DD143617A1 - PROCESS FOR THE PREPARATION OF 2-NITRO AND 2-AMINO-5-OXO-PERHYDRO-PYRAZOLO SQUARE BRACKET ON 1,2-A CORNER CLAUSE TO PYRAZOLES - Google Patents

Abstract

The above new compounds show anti-inflammatory bactericidal and vasoactive effects. They are made by Pyrazoiidone- (3) azomethine imines with E-ß-nitrostyrenes in one indifferent solvent at 20 ° C to boiling point of Solvent in a molar ratio of 1: 1 to 2 are reacted. The process according to the invention yields in yields of more than 90% Surprisingly, mixtures of only 2 isomers, with the usual Methods, e.g. by crystallization or column chromatography, are separable.

Description

Title of the invention

Process for the preparation of 2-nitro- and 2-amino-5-oxo-perhydro-pyrazolo / 1,2-a-pyrazoles

Field of application of the invention

The invention relates to a process for the preparation of novel, regio- and stereochemically defined 2-nitro and 2-amino-5-oxo-perhydro-pyrazolo / i, 2-a / pyrazoles of the general formula I in which

1 3 R and R = phenyl or with 1 to 2 halogen atoms, 1'bis

2 methoxy groups, 1 to 2 alkyl radicals with 1 to

4 C atoms or with an alkoxycarbonyl group

13 1 substituted phenyl _s wherein R «= R or R

R can be; R ² = NO or NH;

including their salts with physiologically acceptable

2 2

Bases (R = N0 _? "General formula Ia) or acids (R = NH ₂ - general formula Ib), wherein the salts of the compounds of general formula Ia with bases the general For«

13 mel VI have _e in which R and R have the same meaning as in the general formula I and Me is a monobasic or 0.5 dibasic metal ion. "

The compounds of general formula Ia and their salts of general formula VI have anti-inflammatory and bactericidal effects! the compounds of the general formula Ib and their salts with acids are vasoactive. compounds of the general formula I are of interest as pharmaceuticals.

Characteristics of the known technical solutions Compounds of general formula I have hitherto been unknown «

Object of the invention

The aim of the invention is * to develop a simple, technically feasible process which gives industrially available starting materials 2'-nitro and 2-amino-5-oxo-perhydro-pyrazolo / 2, 7-pyrazole, the regio »And stereochemically uniform«

Explanation of the essence of the invention

This object is achieved according to the invention by pyrazolidone «(3)« azomethinimine of the general formula VII _# in the R has the same meaning as in the general formula I, with

3 E-ß ~ Nitro ~ styrenes of the general formula VIII ^ in which R has the same meaning as in the general formula I, in an inert solvent at 20 ⁰ C to boiling point of the solvent in the molar ratio IiI to 2 urr.ge · Be used as solvents are preferably dichloromethane, chloroform, benzene, toluene, dioxane or Tetrahy * * drofuran. The preferred molar ratio is isi.

According to current state of international theory and technology "* technology would OCE from compounds general formulas VII and VIII, respectively mixtures of four isomers produced with different chemical and physical properties, namely the stereoisomeric compounds of the For ~ times I and the formula II and their both regions

2 ^Q isomers in which the positions of R / R ^ on the C atoms

1 3 2 and 3 are reversed; in all cases, R and R have the same meaning as in the general formula I and

2 is R = N ^ p * ^ ^{0 w} ^ ^{re only "1} ^ * ^e" - ⁿ e ^m very much effort and loss possible ,, to separate such isomers · It is generally not possible in two or more of the above said isomers by chemical or physical operations to make a uniform connection,

1 2838

Surprisingly, only the compounds of the general formula Ia and their stereo-isomers of the general formula IIIa in which R and R are obtained by the process according to the invention in yields of more than 90% of theory from the compounds of general formulas VII and VIII. This is technically and theoretically completely new · It is obtained neither the above 3 isomers of compounds of general formula I, d _# h "not compounds of general formula II and not the regioisomers of compounds of General Formeini and II »nor the 3 formally possible isomers of compounds of general formula III, h. not compounds of the general formula IV and not the regioisomers of compounds of the general formulas III and IV »

The process according to the invention thus provides mixtures of only 2 isomers, namely compounds of the general formulas I and III which can be separated by conventional methods, eg B, by crystallization or column chromatography *. From the isomer mixture obtained according to the invention, consisting of the compounds of the general formulas Ia and HIa, in the

13 2

R una R have the meaning given above and R is NO _2, obtained according to the invention the single compounds aer general formula Ia by reacting it with the addition of equimolar amount of an alkali metal barren a Metallhydroxida or metal alkoxides of the general formula V '

4 I

in which R = H or alkyl having 1 to 5 C atoms and Me Li, Na ₄ K, 0.5 Mg or 0 _c 5 Ca or 0.5 Ba, in alcohol, water or an alcohol-water mixture in the salts aer general formula VI ₄ converts ".and subsequently the solution, preferably in water from O to 5 ⁰ C, acidified with a mineral acid * it can be the salts of the general formula VI isolate _e verzugswoisa when it gains in a lower alcohol, but you can also acidify your solutions directly *

The compounds of general formula Ib are dor in a customary per se by catalytic hydrogenation of the compounds dsr allgenisinen formula Ia, preferably with precious metal

Catalysts, eg "ADAMS-Pt," obtained in alcohols. Their salts with inorganic and organic acids are obtained in a conventional manner from equimolar amounts of compounds of the general formula Ib and acid, preferably in lower alcohols.

Embodiments.

Example It

17 "4 g (0.1 mol) of 1-benzylidene-pyrazolidone- (3) -azomethinimine (VII, R ¹ = CJ ^), 14.9 g (0.1 mol) of E-β-nitro-styrene (VIII · 3

R β C ₀ H _1. ) And 90 ral Oichlormethan be heated for 21 hours in a bath of 70 ⁰ C under exclusion of water in a equipped with a Rückkühlkühler apparatus »Then the feedstock VII is consumed« The termination of the reaction can easily by thin layer chromatography can be kon trolliert ^ (silica gel G, eluent n-propanol, 3odent ~ development). The R _p values are for VII (R ¹ = C ₅ H) x 0.23, for VIII (R ¹ = C ₆ H ₅ ) 0.88 and for Ia and HIa (R * R ^{3 B} -C ₆ H ₅ ) 0.76 * The dichloromethane is then distilled off and can be reused. "The residue is washed with ether or benzene. It consists of lref, 3trans-diphenyl-2-cis-nitro-5-oxo-perhydro-pyrazolo. i, 2-a / pyrazole Ia (R ~ R = ^C 6 ^M fi) ^and Iref 3-tris-diphene-2-yl-nitro-oxo-2-hydroxy-razolo ^ i, 2-a7pyrazole IIIa (R. ¹ = R ² β Ο_Η _Κ ) with an overall yield of 92 to 97 % of theory in the molar ratio of the two stereoisones Ia: IHa = 7 to 7 _e 5: 3 to 2.5 "Further isomers are not formed in this process * Ia and IIIa are "organization separated by fractional Umkristalli · n-propanol, Ia (yellow leaves), m.p.« 161 to 163 ⁰ C, XIIa (colorless prisms), mp «146-147 ° C _e

Example 2:

To solve vonlO _e 2 g Ia (R ¹ m H _n-Cp) in 150 ml of methanol is added 28.1 ml of l, 125n Esethanolisches sodium methylate at 20 C, then the solution is concentrated in WasseiStrahlvakuum

and wash the crystalline residue with a little cold n-propanol. It is dried in vacuo. at 80 ^° C. to obtain 10.4 g (95 % of theory) of VI (R ¹ »R ^{3 C} ₆ ^H ₅ ^{.ββ. β Na} )» mp.

208-209 ⁰ C * Analogously to Example 2 is 10.2 g Ilia (R ^C 6 ^H s) ^{to utld} receives 95% of theory VI (R ¹ = R ³ = C ₆ H _5, Me = Na ^1), m.p. 208 to 209 ⁰ C.

Example 3:.

1 ~ Benzylidene-pyrazolidone- (3) -azomethinimine and E-.beta.-nitro-styrene are reacted as described in Example 1. After distilling off the dichloromethane, the residue is dissolved in methanol in which 0. 1 mol of NaOH or KOH is dissolved is at room temperature and then distilled off in a water-jet vacuum, the solvent. The crystalline residue is dissolved in water, the aqueous solution is cooled to 0 to 10 ^° C.,. Add pieces of ice and then allowed with stirring 0.11 mol of a 2 to 4n mineral acid, eg, "hydrochloric acid, enter" Man sucks

1 3 then quickly the crystalline precipitated Ia (R »R c C ₆ H ₅ ) 8b, washed with water free of acid and dried i * Vak. at 80 ^° C. 91 to 96 % of the theory Ia (R ¹ RR ³ CC ₆ H ₅ ) are obtained.

Example 4:

It is analogous to Example 1 0.1 mol l - (& - Methoxy ° benzylidene) -pyrazolidon- (3) ~ azomeihinimin (VII, R = CgH -OMe-4) and 0 * 1 mol of 4 ~ methoxy »E-ß ~ nitro- styrene (VIII, R ³ = C _g H -OMe) and proceeds after distilling off the dichloromethane, as described in Example 3 * lref _p 3trans ~ Bis (4 "methoxy ^ pheny1) ~ 2cis-nitro-5" oxo ~ pe rhydro-pyrazolo / 1,2-a /

3 3 "

pyrazole Is (R a R -C ₅ H -OMe) as yellow crystals, m.p.

170 to 172 ⁰ C (from ethanol) *

Example 5;

Analogously to Example 1, 0.1 mol of 1- (4-chlorobenzylidene) -pyratolidone- (3) azomethine.maxn (VII _e R ¹ = C ₆ H ₄ -Cl) and 0.1 mol of 4-chloro are used -E ~ ß ~ nitro ~ sty col (VIII ₉ R ³ = CgH »C1-4)

in 160 ml of dichloromethane u'ia The reaction time is 45 hours, "then is distilled off, the dichloromethane and worked up analogously to Example 3 continue" is obtained in a yield of 93 to 97% of the theory Iref, 3trans-bis (4 "chlorophenyl) -2cis nitro-5-oxo-perhydro-pyrazolo / 1,2-a-pyrazole Ia (R ¹ * R ³ = C _g H ₄ -Cl 4) _# yellow flakes (from ethanol) or yellow cuboids (from dichloromethane) _β Schmp # 195 bis

1S7 ⁰ C /; ,

1 3

The stereoisomer H 1a (R = R = C ₆ H-Cl-4) is formed next to Ia as a single isomer in the dichloromethane reaction solution. It can be prepared before the further processing of the isomer mixture (Ia + IIIa), which analogously to Example 3 only pure

13 Ia (R = R β C H.-C1-4) provides, separated, by fractionating the Isomerengemisch (Ia · «IXIa) from Dichlornnsthan and ethanol recrystallized«. In both solvents the isomer is Iref, 3t rans ~ Bis (4-chlorophenyl) '- 2trans ⁱ -nitrQ ~ 5 ~ oxo »» perhydro-pyrazolo / l, 2 ~ a / pyrazal IHa (colorless cubes of ethanol, m.p. , 190 to 192 ^° C) are more soluble than

1 3

the isomer Ia (R = R "C H ^ -Cl-4). In order to obtain the pure isomer Ia during further processing analogously to Example 3, the separation of the isomer IHa from the mixture (Ia ψ IHa) is not necessary.

Example 6s

Analogously to Example 2, a solution of 0.01 mol of Ia

13 (R-R = CgH ₄ -Cl) in hot methanol or ethanol to a methanolic or ethanolic solution of 0.01 mol of the corresponding sodium alcoholate distilled off under reduced pressure from the alcohol, the residue is washed with a little cold n-propanol and dried at 80 ^° C. This gives 96 to 97 % of the theory VI (R ¹ RR ³ =: CHCH-Cl-4, Me ^X Na Na), mp 235 to 236 ⁰ C,

_128 3 8

Example 7:. ,

Analogously to Example 6, 0, Ol mol of IHa (R ¹ R CgH -Cl-4) is reacted with sodium alcoholate and obtained with 96 to

97% yield VI (R ¹ = R ³ = CgH 4 Cl-4, Me ¹ = Na)

Example 8:

32.34 g (0.1 mol) of Ia (R ¹ = R ³ = ^; Cg-H ₅ ) in 1.2 liters of methanol with the addition of 1.5 g of PtO ₂ (according to ADAMS) at 20 to 30 ⁰ C. The theoretical amount of hydrogen (6.72 liters) is rapidly absorbed under atmospheric pressure. After separation of the catalyst, the residue is concentrated in 55 ml of 2N HCl and water at 20 ^° C., filtered, and the filtrate is immediately removed with 11.1 colorless, crystalline 2cis-amino-Iref, 3tra: ns-d-phenyl-5-oxo-perhydro-pyrazolo / i _e 2-a7pyr-3-ol Ib (R ¹ = R ³ = ^C ₆ ^H ₅ ) Monohydrate from mp 115-116 ⁰ C in a yield of 75 to 85% of theory

Example 9:

4.67 g of the product obtained according to Example 8 and 0 _e 87 g of maleic acid are combined as ethanolic solutions, then the ethanol is distilled off under reduced pressure from the clear solution. The crystalline residue is taken with

worked through warm petroleum ether and after cooling the

1 3 Maleinate of Ib (R = R = C-H) aspirated, mp, Io9 to 110 ° c.

Example 10:

Ilia (R ¹ = R ³ χCgH) is hydrogenated analogously to Example 8, giving 2trans-amino-1-fluoro, 3-trans-diphenyl-5-oxo-perhydro-pyrazoles, 2-a-.pyrazole IIIb (R ¹ = R ³ = CgH ₅ ) as colorless prisms (from ethanol) of mp * 173 to 175 ⁰ C, -

)

.lsi

 Η

Ια

• H-

ib

* - H --- Ν / Η,

R ^s

ill

.13

--H

"M.

3 _Jl

^ -H

vi

H--

r - H

la.

R ^:

VIi

• YSi

Claims (7)

$ g, 1 £> ü ö ü ^ claim for invention 1 · R has the same meaning as in the general formula I, with E »ß ~ Nitro ~ styrenes of the general formula VIII in which R has the same meaning as in aer general formula I, in an inert solvent at 20 C to the boiling point of the solvent in the molar ratio 1: 1 are reacted to 2 » 1 3 sen the general formula VI have, in which R and R have the same meaning as in general formula I and Me is a monobasic or dibasic 0.5 metal ion, characterized in that pyrazolidone "(3) of the general formula VII -azomethinimine ₈ in the 1 3 · 1 3 where R = · R or R R, R ² = NO ₂ or NH ₂ , including their salts with physiologically acceptable 1 to 2 methoxy groups, 1 to 2 alkyl radicals with 1 to 4 carbon atoms or with one Alkoxycarbonyl substituted phenyl, 1 3 R and R s are phenyl or having 1 to 2 halogen atoms, 1 · Process for the preparation of 2-nitro- and 2-amino «= 5-oxo-hydro-pyrazolo / i _i 2-a7pyrazoles of the general formula I _e in which 2 # Process according to item I _4, characterized in that the solvent used is dichloromethane, chloroform, benzene, toluene, dioxane or tetrahydrofuran. 2
lent bases (R = NO ₀ = general formula Ia) or Acids (R = NH ₂ = general formula Ib) ₈ where the salts of the compounds of general formula Ia with 3, process according to items 1 and 2, characterized in that the starting materials of the general formulas VII and VIII are used in a molar ratio of 1: 1, 4
my formula V, in which R = H or alkyl with 1 to 5 C atoms and Me Li, Na , K, 0.5 Mg or 0.5 Ca or 0.5 Ba, in alcohol, water or an alcohol Water mixture is converted into the salts of general formula VI and then the solution, preferably in water from 0 to 5 ° C _{f is} acidified with a mineral acid » 4.Verfahren according to item 1 and 2, characterized in that the mixture of isomers of the compounds of the general formulas Ia and HIa for obtaining the uniform compounds of the general formula Ia with the addition of the equimolar amount of an alkali metal carbonates or 21283 of a metal hydroxide or metal alcoholate of the general 5 * Process according to items 1 to 3, characterized in that compounds of the general formula Ib are obtained in a conventional manner by catalytic hydrogenation of the compounds of general formula Ia » 6 »Process according to item 5, characterized in that the catalyst used is ADAMS ~ Pt · 7 »process according to item 5 and 6, characterized in that the compounds of general formula Ib are converted into their salts with inorganic or organic acids in lower alcohols * For this 1 page formulas