IE49396B1 - Oximinoacetic acid derivatives - Google Patents

Description

This invention provides compounds of formula I ^°R'l III R‘3 - C - COOH in which R1^ is hydrogen, alkyl, phenylalkyl, carbalkoxyalkyl, acyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, or carbamoylalkyl, R'3 is a pyrazolyl radical, unsubstituted or mono- or di-substituted by alkyl, phenyl, alkoxy, alkylthio, carbamoyl, carbamoylalkyl, alkylsulphonyl, azido, acylamino, acylhydrazino, alkyliden^ydrazino, furylidenjiydrazino, carbalkoxy or a group NH^ provided that the nitrogen atoms and the 4-position of the pyrazole nucleus are either unsubstituted or substituted by alkyl, phenyl, or carbalkoxy, and reactive derivatives thereof.

Examples of reactive derivatives of the acid of formula I include 15 acid halides or acid anhydrides, for example with oxplic or pivalic acid or carbonic acid half-esters, activated complexes with dimethyl formamide/phosphorcus oxychloride, acid azides or activated esters, for example derived from phenols, cyclic N-hydroxyimides or heterocyclic thiols, e.g. 2-pyridenethiol or 2,2'-dithiopyridine.

The group -OP.η. in.,the., compsundsofthe^ invention may be in the syn or anti-configuration. It is to be understood that the invention includes both isomeric forms as 'well as mixtures thereof. (The syn isomers or isomeric mixtures in which the syn isomer predominates, e.g. to the extent of at least 75%, more particularly at least 90%, . are however preferred). ' 49396 - 2 In the radical R'y the pyrazole nucleus may, when the nitrogen atoms thereof are unsubstituted, exist in tautomeric forms:- H The position of the tautomeric equilibrium will of course depend on known factors such as temperature, aggregation condition, solvent, pH and substituents on the nucleus. Naturally, the invention is not limited to any particular tautomeric form.

The invention also provides processes for the production of compounds of formula III as illustrated by the following reaction schemes: Scheme I: N.OR, Μ M | r8-ch2-c-c-coor9 IV VI + NH2.NH.Rn N I R.

COOR, R, Vila ‘9 ‘11 VII COOR lo COOR lo N.OR. Π II x H3C-C-C - COORg Va Vb + NaOCjHg O 0 N.OR.

II II II 1 R. OOC-C-CH^- C - C - COCR_ lo i 9 Via + NH2NH2 Εΐο°0ςΊΤ~Π N ., U-C-COOR, R._.HN.OC___ 12 "fi HOOC.

C-CCORq II , 9 N.ORj.

Vllb Vile jj-C-CC --CCOR„ II . 9 H N.OR^ Vllf Vlld Schema III: * 49396 N.OR.

II II * HjC-C-C - COORg Vc +CS2+R12J Y „ c o n.or' C = CH-C-C-COORn +KHnNH r12sZ VIb R, _S 2 .. 12 ~fi +R13.CO.NHNH2 «.J-c-coo*,, vug I ’''"I Oxidation R. ,-co-nh-n. 13 <: N.OR. II II XR12S VIC R. ,CO.NH.NH_r13 TJ +nh2nh2 O-C-COORg vnj | ^0Ri +HNOν3-ιγ~π N ^C-COORg vin I Ν·°*1 N.OR.

Vila Vllf In these formulae, βθ in hydrogen, alkyl or phenyl, Rg is alkyl, benzyl, 4-nitrophenyl, 2,2,2-trichloroethyl, phenyl or substituted phenyl, R1Q is alkyl, R^ is hydrogen, alkyl or phenyl, Rg2 is lower alkyl, is alkyl, alkoxy, phenyl, phenylalkyl, or phenylalkoxy, and alkylidene or furylidene.

The resulting compounds of formulae VII to Vllm may be converted into the corresponding compounds of formula III in conventional manner, by hydrolysis. Compounds unsubstituted on the nitrogen '0 atoms or at the 4-position of the pyrazole ring may be alkylated or phenylated in conventional manner at any apporpriate stage in the syntheses described, particularly at a point where there are no other sensitive groups in the molecule.

The compounds of formula III are useful intermediates in the preparation of chemotherapeutically active compounds such as those of formula I ,0R. acyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, or carbamoyl alkyl, R2 is hydrogen, pivaloyloxymethyl or the residue of another easily splittable ester grouping, Rg is a pyrazolyl radical, unsubstituted or mono- or di-substituted by alkyl, phenyl, alkoxy, alkylthio carbamoyl, carbamoylalkyl, alkyl sulphonyl, azido, 9 39 - 6 acylamino, acylhydrazino, alkylidenhydrazino, furylidenhydrazino, carbalkoxy or a group , provided that the nitrogen atoms and the 4-position of the pyrazole nucleus are either unsubstituted or substituted by alkyl, phenyl, or carbalkoxy, and R4 is hydrogen, acetoxy, carbamoyloxy or -S-Rh, in which Rh is a heterocyclic radical, as described and claimed in fokrtb ^eci|ic«tie>n nIO. AH3Hj£ Alkyl radicals or radicals containing alkyl radicals, preferably contain 1 to 4 carbon atoms in the alkyl parties thereof, more preferably 1 to 2 carbon atoms. t Rj can be hydrogen. Alternatively, it may be alkyl, such as 15 methyl or phenylalkyl such as benzyl. Suitable carbalkoxyalkyl radicals include carbalkoxymethyl radicals, e.g. carbethoxymethyl. Suitable acyl radicals include C2_galkanoyl or alkoxycarbonyl. Carbamoylalkyl may for example be carbamoylmethyl. Cyanoalkyl may be cyanomethyl; hydroxyalkyl is suitably hydroxymethyl and alkoxy20 alkyl is suitably alkoxymethyl, e.g. methoxymethyl. In preferred compounds R^ is alkyl, carbalkoxyalkyl and carbamoylalkyl. nR The preferred pyrazolyl groups for Rg are linked to the N -C-COOH radical at the 3- or 5-position of the nucleus. Preferably, the nucleus is unsubstituted in the 4-position.

The nitrogen atom available for substitution may be unsubstituted. Alternatively, it may be substituted by alkyl, e.g. methyl·, by phenyl; or by carbalkoxy, e.g. isobutyloxycarbonyl.

The remaining position of the pyrazole nucleus may be - 7 unsubstituted. Alternatively, it may be substituted by alkyl; by phenyl; by alkoxy, e.g. ethoxy; by alkylthio, e.g. methylthio; by carbamoyl; by carbamoylalkyl; by alkylsulphonyl, e.g. methylsulphonyl; by azido; by acylamino, in particular Cg-galkanoylamino or C^_dalkoxy- or benzyloxy-carbonylami no; by acylhydrazino, e.g. C,,_[-alkanoylhydrazino; by alkylidenehydrazino; by furylideneaminohydrazino; by carbalkoxy, e.g. carbethoxy; or by NHg.

The preferred radical Rg is unsubstituted pyrazolyl-3 (or -5).

Insofar as the production of compounds of formula III is not VO described, these may be produced by conventional methods such as described in the following examples.

The following Examples in which all temperatures are indicated in °C illustrate the invention. Unless otherwise indicated, the compounds of formula I are obtained in the form of syn/anti isomeric mixtures. - 8 A) (Pyrazolyl-3)methoxyiminoacetic acid a) i&z2iUJ§ii’ylamingacry3oyl^methoxYiminoecetlc_acid_roethYl _ester 212.4 g of α-Methoxyiminoaeetoacetic acid methyl ester and 390 ml of Ν,Ν-dimethylformamide-dimethylacetal are boiled under reflux in 300 ml of benzene for 10 hours. After cooling, the mixture is evaporated to dryness and a dark residue is recrystallised from ethanol to obtain yellow crystals of the heading compound, m.p. 63-64°. b) £ EZ ESSSlYizSiTS ti cac i dmeth^les ter 21.4 g of(p-dimethylaminoacryloyl)methoxyimino acetic acid methyl ester are suspended at room temperature in 200 ml of water and, after addition of 20g of hydrazine monohydrochloride and 20 ml of 2-propanol, boiled for 30 minutes. The heading compound, crystallises on cooling m.p. 70’. c) ί ΕϊΓ222ΐΥΐ;5)52ί!!22Χ25!Ϊ222£2£Ϊ£.5£Ϊ^ 38.8 g of (Pyrazolyl-3)methoxymino acetic acid methyl ester are wanned in 100 ml of ethanol/50 ml of 4N NaOH for 3 hours at 90°. After cooling to 0°, the mixture is acidified to pH 1 with cone, hydrochloric acid and concentrated to about 20 ml. The resulting precipitate is recrystallised from 100 ml of water to obtain the heading compound in the form of a syn/anti mixture (4:1), m.p. 150°.

B) (l-Methylpyrazolyl-3)methoxyiininoacetlc acid a) ί EYr522lYlz3l5?eihoxyinjinoacetic_aci d_e thyj_ester The heading compound may be obtained as a colourless oil in manner described under A) above. b) (l-Hethylpyrazolyl-3)rretaoxyiroinoacetic_acidethyl.ester To a suspension of 1.65 g of NaH in 20 ml of absolute tetrahydrofuran is added at 0° a solution of (pyrazo1yl-3)methoxyimino- 9 acetic acid ethyl ester in 200 ml of tetrahydro furan. After hydrogen evolution ceases, 9.5 ml of methyl iodide are added dropwise and the mixture is stirred for 20 hours at room temperature. The mixture is evaporated and the residue is divided between 200 ml of ethyl acetate and water to yield after evaporation of the organic phase the heading compound as a colourless oil.

NMR (CDC13); 1.3 (t, 3H); 3.85 (s, 3H); 3.90 (s, 3H); 6.45 (d, 1H); 7.65 (d, 1H). c) (1-Methy1pyrazolyl;3}methoxyiminoacetic_acid 3.2 g of (l-methylpyrazolyl-3)methoxyimino acetic acid ethyl ester and 720 mg of lithium hydroxide are stirred in 30 ml of water for 18 hours at room temperature. The mixture is acidified to pH 1 with cone, hydrochloric acid and the product filtered off to obtain the heading compound, m.p. 160-152°.

C) [(Pyrazolyl-3)carbethoxymethoxyimino]acetic acid a) Y !ί Γ2ϊΥίΤί22££2ί25££ ί Ϊ £.2Sii!;tert. ;bu tyles ter To a mixture of 158 g of aceto acetic acid-tert.-butylester and 1000 ml of glacial acetic acid is added dropwise, while maintaining the temperature at 5°, a solution of 86.4 g of NaNO^ in 500 ml of water. After 4 hours stirring at 5°, the mixture is extracted 5 times with ether, the purified ether extracts are washed 5 times with water and twice with saturated sodium chloride and evaporated to dryness to obtain the heading compound, m.p. 55-63° b) ?;Ϊ2ίί!2ϊϊί!Ρ222222ϊ93£2ίΪ£.22Ϊ^棧£t"Zbutyl ester To a solution of 215 g of NagCOj in 2200 ml of water is added at room temperature a solution of 128 g of 2-hydroxyiminoacetoacetic acid-tert.-butyl ester in 475 ml of methanol. 255 g of dimethyl sulphate are added, dropwise, at 8-10°, and after 3 hours at 8-10° and 15 hours at room temperature, the mixture is filtered. 493 - 10 The filtrate is extracted 3 times with ethyl acetate, dried over magnesium sulphate and evaporated to obtain the heading compound.

NMR (CDClg); 1.55 (s, 9H); 2.3 (s, 3H); 4.0 (s, 3H). c) ?τί 1;!5§ί!!Υΐζ1ζ!ϋξί!!9ϊΥ)?ϊ!!2ίΥ ter To a solution of 187 g of 2-methoxyiminoacetic acid tert.-butyl ester in 200 ml of dichloromethane is added 2 g of a strong acid ion exchanger. 200 ml of isopropanylmethyl ether are added with ice cooling, dropwise. After 18 hours at room temperature the ion exchanger is filtered off and the mixture is evaporated to dryness.

The resulting oil is used, in thenext step without further purification. ' NMR (CDC13); 1.55 (s, 15H);. 2.4 (s, 3H); 3.3 (s, 3H). d) 5:Si2Sii!yiaininomethylene;2;(l;methyl;I;methoxy)ethoxyiminoaceto; 255 g of 2-(l-methyl-l-methoxy)ethoxyirainoaceto acetic acid tert.butyl ester and 280 ml of Ν,Ν-dimethylformamide dimethylacetal are heated to boiling in 300 ml of toluol for 3 hours. The mixture is cooled to 0° and the precipitate is filtered off to obtain the heading compound, m.p. 85-89°. e) (Pyrazolyl-3-)(l-methyl-l-niethoxy)ethoxyiminoacetic acid-tert.; butyl_ester To a solution of 215 g of 4-dimethylaminomethylene-2-(l-methyl-lmethoxy)ethoxyiminoaceto acetic acid tert.-butyl ester in 1500 ml of methanol is added a mixture of 70 g of acetic acid and 35 g of hydrazine hydrate. After 50 hours at room temperature, the mixture is evaporated to dryness, the residue is taken up in 1500 ml of ethyl acetate. The mixture is washed with saturated sodium bicarbonate solution and evaporated to dryness to obtain the heading compound, m.p. 102-106°. -11 f) I2Yr5?2lXlc3}hydroxyiminoacetic_acid_tert1;butyl_ester 173 g of (Pyrazolyl-3)(l-methyl-l-methoxy)ethoxyiminoacetic acid tert.-butyl ester are stirred in 1500 ml over 2 g of a strong acid ion exchange resin for 8 hours at room temperature. After filtration and evaporation to dryness the residue is rubbed with petroleum ether, to obtain the heading compound, m.p. 152-159°. 9) £I?Yr222lYlz3}carbethoxymethoxyimino]acetic_acid_tert.;but);l_ester To a solution of 24 g of (pyrazolyl-3)hydroxyiminoacetic acid tert.-butyl ester and 17 g of bromoacetic acid ethyl ester in 100 ml of di chioromethane is added dropwise, at room temperature, slowly, a soltuion of 15 g of 1,5-diazobicyclo[5,4,0]undec-5-en in 50 ml of di chioromethane. After 24 hours at room temperature, the mixture is evaporated to dryness, the residue is distributed between ethyl acetate and IN HCl and the concentrated residue of the ethyl acetate is chromatographed over silica gel to obtain the heading compound, m.p. 84-85°. h) I ί EYCazolYl^lcarbethoxyrethoxy imi nolaceti c_aci d 2.4 g [(Pyrazolyl-3)carbethoxymethoxyimino]acetic acid tert.butyl ester are stirred in 20 al of trifluoro acetic acid for 30 minutes at room temperature. The mixture is evaporated to dtyness in vacuo, the residue is taken up in toluene, and the mixture is evaporated to dryness. The residue is rubbed with ether to obtain the heading compound, m.p. 124-129°.

D) [(Pyrazolyl-3)carbamoylmethoxyimino]acetic acid 25 a) E(Exra22lYiz3}carbamgylroethoxywno3acetic_acid_tert.;butjjl eester a) 5 g [(Pyrazolyl-3)carbethoxymethoxyimino]acetic acid tert.-butyl ester are stirred in 200 ml of a solution of ansnonia in methanol for 24 hours at room temperature. After evaporation to dryness, the heading compound is obtained by rubbing with ether, m.p. 112-118°. 4-9396 - 12 b) tIPyrazolyl-3-]carbamoylmethoxyimino]acetic_acid g [(Pyrazolyl-3)carbamoy1methoxyimino]acetic acid tert.-butyl ester are reacted in manner analogous to that described above under C/h, to obtain the heading compound, m.p. 155-159°.

E) [(Pyrazolyl-3)cyanomethoxyiminoacetic acid a) £iPyra22lx!;3}eyanpmethoxzinino3acetic_acid_tert.;;butyl ester To a solution of 2 g of E(pyrazolyl-3)carbamoylmethoxyimino]acetic acid tert.-butyl ester in 100 ml of absolute toluene and 5 ml of triethylamine is added at room temperature with stirring in small portions 2 g of phosphorous pentoxide. The mixture is heated for 3 hours at 30°, cooled to 0°, and divided between 100 ml of ethyl acetate, and 50 ml of ice water. The organic phase is evaporated and the residue is chromatograpned over silica gel. The heading compound results as a colourless oil. NMR (CDClg): 1.5 (s, 9H); 4.65 (s, 2H); 6.6 (d, 1H); 7.5 (d, 1H). b) ΕίΡϊΓ222ΐζ!;3ΐ£ϊ222ϊ2ί!322Υίθίθ235£2ίΐ£_3οϊ d 550 mg of [(Pyrazolyl-3)cyanomethoxyimino]acetic acid tert.butyl ester are reacted in manner analogous to that described under C/h, to obtain the heading compounds, m.p. 182-186°.

F) (Pyrazolyl-3)benzyloxyiminoacetic acid a) ίEYCa?2lYl:?}benzyloxyi!ninoacetic_acid_tert.;butyl_ester 2.11 g of (Pyrazolyl-3)hydroxyiminoacetic acid tert.-butyl ester and 1.71 g of benzylbromide are stirred for 16 hours at room temperature in a mixture of 1.38 g of KgCOg in 10 of water and 100 ml of acetone. Evaporation to dryness and distribution of the residue between 100 ml of ether and water yields the heading compound.

NMR (CDClg): 1.6 (s. 9H); 5.25 (s, 2H); 6.55 (d, 1H); 7.3 (s, 5H); 7.5 (d, 1H) 493S6 - 13 b) (Pyrazolyl-3)benzyloxyiminoacetic acid g of (Pyrazolyl-3)benzyloxyiminoacetic acid tert.-butyl ester are reacted in manner analogous to that of C/h above, to obtain the heading compound, m.p. 126-128°.

G) [(Pyrazolyl-3)roethoxymethoxyin)inoacetic acid To a suspension of 4.13 g of 80% NaH in 50 ml of dry tetrahydrofuran are added successively at 0° 18.14 g of 2-hydroxyiminoaceto acetic acid methyl ester and 9 g of chloromethylmethylether. After minutes at room temperature, the mixture is divided between 200 ml of ethyl acetate and aqueous buffer (pH 5.5). The contents of the ethyl acetate phase are bulb distilled to obtain the heading compound, m.p. 115-120°/0.1 Torr. b) 4;pimethylamingmethylene;2;(methoxymethoxyimino)acetgacetic acld-methyl.-ester 6.4 g of 2-(methoxymethoxyimino)acetoacetic acid methyl ester in 30 ml of toluene are heated with 9 ml of N,N-dimethylformamidedimethylacetal for 5 hours at boiling. After cooling, the semicrystalline residue is dissolved by heating in di isopropylether, the mixture is filtered. The precipitate obtained after cooling is filtered and dried to obtain the heading compound, m.p. 99-100°. c) Ii ΕϊΕ® ίθίγΐ thoxYrnsthoxyiriino ]acetic_acf d_n;sthYl _es ter To a mixture of 0.6 ml of hydrazine hydrate (100%) and 1.2 ml of the glacial acetic acid in 50 ml of methanol is added at room temperature, with stirring, 2.5 g of 4-dimethylaminomethylene-2(methoxymethoxyimino)acetoacetic acid methyl ester. After 3 days at room temperature, the mixture is evaporated in vacuo, and the residue is distributed between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase is evaporated to dryness 3) and the residue is rubbed with petroleum benzene to obtain the heading compound, m.p. 87-89°. - 14 d) liBYrazoIyk^Jniethoxymethoxyiminolaceti^acid g of [(Pyrazolyl-3)methoxymethoxyimino]acetic acid methyl ester and 4.6 g of LiOH are stirred in 60 ml of water for 30 minutes at 80°. After cooling, the pH is adjusted to 1.5 by addition of a strongly acidic ion exchange resin. The mixture is filtered and the filtrate is freeze dried. The heading compound is obtained as an amorphous, colourless powder.

NMR (DMS0d6/CDCl3): 3,3 (s, 3H); 5.1 (s, 2H); 6.5 (d, IH); 7.6 (d, 1H). H) (3-Carb amoylpyrazolyl-l)methoxyirainoacetic acid a) 4zCarbethgxycarbonyl=2z£methoxyi.ininoiacetoaceti£_aci d_tertiZ butyl_ester To a solution of 5.75 g of sodium in 500 ml of absolute ethanol is added, dropwise, with stirring, and in the absence of moisture, at 0° a solution of 50.4 g of 2-(methoxyimino)acetoacetic acid tert.15 butyl ester and 33.8 g of oxalic acid diethylester in 50 ml of dry ether. After 50 hours at room temperature the mixture is evaporated to dryness, the residue is taken up in 100 ml of water, and the mixture is acidified to pH 5 with IN HC1. Ethyl acetate extraction and silica gel chromatography of the resulting crude product yields the heading compound as a yellow oil. b) (3-Carbethoxypyrazolyl-5)methoxyiminoacetic acid tert.-butylnescer To a solution of 10 g of 4-carbethoxycarbonyl-2-(methoxyiraino)acetoacetic acid tert.-butyl ester in 70 ml of methanol and 4 ml of acetic acid are added, dropwise, at room temperature, with stirring, 3.4 ml of 100% hydrazine hydrate. The mixture is allowed to stand for 30 hours at room temperature and evaporated to dryness. The residue is distributed between 100 ml of ethyl acetate and 50 ml of IN HC1.

The content of the organic phase is chromatographed on silica gel to obtain the heading compound as a colourless oil.

NMR (COC13): 1.3 (t, 8Hz, 3H); 1.6 (s, 9H); 3.95 (s, 3H); 4.3 (q, 8Hz, 2H); 6.9 (s, IH). - 15 e) i3;Carbamo¥lgYrazolyl;5]methoxyi d) ί 3;Carbamoylgyrazolyl;5}:zethoxYirainoaceti c_aci d g of (3-Carb amoylpyrazolyl-5)methoxyiminoacetic acidtert.-butyl ester are reacted in manner analogous to that under C/h above, to obtain the heading compound above, m.p. 217° (decomp.).

I) (1-Phenylpyrazolyl-5)methoxyiminoacetic acid 22.7 g of (3-Dimethylaminoacryloyl)methoxyiminoacetic acid ethyl ester and 14.5 of phenyl hydrazine HCI are heated at boiling in 200 ml of methanol for 3 hours. The mixture is evaporated to dryness in vacuo and the residue is distributed between water and chloroform. Evaporation to dryness of the chloroform phase yields a yellow oil. This product is heated to boiling with 4 g of lithium hydroxide in 200 ml of water. After cooling, the mixture is acidified to pH 1 with cone. HCI. The precipitate is filtered off, washed with water and dried to obtain the heading compound, m.p. 124-128°.

J) (3-Benzyloxycarbonylaminopyrazolyl-5)methoxyiinino acetic acid a) i3;HydrazingcarbonylByrazgl^l;5}methoxyimino_acetic_acid;tert.; hutvl_ester 4.11 g of (3-carbethoxypyrazolyl-5)methoxyimino acetic acid tert.-butyl ester and 1 ml of hydrazine hydrate are heated in 20 ml of ethanol for 20 hours, at boiling. After evaporation to dryness, the residue is chromatographed on silica gel to obtain the heading compound, m.p. 180° (decomp.). • 49396 - 16 b) £3-Benzyl oxycarbony22Ti22BiirS22lyls§l(i?§ib2iyi!I?iD2_5??5i?_aci dί?ΓίιΙ^ϋίϊ1_®5ίθΓ g of (3-Hydrazinocarbonylpyrazolyl-5)methoxyimino acetic acidtert.-butyl ester are dissolved in 10 ml of IN HCl with toluene; a solution of 250 mg NaNOj in 2 ml of water is added, dropwise, at 0°, and the mixture is stirred for 30 minutes. The phases are separated, and the toluene phase is dried well with KjCOj. After addition of 1 ml of benzyl alcohol, the mixture is warmed to 90° and, after 1 hour, evaporated to dryness. The residue is chromatographed on silica gel to obtain the heading compound as a colourless oil.

NMR (COC13): 1.6 (s, 9H); 3.9 (s, 3H); 5.1 (s, 2H); 6.5 (s, 1H); 7.2 (s, 5H). c) ί 2;§®D2Xl2iX£Sr&2QXlS!!!i02EXrS?Sll!l:§}!!Si!!22Yi3iS2-3£§ii5_35i^ 520 g of (3-benzyloxycarbonylaminopyrazolyl-5)methoxyimino acetic acid-tert.-butyl ester are reacted in manner analogous to that of C/h above to obtain the heading compound, m.p. 157-160°.

K) (3-Methylmercaptopyrazolyl-5)iwethoxyimino acetic acid a) i2;Mei{!Yli!erca|>tog^razol£l;5}!iiethoxYimingacetic_acid_eth^l_ester 13.85 g of 2-methoxyimino-3-oxo-5,5-bis-roethylmercapto-pent-420 en-carboxylic acid ethyl ester in 150 ml of N-butanol are boiled for 30 minutes with 5.7 ml of glacial acetic acid and 4.9 ml of hydrazine hydrate. After cooling, the mixture is distributed between 200 ml of ethyl acetate and saturated aqueous sodium bicarbonate solution and the content of the organic phase is chromatographed on neutral aluminium oxide to obtain the heading compound, m.p. 77-80°. b) (3-Methylmercaptopyrazoly'l-5)methoxyiminp acetjc^acid g of (3-methylmercaptopyrazolyl-5)methoxyimino acetic acid ethyl ester are wanned in 20 ml of ethanol and 50 ml of 10% sodium hydroxide for 3 hours at 80*. After cooling, the mixture is 48386 - 17 extracted with ethyl acetate and the aqueous phase is acidified to pH 1.5 by addition of a strongly acidic ion exchange. After filtrarion of the ion exchange resin, the filtrate is freeze dried and the residue is rubbed with ether to obtain the heading compound, m.p. 146-153°.

L) (3-Azidopyrazolyl-S)methoxyimino acetic acid a) 2-Hethoxyimino;3-oxo;525-bis;methylmercagto-4-gentenecsrboxyXicacid_ethyj_ester 11.9 g of NaH are suspended in 500 ml of dry tetrahydrofuran and the mixture is heated to boiling with stirring. To the boiling suspension is added one-third of a solution of 25.1 ml of methyl iodide and 34.6 g of 2-roethoxyiminoaceto acetic acid ethyl ester in 13 ml of carbon disulphide. After the reaction begins (1-3 hours), the remainder of the solution is slowly added, dropwise. The mixture is stirred overnight at room temperature and evaporated to dryness. The residue is distributed between 500 ml of ether and a mixture of 250 ml of water and 250 g of ice. The organic phase is washed with water, dried, and concentrated to remove the solvent to obtain the heading compound, 80-83°. b) 2;MetlJoxyimino;3;Oxo;5;CN;itert.zbutoxycarbonyThydrazono}z §;Τ2ί!!Υΐ!52ί£5Ρί222ΰ£52έ.££Γ^25ΣΐΪ£.2£Ϊ^_2£!ΐΥΐ_22£®Ε A mixture of 1.38 g of 2-methoxyimino-3-oxo-5,5-bis-mercaptomethyl-4-pentenecarboxylic acid ethyl ester, 6.6 g of tert.-butylcarbazate, 1.5 g of acetic acid and 100 ml of n-butanol are heated S at reflux for 90 minutes. The mixture is concentrated under high vacuum (IO*2 Torr) at 50-60° bath temperature. The resulting oily residue is distributed 3 times against ethyl acetate/0.1 N HC1, and then against NaKCO-j. The remaining organic phase is dried with MgSO^ and is concentrated on a rotary evaporator. The residue is - 18 chromatographed over silica with dichloromethane to obtain the heading compound in the form of an oil.

NMR (COC13): 1.27 (t, 3H); 1.5 (s, 9H); 2.5 (s, 3H); 3.35 (q, 2H); 3.9, (s, 3H); 4.2 (q, 2H). c) ^Ci^zNxterU^butoxYcarbgnyljhydrazinogyrazolyVSl^methoxvimino 2£Sii£_32i^-Sii!Yl_®5ier_isyn} A mixture of 360 mg of 2-methoxyimino-3-oxo-5-[(N-tert.-butoxycarbonyl )hydrazono-5-methylmercaptopentane carboxylic acid ethyl ester, 120 mg of acetic acid, 100 mg of hydrazine hydrate and 10 ml of n-butanol is maintained at reflux for 60 minutes. The reaction mixture is concentrated at 10~2 Torr and a bath temperature of approx. 40-50°. The residue is taken up in ethyl acetate and distributed 3 to 4 times in 0.1N HC1 and then against aqueous NaHCOg (about 10%).

The resulting organic phase is dried with magnesium sulphate and evaporated to yield a crystalline residue, which is washed once to twice on glass chips with dichloromethane to obtain the heading compound, 150-151°. d) (3-Hydrazinqpyrazolyl-51methoxylmino acetic acid ethyl ester (syn) 220 mg of 3-[(2-N-tert.-butoxycarbonyl)hydrazinopyrazolyl-5]20 methoxyimino acetic acid ethyl ester are introduced at 0’ into 5 ml of trifluoroacetic acid and the mixture is maintained at room temperature for 30 minutes. The mixture is evaporated in vacuo (12 Torr/20’ bath temperature) and the residue is taken up in ethyl acetate and distributed twice against aqueous sodium bicarbonate.

The organic phase is dried with KgSOj and then evaporated in vacuo (12 Torr/20’ bath temperature) to obtain the heading compound.

NMR (CDClg): 1.37 (t, 3H); 3.95 (s, 3H); 4.35 (q, 2H); 5.46 (sb, 4H); 5.78 (s, 1H). • 19 ' By alkaline hydrolysis, (3-hydrazinopyrazolyl-5)methoxyimino acetic acid may be obtained· e) i3;Azidogyrazolyl;5)methoxyimino_acetic_acid_ethyl_ester_(syn} 347 mg (3-Hydrazinopyrazoly1-5)methoxyimino acetic acid ethyl ester are dissolved in 20 ml of IN HCl and mixed at 0° With 130 mg of NaN02 in 30 ml of water. After 30 minutes reaction time, the mixture is diluted with 100 ml of water, extracted three times with ethyl acetate and the organic phase washed with aqueous sodium bicarbonate and dried with MgSO^. After evaporation in vacuo (12 Torr/20’ bath temperature) the crystalline heading compound remains, m.p.61-63° g of (3-Azidopyrazolyl-S)methoxyimino acetic acid ethyl ester and 1.7 g of lithium hydroxide are stirred in 150 ml of water for 20 hours at room temperature. After filtration of a little insoluble material, the pH is adjusted to pH.1 with cone. HCl and the resulting precipitate is washed with water and dried to obtain the heading compound, m.p. 155-157°.

H) (l-Methylpyrazolyl-5)methoxyimino acetic acid g of Monomethylhydrazines 29.5 g of oxalic acid and 35 g of (p-dimethylaminoacryloyl)methoxyimino acetic acid methyl ester are boiled for 30 minutes in 500 ml of methanol. After cooling and evaporation to dryness, the residue is divided between ether and saturated sodium chloride solution and the ether phase is evaporated The residual oil is chromatographed on 2.5 kg of silica gel to obtain (l-methylpyrazolyl-S)methoxyimino acetic acid methyl ester (colourless oil).

NMR (CDClg, ppm in 4.08 (s, 3H, NCH3); 4.02 (s, 3HS NOCHg); 3.91 (s, 3H, C00CH3).

Also obtained is (l-methylpyrazo1yl-3)acetic acid methyl ester, 49386 - 20 m.p. 160-165°.

NMR (CDC13, ppm in 6 ): 7.33 (d, 2.5Hz, 1H); 6.57 (d, 2.5Hz, 1H); 3.99 (s, 3H, N0CH3); 3.94 (s, 3H, COOCHj); 3.88 (s, 3H, NC«3).

Alkaline hydrolysis of this yields (1-methylpyrazolyl-5Jmethoxyimino acetic acid, m.p. 155-158°.

N) (3-Furylidenehydrazinopyrazolyl-5)methoxyiniino acetic acid A solution of 2.27 g of (3-hydrazinopyrazoly1-5)methoxyimino acetic acid etftyl ester and 15 g of sodium acetate in 100 ml of 50% ethanol is mixed with 960 mg of Furfural. After 20 minutes, the mixture is evaporated in vacuo, and the residue is mixed with water and the resulting crystals are filtered off to obtain the heading compound.

NMR {CDC13): 1.30 (t, 3H); 3.9 (s, 3H); 4.3 (q, 2H); 6.0 (s, TH); 6.4 (m, 3H); 7.2 (d, 1H); 7.55 (s, 1H); 9.10 (sb, 1H).

The free acid may be obtained by alkaline hydrolysis.

O) [3-Amino-2-(N-isobuty1oxycarbonyl)pyrazo1yl-53methoxyimino acetic acid a) ί 3Σ^!5Ϊ22ΒΪΓδ22ΐΧΐχ§ΐΕ2ΐί!25Χί5!Ϊ52-δ£2ίΪ£.52ί4-§ί!35!ΐ_2Ιϊ?Γ To a solution of 100 mg of (3-azidopyrazolyl-5)methoxyimino acetic athyl ester and 200 mg of triethylamine in 20 ml of methanol is added, dropwise, with stirring, 250 mg of propane-1,3-dithiol. After a reaction time of 5 minutes, the mixture is evaporated in vacuo and the residue is mixed with diisopropylether and filtered to obtain the heading compound. 49386 - 21 b) [3-Aminopyrazolyl;5]methoxyinnno_acetic_acid A mixture of 1 g of (3-aminopyrazolyl-5)methoxyimino acetic acid ethyl ester, 40 ml of water, 5 ml off methanol and 225 ml of lithium hydroxide is stirred for 90 minutes at room temperature, is then acidified to pH 2.0 by addition of IR ion exchanger and filtered. The filtrate is lyophilysed to obtain the heading compound. NMR (CDClj/DMSO): 3.93 (s„ 3H); 4.9 (sb, 4H); 5.7 (s, IH). c) P;Amino-2;{N;isobutyloxycarbonyl}pyrazglyl;5]methoxyircino ?cetic_acid To a mixture of 1.34 g of (3-aminopyrazolyl-5)methoxyiraino acetic acid, 2.36 g of triethylamine and 60 ml of methylene dichloride is added, dropwise, at 4°, a solution of 2.19 g of chloroformic acid isobutyl ester in 10 ml of dichloromethane. After 3 hours at 4°, the mixture is extracted with water and the aqueous phase is acidified to pH 2.5 with HC1. The resulting crystals are separated to obtain the heading compound.

NMR (CDCiyOMSO): 0.90 (s, 3H); 1.0 (s,3H); 1.0 (s, 3H); 3.90 (s, 3H); 4.15 (d, 2H); 5.55 (s, IH); 6.05 (sb, 3H).

P) (5-Azido-l-methylpyrazolyl-3)niethoxyinino acetic acid a) ί^Ajido-1^methylgyrazolylz5)methoxyimino_acetic_acid_ethyl ®5£2r-20iL(5;Azido-1^methylpyrazolylz3]methgxyimino_acetic To a solution of 1.2 g of (3-azidopyrazo1yl-5)methoxyinrino acetic acid ethyl ester in 100 ml of tetrahydrofuran is added, at room temperature, 250 mg of 50% sodium hydride and after 10 minutes reaction time 5 ml of methyl iodide. After a further 20 minutes, the mixture is evaporated in vacuo, and the residue is taken up in ethyl acetate. The mixture is shaken with 0.5N HC1 and once with T0% NaHCO-j, and then with sodium chloride solution. The organic phase is dried - 22 with MgSO^ and evaporated in vacuo. The oily crystalline residue is chromatographed with dichlorcmethane over silica, to obtain the heading compounds. (3-Azido-'l-methylpyrazolyl-5)methoxyimino acetic acid ethyl ester, m.p. 45°: NMR (CDClj): 1.34 (t, 3H); 3.95 (s, 3H); 4.00 (s, 3H); 4.32 (q, 2H); 5.86 (s, 1H). (5-Azido-l-methylpyrazolyl-3)methoxyimino acetic acid ethyl ester, m.p. 106-107°: NMR (CDClg): 1.4 (t, 3H); 3.6 (s, 3H); 3.95 (s, 3H); 4.35 (a, 2H); 6.25 (s, 1H). b) i§l6zi do^bme thyl gyrazolyl ;3Jmethoxyimino_ace tic_aci d To a solution of 4 g of (5-azido-l-methylpyrazolyl-3)methoxyimino acetic acid ethyl ester in 17 ml of methanol is added a solution of 950 mg of lithium hydroxide dissolved in 130 ml of water. After 4 hours reaction time, the mixture is mixed with enough ion exchanger to bring the pH value to 2.3. The mixture is separated on glass chips and the filtrate is evaporated in vacuo to obtain the heading compound, m.p. 145-150°.

NMR (CDC13/DMSO): 3.55 (s, 3H); 3.86 (s, 3H); 6.26 (s, 1H); 7.22 (sb, 2H).

Q) (3-Methylsulphony!pyrazolyl-5)methoxyimino acetic acid To a solution of 1.21 o of (3-methylmercaptopyrazolyl-5)methoxyimino acetic acid ethyl ester in 40 ml of acetic acid is added, dropwise, with stirring, at room temperature, a solution of 2.6 g of KMnO^ in 40 ml of water. After 40 minutes, sulphur dioxide is introduced to reduce the resulting magnanese dioxide and the mixture is evaporated in vacuo. The residue is mixed with water and sodium bicarbonate and is extracted with ethyl acetate. The .-iruimwii 9 6 - 23 organic phase is dried with MgSOj and evaporated in vacuo to obtain the ethyl ester of the heading compound as an oil.

NMR (CDC13): 1.4 (t, 3H); 3.24 (s, 3H); 4.03 (s, 3H); 4.45 (a. 2H); 7.0 (s, 1H).

The free carboxylic acid may be obtained by alkaline hydrolysis thereof.

R) (3-Azido-l-methylpyrazolyl-5)methoxyimino acetic acid To a solution of 4 g of (3-azido-l-methylpyrazolyl-5)raethoxyimino acetic acid ethyl ester is added 950 mg of lithium hydroxide dissolved in 130 ml of water. After 4 hours, the mixture is mixed with enough ion exchanger to bring the pH to 2.3. The mixture is filtered over glass chips and evaporated in vacuo to obtain the heading compound, m.p. 153-157°.

S) (3-Antino-1-methylpyrazolyl-5)methoxyimino acetic acid To a solution of 4 g of (3-azido-l-methylpyrazolyl-5)methcxyimino acetic acid ethyl ester in SO m! of methanol is added, dropwise, at 10°, with stirring, 1.76 g of triethylamine and then 1.89 g of 1,3-propane dithiol. After 2 hours, the crystallisate is separated on glass chips. The mother liquor is evaporated in vacuo. The remaining crystallisate is digested on the galss chips with a little ethanol and the filtrate is evaporated and the residue dried in vacuo to obtain the heading compound, m.p. 81-83°. b) l 3Σί!5ΪΠ9ΣΐΣ5?ίί}ΧΐδΥΕ9ί2ΐΥΐΣ§)5!§ί!ϊ9ίίϊΪ5·Ϊ92_9£2ίΪ£-99Ϊ^ To a solution of 3 g of (3-amino-l-methylpyrazolyl-5)methoxyimino acetic acid ethyl ester in 50 ml of methanol is added 940 ml of lithium hydroxide dissolved in 50 ml of water. After 2 hours reaction time, the solution is mixed with ion exchanger until the 4938 • 24 pH is 2.5. The ion exchanger is filtered off and the filtrate is evaporated in vacuo to obtain the heading compound.

T) (5-Amino-l-methylpyrazolyl-3)methoxyimino acetic acid The heading compound is obtained in a manner analogous to that described under S) above. a) i5;Amino;l;methylByrazolyl:3)methoxyimino_acetic_acid_ethyl_ester, b) i§;Amino;l;methylByrazolyl;3]methtf

Claims (6)

1. Claims,:

1. Compounds of formula I X'^'l I R‘ 3 - C - COOH inwhich R'j is hydrogen, alkyl, phenylalkyl, carbalkoxyalkyl, acyl, alkoxyalkyl, hydroxyaikyl, cyanoalkyl, or carbamoylalkyl, 5 R' 3 is a pyrazolyl radical, unsubstituted or mono- or di-substituted by alkyl, phenyl, alkoxy, alkylthio, carbamoyl, carbamoylalkyl, alkylsulphonyl, azido, acylamino, acylhydrazino, alkylide^iydrazino, furylider^ydrazino, carbalkoxy or a group NHj 10 provided that tne nitrogen atoms and the 4-po^ition of the pyrazole nucleus are either unsubstituted or substituted by alkyl, phenyl, or carbalkoxy. and ' reactive derivatives thereof.

2. A compound as claimed in Claim 1, wherein R' 3 represents 15 pyrazol-3-yl.

3. A compound according to Claim 2, wherein R'j represents methyl.

4. A compound according to Claim 2, wherein R'^ represents ethoxycarbonylmethyl. 20

5. A compound according to Claim 1, substantially as hereinbefore described with reference to any one of Examples A to T.

6. A process for preparing a compound of formula 1 as defined in Claim 1, substantially as hereinbefore described with reference to any one of Examples A to T.