DE1012609B - Process for the preparation of substituted phenylhydrazines - Google Patents

Description

GERMAN

It has been found that the hitherto unknown phenylhydrazines of the general formula

Method of manufacture
substituted phenylhydrazines

: n — ch, —co — n-

-N-CO-R ₄

CTT "D

Q XIg XVg

in which R ₁ and R _{4 are} hydrogen or a lower alkyl having 1 to 5 carbon atoms, R _{2 is} a lower alkyl and R _{3 is} alkyl or phenyl and in which R ₁ and R _{2 can} also be members of a ring system, have excellent analgesic and anti-inflammatory activity and that some of them are more effective, but are consistently considerably less toxic than the similarly acting pyrazolones, which are built analogously with regard to individual atom groupings, such as, for. B. 4-dimethylamino-1-phenyl-2, 3-dimethyl-pyrazolone- (5) and 1, 2-diphenyl-3, 5-dioxo-4-n-butyl-pyrazolidine.

Accordingly, the present invention relates to a process for the preparation of substituted phenylhydrazines of the formula given above, which consists either in the fact that one substituted phenylhydrazines the general formula

C ₆ H ₅ -NH-N-CO-R ₄

wherein R ₃ and R _{4 have the} same meaning as above, reacts with haloacetyl halide and then treated with a primary or secondary amine, or that a phenylhydrazine of the general formula C ₆ H ₃ -NH-NH-CO-R _{4 is} reacted with haloacetyl halide, then converted into the corresponding α-mono- or α-dialkylaminoacetyl-yff-acylphenylhydrazine by treatment with a primary or secondary amine and this treated with alkylating agents.

The starting material for the first-mentioned process can e.g. B. based on a regulation von Stühmer and Elbrächter (Archiv der Pharmazie, Vol. 285 [1952], pp. 161 to 165). The acylation is carried out in an inert solvent such as benzene, toluene, carbon tetrachloride, or carried out without solvents at boiling temperatures. The formed with elimination of hydrogen chloride α - haloacetyl - / J-alkyl-ß-acyl-phenylhydrazine is by prolonged standing or boiling with an excess of mono- or dialkylamine with or without Solvent implemented. The precipitated mono- or dialkylamine hydrohalide is separated off, the filtrate evaporated and the remaining compound distilled in vacuo or to crystallize brought.

Applicant:

E. Merck Aktiengesellschaft,
Darmstadt, Frankfurter Str. 250

Dr. Otto Zima and Dr. Gustav Schorre,

Darmstadt-Eberstadt,
have been named as inventors

According to the other method, a phenylhydrazine of the general formula C ₆ H ₅ —NH — NH — CO — R _{4 is} converted into an α-mono- or α-dialkylaminoacetyl - / - acylphenylhydrazine by treatment with haloacetyl halide and mono- or dialkylamine and alkylates this compound by methods known per se, for example with dialkyl sulfate, according to Stühmer and Elbrächter (loc. cit.) or according to Titherley (Journal of the Chemical Society [London], Vol. 79 [1901], p. 393) to give α-mono - or α-Dialkylammoacetyl-zS-alkyl-jO-acyl-phenylhydrazines. This process can easily be used to produce compounds in which R _{1 is} not equal to R ₂ but is equal to R ₃ . This procedure was not carried out _{for R 3 = phenyl.}

Instead of the mono- or dialkylamines, heterocyclic compounds can also be used in both processes which contain at least one secondary nitrogen atom in the ring.

example 1

81 g / J-methyl-iS-acetyl-phenylhydrazine are boiled in 300 ecm of anhydrous benzene with 60 g of chloroacetyl chloride for 2 hours and the product, which has been concentrated in vacuo, is distilled in vacuo. The resulting a-chloroacetyl - /? - methyl - /? - acetyl-phenylhydrazine has a bp _0-4 . 180 to 181 °; 69 °; Yield 103 g.

6 g a-chloroacetyl-zS-methyl-jS-acetyl-phenylhydrazine,

dissolved in 10 ecm benzene, a solution of 2 g methylamine in 20 ecm benzene was added while cooling with ice and the mixture was left to stand overnight at room temperature. The methylamine hydrochloride was filtered off with suction, the filtrate was concentrated and treated with alcoholic hydrochloric acid. The precipitated crystals of hydrochloric acid a-methylaminoacetyl - ^ - methyl -β- acetyl-

709 589l'29O

phenylhydrazine were filtered off with suction and recrystallized from absolute alcohol. Mp 231 °, yield 4 g.

Example 2

To a solution of 103 g of α-chloroacetyl - ^ - methyljff-acetyl-phenylhydrazine (prepared according to Example 1), 73 g of diethylamine were added dropwise with ice-cooling, left to stand for 2 hours at room temperature and refluxed for 1 hour. The precipitated diethylamine hydrochloride is filtered off with suction, the filtrate is evaporated and the residue is distilled in vacuo. Kp ₀₂ . 182 to 184 °; 38 °, yield 51 g. '

Example 7

i5.2 g of α-chloroacetyl- β- methyl- β- formyl-phenylhydrazine (prepared according to Example 5) in 150 ecm of benzene are left to stand overnight with 60 g of di-n-butylamine, then boiled for about an hour, the resulting dibutylamine hydrochloride is suctioned off, the filtrate evaporated and the resulting a-di-n-butylaminoacetyl - ^ - formyl - ^ - methyl-phenylhydrazine in vacuo

Vacuum distilled. Kp _Oil . 163 to 164 °, yield distilled. Kp _Oi01 . 189-190 °, yield 52 g.
105 g crDiethylaminoacetyl - /? - methyl - /? - acetyl-phenyl-

hydrazine. Example 8

Example 3

a) 136 g /? - formyl-phenylhydrazine were used in 350 ecm of absolute benzene with 125 g of chloroacetyl chloride boiled for 2 hours and then the solution evaporated in vacuo. The residue,

48 g of a-chloroacetyl-jff-methyl - ^ - acetyl-phenylhydrazine
(prepared according to Example 1) in 150 ecm benzene were left to stand with 45 g of dipropylamine for 2 hours at room temperature and then the mixture from α-chloroacetyl - ^ - formyl-phenylhydrazine was boiled on the steam bath for 1 hour. Dipropylamine hydro- crystallizes when rubbed with ether. the

Substance was recrystallized from alcohol. Yield 181 g, mp 119 °.

b) 13 g of the a-chloroacetyl - /? - formyl-phenyl-hydrazine prepared according to a) were dissolved in 35 ecm diethylamine and refluxed for about an hour. The diethylamine hydrochloride is filtered off with suction and the filtrate is evaporated. The resulting a-diethylaminoacetyl - /? - formyl-phenylhydrazine is made from chloro-

dissolved in absolute benzene were redissolved with 23 g of chlorine form petroleum ether. 98 to 99 °; yield acetyl chloride boiled for 2 hours and after evaporation 12 g.

of the benzene the resulting a-chloroacetyl-ß-ethyl c) 25 g of α - diethylaminoacetyl - β - formyl - phenyl

/? - acetyl-phenylhydrazine distilled in vacuo. Kp _{0> 1} . hydrazine are suspended in 100 ecm of water and 177 to 180 °. Yield 79%. 13 g of dimethyl sulfate and 50 ecm 2 η - sodium hydroxide solution

10 g of α-chloroacetyl - /? - ethyl / 3-acetyl-phenylhydrazine 35 were added dropwise with stirring in 4 hours (temperature was in 25 ecm benzene with ice cooling with a 15 to 20 °). After 12 hours of dissolving 6 g of diethylamine in 20 ecm of benzene, the solution is extracted with chloroform, treated with sodium sulfate, left to stand overnight, the diethylamine is dried and, after the hydrochloride solution has been evaporated, the filtrate is concentrated and the residue obtained is im Distilled in vacuo, resulting α-diethylaminoacetyl- β -ethyl- β- acetyl- 40 Kp _0>) . 170 to 172 °; 38 to 39 °; Yield 14 g of phenylhydrazine distilled in vacuo. Kp ₀₁ . 168 bis a - diethylaminoaetyl - /? - formyl - β - methyl - phenyl-170 °. Yield 10.7g.

p g ppyy

chloride was suction filtered, the filtrate evaporated and the precipitated a-Dipropylaminoacetyl-.beta.-methyl-.beta.-acetyl phenylhydrazine distilled in vacuo. Kp _{0> 0S} . 178-179 °, yield 52 g.

Example 4

32 g /? - ethyl - /? - acetyl-phenylhydrazine in 100 ecm l d i

hydrazine.

Example 5

50 g of ^ -Methyl - ^ - formyl-phenylhydrazine were suspended in 150 ecm of absolute benzene, 40 g of chloroacetyl chloride were added and the mixture was refluxed for 2 hours. The benzene was evaporated and the resulting a - chloroacetyl - β - methyl -β- formyl - phenylhydrazine distilled in vacuo. Kp _{0> 2} . 170-173 °, m.p. 95 °, yield 90%. 50 g of dimethylamine were introduced into a solution of 68 g of a- chloroacetyl -β- methyl - /? - formyl-phenylhydrazine in 400 ecm benzene, the solution was allowed to stand overnight, the dimethylamine hydrochloride was filtered off with suction, the filtrate was concentrated and the residue, a -Dimethylaminoacetyl - /? - methyl - /? - formyl-phenylhydrazine, distilled off in vacuo. Kp _{0> 4} . 165 to 169 °; M.p. 76 ° (recrystallized from benzene-hexane), yield 62 g. At sρ i el 9

To a solution of 23.6 g of a-chloroacetyl-ß-methyl - /? - formyl-phenylhydrazine (prepared according to Example 5) in 120 ecm of absolute benzene were 18 g of piperidine slowly added dropwise, after the reaction has subsided, heated on the steam bath for about an hour, the hydrochloride suctioned off and the filtrate concentrated. The a-piperidinoacetyl - ^ - methyl - ^ - formyl-phenylhydrazine crystallizes out when rubbed with ether. From hexane, mp 89 °. Yield 25g.

Example 10 Example 6

45.2 g of α-chloroacetyl - /? - methyl - /? - formylphenylhydrazine (prepared according to Example 5) are left to stand overnight at room temperature in a mixture of 100 ecm benzene and 100 ecm ether with 45 g diethylamine Sucked off diethylamine hydrochloride and evaporated the filtrate in vacuo at 30 to 40 °. The a-diethyl-23.6 g of a -chloroacetyl- /? -methyl - /? - formyl-phenylhydrazine (prepared according to Example 5) were mixed with 20 g of morpholine in 120 ecm benzene as in Example 9 and worked up. 23 g of α-morpholinoacetyl - /? - methyl - /? - formylphenylhydrazine were obtained. Kp _0i2 . 201 to 202 °.

Example 11

11.3 g of N-acetylhydrazobenzene were in 50 ecm absolute benzene with 5 g of chloroacetyl chloride refluxed for 1 hour, the solution evaporated in vacuo and the resulting N-acetyl-N'-chloroacetylhydrazobenzene recrystallized from benzene-hexane

aminoacetyl-ß-methyl - ^ - formyl-phenylhydrazine from, 70 siert. F. 92 °. Yield 12g.

10

A solution of 5 g of N-acetyl-N'-chloroacetylhydrazobenzene was added to a solution of 2 g of methylamine in 25 ecm of benzene added in portions, the precipitated after standing for 24 hours at room temperature Sucked off methylamine hydrochloride and evaporated the filtrate. The residue consists of N - acetyl - N '- methylaminoacetyl - hydrazobenzene and is recrystallized from ethyl acetate. 152 ° F. yield 2.5 g.

Example 12

To a solution of 30 g of N-acetyl-N'-chloroacetylhydrazobenzene (prepared as in Example 11) in 200 ecm benzene were 10 g of dimethylamine with ice cooling initiated and the solution shaken for 5 hours at room temperature. The dimethylamine hydrochloride was filtered off with suction, benzene was evaporated, the residue was taken up in ethyl acetate and washed with extracted from dilute hydrochloric acid. The hydrochloric acid solution was filtered with the addition of animal charcoal, the filtrate was made alkaline with sodium carbonate solution while cooling with ice and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated. The N-acetyl-N'-dimethylaminoacetyl-hydrazobenzene remained as a pale yellowish oil. Yield 24g. F. 63 to 64 ° (Isopropyl ether).

Example 13

30 g of N-acetyl-N'-chloroacetyl-hydrazobenzene (manufactured according to Example 11), 15 g of diethylamine were added in 200 ecm of absolute benzene and 48 hours left to stand at room temperature. The diethylamine hydrochloride was filtered off with suction, the filtrate was evaporated, the residue dissolved in chloroform and extracted with 1 η hydrochloric acid. The hydrochloric acid extract was treated with sodium bicarbonate solution, extracted with chloroform, dried over sodium sulfate and evaporated in vacuo. The N-acetyl-N'-diethylaminoacetylhydrazobenzene was left behind as a Oil. Yield 20g. F. 50 to 51 ° (isopropyl ether).

Claims (1)

Claim Process for the preparation of substituted phenylhydrazines the general formula N-CH ₂ -CO-N N-CO-R ₄ JlVo '' ' ρ TT -r> L * g XI5 IV ₃ in which R ₁ and R _{4 are} hydrogen or a lower alkyl radical with 1 to 5 carbon atoms, R _{2 is} lower alkyl and R _{3 is} alkyl or phenyl and in which R ₁ and R _{2 can} also be members of a ring system, characterized in that substituted phenylhydrazines are the general formula NH - N-CO-R ₁ CTT T> in which R ₃ and R _{4 have the} same meaning as above, are reacted with haloacetyl halide and then treated with a primary or secondary amine, or a phenylhydrazine of the general formula NH-NH-CO-R ₄ reacted with haloacetyl halide, then by treatment with a primary or secondary Amine converted into the corresponding α-mono- or ct-dialkylaminoacetyl-jff-acyl-phenylhydrazine and treated this with alkylating agents. © 709 58 * 290 T.