CA1134834A - Process for production of 4-substituted 1, 2-diphenyl-3,5-dioxopyrazolidines - Google Patents
Process for production of 4-substituted 1, 2-diphenyl-3,5-dioxopyrazolidinesInfo
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- CA1134834A CA1134834A CA000325093A CA325093A CA1134834A CA 1134834 A CA1134834 A CA 1134834A CA 000325093 A CA000325093 A CA 000325093A CA 325093 A CA325093 A CA 325093A CA 1134834 A CA1134834 A CA 1134834A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
ABSTRACT
This invention is concerned with a novel process for production of 4-substituted 1,2-diphenyl-3,5-dioxopyrazolidines of general formula I
where R and R1, which by be identical to or different from each other, represent a hydrogen atom, a lower alkyl group, a phenyl group or the group -COOR" (where R" means hydrogen or a lower alkyl group) and A a hydrogen atom or a hydroxyl group. Compounds of general formula I exist in the so-called Z- and in the isomeric E-form, which fall both under the general formula designated above (as well as mixtures thereof). The compounds of formula I
are prepared by either (a) reacting a cyclosemiacetal of general formula II
where A' represents hydrogen or an etherified hydroxyl group, preferably the .beta.-methoxyethoxymethoxy (=MEM) group, with a triarylphosphorane derivative of general formula III
where R and R' have the above-mentioned meanings and Ar represents a phenyl group (optionally substituted with an inert group such as methyl, methoxy or phenyl) and, subsequently, optionally liberating the etherified hydroxy group by means of a mild Lewis-acid; or reacting the aldehyde of the formula IIa with a compound of formula III as defined above. The compounds of formula I are valuable antiphologistically active compounds. The inter-mediates of formulae II and IIa are novel and form part of this invention.
They are prepared by rearrangement or deketalisation of the corresponding cyclic acetals of general formula IV
where A' has the meanings indicated above. This rearrangement may be effected, for example, by means of simple heating in aqueous ethanol.
This invention is concerned with a novel process for production of 4-substituted 1,2-diphenyl-3,5-dioxopyrazolidines of general formula I
where R and R1, which by be identical to or different from each other, represent a hydrogen atom, a lower alkyl group, a phenyl group or the group -COOR" (where R" means hydrogen or a lower alkyl group) and A a hydrogen atom or a hydroxyl group. Compounds of general formula I exist in the so-called Z- and in the isomeric E-form, which fall both under the general formula designated above (as well as mixtures thereof). The compounds of formula I
are prepared by either (a) reacting a cyclosemiacetal of general formula II
where A' represents hydrogen or an etherified hydroxyl group, preferably the .beta.-methoxyethoxymethoxy (=MEM) group, with a triarylphosphorane derivative of general formula III
where R and R' have the above-mentioned meanings and Ar represents a phenyl group (optionally substituted with an inert group such as methyl, methoxy or phenyl) and, subsequently, optionally liberating the etherified hydroxy group by means of a mild Lewis-acid; or reacting the aldehyde of the formula IIa with a compound of formula III as defined above. The compounds of formula I are valuable antiphologistically active compounds. The inter-mediates of formulae II and IIa are novel and form part of this invention.
They are prepared by rearrangement or deketalisation of the corresponding cyclic acetals of general formula IV
where A' has the meanings indicated above. This rearrangement may be effected, for example, by means of simple heating in aqueous ethanol.
Description
~3~4 The inventian is concerned with a novel process for production of 4-substit~lted 1,2-diphenyl-3,5-dioxopyrazolidines of general formula R \ / CO- N ~ - A
/ 2 \ ¦ ~ I
where R and R', which may be id ntical to or different from each other, repre-sent a hydrogen atom, a lower aIkyl group, a phenyl group or the group -COOR"
(where R" means hydrogen or a lower aIkyl group) and A a hydrogen atom or a hydroxyl group. Compound~s of general formula I exist in the so-called Z- and in the isomeric E-form, which fall both under the general formula designated above (as well as mixtures thereof).
From British Patent 1 301 857 it has already been known that, amcng others, compounds of general formula I are valuable antiphlogistically active compounds, which are superior to the butazolidine - simLlar to them in structure - as far as the main actian and the absence of side effects are concerned.
There have been described as well several processes for prcduction of these oomr pounds.
It has been found now, that oompounds of general formula I are also produced by reacting a cyclosemiacetal of general formula D
CH2 C - 00--N ~
where A' represents hydrogen or an etherified hydroxyl group, preferably the L~
'~
~. .
.. ~ . . ..
~: :
.
.
1~3~
~-methoxyethoxymethoxy (=0-MEM) group, with a triarylphosphorane derivative of general formula R \ / Ar C = P \ Ar III
R' Ar where R and R' have the above-mentioned meanings and Ar represents a phenyl group (optionally substituted with an inert group such as methyl, methoxy or phenyl) and, subsequently, optionally liberating the etherified hydroxyl grollp by means of a mild Lewis-acid. As suitable Lewis-acids may be considered TiC14 and ZnBr2, but ZnC12, ZnJ2, SnCL4, SnBr4, MgBr2 and similar metal halides as well.
Reaction of the compounds II and III may be effected within an aprotic solvent such as dimethylfoxmamide or, preferably, dimethylsulfoxide under anhydrous conditions.
Instead of the cyclosemlacetals of general formula II, there may be used in the reaction, in case A represents hydrogen, also the aldehyde of general formula H \ / CO N ~
C - CH2 - CH \ ¦ ~ IIa on which they are based.
The oc~pounds of formula III may also be produced insitu from the corresponding, saturated phosphonium salt of general formula R / Ar ( ) / CHP \ Ar X IIIa Rl Ar ~, ~
113~t~34 where R, R' and Ar have the meanings mentioned above and X( ) represents a halogen ion, by splitting off hydrogen halide by means of a suitable metal rea-gent, such as, for example, sodium hydride, sodium amide, butyl-lithium or phenyl lithium.
The process may be effected in such a way, that the reaction mixture -after stirring at room temperature - is heated to a temperature between 30 and loo&, preferably at 50 to 70&, then it is allowed to cool off and stirred afterwards at room temperature.
After the reaction has been finished, the reaction mixture may be worked up by pouring it on ice, extracting with a suitable organic solvent such as ethylacetate, or dichloromethane and column-chrcmatography, or else reextrac-tion of the organic solvent with a basic, aqueous medium. In the latter case, the product will only be obtained after acidification with a mineral acid (for example hydrochloric acid) and extraction with a suitable solvent. Additional purification as well as separation of the geometrical (E,Z)-isomers may be ab-tamed by column-chromatography.
If in the starting co~pounds A represents an etherified hydroxyl group, this OH group protected during the reaction must subsequently be liberated in order to abtain compounds of form~la I with A = OH. This may, for example, be carried out in such a way, that the etherified OH group, converted, for example, into the ~-methoxyethoxymethyl (=MEM)- ether, is split off after the finished reaction of the etherified cyclosemiacetal II with the triphenyl phosphorane derivative of formula III with mild Lewis-acids (for example TiC14 in dichloro-methane).
The compounds of formLla I, where R is CH3 and R' is C0OH, are ob-tained by mild alkaline saponification of the corresponling esters (R = CH3, R' = COOR").
113~34 The compounds of general formula II may be obtained in a simple way by rearr~mgement of the corresponding cyclic acetals of general formula CH2- - 0 / C0 - N - ~ - A' ( H2__ o/ CO I ~ ~
where A' has the meanings indicated above. This rearrangement may be effected, for example, by means of simple heating in aqueous ethanol.
The compounds of general formula IV in their turn may be obtained by reacting diethyl 2-(2-ethylenedioxyethyl)malonate of formula I CH ~ CH2 ~ CH \ V
CH ~ 0 COOC2H5 with hydrazobenzene or an etherified p-hydroxyhydrazobenzene such as hydrazo-benzene-~ methoxyethoxymethyl-(=MEM)-ether, in the presence of a suitable condensing agent such as a solution of sodium in anhydrous ethanol.
The compound of formula V may be obtained by measures known per se, for example by condensation of 2-ethylenedioxyethylbromide with diethylmalonate in the benzene/dimethylformamide in the presence of sodium hydride.
The aldehydes of formula IIa may be obtained by deketalizing of the compound of formula IV with A' = hydrogen; deketalization may be effected, for example, within anhydrous dichloromethane with borotribromide.
The process according to the invention runs smoothly and results in high yields without substantial amounts of side products, as the introduction of the double bond takes place as envisaged and the formation o~ disubstituted products at C-4 of the pyrazolidine ring is avoided.
1~3~83~
The follcwing examples illustrate the invention without restricting its sccpe:
Exan~
F~Hydro ~ azobenzene-~-methoxyethQ~methylether(MEM) To a stirred suspension of 66.14 g (1.516 mol) of sodium hydride (55%
dispersion in mineral oil) in tetrahydrofuran (400 ml) is added dropwise a solu-tion of p-hydroxyazobenzene (191 g, 0.963 mol) in 810 ml of tetrahydrofuran.
After having stirred for 15 minutes the solution is cooled off. Then are dropped in at o& 144 g (1.156 mol) MEM}chloride (E.J. Corey, J.L. Gras and P.
Ulrich, Tetrahedron Lett.t 809 (1976)) and the mixture is stirred for 30 minutes at this temperature. Stirring is continued for one hour at room temperature, the excess sodium hydride is decomposed under the a~;tion of water and the mix-ture is evaporated in vacuo. The residue is taken up in ether and washed suc oe ssively with water, 5% sodium hydroxide and water until it remains neutral.
The ether extract is dried and evaporated under decreased pressure. In doing so, the title oompound is formung as thick, reddish oil (271.44 g 98%), which is used without further purification.
Exa~ple 2 p-Hydroxyhvdrazokenzene-MEM~ether A solution of p,hydroxyazobenzene-MEM-ether (220 g, 0.768 mol) in 1300 ml of ethanol is hydrogenated in the presen oe of 2.2 g Pd/C at room temperature and atmospheric pressure. After absorbing the calclllated quantity of hydrogen, the solution is filtered and evaporated until 220 g (99%) of a thick, yellow oil remains that has been used again immediately in the next step due to its easy oxidizability.
113'~834 Example 3 Diethyl-2-~2-ethylenedioxyethyl)-malonate To a stirred suspension of 141.38 g (3.24 mol) of sodium hydride (55%
dispersion in mineral oil) in dimethylformamide (1300 ml) and benzene (500 ml) is added dropwise diethylmalonate (471.8 g, 2.94 mol). After stirring at room temperature until the H2-develcpment is finished, 2-ethylenedioxyethyIbromide (S.M. Gurvich Zh. Obshch. Khim., 27, 2888(1957) (492 g, 2.94 mol) is added in 500 ml of benzene and the solution is stirred for 16 hours at 80&. Then, the mixture is cooled off, poured into excess ice-w~ater and the product is isolatedwith ether. After evaporation of the dried extract, 2-(2-ethylenedioxyethyl)-malonate is obtained.
Boiling point 105 - 108C (0,5 mm).
Analysis for CllH18O6: found: % C 53.42 H 7.42 calcul. % C 53.65 H 7.37 Example 4 4-(2-Ethylenedioxyethyl)-1,2-diphenyl-3,5-dioxopyrazolidine Hydrazob~nzene (58.4 g, 0.317 mol) is added while stirring to a sodium solution (8.02 g, 0.348 mol) in 480 ml of anhydrous ethanol, then diethyl-2-(2-ethylenedioxyethyl)-malonate (78.05 g, 0.317 mol) is drcpped in during 2 hours at reflux temperature. Additionally, the mixt~lre is heated for one hour, the solvent is gradually evaporated to dryness and the residue heated under de-creased pressure (15 mm) for one hour at 130 to 140 &. m e reaction prcduct is cooled, taken up in water, washed with ether and filtered w~ith active charcoal.While oooling the solution is acidified. This yields a white solid material (72.95 g, 68%), is dried in vacuo over phosphorus pentoxide and is used without further purificatian in the next step.
113~ii3~
Melting point: 150 C.
Analysis for ClgH18N2C)4: found ~ C 67.71H 5.33 N 8.23 calc. % 67.44 5.36 8.28 Example 5 .
4-(2-Ethylenedioxyethyl)-l-(ptMEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine p-Hydroxyhydrazobenzene-MEM~ether (137 g, 0.475 mol) in 140 ml of anhydrous ethanol is added while stirring to a solutian of sodium (1092 g, 0.475 mol) in ethanol (330 ml) and then diethyl-2-(2-ethylenedioxyethyl)-malonate (117 g, 0.475 mol) in 120 ml of ethanol is drcpped in under reflux temperature during 2 hours. Then, the mixture is refluxed for 1 hour more, the solvent is evaporated gradually to dryness and the residue is heated under de-creased pressure for 1 hour to 130 to 140 &. The reaction prcduct is ccoled, taken up in water, washed with ether and filtered over active charcoal. The solution is acidified with 10% hydrcchloric acid to pH4 and the separating oil is extracted with ethylaoetate. The dried extract that is evaporated to dryness leaves an oily residue the latter being dissolved in a saturated solution of piperazine in aoe tone. The crystallized piperazine salt of the 4-(2-ethylene-dioxyethyl)-l-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, which separated while standing is filtered and then dissolved in water. After acidifying with glacial aoe tic acid the product is isolated with ether. When evaporating the dried extract, the desired pyrazolidine formed as slightly yellow oil (105 g, 50%), which is pure enough to be converted into 1,2,4,5-tetrahydro,l-(p-MEM~
oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-ane.
Example 6 1,2,4,5-Tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one A solution o~ 4-(2-ethylenediaxyethyl)-1,2-diphenyl-2,5~diQxo-li3'~3~
pyrazolidine (51.36 g, 0.152 mDl) in 510 ml of 50% aqueous ethanol is refluxed for 3 hours. The solid naterial that crystallizes out of the still hot solution, is collected by means of filtering and dried in vacuo. 36.66 g (82~) of the 1,2,4,5--tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo-[2,3-c]pyrazole-3-one are ob-tained.
Melting point: 267 C decomposition.
Analysis for C17H14N2O3: found % C 69.18 H 4.75 N 9.63 calc. % 69.37 4.809.52 Examele 7 1,2,4,5-Tetrahydro-l-(p-MEM~oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one A solution of 4-(2-ethylenedioxyethyl)-1-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine (130 g, 0.294 1) in 1200 ml of 75~ ethanol is refluxed for 6 hours and then evaporated to dryness. The obtzined residue is recrystal-lized from ethylaoe tate and yields 66 g (56%) of the 1,2,4,5-tetrahydro-1-(p-MEM~oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]pyrazole-3-one as colourless crystal.
Melting point: 203 C decomposition.
Analysis for C21H22N2&: found % C 62.99 H 5.49 N 6.95 calc. % 63.31 5.57 7.03 Example 8 4-(2-Formylmethyl)-1,2-diphenyl-2,5-dioxopyrazolidine To a solution of 4-(2-ethylenedioxyethyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine (2.54 g, 7.5 mol) in 400 ml of dichloromethane is added a solution of borotribromide (18.79 g, 75 mol) in 50 ml of dichloromethane at -70 & drop-~.i ~ , .
1134~34 wise while stirring. At this temperatuLe stirring is continued for 24 hours.Then the temperature is allowed rise to room temperature and the mixture is poured on excess ice-water.
The organic layer is separated and washed (NaHCO3-solution) until it is neutral, dried (M~SO4) and evaporated to dryness.
The viscous residue is crystallized frcm ethylether-dichlorcmethane (8:2) and yields 0.7 g (3147%) of the desired pyrazolidine as colourless solid.
Melting point: 240 - 242 C.
Analysis for C17H14N2O3: found ~ C 69.54H 4.92 N 9-44 calc. ~ 69.37 4.80 9.52 Example 9 4-(3-Methyl-2-butenyl)-1,2-diphenyl-2,5-dioxopyrazolidine A solution of isopropyl-triphenylphosphoniumiodide (45.24 g, 0.1 mDl) [G. Wittig and D. Wittenberg, Ann., 606, 1 (1957)] in 180 ml of dimethyl-sulfoxide is ad~ed dropwise to a stirred suspension of sodium methylsulfinyl methide at 20 to 25 & (R. Greenwald, M. Chaykovsky and E.J. Corey, J. Org. Chem., 28, 1128 (1963)), that has been prepared in situ from 4.15 g (0.095 mol) of a 55% dispersion of sodium hydride in mineral oil and 120 ml of dimethylsulfoxide.
The mixture is stirred for 30 mlnutes at room temperature and then 1,2,4,5-tetrahydro~l,2-diphenyl-3H-5-hydroxy-furo[2,3-c]pyrazole-3-one (14 g, 0.047 mol) is added in portions. The mixture is stirred for 2 hours at room temperature and for a further hour heated to 70&.
After stirring at room temperature for 16 hours, the reaction mixture is poured into exoess water and extracted with dichlorcmethane. The organic phase is separated, washed with water, dried cver MgS04 and then evaporated to dryness. The obtained residue is dissolved in benzene and adsorbed on a _ g _ ' . . ..
...
'.
113~4 silicagel column. The elution with 10% aoe tone in benzene yields 8.79 g (58.4%) of the desired pyrazolidine as colourless solid.
Melting point: 155 - 157 &.
Analysis for C20H20N2O2: found % C 75.20H 6.23 N 8.64 calc. % 74.98 6.29 8.74 Example 10 4-(2-Propenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This oompound is produced in a similar manner as described in example 9, by starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and methyltriphenylphosphoniumiodide [C.H.
Collins and G.S. Hammcnd, J. Org. Chem., 25, 1434 (1960)] (17.78 g, 0.044 mol), using sodium methylsulfinylmethide (0.04 mol) in dimethylsulfoxide (prepared as described above). The title compc~nd is obtained after column-chromatography on silicagel (10% aoetone in benzene) as colourless solid (64.5%).
Melting point: 133 - 135C (EtOH 95~).
Analysis for C18H16N202: found % C 74.12 H 5.63 N 9.37 calc. % 73.95 5.529.58 Example 11 (E,Z)-4-(2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This oompound is produoed as described in example 9, starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3~1-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and ethyltriphenylphosphone bromide (16.33 g, 0.044 mol) [G. Wittig and D. Wittenberg Ann., 606, 1 (1957)], using sodium methylsulfinylmethide (0.04 mol) in dimethylsulfoxide prepared as described above. The compcNnd is obtained after column-chromatography on silicagel (10% aoetone in benzene) as 113~834 mixture of the E- and Z-forms, wherein the Z-iso~ere is prevailing (60%).
Melting point: 167 & (EtOH/H2O 1:1) literature melting p~int: 128& for the compcund, obtained in the conventional malonate-hydrazobenzene way.
Analysi!3 for ClgH18N2O2 fcund % C 74.32 H 5.87 N 9.22 calc. % 74.49 5.92 9.15 Example 12 (E,Z)-4-(3-phenyl-2-prGpenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This compound is produced as described in example 9, starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and benzyltriphenylphosphone chloride (17.11 g, 0.044 mol) [G. Wittig and M. Schollkopf, Chem. Ber. 87, 1318 (1954)], using sodium methylsulfinyl-methide (0.04 mol) in dimethylsulfoxide, as described above. The co~pound is obtained as crude material in a yield of 64%.
The Z- and E-forms may be separated by column-chromatography on ~ilicagel (10% aoe tone in benzene).
(Z)-isomere: melting point 124 C (EtOH 95).
Analysis for C24H20N2O2: found % C 78.29 H 5.31 N 7.48 calc. % 78.23 5.47 7.60 (E)-isomere: melting point 133 C (EtOH 95) C24H20N2O2: found % C 78.42 H 5.54 N 7.46 calc. % 78.23 5.47 7.60 Example 13 (E,Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine ~ mixture of ~-carbethoxyethylidene-triphenylphosphorane O. Isler, Helv. Chim. Acta, 40, 1241 (1957) (63.53 g, 0.175 mol) and 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (26 g, 0.088 mol) in 400 ml of anhydrous dimethylsulfo~ide is stirred for one hour at roam temeerature and for another hour to 60C. After the reaction mixture has been stirred for 15 hours at room temperature, it is poured into excess water and extracted with ethylacetate. The organic phase is separated and extracted several times with an aqueous 5% piperazine solution. The united aqueous extracts are acidified to pH 8 with 10% hydrochloric acid and the waxlike solid that separated is filtered off and abandoned. me fil~ered solution is treated with charcoal, acidified to pH 5.5 and extracted with ethylacetate. After evaporation of the dried extract, the crude isomeric mixture of th,e OE)- and (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine is obtained as a brawn, thick oil, which is dis-solved in aoetone and purified by its 2-amino-2-thiazoline salt. The working up of this salt, effected as described in example 5, delivers after extraction with ethylaaetate and evaporation of the dried extract 19.5 g of an oily mixture of the desired pyrazolidine, wherein the (E)-form prevailed. The mixture is dis-solved in benzene and adsorbed on a silicagel column. The elution with 10%
ethylaoe tate in benzene yields 1.36 g (4%) of the (Z)-form as colourless solid.
Melting point: 151C.
Analysis for C22H22N204: found % C 69.59 H 5.97 N 17.02 calc. % 69.82 5.86 16.91 Further elution with the same agent yields an intermediate fraction oonsisting of a mixture of 2 isomeres, and then a fraction of 14 g (42%) of the (E)-form as colourless solid, which is recrystallized from cyclohexane.
Melting point: 93C.
113~834 Example 14 (E,Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine The compound is produoe d as described in example 13, starting frcm u-carbethoxyethylidene triphenylp~osphorane (1.46 g, 4 mol) and 4-(2-formyl-methyl)-1,2-diphenyl-3,5-dioxopyrazolidine (0.59 g, 2 mDl) in 12 ml of dimethyl-sulfo~ide, whereby 0.24 g (31.7%) of the title compcNnd is obtained. The physico-chemical and analytical data and also the E/Z-isomeres-proportion are almDst identical to the data obtained in the previous example.
Example 15 (E,Z)-4-(3-car~ethoxy-2-butenyl)-1-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxo-pyrazolidine _ A mixture of ~-carbethoxyethylidene triphenylphosphorane (14.49 g, 0.04 mol) and 1,2,4,5-tetrahydro-1-(p-MEM~oxyphenyl) 2-phenyl-3H-5-hydroxy-furo [2,3-c]-pyrazole-3-one (15.96 g, 0.04 mol) in 90 ml of anhydrous dimethyl-sulfoxide is allowed to react as described in example 13. Then, the reaction mixture is poured into exoess water, extracted with ethylaoetate and extracted once mDre with 5% aqueous piperazine solution. After acidifying the aqueous phase to pH 6, the product is isolated with ether and yields, after evaporation of the dried extract, 10.2 g of an oily mixture of the desired pyrazolidine, wherein the (E)-form prevailed. The mixture is dissolved in benzene and ad-sorbed at a silicagel column. me elution with dichloromethane yields 0.58 g (3%) of the (Z)-form as yellow oil. After a fraction oonsisting of a mixture of
/ 2 \ ¦ ~ I
where R and R', which may be id ntical to or different from each other, repre-sent a hydrogen atom, a lower aIkyl group, a phenyl group or the group -COOR"
(where R" means hydrogen or a lower aIkyl group) and A a hydrogen atom or a hydroxyl group. Compound~s of general formula I exist in the so-called Z- and in the isomeric E-form, which fall both under the general formula designated above (as well as mixtures thereof).
From British Patent 1 301 857 it has already been known that, amcng others, compounds of general formula I are valuable antiphlogistically active compounds, which are superior to the butazolidine - simLlar to them in structure - as far as the main actian and the absence of side effects are concerned.
There have been described as well several processes for prcduction of these oomr pounds.
It has been found now, that oompounds of general formula I are also produced by reacting a cyclosemiacetal of general formula D
CH2 C - 00--N ~
where A' represents hydrogen or an etherified hydroxyl group, preferably the L~
'~
~. .
.. ~ . . ..
~: :
.
.
1~3~
~-methoxyethoxymethoxy (=0-MEM) group, with a triarylphosphorane derivative of general formula R \ / Ar C = P \ Ar III
R' Ar where R and R' have the above-mentioned meanings and Ar represents a phenyl group (optionally substituted with an inert group such as methyl, methoxy or phenyl) and, subsequently, optionally liberating the etherified hydroxyl grollp by means of a mild Lewis-acid. As suitable Lewis-acids may be considered TiC14 and ZnBr2, but ZnC12, ZnJ2, SnCL4, SnBr4, MgBr2 and similar metal halides as well.
Reaction of the compounds II and III may be effected within an aprotic solvent such as dimethylfoxmamide or, preferably, dimethylsulfoxide under anhydrous conditions.
Instead of the cyclosemlacetals of general formula II, there may be used in the reaction, in case A represents hydrogen, also the aldehyde of general formula H \ / CO N ~
C - CH2 - CH \ ¦ ~ IIa on which they are based.
The oc~pounds of formula III may also be produced insitu from the corresponding, saturated phosphonium salt of general formula R / Ar ( ) / CHP \ Ar X IIIa Rl Ar ~, ~
113~t~34 where R, R' and Ar have the meanings mentioned above and X( ) represents a halogen ion, by splitting off hydrogen halide by means of a suitable metal rea-gent, such as, for example, sodium hydride, sodium amide, butyl-lithium or phenyl lithium.
The process may be effected in such a way, that the reaction mixture -after stirring at room temperature - is heated to a temperature between 30 and loo&, preferably at 50 to 70&, then it is allowed to cool off and stirred afterwards at room temperature.
After the reaction has been finished, the reaction mixture may be worked up by pouring it on ice, extracting with a suitable organic solvent such as ethylacetate, or dichloromethane and column-chrcmatography, or else reextrac-tion of the organic solvent with a basic, aqueous medium. In the latter case, the product will only be obtained after acidification with a mineral acid (for example hydrochloric acid) and extraction with a suitable solvent. Additional purification as well as separation of the geometrical (E,Z)-isomers may be ab-tamed by column-chromatography.
If in the starting co~pounds A represents an etherified hydroxyl group, this OH group protected during the reaction must subsequently be liberated in order to abtain compounds of form~la I with A = OH. This may, for example, be carried out in such a way, that the etherified OH group, converted, for example, into the ~-methoxyethoxymethyl (=MEM)- ether, is split off after the finished reaction of the etherified cyclosemiacetal II with the triphenyl phosphorane derivative of formula III with mild Lewis-acids (for example TiC14 in dichloro-methane).
The compounds of formLla I, where R is CH3 and R' is C0OH, are ob-tained by mild alkaline saponification of the corresponling esters (R = CH3, R' = COOR").
113~34 The compounds of general formula II may be obtained in a simple way by rearr~mgement of the corresponding cyclic acetals of general formula CH2- - 0 / C0 - N - ~ - A' ( H2__ o/ CO I ~ ~
where A' has the meanings indicated above. This rearrangement may be effected, for example, by means of simple heating in aqueous ethanol.
The compounds of general formula IV in their turn may be obtained by reacting diethyl 2-(2-ethylenedioxyethyl)malonate of formula I CH ~ CH2 ~ CH \ V
CH ~ 0 COOC2H5 with hydrazobenzene or an etherified p-hydroxyhydrazobenzene such as hydrazo-benzene-~ methoxyethoxymethyl-(=MEM)-ether, in the presence of a suitable condensing agent such as a solution of sodium in anhydrous ethanol.
The compound of formula V may be obtained by measures known per se, for example by condensation of 2-ethylenedioxyethylbromide with diethylmalonate in the benzene/dimethylformamide in the presence of sodium hydride.
The aldehydes of formula IIa may be obtained by deketalizing of the compound of formula IV with A' = hydrogen; deketalization may be effected, for example, within anhydrous dichloromethane with borotribromide.
The process according to the invention runs smoothly and results in high yields without substantial amounts of side products, as the introduction of the double bond takes place as envisaged and the formation o~ disubstituted products at C-4 of the pyrazolidine ring is avoided.
1~3~83~
The follcwing examples illustrate the invention without restricting its sccpe:
Exan~
F~Hydro ~ azobenzene-~-methoxyethQ~methylether(MEM) To a stirred suspension of 66.14 g (1.516 mol) of sodium hydride (55%
dispersion in mineral oil) in tetrahydrofuran (400 ml) is added dropwise a solu-tion of p-hydroxyazobenzene (191 g, 0.963 mol) in 810 ml of tetrahydrofuran.
After having stirred for 15 minutes the solution is cooled off. Then are dropped in at o& 144 g (1.156 mol) MEM}chloride (E.J. Corey, J.L. Gras and P.
Ulrich, Tetrahedron Lett.t 809 (1976)) and the mixture is stirred for 30 minutes at this temperature. Stirring is continued for one hour at room temperature, the excess sodium hydride is decomposed under the a~;tion of water and the mix-ture is evaporated in vacuo. The residue is taken up in ether and washed suc oe ssively with water, 5% sodium hydroxide and water until it remains neutral.
The ether extract is dried and evaporated under decreased pressure. In doing so, the title oompound is formung as thick, reddish oil (271.44 g 98%), which is used without further purification.
Exa~ple 2 p-Hydroxyhvdrazokenzene-MEM~ether A solution of p,hydroxyazobenzene-MEM-ether (220 g, 0.768 mol) in 1300 ml of ethanol is hydrogenated in the presen oe of 2.2 g Pd/C at room temperature and atmospheric pressure. After absorbing the calclllated quantity of hydrogen, the solution is filtered and evaporated until 220 g (99%) of a thick, yellow oil remains that has been used again immediately in the next step due to its easy oxidizability.
113'~834 Example 3 Diethyl-2-~2-ethylenedioxyethyl)-malonate To a stirred suspension of 141.38 g (3.24 mol) of sodium hydride (55%
dispersion in mineral oil) in dimethylformamide (1300 ml) and benzene (500 ml) is added dropwise diethylmalonate (471.8 g, 2.94 mol). After stirring at room temperature until the H2-develcpment is finished, 2-ethylenedioxyethyIbromide (S.M. Gurvich Zh. Obshch. Khim., 27, 2888(1957) (492 g, 2.94 mol) is added in 500 ml of benzene and the solution is stirred for 16 hours at 80&. Then, the mixture is cooled off, poured into excess ice-w~ater and the product is isolatedwith ether. After evaporation of the dried extract, 2-(2-ethylenedioxyethyl)-malonate is obtained.
Boiling point 105 - 108C (0,5 mm).
Analysis for CllH18O6: found: % C 53.42 H 7.42 calcul. % C 53.65 H 7.37 Example 4 4-(2-Ethylenedioxyethyl)-1,2-diphenyl-3,5-dioxopyrazolidine Hydrazob~nzene (58.4 g, 0.317 mol) is added while stirring to a sodium solution (8.02 g, 0.348 mol) in 480 ml of anhydrous ethanol, then diethyl-2-(2-ethylenedioxyethyl)-malonate (78.05 g, 0.317 mol) is drcpped in during 2 hours at reflux temperature. Additionally, the mixt~lre is heated for one hour, the solvent is gradually evaporated to dryness and the residue heated under de-creased pressure (15 mm) for one hour at 130 to 140 &. m e reaction prcduct is cooled, taken up in water, washed with ether and filtered w~ith active charcoal.While oooling the solution is acidified. This yields a white solid material (72.95 g, 68%), is dried in vacuo over phosphorus pentoxide and is used without further purificatian in the next step.
113~ii3~
Melting point: 150 C.
Analysis for ClgH18N2C)4: found ~ C 67.71H 5.33 N 8.23 calc. % 67.44 5.36 8.28 Example 5 .
4-(2-Ethylenedioxyethyl)-l-(ptMEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine p-Hydroxyhydrazobenzene-MEM~ether (137 g, 0.475 mol) in 140 ml of anhydrous ethanol is added while stirring to a solutian of sodium (1092 g, 0.475 mol) in ethanol (330 ml) and then diethyl-2-(2-ethylenedioxyethyl)-malonate (117 g, 0.475 mol) in 120 ml of ethanol is drcpped in under reflux temperature during 2 hours. Then, the mixture is refluxed for 1 hour more, the solvent is evaporated gradually to dryness and the residue is heated under de-creased pressure for 1 hour to 130 to 140 &. The reaction prcduct is ccoled, taken up in water, washed with ether and filtered over active charcoal. The solution is acidified with 10% hydrcchloric acid to pH4 and the separating oil is extracted with ethylaoetate. The dried extract that is evaporated to dryness leaves an oily residue the latter being dissolved in a saturated solution of piperazine in aoe tone. The crystallized piperazine salt of the 4-(2-ethylene-dioxyethyl)-l-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, which separated while standing is filtered and then dissolved in water. After acidifying with glacial aoe tic acid the product is isolated with ether. When evaporating the dried extract, the desired pyrazolidine formed as slightly yellow oil (105 g, 50%), which is pure enough to be converted into 1,2,4,5-tetrahydro,l-(p-MEM~
oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-ane.
Example 6 1,2,4,5-Tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one A solution o~ 4-(2-ethylenediaxyethyl)-1,2-diphenyl-2,5~diQxo-li3'~3~
pyrazolidine (51.36 g, 0.152 mDl) in 510 ml of 50% aqueous ethanol is refluxed for 3 hours. The solid naterial that crystallizes out of the still hot solution, is collected by means of filtering and dried in vacuo. 36.66 g (82~) of the 1,2,4,5--tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo-[2,3-c]pyrazole-3-one are ob-tained.
Melting point: 267 C decomposition.
Analysis for C17H14N2O3: found % C 69.18 H 4.75 N 9.63 calc. % 69.37 4.809.52 Examele 7 1,2,4,5-Tetrahydro-l-(p-MEM~oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one A solution of 4-(2-ethylenedioxyethyl)-1-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine (130 g, 0.294 1) in 1200 ml of 75~ ethanol is refluxed for 6 hours and then evaporated to dryness. The obtzined residue is recrystal-lized from ethylaoe tate and yields 66 g (56%) of the 1,2,4,5-tetrahydro-1-(p-MEM~oxyphenyl)-2-phenyl-3H-5-hydroxy-furo[2,3-c]pyrazole-3-one as colourless crystal.
Melting point: 203 C decomposition.
Analysis for C21H22N2&: found % C 62.99 H 5.49 N 6.95 calc. % 63.31 5.57 7.03 Example 8 4-(2-Formylmethyl)-1,2-diphenyl-2,5-dioxopyrazolidine To a solution of 4-(2-ethylenedioxyethyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine (2.54 g, 7.5 mol) in 400 ml of dichloromethane is added a solution of borotribromide (18.79 g, 75 mol) in 50 ml of dichloromethane at -70 & drop-~.i ~ , .
1134~34 wise while stirring. At this temperatuLe stirring is continued for 24 hours.Then the temperature is allowed rise to room temperature and the mixture is poured on excess ice-water.
The organic layer is separated and washed (NaHCO3-solution) until it is neutral, dried (M~SO4) and evaporated to dryness.
The viscous residue is crystallized frcm ethylether-dichlorcmethane (8:2) and yields 0.7 g (3147%) of the desired pyrazolidine as colourless solid.
Melting point: 240 - 242 C.
Analysis for C17H14N2O3: found ~ C 69.54H 4.92 N 9-44 calc. ~ 69.37 4.80 9.52 Example 9 4-(3-Methyl-2-butenyl)-1,2-diphenyl-2,5-dioxopyrazolidine A solution of isopropyl-triphenylphosphoniumiodide (45.24 g, 0.1 mDl) [G. Wittig and D. Wittenberg, Ann., 606, 1 (1957)] in 180 ml of dimethyl-sulfoxide is ad~ed dropwise to a stirred suspension of sodium methylsulfinyl methide at 20 to 25 & (R. Greenwald, M. Chaykovsky and E.J. Corey, J. Org. Chem., 28, 1128 (1963)), that has been prepared in situ from 4.15 g (0.095 mol) of a 55% dispersion of sodium hydride in mineral oil and 120 ml of dimethylsulfoxide.
The mixture is stirred for 30 mlnutes at room temperature and then 1,2,4,5-tetrahydro~l,2-diphenyl-3H-5-hydroxy-furo[2,3-c]pyrazole-3-one (14 g, 0.047 mol) is added in portions. The mixture is stirred for 2 hours at room temperature and for a further hour heated to 70&.
After stirring at room temperature for 16 hours, the reaction mixture is poured into exoess water and extracted with dichlorcmethane. The organic phase is separated, washed with water, dried cver MgS04 and then evaporated to dryness. The obtained residue is dissolved in benzene and adsorbed on a _ g _ ' . . ..
...
'.
113~4 silicagel column. The elution with 10% aoe tone in benzene yields 8.79 g (58.4%) of the desired pyrazolidine as colourless solid.
Melting point: 155 - 157 &.
Analysis for C20H20N2O2: found % C 75.20H 6.23 N 8.64 calc. % 74.98 6.29 8.74 Example 10 4-(2-Propenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This oompound is produced in a similar manner as described in example 9, by starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and methyltriphenylphosphoniumiodide [C.H.
Collins and G.S. Hammcnd, J. Org. Chem., 25, 1434 (1960)] (17.78 g, 0.044 mol), using sodium methylsulfinylmethide (0.04 mol) in dimethylsulfoxide (prepared as described above). The title compc~nd is obtained after column-chromatography on silicagel (10% aoetone in benzene) as colourless solid (64.5%).
Melting point: 133 - 135C (EtOH 95~).
Analysis for C18H16N202: found % C 74.12 H 5.63 N 9.37 calc. % 73.95 5.529.58 Example 11 (E,Z)-4-(2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This oompound is produoed as described in example 9, starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3~1-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and ethyltriphenylphosphone bromide (16.33 g, 0.044 mol) [G. Wittig and D. Wittenberg Ann., 606, 1 (1957)], using sodium methylsulfinylmethide (0.04 mol) in dimethylsulfoxide prepared as described above. The compcNnd is obtained after column-chromatography on silicagel (10% aoetone in benzene) as 113~834 mixture of the E- and Z-forms, wherein the Z-iso~ere is prevailing (60%).
Melting point: 167 & (EtOH/H2O 1:1) literature melting p~int: 128& for the compcund, obtained in the conventional malonate-hydrazobenzene way.
Analysi!3 for ClgH18N2O2 fcund % C 74.32 H 5.87 N 9.22 calc. % 74.49 5.92 9.15 Example 12 (E,Z)-4-(3-phenyl-2-prGpenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This compound is produced as described in example 9, starting from 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (5.88 g, 0.02 mol) and benzyltriphenylphosphone chloride (17.11 g, 0.044 mol) [G. Wittig and M. Schollkopf, Chem. Ber. 87, 1318 (1954)], using sodium methylsulfinyl-methide (0.04 mol) in dimethylsulfoxide, as described above. The co~pound is obtained as crude material in a yield of 64%.
The Z- and E-forms may be separated by column-chromatography on ~ilicagel (10% aoe tone in benzene).
(Z)-isomere: melting point 124 C (EtOH 95).
Analysis for C24H20N2O2: found % C 78.29 H 5.31 N 7.48 calc. % 78.23 5.47 7.60 (E)-isomere: melting point 133 C (EtOH 95) C24H20N2O2: found % C 78.42 H 5.54 N 7.46 calc. % 78.23 5.47 7.60 Example 13 (E,Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine ~ mixture of ~-carbethoxyethylidene-triphenylphosphorane O. Isler, Helv. Chim. Acta, 40, 1241 (1957) (63.53 g, 0.175 mol) and 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo[2,3-c]-pyrazole-3-one (26 g, 0.088 mol) in 400 ml of anhydrous dimethylsulfo~ide is stirred for one hour at roam temeerature and for another hour to 60C. After the reaction mixture has been stirred for 15 hours at room temperature, it is poured into excess water and extracted with ethylacetate. The organic phase is separated and extracted several times with an aqueous 5% piperazine solution. The united aqueous extracts are acidified to pH 8 with 10% hydrochloric acid and the waxlike solid that separated is filtered off and abandoned. me fil~ered solution is treated with charcoal, acidified to pH 5.5 and extracted with ethylacetate. After evaporation of the dried extract, the crude isomeric mixture of th,e OE)- and (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine is obtained as a brawn, thick oil, which is dis-solved in aoetone and purified by its 2-amino-2-thiazoline salt. The working up of this salt, effected as described in example 5, delivers after extraction with ethylaaetate and evaporation of the dried extract 19.5 g of an oily mixture of the desired pyrazolidine, wherein the (E)-form prevailed. The mixture is dis-solved in benzene and adsorbed on a silicagel column. The elution with 10%
ethylaoe tate in benzene yields 1.36 g (4%) of the (Z)-form as colourless solid.
Melting point: 151C.
Analysis for C22H22N204: found % C 69.59 H 5.97 N 17.02 calc. % 69.82 5.86 16.91 Further elution with the same agent yields an intermediate fraction oonsisting of a mixture of 2 isomeres, and then a fraction of 14 g (42%) of the (E)-form as colourless solid, which is recrystallized from cyclohexane.
Melting point: 93C.
113~834 Example 14 (E,Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine The compound is produoe d as described in example 13, starting frcm u-carbethoxyethylidene triphenylp~osphorane (1.46 g, 4 mol) and 4-(2-formyl-methyl)-1,2-diphenyl-3,5-dioxopyrazolidine (0.59 g, 2 mDl) in 12 ml of dimethyl-sulfo~ide, whereby 0.24 g (31.7%) of the title compcNnd is obtained. The physico-chemical and analytical data and also the E/Z-isomeres-proportion are almDst identical to the data obtained in the previous example.
Example 15 (E,Z)-4-(3-car~ethoxy-2-butenyl)-1-(p-MEM~oxyphenyl)-2-phenyl-3,5-dioxo-pyrazolidine _ A mixture of ~-carbethoxyethylidene triphenylphosphorane (14.49 g, 0.04 mol) and 1,2,4,5-tetrahydro-1-(p-MEM~oxyphenyl) 2-phenyl-3H-5-hydroxy-furo [2,3-c]-pyrazole-3-one (15.96 g, 0.04 mol) in 90 ml of anhydrous dimethyl-sulfoxide is allowed to react as described in example 13. Then, the reaction mixture is poured into exoess water, extracted with ethylaoetate and extracted once mDre with 5% aqueous piperazine solution. After acidifying the aqueous phase to pH 6, the product is isolated with ether and yields, after evaporation of the dried extract, 10.2 g of an oily mixture of the desired pyrazolidine, wherein the (E)-form prevailed. The mixture is dissolved in benzene and ad-sorbed at a silicagel column. me elution with dichloromethane yields 0.58 g (3%) of the (Z)-form as yellow oil. After a fraction oonsisting of a mixture of
2 isomeres, the further elution yields a fraction of 6.05 g (31%) of the (E)-isomere as yellow oil.
'` '~` :
:' 113~34 Example 16 (E)-4-(3-carbethoxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxo-pyrazolidine To a stirred solution of titanium tetrachloride (77.26 g, 0.407 mDl) in 750 ml of dichlorc~ethane is added dropwise at o& a solution of (E)-4-(3-carbethoxy-2-butenyl)-1-(p-MEM-oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, pre-pared as described in example 15, (39.3 g, 0.081 mol) in 400 ml of dichloro-methane. Stirring is continued for 1 hour and the mixture is poured into excess ioe-water. The organic phase is separated and yields an oily residue, dissolved in dichloromethane and adsor~ed on a silicagel column. The elution in 10%
methanol in dichloromethane yields 25.4 g (79%) of the title cowpound as colour-less solid.
Melting point: 70 to 74 &~
Analysis for C22H22N2O5: found ~ C 66.84H 5.51 N 6.92 calc. % 66.99 5.62 7.10 Example 17 (E)-4-(3-carboxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine A solution of (E)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine, prepared as described in example 13, (2.25 g, 5.28 mol) in 10 ml of 10% sodium hydroxide is stirred for 30 minutes at room temperature and then acidified with 10~ hydrochloric acid. The precipitating product is isolated with dichloromethane and yields, after evaporation of the dried extract, a viscous residue which is recrystallized from ethylether (1.05 g, 56.75%).
Melting point: 141&.
Analysis for C20H18N2O4: found % C 68.28 H 5.19 N 7.97 calc. ~ 68.56 5.18 8.00 ~i3~34 Example_l ~Z)-4-(3-carboxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This compound is prcduoe d as described in example 17, by means of hydrolyz my the (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine, prepared as described in example 13 (1 g, 2.6 mol) with 10% sodium hydroxide (20 ml). After working up in the conventional way, the campound is crystallized from ethylether and yields 0.6 g (61%) of the desired pyrazolidine as colourless crystals.
Melting point: 65&.
Analysis for C20H18N2O4: found % C 68.37H 5.28 N 7.88 calc. % 68.56 5.28 7.88 Example 19 (E)-4-(3-carboxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxopyrazolidine The oompound is prepared m a similar manner by hydrolysis of the ~E)-4-(3-carbethoxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, which is prepared as descr;h~d in example 16 (10 g, 25 mol) with 10% sodium hydroxide (200 ml). The obtained ccmpound is recrystallized from acetanitrile.
This yields 2.15 g (23.2%) of the title compound as colourless crystals.
Melting point: 170 &.
Analysis for C20H18N2O5: found % C 65.30H 5.01 N 7.61 calc. % 65.56 4.95 7.66
'` '~` :
:' 113~34 Example 16 (E)-4-(3-carbethoxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxo-pyrazolidine To a stirred solution of titanium tetrachloride (77.26 g, 0.407 mDl) in 750 ml of dichlorc~ethane is added dropwise at o& a solution of (E)-4-(3-carbethoxy-2-butenyl)-1-(p-MEM-oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, pre-pared as described in example 15, (39.3 g, 0.081 mol) in 400 ml of dichloro-methane. Stirring is continued for 1 hour and the mixture is poured into excess ioe-water. The organic phase is separated and yields an oily residue, dissolved in dichloromethane and adsor~ed on a silicagel column. The elution in 10%
methanol in dichloromethane yields 25.4 g (79%) of the title cowpound as colour-less solid.
Melting point: 70 to 74 &~
Analysis for C22H22N2O5: found ~ C 66.84H 5.51 N 6.92 calc. % 66.99 5.62 7.10 Example 17 (E)-4-(3-carboxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine A solution of (E)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine, prepared as described in example 13, (2.25 g, 5.28 mol) in 10 ml of 10% sodium hydroxide is stirred for 30 minutes at room temperature and then acidified with 10~ hydrochloric acid. The precipitating product is isolated with dichloromethane and yields, after evaporation of the dried extract, a viscous residue which is recrystallized from ethylether (1.05 g, 56.75%).
Melting point: 141&.
Analysis for C20H18N2O4: found % C 68.28 H 5.19 N 7.97 calc. ~ 68.56 5.18 8.00 ~i3~34 Example_l ~Z)-4-(3-carboxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine This compound is prcduoe d as described in example 17, by means of hydrolyz my the (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine, prepared as described in example 13 (1 g, 2.6 mol) with 10% sodium hydroxide (20 ml). After working up in the conventional way, the campound is crystallized from ethylether and yields 0.6 g (61%) of the desired pyrazolidine as colourless crystals.
Melting point: 65&.
Analysis for C20H18N2O4: found % C 68.37H 5.28 N 7.88 calc. % 68.56 5.28 7.88 Example 19 (E)-4-(3-carboxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxopyrazolidine The oompound is prepared m a similar manner by hydrolysis of the ~E)-4-(3-carbethoxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-3,5-dioxopyrazolidine, which is prepared as descr;h~d in example 16 (10 g, 25 mol) with 10% sodium hydroxide (200 ml). The obtained ccmpound is recrystallized from acetanitrile.
This yields 2.15 g (23.2%) of the title compound as colourless crystals.
Melting point: 170 &.
Analysis for C20H18N2O5: found % C 65.30H 5.01 N 7.61 calc. % 65.56 4.95 7.66
Claims (24)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of compounds of the formula II
or IIa wherein A' represents hydrogen or a readily splittable ether group, which comprises reacting diethyl 2-(2-ethylenedioxyethyl)malonate of the formula V
with a hydrazobenzene compound of the general formula in the presence of a suitable condensing agent, to form a compound of the general formula IV
and, where a compound of formula II is required, rearranging the compound of formula IV by heating in aqueous-alcoholic solution or, where a compound of formula IIa is required, deketalizing a compound of formula IV wherein A' is hydrogen.
or IIa wherein A' represents hydrogen or a readily splittable ether group, which comprises reacting diethyl 2-(2-ethylenedioxyethyl)malonate of the formula V
with a hydrazobenzene compound of the general formula in the presence of a suitable condensing agent, to form a compound of the general formula IV
and, where a compound of formula II is required, rearranging the compound of formula IV by heating in aqueous-alcoholic solution or, where a compound of formula IIa is required, deketalizing a compound of formula IV wherein A' is hydrogen.
2. Process as claimed in claim 1, wherein a compound of formula II is prepared by rearranging a compound of formula IV.
3. Process as claimed in claim 1, wherein a compound of formula IIa is prepared by deketalizing a compound of formula IV
wherein A' is hydrogen.
wherein A' is hydrogen.
4. Process according to claim 2 for production of substituted 1,2-diphenyl-3,5-dioxopyrazolidines of the general formula I
where R and R', which are identical to or different from each other, represent a hydrogen atom, a lower alkyl group, a phenyl group or the group COOR" (where R" represents hydrogen or a lower alkyl group) and A a hydrogen atom or a hydroxyl group, which process includes the step of (a) reacting compounds of the general formula II
where A' represents hydrogen or a readily splittable ether group, with compounds of the general formula III
where R and R' possess the above-mentioned meanings and Ar means an unsubstituted or inertly substituted phenyl group, and, where required, splitting an ether group A' in the product by the action of a mild Lewis-acid to obtain compounds of general formula I
where A is OH.
where R and R', which are identical to or different from each other, represent a hydrogen atom, a lower alkyl group, a phenyl group or the group COOR" (where R" represents hydrogen or a lower alkyl group) and A a hydrogen atom or a hydroxyl group, which process includes the step of (a) reacting compounds of the general formula II
where A' represents hydrogen or a readily splittable ether group, with compounds of the general formula III
where R and R' possess the above-mentioned meanings and Ar means an unsubstituted or inertly substituted phenyl group, and, where required, splitting an ether group A' in the product by the action of a mild Lewis-acid to obtain compounds of general formula I
where A is OH.
5. Process as claimed in claim 4, which includes the step of producing the compounds of general formula III in situ by splitting hydrogen halide off compounds of general formula IIIa where R, R' and Ar possess the above-mentioned meaning and X(-) represents a halogen ion.
6. Process as claimed in claim 4, wherein the reaction of compounds II with compounds of general formula III is effected in an aprotic solvent.
7. Process as claimed in claim 6, wherein the aprotic solvent is dimethylsulfoxide.
8. Process as claimed in claim 4, 5 or 6, wherein the reaction is effected at 50° to 70°C.
9. Process as claimed in claim 4, wherein the splitting off of an ether group A' to form the OH group is effected in a suitable organic solvent.
10. Process as claimed in claim 9, wherein anhydrous dichloromethane is used as the solvent.
11. Process as claimed in claim 4, wherein A' represents hydrogen or the .beta.-methoxyethoxymethoxy group.
12. Process as claimed in claim 4, 5 or 6, wherein Ar is phenyl, methylphenyl, methoxyphenyl or phenylphenyl.
13. Process as claimed in claim 4 wherein in the compound of formula III, R is methyl and R' is -COO(lower alkyl).
14. Process as claimed in claim 13 wherein the product is subjected to the further step of hydrolysis of the ester group to produce a corresponding product of formula I in which R' is -COOH.
15. Process as claimed in claim 4, wherein a compound of formula II in which A' represents hydrogen is employed.
16. Process as claimed in claim 4, wherein a compound of formula II in which A' represents a readily splittable ether group is employed.
17. Process as claimed in claim 4, wherein a compound of formula II in which A' represents .beta.-methoxyethoxymethoxy is employed.
18. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R and R' both represent hydrogen is employed.
19. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R and R' both represent methyl is employed.
20. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R represents hydrogen and R' represents methyl is employed.
21. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R represents hydrogen and R' represents phenyl is employed.
22. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R represents methyl and R' represents ethoxy is employed.
23. Process as claimed in claim 15, 16 or 17, wherein a compound of formula III in which R represents methyl and R' represents ethoxy is employed, and wherein the ethoxy group is thereafter hydrolysed to the carboxy group.
24. Compounds of the formulae II and IIa, as defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2815302.8 | 1978-04-08 | ||
| DE19782815302 DE2815302A1 (en) | 1978-04-08 | 1978-04-08 | NEW PROCESS FOR THE PREPARATION OF 4-SUBSTITUTED 1,2-DIPHENYL-3,5-DIOXOPYRAZOLIDINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1134834A true CA1134834A (en) | 1982-11-02 |
Family
ID=6036514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000325093A Expired CA1134834A (en) | 1978-04-08 | 1979-04-06 | Process for production of 4-substituted 1, 2-diphenyl-3,5-dioxopyrazolidines |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS54141770A (en) |
| AR (1) | AR220377A1 (en) |
| AT (1) | AT370726B (en) |
| CA (1) | CA1134834A (en) |
| CH (1) | CH639074A5 (en) |
| DE (1) | DE2815302A1 (en) |
| DK (1) | DK143279A (en) |
| ES (1) | ES479422A1 (en) |
| FI (1) | FI70707C (en) |
| FR (1) | FR2421886A1 (en) |
| GR (1) | GR66638B (en) |
| IN (1) | IN150827B (en) |
| IT (1) | IT1193754B (en) |
| NL (1) | NL7902731A (en) |
| NO (1) | NO152006C (en) |
| PL (1) | PL117473B1 (en) |
| PT (1) | PT69449A (en) |
| SE (1) | SE448165B (en) |
| YU (1) | YU41152B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02166236A (en) * | 1988-12-19 | 1990-06-26 | Kawasaki Steel Corp | Floater having side plate |
| JPH0331465A (en) * | 1989-06-27 | 1991-02-12 | Kawasaki Steel Corp | Method for correcting meandering in floater |
-
1978
- 1978-04-08 DE DE19782815302 patent/DE2815302A1/en not_active Withdrawn
-
1979
- 1979-03-26 IN IN198/DEL/79A patent/IN150827B/en unknown
- 1979-03-28 GR GR58712A patent/GR66638B/el unknown
- 1979-03-30 AT AT0236979A patent/AT370726B/en not_active IP Right Cessation
- 1979-04-02 AR AR276032A patent/AR220377A1/en active
- 1979-04-04 CH CH313779A patent/CH639074A5/en not_active IP Right Cessation
- 1979-04-05 YU YU815/79A patent/YU41152B/en unknown
- 1979-04-06 SE SE7903095A patent/SE448165B/en not_active IP Right Cessation
- 1979-04-06 CA CA000325093A patent/CA1134834A/en not_active Expired
- 1979-04-06 PL PL1979214738A patent/PL117473B1/en unknown
- 1979-04-06 DK DK143279A patent/DK143279A/en not_active IP Right Cessation
- 1979-04-06 FI FI791139A patent/FI70707C/en not_active IP Right Cessation
- 1979-04-06 NL NL7902731A patent/NL7902731A/en unknown
- 1979-04-06 NO NO791161A patent/NO152006C/en unknown
- 1979-04-06 JP JP4188579A patent/JPS54141770A/en active Granted
- 1979-04-06 FR FR7908855A patent/FR2421886A1/en active Granted
- 1979-04-06 IT IT48654/79A patent/IT1193754B/en active
- 1979-04-06 PT PT69449A patent/PT69449A/en unknown
- 1979-04-07 ES ES479422A patent/ES479422A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| YU41152B (en) | 1986-12-31 |
| SE7903095L (en) | 1979-10-09 |
| AT370726B (en) | 1983-04-25 |
| SE448165B (en) | 1987-01-26 |
| AR220377A1 (en) | 1980-10-31 |
| FI70707B (en) | 1986-06-26 |
| DE2815302A1 (en) | 1979-10-18 |
| CH639074A5 (en) | 1983-10-31 |
| PL117473B1 (en) | 1981-08-31 |
| PT69449A (en) | 1979-05-01 |
| JPS6213951B2 (en) | 1987-03-30 |
| PL214738A1 (en) | 1980-06-16 |
| ATA236979A (en) | 1982-09-15 |
| NO791161L (en) | 1979-10-09 |
| YU81579A (en) | 1983-06-30 |
| FR2421886B1 (en) | 1983-09-09 |
| NL7902731A (en) | 1979-10-10 |
| DK143279A (en) | 1979-10-09 |
| FR2421886A1 (en) | 1979-11-02 |
| FI791139A (en) | 1979-10-09 |
| IT1193754B (en) | 1988-08-24 |
| NO152006B (en) | 1985-04-09 |
| IN150827B (en) | 1982-12-25 |
| FI70707C (en) | 1986-10-06 |
| IT7948654A0 (en) | 1979-04-06 |
| ES479422A1 (en) | 1980-02-01 |
| JPS54141770A (en) | 1979-11-05 |
| NO152006C (en) | 1985-07-17 |
| GR66638B (en) | 1981-04-03 |
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