NO152006B - PROCEDURE FOR PREPARING 4-SUBSTITUTED 1,2-DIPHENYL-3,5-DIOXOPYRAZOLIDINES - Google Patents

Abstract

PROCEDURE FOR THE PREPARATION OF 4-SUBSTITUTED 1,2-DIPHENYL-3,5-DIOXOPYRAZOLIDINES.

Description

The invention relates to a new process for the preparation of 4-substituted 1t2-diphenyl-3t5-dioxopyrazolidines with the general formula

where R and R'f which are the same or differentf mean a hydrogen atom (a lower alkyl group# a phenyl group or the residue -COOR"

(in which R" is hydrogen or a lower alkyl group) and A means a hydrogen atom or a hydroxyl group. Compounds of the general formula L> exist in the so-called Z-form and in the isomeric E-form# and both (and also mixtures thereof ) falls within the general formula stated above.

From GB patent document no. 1,301,857 it is already known that i.a. compounds of the general formula I are valuable antiphlogistically active compounds which are superior to the structurally similar butazolidine with regard to main action and freedom from side effects. In this patent, several methods for producing these compounds are also described.

It has now been found that compounds with the general formula I can also be prepared by reacting a cyclohemiacetal with the general formula where A1 means a hydrogen atom or an etherified hydroxyl group, preferably a P)-methoxyethoxymethoxy (=MEM) group t with a tria- rylphosphorane derivative of the general formula

where R and R' have the meanings given above and Ar means a (optionally substituted with an inert residue such as methyl t methoxy or phenyl) phenyl groupj and then optionally exposes the etherified hydroxyl group with the help of a weak Lewis acid. Suitable Lewis acids which are relevant^ are especially TiCl^ and ZnBr2/ but also ZnCl2f ZnJ2f SnBr4f MgCl2f MgBr2 and similar metal halides.

The reaction of the compounds II and III takes place in an aprotic solvent such as dimethylformamide or preferably dimethylsulfoxide^ under anhydrous conditions.

The method is carried out by the reaction mixture, after stirring at a temperature between 30 and 100°C, preferably 50 to 70°C, being cooled and then stirred at room temperature.

The processing after the end of sales can e.g. take place by pouring the reaction mixture on ice, extraction with a suitable organic solvent, such as ethyl acetate or dichloromethane, by column chromatography or after re-extraction of the organic solvent with a basic aqueous medium. In the latter case, the product is only obtained after acidification with a mineral acid (e.g. hydrochloric acid) and extraction with a suitable solvent. Further purification and also separation of the geometric (E,Z) isomers can be achieved by column chromatography.

When A in the starting compound means an etherified hydroxyl group, this OH group protected during the reaction must then be exposed, to give a compound of formula I with A = OH. This can e.g. take place in that the preferred party, e.g. OH group transferred to B-methoxyethoxymethyl (=MEM)-ether after completion of the reaction cleaves the cyclohemiacetal II etherified with the triphenylphosphorane derivative of formula III with weak Lewis acids (e.g. TiCl^ in dichloromethane).

Such compounds with the general formula I where R = CH^ and R<*> = COOH are obtained by weak alkaline saponification of the corresponding ester (R = CH3, R<*> = COOR").

The compounds of the general formula II can be obtained in a simple way by conversion of the corresponding cyclic acetal of the general formula

' vor A1 has the above meaning. This conversion can, for example, be effected by simple heating in aqueous ethanol. The compounds with the general formula IV can in turn be obtained by reacting diethyl 2-(2-ethylenedioxyethyl)malonate with the formula

with hydrazobenzene, respectively etherified p-hydroxyhydrazobenzene-B-methoxyethoxymethyl-(=MEM)-ether in the presence of a solution of sodium in anhydrous ethanol.

The compounds of formula V can be obtained in a manner known per se, e.g. by condensation of 2-ethylenedioxyethyl bromide with diethyl ionate in benzene/dimethylformamide in the presence of sodium hydride..

The process according to the invention proceeds easily and with a high yield without significant by-products, as the introduction of the double bond at the specific location is successful and the formation of disubstituted products at C-4 in the pyridazolidine ring is avoided.

The following examples illustrate the invention without limiting it.

Intermediate 1

p-hydroxyazobenzene-Pj-methoxyethoxymethyl ether (MEM)

To a stirred suspension of 66#14 g (1#516 mol) sodium hydride (55% dispersion in mineral oil) in tetrahydrofuran (400 ml) was added dropwise a solution of p-hydroxyazobenzene (191 g# 0f963 mol) in 810 ml tetrahydrofuran. After stirring for 15 minutes, the solution was cooled and then MEM chloride (144 g# 1#156 mol) was added dropwise at 0 C and the mixture was stirred at this temperature for 30 minutes. It was then stirred further at room temperature for one hour, then the excess sodium hydride was destroyed by the addition of water and the mixture was concentrated in vacuo. The residue was taken up in ether and washed with water (5% sodium hydroxide) and water successively until neutral. The ether extract was dried and evaporated under reduced pressure. Then the title compound was formed as a thick reddish oil (271f44 gt 98% } which was applied without further purification.

^E.J. Coreyf J.L. Gras and P. Ulrich# Tetrahydron Lett.# 809 (1976)

Intermediate product 2

p-hydroxyhydrazobenzene ether MEM

A solution of p-hydroxyazobenzene MEM ether (220 gt 0f786 rnol) in 1300 ml ethanol was hydrated in the presence of 2#2 g Pd/C at room temperature and atmospheric pressure. After absorbing the calculated amount of hydrogen, the solution was filtered and evaporated until 220 g (99%) of a thick, yellow oil remained, which, due to its easy oxidizability, was immediately used in the next step.

Intermediate product 3

Diethyl-2-(2-ethylenedioxyethyl)-malonate

Diethyl malonate (471.8 g, 2, 94 mol) „ After stirring at room temperature until H2~ evolution had ceased, 2-ethylenedioxyethyl bromide<*****> (492 gt 2.94 mol) in 500 ml of benzene was added, and the solution was stirred for 16 hours at 80 ° C. Then the mixture was cooled, poured into an excess of ice water and the product was isolated with ether. After evaporation of the dried extract, 2-(2-ethylenedioxyethyl)malonate was obtained

Boiling point 105 - 180°C (0.5 mm)„

Analysis for

C,,H,Q0C s found % C 53 42 H 7 42

11 18 6 ' '

calculated % 53.65 7.37

^S.H. Gurvich Zh„ Obshch0 Khim. ff 2— 7 ff 2888 (1957)

Intermediate product 4

4-( 2- ethylenedioxyethyl)- 1. 2- diphenyl- 3 5- dioxopyrazolidine

Hydrazobenzene (58.4 g, 0.317 mol) was added with stirring to a solution of sodium (8.02 g, 0.348 mol) in 480 mL of anhydrous ethanol, and then diethyl 2-(2-ethylenedioxyethyl)-malonate (78.05 g , 0.317 mol) was added dropwise over 2 hours at reflux temperature. The mixture was then heated at reflux for one hour, and then the solvent was slightly evaporated to dryness and the residue was heated for 1 hour at 130 to 140°C under reduced pressure ( 15 mm) „ The reaction product was cooled, taken up in water, washed with ether and then filtered with activated carbon. On cooling, the solution was acidified to give a white solid (72.95 g, 68%), which was dried in vacuo over phosphorus pentoxide and used in the next step without further purification.

Melting point; 150°Co

Analysis for

C19H18N2°4: found % C 61 11 H 5.33 N 8.23

calculated % 67.44 5.36 8f28

Intermediate 5

4-( 2- ethylenedioxyethyl)- 1-( p- MEM-oxypheny1- 3p 5- dioxo-pyrazolidine.

p-Hydroxyhydrazobenzene MEM ether (137 g, 0.475 mol) in 140 mL of anhydrous ethanol was added with stirring to a solution 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 was added dropwise over 2 h under reflux. °C for 1 hour under reduced pressure. The reaction product was cooled, taken up in water, washed with ether and filtered over activated carbon. The solution was acidified with 10% hydrochloric acid to pH 4, and the oil that separated was extracted with vinegar.

The dried extract, which was evaporated to dryness, left an oily residue which was dissolved in a saturated solution of piperazine in acetone. The crystalline piperazine salt of 4-(2-ethylenedioxyethyl)-1-(p-MEM-oxyphenyl)-3,5-dioxo-pyrazolidine, which separated on standing, was filtered and then dissolved in water. After acidification with glacial acetic acid, the product was isolated with ether. Evaporation of the dried extract gave the desired pyrazolidine as a pale yellow oil (105 g, 50%), which was pure enough to be converted to 1,2,4,5-tetrahydro-1-(p-MEM-oxyphenyl)- 2-phenyl-3H-5-hydroxy-furo(2,3-c)-pyrazol-3-one.

Intermediate 6

1f 2 f 4 r 5- tetrahydro- 1, 2- diphenyl- 3H- 5- hydroxy- furo( 2 3- c)-pyrazol- 3- one

A solution of 4-(2-ethylenedioxyethyl)-1,2-diphenyl-3,5-dioxopyrazolidine (51.36 g, 0.152 mol) in 510 mL of 50% aqueous ethanol was refluxed for 3 hours. The solid which crystallized from the still warm solution was collected by filtration and dried in a vacuum. 36.66 g (82%) of 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo-(2,3-c)pyrazol-3-one was obtained.

Melting point: 267°C, decomposition.

Analysis for

C. _,H, .N.O, : found % C 69 18 II 4 75 N 9 63

17 14 2 3 » i i

calculated % 69.37 4.80 9.52

Intermediate product 7

1 m2. 4, 5-tetrahydro-1-(p-MEM-oxyphenyl)-2-phenyl-3H-5-hydroxy-furo(2f3-c)-pyrazol-3-one. A solution of 4-(2-ethylenedioxyethyl)-1-(p-MEM-oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine (130 g, 0.294 mol) in 1200 ml of 75% ethanol was boiled for 6 h at reflux and then evaporated to dryness. The residue obtained was recrystallized from ethyl acetate and gave 66g (56%) of 1,2,4,5-tetrahydro-1-(p-MEM-oxyphenyl)-2-phenyl-3H-5-hydroxy

-furo(2,3-c)pyrazol-3-one as colorless crystals.

Melting point: 203°C, decomposition.

Analysis for

C_1H~_N-0,- : found % C 62 99 H 5 49 N 6 95

21 22 2 6 » » h

calculated % 63.31 5.57 7.03

Intermediate 8

4-(2-formylmethyl)-1,2-diphenyl-2.5-dioxopyrazolidine0

A solution of boron tribromide (18.79 g, 75 mmol) in 50 ml of dichloromethane at -70°C with stirring. At this temperature it was stirred for 24 hours. Then the temperature was allowed to rise to room temperature and then the mixture was poured into an excess of ice water.

The organic layer was separated and washed (NaHCO 3 - solution) until neutral, dried (MgSO 4 ) and evaporated to dryness. The tough residue was recrystallized from ethyl ether-dichloromethane (8:2) to give 0.7 g (31 7%) of the desired pyrazolidine as a colorless solid.

Melting point: 240-242°C.

Analysis for

C,.7H1.N-0, : found C 69 54 Pl 4 92 N 9 44

calculated ,o 69 37 4 80 9 52

Example 1;

4-( 3- methyl- 2- butenyl)- 1, 2- diphenyl- 2m 5- dioxopyrazolidine

A solution of isopropyl-triphenylphosphonium iodide (45.24 g, 5 0.1 mol) (G. Wittig and D. Wittenberg, Ann., 606, 1 (1957)) in 180 ml of dimethylsulfoxide was added dropwise to a stirred suspension of sodium methylsulfinyl methide at 20-25°C (R. Greenwald, M. Chaykovsky,

and E.J. Corey, J. Org. Chem., 28, 1128 (1963)), which was prepared in situ from 4.15 g (0.95 mol) of a 55% dispersion of sodium

hydride in mineral oil and 120 ml of dimethyl sulphoxide. The mixture was stirred at room temperature for 30 minutes and then portionwise added

put 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo(2,3-c)pyrazole

-3-one (14 g, 0.047 mol). The mixture was stirred for 2 hours at room temperature.

temperature and was then heated for a further hour at 70°C.

After stirring for 16 hours at room temperature, the reaction mixture was poured into an excess of water and extracted with dichloromethane

tan. The organic phase was separated, washed (H 2 O), dried (MgSO 4 ) and then evaporated to dryness. The residue obtained was dissolved in benzene and absorbed on a silica gel column. Elution with 10% acetone i

benzene gave 8.79 g (58.4%) of the desired pyrazolidine as a colorless solid. Melting point: 155-157°C.

Analysis for

C-nH„_N.0_ : found % C 75 20 H 6 23 N 8 64 20 20 2 2 * i i

calculated % 74.98 6.29 8.74

Example 2

4-(2-propenyl)-1,2-diphenyl-3,5-dioxopyrazolidine

This compound was prepared in a similar manner to that described in example 1, 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 methyltriphenylphosphonium iodide (C.H. Collins and G.S. Hammond, J. Org. Chem., 25, 1434 (1960)) (17.78 g, 0.044 mol) and used in sodium methylsulfinyl methide (0.04 mol) in dimethylsulfoxide (prepared as described above). The title compound was obtained after column chromatography on silica gel (10% acetone in benzene) as a colorless solid (64.5%). Melting point: 133-135°C (EtOH 95%)

in

Analysis for

CloHlcK_0_ : found % C 74 12 H 5 63 N 9 37 18 16 2 2 ' > » calculated % 73f95 5f52 9#58

Example 3

( EtZ )- 4-( 2- butenyl)- 1>2- diphenyl- 3 f 5- dioxypyrazolidine

This compound was prepared as described in example 1# starting from 1 t2f4f5-tetrahydro-1 2-diphenyl-3H-5-hydroxy-furo-(2f3-c)-pyrazol-3-one (5^88 gf 0 #02 mol) and ethyltriphenylphosphonobromide (16#33 g( 0^044 mol) (G. Wittig and D„ Wittenberg Ann.( 606, 1 (1957))# whereby sodium methylsulfinyl methide (0#04 mol) in dimethylsulfoxide# as was prepared as described above was used. The compound was< after column chromatography on silica gel (10% acetone in benzene) (obtained as a mixture of the E and Z forms/ and the Z isomer was predominant (60%). Melting point: 167°C (EtOH/

^O 1:1). Literature melting point 128°C for the compound obtained by the usual malonate-hydrazobenzene method.

Analysis for

C1QH1DN_0_ : found % C 74 32 H 5 87 N 9 22 19 18 2 2 » » » calculated % 74r49 5#92 9.15

Example 4

( EfZ )- 4-( 3- phenyl- 2- propenyl)- 1a2- diphenyl- 3t5- dioxopyrazolidine

This compound was prepared as described in example 1f starting from 1#2 f4f5-tetrahydro-1f2-diphenyl-3H-5-hydroxy-furo(2f3-c)-pyrazol-3-one (5#88 gf 0f02 mol) and benzyltri-phenylphosphonochloride (17.11 g# 0f44 mol) (G. Wittig and M. Schøllkopf/ Chem. Ber. _87 1318 (1954)) and used sodium methylsulfinyl methide (o 04 mol) in dimethylsulfoxide, which was prepared as described above . The compound was obtained as raw material in 64% yield. The Z and E forms could be separated by column chromatography on silica gel (10% acetone in benzene). (Z)-isomer: Melting point: 124°C (EtOH 95°).

Analysis for

C-.H-nN.0, : found h C 76 29 H 5 31 N 7 48 24 20 2 2 •)! calculated 7 8 2 3 5 47 7 60

J often

(E)-isomer: Melting point 133°C (EtOH 95°)

C24H20N2°2 : found % C 78.42 H 5.54 N 7.46

calculated % 78.23 5.47 7.60

Example 5

( E Z )- 4—( 3- carbetoxv- 2- butenyl)- 1 j2 - diphenyl- 3j5- dioxo- pyrazolidine

A mixture of «^-carbethoxyethylidine-triphenylphosphorane

(63.53 g, 0.175 mol) and 1,2,4,5-tetrahydro-1,2-diphenyl-3H-5-hydroxy-furo(2,3-c)-pyrazol-3-one (26 g, 0p88 mol) in 400 ml of anhydrous dimethylsulfoxide was stirred for one hour at room temperature and heated for one hour at 60°C. After the reaction mixture was stirred for 15 hours at room temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was separated and extracted several times with an aqueous 5% piperazine solution. The combined aqueous extracts were acidified to pH 8 with 10% hydrochloric acid and the waxy solid that separated was filtered off and discarded. The filtered solution was treated with activated carbon, then acidified to pH 5.5 and extracted with ethyl acetate. After evaporation of the dried extract, the crude isomeric mixture of (E)- and (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine was obtained as a brown, thick oil, which was dissolved in acetone and purified by its 2-amino-2-thiazolidine salt. The work-up of this salt described in intermediate 5 gave, after extraction with ethyl acetate and evaporation of the dried extract, 19.5 g of an oily mixture of the desired pyrazolidine, in which the (E) form predominated. This mixture was dissolved in benzene and absorbed on a silica gel column. Elution with 10% ethyl acetate in benzene gave 1.36 g (4%) of the (Z) form as a colorless solid.

Melting point: 151°C

<**>0. Isler, Helv.Chim.Acta, 40, 1242 (1957)

Analysis for

C.-H^-N-O. : found % C 69 59 H 5 97 N 17 02

22 22 2 4 » » »

calculated % 69.82 5.86 16.91

Further elution with the same agent gave an intermediate fraction consisting of a mixture of 2 isomers, and then a fraction of 14 g (42%) of the (E) form as a colorless solid, which was recrystallized from cyclohexane. Melting point: 93°C.

Analysis for

C.-H.-<N>.<O>. <:> found % C 69 87 H 5 81 N 16 80

ZZ ZZ Z «* at t

calculated % 69 82 5 86 16 91

Example 6

( E . Z )- 4-( 3- carbetoxv- 2- butenyl)- 1. 2- diphenyl- 3 j 5- dioxopyrazolidine

This compound was prepared as described in Example

5 f starting from ^-carbethoxyethylidenetriphenylphosphorane (1.46 g, 4 mol) and 4-(2-formylmethyl)-1,2-diphenyl-3,5-dioxopyrazolidine (0.59 g# 2 mmol) in 12 ml dimethylsulfoxide, and 0ff24g (31.7%) of the title compound was obtained.

The physicochemical and analytical data and also the E/Z isomer ratio were almost identical to those obtained in the previous example.

Intermediate 9

( E s Z )- 4-( 3- carbethoxy- 2- butenyl)- 1-( p- MEM- oxyphenyl)- 2- phenyl- 3,5-dioxopyrazolidine

A mixture of ^-carbethoxyethylidinetriphenylphosphorane (14.49 gt 0p04 mol) and 1 t2t4f5-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 dimethylsulfoxide was allowed to react as described in example 5.

Then the reaction mixture was poured into an excess of water, extracted with ethyl acetate and extracted once more with 5% aqueous piperazine solution» After acidifying the aqueous phase to pH 6, the product was isolated with ether, and after evaporation gave of the dried extract, 10.2 g of an oily mixture of the desired pyrazolidines in which the (E) form predominated. The mixture was dissolved in benzene and absorbed on a silica gel column. Elution with dichloromethane gave 0.58 g (3%) of the (Z) form as a yellow oil. Further elution gave a fraction consisting of a mixture of 2 isomers, a fraction of 6.05 g (31%) of the (E) isomer as a yellow oil.

Example 7

( E )- 4-( 3- carbethoxy- 2- butenyl)- 1-( p- hydroxyphenyl)- 2- phenyl- 3 5-dioxopyrazolidine

To a stirred solution of titanium tetrachloride (77.26 g, 0.407 mol) i

A solution of 750 ml of dichloromethane was added dropwise at 0°C

(E)-4-(3-carbethoxy-2-butenyl)-1-(p-MEM-oxyphenyl)-2-phenyl-3,5-dioxopyrazolidine (39.3 g, 0.081 mol), prepared as in intermediate 9

in 400 ml of dichloromethane. It was stirred for a further hour and the mixture was poured into excess water. The organic phase was separated, dried and evaporated to give an oily residue which was dissolved in dichloromethane and absorbed on a silica gel column. Elution in 10% methanol in dichloromethane gave 25.4 g (79%) of the title compound as a colorless solid. Melting point: 70 to 74°C.

Analysis for

C__H__N_Oc : found % C 66 84 H 5 51 N 6 92

calculated % 66.99 5.62 7.10

Example 8

(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-dioxopyrazolidine, prepared as described in Example 5 (2.25

g, 5.28 mol) in 10 ml of 10% sodium hydroxide, was stirred for 30 minutes at room temperature and then acidified with 10% hydrochloric acid. The precipitated product was isolated with dichloromethane, and after evaporation of the dried extract gave a gummy residue which was crystallized from ethyl ether (1.05 g, 56.75%).

Melting point: 141°C.

Analysis for

C-.H..K.0, : found % C 68 28 H 5 19 N 7 97

calculated % 68.56 5.18 8.00

Example 9

( Z )- 4-( 3- carboxy- 2- butenyl)- 1 2- diphenyl- 3 5- dioxopyrazolidine

This compound was prepared as described in Example

8, and indeed by hydrolysis of (Z)-4-(3-carbethoxy-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine (1 g, 2.6 mol), prepared as in Example 13, with 10% sodium hydroxide (20 ml). After the usual work-up, the compound was crystallized from ethyl ether, and this gave 0.6 q (61%) of the desired pyrazolidine as colorless crystals.

Melting point: 65°C

Analysis for

C, 'rL.K.O, : found % C 68 37 K 5 28 N 7 88

20 18 2 4 ' t > calculated % 68 56 5 28 7 88

^ tit Example 10

( E )- 4-( 3- carboxy- 2- butenyl)- 1-( p- hydroxyphenyl)- 2- phenyl- 3 5-dioxopyrazolidine

This compound was prepared in a similar manner by hydrolysis of (E)-4-(3-carbethoxy-2-butenyl)-1-(p-hydroxyphenyl)-2-phenyl-35-dioxopyrazolidine, which was formed as described in example 16 (10 g, 25 mmol) with 10% sodium hydroxide (200 ml). The compound obtained was recrystallized from acetonitrile. This gave 2.15 g, (23.2%) of the title compound as colorless crystals.

Melting point: 170°C.

Analysis for

C_nH1QN_Oc : found % C 65 30 H 5 01 N 7 61

ZV lo Z D tit calculated % 65.56 4.95 7.66

Claims (1)

Process for the preparation of substituted 1,2- diphenyl-3,5-dioxopyrazolidines of the general formula where R and R', which are the same or different, mean a hydrogen atom, a lower alkyl group, a phenyl group or the residue -COOR" (in which R" is hydrogen or a lower alkyl group), and A means a hydrogen atom or a hydroxyl group, characterized by reacting compounds with the general formula where A< means a hydrogen atom or an etherified hydroxyl group, preferably a f}-methoxyethoxymethoxy (=MEM) group, with compounds of the general formula where R and R<1> have the meanings given above and Ar means a (optionally substituted with an inert residue such as methyl, methoxy or phenyl) phenyl group in an aprotic solvent, especially dimethylsulfoxide, at a temperature from 30 to 100°C, preferably from 50 to 70°C, and optionally, to obtain compounds of the general formula I where A = OH, cleave the ether group by means of weak Lewis acids.