetyljvý, pipčridinjprj ^{pi jnyljvý,} PRJ ^p ijnylj ⁱⁿ Y, tonzoylový or salicylcwý radical, and their SOD vyznnauUjcí in that a compound of 'the formula II _R-NH-CH2 - CH ₂ -C-NH ₂ ² I ² (II)

OR wherein ^R and ^R4 mmaí Uve ^d Eny above ^meaning, or a salt thereof is reacted with antydridem or chlorddem acid as acylating činideem or ester. of an acid of formula III

R ⁵ -O-R ⁶ (III) wherein

R is C 2 -C 6 alkanoyl optionally substituted by morphollryyl, pyrrolidinyl or piperidinyl, or benzyl, and

R represents an alkyl group having 1 to 6 carbon atoms ^and _ ^j e * where t ^o required - thus obtained stouíenina of formula I wherein ^R4 is ^plated walk was subjected to N-aceyaci or a compound of formula I wherein R4 is ed above for ^{the en} ^^^ ý ý residue nsαcyltjn ^{d to} give the ^^ Enina rbecné ^h. wherein R ⁴ is hydrogen, or the product so obtained is optionally converted into its salt.

The compounds of formula (I) may exist in three tautomeric forms. The invention relates to the preparation of all these tautomeric forms.

In formula (I), R represents an optionally substituted alkyl radical, a cycloalkenyl radical or an optionally substituted phenyl or naphthyl radical, wherein R cannot be an unsubstituted phenyl radical.

The alkyl moiety (both an R and an alkyl moiety) has this straight or branched chain alkyl moiety such as methyl, ethyl, propyl, isopropyl, iso-style, etc. The alkyl moiety may be at least one substituent, such as halogen atoms, for example fluorine or bromine, one or two phenyl groups optionally substituted with 1 to 2 carbon atoms or naphthyl. a phenyl or naphthyl radical may be attached at least one substituent such as halogen, for example chlorine or bromine, nitro, alkyl having 1-2 carbon atoms or elkoxyskupiny having 1-2 carbon atoms. _T

The term cycloalkyl radical as used in this application means radicals containing 3 to 6 carbon ring atoms, such as a cyclopentyl or cyclohexyl radical.

OObzláště preferred compounds of formula I are those derivatives wherein R is an alkyl radical having 1 to 4 carbon atoms, a cycloalkyl radical having 5-6 carbon atoms, difluoro-phenyl alkyl radical, a nitrophenyl radical, methyl yfenylový, benzyl or dimethoxyphenethyl or ^f en ^y Target ztytek and ^R4 is ^{l s} aentn Ooy ^p rr ^pi pn ^{NL ROY,} tensor or Sntа-piperddiropropionnlrvý residue.

Salts of compounds of formula I may be addition salts with inorganic acids (e.g. hydrochloric, hydrobromic, sulfuric, nitric, etc.) or organic acids (e.g. acetic, lactic, tartaric, maleic, fumaric, nicotinic, etc.) .

Particularly preferred compounds of formula I are the following derivatives:

1- (p-nitrophenyl) -ZZ-aminr-Δ-pyrazoline »

1r (p-tolyl) -3-amino-β-pyrazoline,

1- (3,3-Diphenylpropyl) -Zn8-rin-D-pyrazoline,

1-Benzyl-3-amino-N-pyrazoline

Ь-2 2 - ⁽ 3, 4-Dimethyl-phenyl-ethyl) -3-amino-N- ⁽ 2-carboxylic acid);

^1- c ^^^ x ^^ -amino-A-pyrazilium ^,

1-n-butnl-3-Δ amiir -pyrazoline, aceVlový derivatives ^and t! - ^{(3, 3} - ^d i ^f ni ro ^{pollen NLP)} - ^- -8mdno-Δ ² - ^{pn razoldit,}

Seta-piperidinopropioilnyl derivative of 1- (3,3-diphenylprropyne) -3-aimino-D-pyrazoline, p

1- (3,3-diphenyl-propyl) -3-aminocaprazinitrile derivative, derived from salic acid, a 1-β-piperazin-3-yl derivative, acetyl derivative ¹ - ^[2 - ^s 3 »4-d ⁱ methyl hoχy ^{e N} er ^ny) n ^t h ^y l] -3-am ⁱ Δ-NR ² - ^{pn razóldit,} oce ^ hunts derivative -ncyrheilnxy 1 - 3-R- The N-β-pyrazoline, and the N-β-yl derivative of 1-i-Sutyl-3-nitro-β-pyrazoline and their salts.

In the process according to the invention, the amidoximes of the general formula II or their salts are reacted with an acid derivative which is an acid anhydride or an acid chloride as an acylating agent or an acid ester. When the compounds of formula II are reacted with an acid anhydride or chloride, the R @ 4 -OH molecule is cleaved in the reaction. When R ^ represents an acyl radical, it may be an alkanoyl radical (for example, a C 1 -C 20 alkanoyl radical or a substituted derivative thereof such as acetyl or propionyl), an aroyl radical (for example the C 6 -C 20 carbon atom or substituted derivatives thereof, such as is benzoyl), an alkylsulfonyl radical (such as a mesyl radical) or an arylsulfonyl radical (such as a phenylsulfonyl or p-tesyl radical). The reaction is preferably performed by heating of amidoxime • ^r, Formula II with an acylating agent in an organic solvent. The acylating agent is preferably acid anhydrides or chlorides such as acetic anhydride, benzoyl chloride, ethyl chloroformate, p-toluenesulfonic acid chloride and the like.

When amidoxime or a salt of formula (II) is used with an acid ester derivative of the acid of formula (III), the reaction is preferably carried out in the presence of an alkali metal or alkaline earth metal alkoxide. The reaction is preferably carried out at elevated temperature, in particular at 50 to 120 ° C. Preferably, the reaction is carried out in an alcoholic medium.

The compounds of formula (I) thus obtained, wherein R ^ represents hydrogen, can be converted to the corresponding acyl derivatives.

Compounds of formula I wherein R, is acyl may be converted to the corresponding compounds of formula I wherein R ⁴ is hydrogen. The reaction may be carried out using a well-known desacylation procedure. Preferably, the acyl derivative of the formula I is reacted with a base. Alkali metal hydroxides such as sodium hydroxide may suitably be used for this purpose. The reaction may be carried out preferably in the presence of an organic solvent. Suitable organic solvents are aliphatic alcohols such as ethanol.

The amidooxime starting compound of formula II can be obtained in good yield by the nitrile of formula IV

R ¹ R ² II R-MH-C-C-CN (IV)

I I H H where

2

R, R and R are as defined above, reacted with hydroxylamine. The nitriles of the general formula (IV) can again be obtained by known methods, for example by reacting the corresponding amine with acrylonitrile or the beta-halonitrile with an amine.

The compounds of formula I thus obtained, wherein R * is hydrogen, may be subjected to N-acylation.

The reaction is carried out according to known methods, preferably using acid halides. In this way, compounds of formula (I) wherein R @ 1 is an acyl radical of an organic carboxylic acid are obtained.

The compounds of the formula I obtained can be converted in their salts with organic or inorganic acids. Salt formation can be achieved by methods known per se, preferably by reacting a compound of formula I in the presence of an organic reagent with an equivalent amount of the corresponding acid.

* 2

The process according to the invention makes it possible to obtain valuable 3-alpha-α-pyrazoline derivatives and can be easily carried out on an industrial scale. The method is fundamentally different from the known processes, since the binding of the Ν-Ng pyrazoline ring is formed during the last cyclization step.

The present invention also provides pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) or a salt thereof together with suitable inert solid or liquid carriers and / or excipients. As carriers, it is possible to use meshes, starch, potassium carbonate, magnesium carbonate, magnesium sulfate, polyethylene glycols, water, etc. The compositions may take the form of a solid, for example, tablets, pills, coated pills, capsules, or a liquid, for example, a suspension, lotion, or injectable preparation. The compositions are prepared by known methods of pharmaceutical industry.

The pharmaceutical compositions containing the active compounds obtained by the process according to the invention, besides the Southern effects, also have effects on the central nervous system and other spontaneous effects, as shown in the table below.

Compound Potentiation of anesthesia achieved by i.v. benefits thiobιвrbitsгáts + (my *, p.o) · Inhibition of electrical shock convulsions in mice, ^ED 5C ' Inhibition of nicotinic toxicity, ED- ₀ Increase in the seizure threshold induced by 200 mg / kg of stricin AND 100 mg / kg, very strong significant, more than three times the control extension 24.6 mg / kg 31.4 mg / kg + 41 žé В 200 mg / kg, ineffective 100 mg / kg 00 mg / kg -26% C 200 mg / kg, ineffective 100 mg / kg 100 mg / kg -8.4% D toxic substance that could not be effected, animals die or suffer from tremors or chronic convulsions, using doses higher than 20 m ^ pkg

A = 1- (3,3-diphenylpropyl) -3-amino-A -ρyrczolinu В = 1 -c tydrochlorid of ^{YKL h} exyl-3-SM-O-; ^ý - ^py razolinu

O

C = 1-Benzyl-3A-amino-N '- pyrazoline hydrochloride

D = hydrocW.or, 1- (ρ-tol ^yl) - ^2-A cmmino -pyrczol ⁱ nu ⁺⁾ SKU ^p in ^s after 10 ^{hours we} IC

Some of the compounds of Formula I are suitable for use as photographic developers in the photographic industry.

The following examples illustrate the invention but do not limit it in any way.

Example 1

1.79 g (0.01 mole) of acid amidoxime beta-phen ^yl aaminopropionoyé dissolved in 1C · ml pyridine and with stirring and cooling such that the temperature does not exceed 20 DEG C., 2.1 g chloride, p-toluenesulfonic acid . The reaction mixture was heated on a water bath for 3 hours, after which pyridine was distilled off under reduced pressure. 4 ml of 1 N aqueous sodium hydroxide solution and 5 ml of 96% ethanol are added to the residue. The precipitated crystalline product is filtered off with suction and washed with water until the reaction is neutral. Recrystallization from ethanol gave 1.06 g of 1-phenyl2 o *.

168 DEG-169 DEG C., corresponding to a yield of 66%.

Example 2

(26.5 g, 01182 mole) of ^.beta.-y fenylaminoprop yiioiirils are dissolved in 150 ml of ethanol, whereupon a solution of 28.6 g hyárochloriůvL hydroxylarinu, 30.4 g of acidic Uihičianu solution and 50 ml of water. The reaction mixture was heated at reflux for 8 hours, after which the alcohol was distilled off and 20 ° ml of water were added to the residue. ^'Aba SKR him at SUNY ntáoty give an oil which soon vylcrlstaltje to give 26.2 g of the amidoxime · kyseeiny ietl fdnylaminjprj ^{P ion-E} in ^80% yield. The point T ^and the sljt ^u ^ e ⁱ n ^y is ^from 92 and ⁸⁸ ° C ^with esters of ^p unchanged from řelk * ystalováním Smee (1: 1) of ethyl acetate and petrjldthert. ,

Analysis; H, 7.32; N, 23.45%. Found: C, 60.6; H, 7.33; N, 23.76.

Examples 3 and 4

The following compounds were obtained as described in Example 2:

Ex. no. Niiril of formula IV Amidoxime of formula II Melting point ° C 3 3- (p-nitro-trino) propanol amidoxime acids 3- (p-nitroainilino) propionic 130 to 135 (from water) 4 3- [p-Methylphenyl] -piperazin-3-ol amidoxime acids 3- (p-me цаппПпю) propionic 100 ALIGN! (ethyl acetate)

Example 5

A mixture of 1.99 g (0.0062 mole) of 1- (3,3-difenylpropyy) ^{-3-amino-d--pyrazoline} acetyoového derivative, 20 ml of 1 N aqueous sodium hydroxide solution and 20 ml of 96% ethanol was heated boiling for 3 hours. The clear yellow solution was cooled, then the precipitated needle crystals were aspirated, washed with water until neutral, and dried under an infrared lamp. There was thus obtained -1.61 g. ^ U ^ -dfen ^ v ^ r ^ yD - ^ - Amino-N - ^ yrazoli ^nu-b ODU ^{th tup 159-161} ° C, in ^92% yield. After recrystallization, the melting point is increased to 163-165 ° C.

Analysis for C ^ q ^R 21 ^N 3 Calculated: C 77.37, H7,50, N 15.13%; Found: C77J7, H7 7.42, N 153.4 56.

The resulting base is converted into dihydrogen chloride by means of ethanol containing hydrochloric acid. The melting point is 160 DEG C. which is not changed by recrystallization from ethanol containing hydrochloric acid.

Analysis for C 16 H 23 N 3 Cl 2: calculated: C 20.10 C 61.40 H 6.58 N 11.92% found:. CL 20.33 c 61.54 H 6.50 N 11.86%.

Examples 6 to 10

The following compounds were obtained as described in the Example:

Ex.

Acyl derivative of the formula I

Amino derivative of the formula I

Either point C beta-1 derivative piperidinoproplonylový í3,3-diphenylpropyl) -З-атхпо ^ д -ругагоИпи-acetyl derivative of 1-benzyl-3-amino-4 ² -pyrazoline acetyl derivative of 1- [2- (3,4- -

-dimethoxyphenyl) ethyl] -3-amino-A ² -pyrrolidine acetyl derivative 1-cyclohexyl-

3-amino-N-pyrazoline acetyl derivative

1-n-butyl-3-amino-A ² pyrazoline

1- (3,3-Diphenylpropyl) -3-amino-N-pyrazoline 163-165 (96% ethanol) 1-Benzyl-3-amino- ^{2 2} -pyrazoline 73 to 80 _ (from cyclohexane); hydrochloride 238 (from anhydrous ethanol) 1- [2- (3,4-dimetho- xylphenyl) ethyl-3-amino-N-pyrazoline 158 to 160 (of ethyl acetate); hydrochloride 182 to 185 (96% ethanol) 1-Cyclohexyl-3-amino-N-pyrazoline 86-88 (from cyclohexane); hydrochloride 233 (from without ethanol) 1-n-butyl-3-amino- ^{2 2} -pyrazoline 65 to 70 (petroleum ether); Hydrochloride 147 (from ethanol)

Example 11

To 24 g (0.08 mol) of beta- (3,3-diphenylpropylamino) -propionic acid amidoxime was added a solution of 19.92 g of ethyl acetate (0.24 mol) and 350 ml of anhydrous ethanol, and the hot mixture was poured into sodium ethylate solution. prepared from 1.84 g of sodium and 50 ml of anhydrous ethanol. The reaction mixture is heated to boiling for 8 hours, after which the alcohol is distilled off, 200 ml of water are added to the residue and the mixture is extracted with chloroform. The extract was dried and evaporated. To the remaining yellow oil (21.6 g) was added 20 mL of ethanol. 1.7 g of the amidoxime starting material are obtained in the form of crystals having a melting point of 157-160 ° C. On standing, an additional amount (4.15 g) of the amidoxime starting material of melting point 157 DEG-160 DEG C. was separated from the aqueous phase. The alcoholic filtrate was evaporated under reduced pressure. The remaining resin product crystallizes by scraping the wall with o

containers. 19.3 g of acetyl derivative of 1- (3,3-diphenylpropyl) -3-amino-N-pyrazoline, m.p. 88 DEG-92 DEG C., are obtained in a yield of 75%.

Examples 12 to 17

Following the procedure described in Example 11, the following compounds were obtained;

Ex. number Starting material The starting ester of formula III Final product of formula I Melting point ° C 12 amidoxime acids ethyl ester beta-piperidino- 119 to 120 3- (3,3-Diphenylpropyl) - beta- propionic derivative (from a mixture of vinegar aminopropionic piperidinopro- 1- (3> 3-Diphenylpro- nu ethylnaté- pionové polyl) -3-amino-A ² -py- ho z petrol- razolin of ether 13 amidoxime acids ethyl ester an acid derivative 178 3- (3,3-Diphenylpropyl) - acid salicylic and (from iso- eminopropionové salicylové 1- (3,3-Diphenyl- propanol) propyl) -3-amino- - N -pyrazoline 14 amidoxime acids ethyl acetate acetyl derivative 145 (from mixture 3-Benzyl-aminopro- 1-Benzyl-3-amino- benzene and cycl- pionové -Δ -pyrazoline lohexane)

04 »04

Ex. number Starting material The starting ester of formula III Final product of formula I Melting point ° C 15 Dec amidoxime acids 3- (2- (3,4-dimethoxyphenyl) ethyl) amino-propionic acid ethyl acetate acetyl derivative of 1- (2- (3,4-eimethoxyfenyl) ethyl ^] - ^, - ^ R ^ EMII c ^ · N ² -pyrazoline 115 (from ethyl acetate) 16 amidoxime acids 3-cyclohexylaminopropionic ethyl acetate acetyl derivative of 1-cyclohexyl-3-amino-42-pyrraoline 130 to 132 (from smmsi sthrlacstats and peerolether) 17 3-n-butylaminopropionic acid amidoxime ethyl acetate acetyl derivative of 1-n-butyl-3-amino-2-nitrazine 63 to 65 (from petr-lsths ru)

Example '18

26.44 g (0.1 mol) of beta- (3,3-diphenylpropylamino) propionitrile are dissolved in 100 ml of ethanol, and a solution of 14 g of hydroxylammonium hydrochloride, 16.8 g of sodium bicarbonate and 50 ml of water is added. The reaction mixture is heated to boiling on a water bath for 4 hours, after which the alcohol is distilled off under reduced pressure, 200 ml of water are added from the aqueous excess, the precipitated product is separated, washed with water and dried. This gives 29 g of crude beta- (3,3-diphenylpropylamino) -pionic acid amidoxime having a melting point of 155-158 ° C in a yield of 97%. The crude product can be used for the next reaction without purification. Recrystallization from ethanol increased the melting point to 158-160 ° C.

Annysis: CjgHgjNjO calculated N 14.13% found N 13.97%

The mixture obtained can be converted into ethylchloroform, m.p. 209 DEG-211 DEG C., using ethanol containing hydrochloric acid.

Analysis for c ₁₈ h ₂₅ ci ₂ n ₃ o

calculated: C 58.40, H 6.81, N 1,35, CL 19.15 % found: C 58.42, H 7,00, N H.17, CL 19.02 %. Example 1 a and y 19 to 22

to give the following compounds:

In the manner shown in the example

Ex. no. The starting oitrile of formula IV The amidoxime II obtained Melting point ° C 19 Dec 3-12- (3,4-dimethoxyphenyl) ethoxy} aminopropion-4H amidoxime acids 3- [2- (3,4-dimethoxyphenyl) ethylyerninopropionic acid 108 to 110 (from stylacyl) 20 May 3 — benzz Ι ^ Ιηο ^ poo and they trii 3-Benzylaminopropionic acid amide xime Oydrlchloгie 167 21 3-cyclohexylaminopropiooitrile 3-Crk1-hexyl-amino-propionic acid amidoxime 119 (from water) 22nd 3-n-buf у ιθιιι many op i they trri 3-n-butylaminopropionic acid amidoxime 82 to 85 (from ethyl acetate and peto-Leter)

Example 23

To 211.3 g (1.0 mole) of 3,3-diphenylpropylamine, with stirring and cooling with water, 53.1 g (1.0 mole) of Bryloyliril are added over a period of 1 hour and the solution is heated in a water bath for about 8 hours. The resulting viscous solution (264 g) was cooled. Scratching the vessel walls gives a good yield of beta- (3,3-diphenylpropilaminooppooionitrile, melting point 54 ° C and boiling point).

195 to 197. ° C / 0.1 torre. her. The crude nitrile can be used for further processing without purification. Analysis for: C13 ^H 2 C ^N 2 ^: vypooteno: C 82.10 H 7.67 N10.64% found: C 81.96 li 7.44 N, 10.56.

Ex. k 1 ad 24

2.79 g (0.01 mol) of amidoxime beta- (3,3-SiphenyPyrpylamino-propionic acid) are dissolved in 15 ml of anhydrous pyridine, and 2.1 g (0.011 mol) of p-chloride are added dropwise at room temperature while stirring and cooling with water. After the addition was complete, the reaction mixture was heated on a water bath for 3 hours, then the pyridine was distilled off under reduced pressure, and 10 ml of 1N aqueous sodium hydroxide solution and 5 ml of 96% ethanol were added to the residue. oddiiHrují crystals, promotes water and dried. There was thus obtained ^2, 0 ^{g of 1} »(3> 3 ^{e p} -methylphenyl RSP ^yl) зЗamino ^a-2 -ρ · razsl ^y ou ^{i b} r a ^d u ^{s 159} and counting ^{161 161} ° C with a yield of 72%.

Example 25

As described in Example 2, 3- (p-chloroanilino-propionic acid nitrile) was obtained from 3- (p-chloroanilino) propionic acid nitrile.

Example 26

To a solution of 34.3 g (0.144 mol) of Opdsdecylamioroorrorionic nitrile in 120 ml

A solution of 20.8 g of hydroxylamine hydrochloride and 25.2 g of sodium bicarbonate was added to 96% ethanol. The mixture was heated at reflux for 6 hours. After cooling, the precipitated crystals are filtered off with suction, washed with water and dried. Zíeká Thus, 28 g (0.103 mol) of amidoxime 3- (n-dodec laminlo ^yl) prroriooové m.p. 85-88 ° C.

Example 27

86.7 g (0.45 mole) of 3- (bsra-naphthyl; laamnnorioop) nitrile are 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 of water is added. After cooling, the precipitated crystals were filtered off with suction and washed with water, and recrystallization gave 94.2 g (0.11 mol) of 3- (bis-naphthylamino) amidoxime. m.p. 148-150 [deg.] C. The product is colored, yield 92%.

Example 28

In 15 ml of anhydrous pyridine, a span of 2.79 g (0.01 mol) of beta- (3,3-diphoyoylpropyaaminoProspis) acid amidoxime was added and the solution was added to the solution while cooling with water.

1.55 g (0.11 mol) of benzylchloride. After the addition was complete, the reaction mixture was heated on a water bath for 2 hours, after which the pyridine was concentrated under reduced pressure. After addition of 10 ml of a 2N aqueous sodium hydroxide solution, the residue is refluxed for 20 hours, after which time the precipitated crystals are filtered off with suction and washed. Vyyušením crystals, 1.5 g (0.054 mol) of 1- ^{(3,3-lp with} ifsny ^iO-propyl) -3-p ^py amiosp4 ² razsl ^and nu ^d bo at point ¹⁵⁷ and ^from I ⁶⁰ ° C. The recovery ^from an offense ^{to s} 54%.

Example 29

2.79 g (0.01 mole) of beta- (3,3-diphenyl-propyl) -mino-propionic acid amidoxime are dissolved in 15 ml of anhydrous pyridine and 1.19 g (0.011 mole) of chloro-ester are added at room temperature from water. The reaction mixture was allowed to stand for 24 hours, then the pyridine was distilled off under reduced pressure, 10 ml of a 2 N aqueous sodium hydroxide solution were added to the residue, and the mixture was heated to boiling for 8 hours. 1.7 g (0.068 mmol) of 1- (3,3-diphenyl-propyl) -3-amino-N- ² -pyrazoline, m.p. 158 DEG-160 DEG C., are obtained, yield 68%.

Example 30

A solution of 10.85 g (0.04 mole) of 3- (n-di-decylamino) -propionic acid amidoxime and 9.96 g (0.12 mole) of ethyl acetate in 80 ml of anhydrous ethanol is added to a solution of 0.92 g of sodium, dissolved in 30 ml of anhydrous ethanol. The mixture was heated under reflux for 8 hours, then the ethanol was separated and 80 ml of water were added. The separated oil was extracted with chloroform. The extract was dried and evaporated and a mixture of benzene and petroleum ether was added to the remaining oil. There were obtained 6.70 g (0.023 mole) of white crystals acstylovéhl derivative of 1-N - ^^ J ^ ^Cy-amino-2 - ^ ^ nu Razo bo ^d by counting ^{with a 45 to 50} ° C. The melting point does not change by rinsing from petroleum. The yield is 75%.

Example 31

To a solution of 8 g (C, 03 mol) amidoxime 3- [3,4-dimethyl-thoxyfslovl (ethyl) ^P -amino3- ropionové and 8.65 g (0.06 mol) of capric acid in 70 ml of anhydrous ethanol add a solution of sodium ethylate prepared from 0,69 g (0,03 mol) of sodium ε 20 ml of anhydrous ethanol. The mixture was heated to boiling for 8 hours, after which the ethanol was distilled off. Water (20 ml) was added to the residue and the solution was extracted with chloroform (3 x 20 ml). The combined extracts were dried and evaporated. There were obtained 6.70 g (0.027 mole) of 1 - [3,4-direeth'lfennll '(ethyl) --- amlnl] - ^ - piyrazolinu on bo ^{th d} u n ^{d 142-152} ° C. ^The VTE ^Z e n ^{e K II 8} 9%. Recrystallization from ethyl acetate / petroleum ether increases the melting point to 158-160 ° C. The product obtained is identical to that of Example 8.

Example 32

In 200 ml of anhydrous ethanol, a span of 26 73 g (0.1 mole) of emidoxime 3- [2- (3,4-dimethoxryennyl) ethyltrinol] aropionic acid and 30.36 g (0.2 mole) of ethyl benzoate was obtained. The resulting solution was added to a solution prepared from 2.3 g (0.1 mol) of sodium and 200 ml of anhydrous ethanol, and the mixture was heated under reflux for 8 hours. It is then distilled off, 200 ml of water are added to the residue and the mixture is extracted three times with 20 ml of chloroform each. The combined extracts were dried and evaporated. The acid residue was crystallized from ethyl acetate / petroleum ether. This afforded 16.9 g (0.068 mole) of 1-, 2- (3,4 ^ 1 ^ ^^ 05x1 01) eth ^l l) - řrrinl] raz®linu of bo u ^{d s} counting ^{154, and 160} ° C. VVT ⁿ that ^{k ≤ 68%} in ^I. ^ ^P roducts twisted is identical to the compound of Example eighth

Example 1 a d 33 o

2.95 g (0.01 mole) of the acetyl derivative of 1-o-di-decyl-3-thiol- ^2- pyrrolidine are heated to boiling for 3 hours, mixed with 20 ml of 1 N aqueous sodium hydroxide solution and 20 ml of 96% ethanol. . Then the ethanol is distilled off, the precipitated crystals are desulfurized, washed with a small amount of

water and dried. 2 g (0.007 mol) of 1-Ndldeyl-3-amino-1H-pyrazoline of melting point 74 DEG-78 DEG C. are obtained. The yield is 70%.

EXAMPLE 34 ^{0.5 g (0 02} mole ° ^ b- ^[2 - ^{(3, 4 th} -dims lχlfsnyl) st ^hy l] зЗřrmino- ^A2 - ^Al rřzoliou ^ sH is extended in 20 ml of benzene and treated with 0 Acetate hydride (24 g, 0.002 mol) was heated in a water bath for 30 minutes, then benzene was distilled off, after recrystallization from ethyl acetate to give 0.4 g (0.00137 mol) of the acetyl derivative. h ^ ox ^ f ^^ ^ en l) e ^{<^} rdl33; -a _<m ^ j ^ ^no-2 A - ^Pd Ra ^of oli ⁿ u. Yield 68%. The product is the same as the compound obtained in Example 15.

Examples 35 to 38

Following the procedure of Example 34, the acetyl derivatives of the following 3-aminopyrazolines are obtained.

PPÍkl. C. Compound Melting point ° C Yield% 35 2 1-benzyl-3-amino-N-pyrazoline 145 76 _w 36 l-cyclo ^h l: l ^χy 3-čminl- ⁴² - ^p drčzolin 130 to 132 81 37 ^{1-n-BTT d} L ^3-aminl-2 H - ^{Pd L} IN rčzo 63 to 65 78 38 ^1- n-dl-ethyl-3-amino-N-pyrazole P 45 to 50 73

Claims (6)

A process for the preparation of 3-amino-4-pyrazoline derivatives of the general formula I N - UMn II ² 4 CH ₂ NHR ⁴ (I) wherein R represents an alkyl radical having 1 to 7 carbon atoms, optionally substituted by at least one halogen atom, one or two phenyl groups optionally substituted with an alkyl group having 1 to 2 carbon atoms, or a naphthyl group, a cycloalkyl radical having 3 to 6 carbon atoms in a ring or phenyl or naphthyl radical optionally substituted by a C1 -C2 alkyl, C1 -C2 alkoxy, C1 -C2 alkoxy, nitro or halogen atom, and R ^{4 A} is H, ^{acetyl, p} i ^p erid ⁿ nopюp ^{he dl-voltage p} ropionylový, benzoyl no ^b of salicyl radical, and their salts, tick-ICI in that a compound of formula II (II) wherein ^R and R ⁴ is as defined above, or a salt thereof is reacted with an anhydride or brick acid as an acylating agent or an acid ester of the formula III R ⁵ -O-R ⁶ (III) wherein: R 5 represents a membered alkynyl group optionally substituted by a morpholiryryl, pyrrolidineddyl or piperidinyl radical having 2 to 8 carbon atoms or a benzyl group, and R @ 1 represents a C1 -C6 alkyl group, and, if desired, the compound of formula (I) in which R @ ⁴ is hydrogen is optionally subjected to a compound of formula (I) in which R @ ⁴ is the above acyl radical. ⁱ t8aay ^y ujt ^, whereby the compound fatherly. Formula 1 ^kd e ^{R4 and} hydrogen or prodiuct thus obtained, optionally converted in 'its salt. 2. A process according to claim 1 for the preparation of 3-amino-A-pyrazoline derivatives of the general formula I, in which R represents an alkyl group having 1 to 7 carbon atoms, optionally substituted by at least one halogen atom, one or two phenyl groups optionally substituted by an alkyl group. C 1 to C 2 carbon atoms or naphthyl; .. phenyl or naphthyl group which is optionally substituted by alkyl having 1-2 carbon atoms, alkoxy with another ^{beta 1-2} carbon atoms nitooskupinou not by a halogen, ^b] ^ l ^g of ^TNT, and ^R4 represents hydrogen and their salts, - , indicate ^ ICI is tm that is a composite of ^b ECN ^eh of formula 1 ^for de ^R and ^R4 maai above ^mentioned meaning, or a salt thereof is reacted with deriváeem acid nappíklad anhydride or clhloridem ^{acid; NY} jatožto acyl ^ him ^{or agent,} for ^the measurement molelku paragraph ^ep ^ ^R4 0H from -NN- form a bond, and if desired, - the thus obtained compound of formula I is subjected to N-acylation or optionally, the product thus obtained are transformed into their salts. 3. Process according to claim 1 or 2, characterized in that the compound of the formula II is reacted with an anhydride or an acidic acid acylating agent, preferably in the presence of an organic solvent, for example pyridine. 4. The process of claim 3 wherein the compound of formula (II) is reacted with an acid anhydride or acyl halide at the boiling point of the solvent used. 5. A process according to any one of Claims 3 and 4, wherein the compound of formula (II) is reacted with acetic anhydride, benzylchloride, ethyl chloroforonium or p-toluenesulfonic acid. 6. The process of Claim 1 wherein the reaction of a compound of the general formula II carries out alkali metal alcoholate or alkaline earth metal alcoholate in an alcohoic environment.