DD296072A5 - PROCESS FOR THE PREPARATION OF NEW 1,1'-DISUBSTITUTED ALPHA, ALPHA'-BIS- [PYRAZOLYLOXY- (3)] VINEGARES AND THEIR SALTS - Google Patents

Abstract

The invention relates to a process for preparing a hitherto unknown type of compound structurally as such secured 1,1-disubstituted * and their salts. The title compounds are obtained with high regioselectivity in good yield as one of 6 possible isomers from tautomer mixtures of 1-substituted 3-hydroxy-pyrazoles and 4-pyrazolin-3-ones with dichloroacetic acid and esters thereof in suitable alcohols, especially in n-propanol or n-butanol, with the addition of anhydrous bases. Under the mild conditions of the invention, the title compounds can be halogenated in the 4,4-position without ether cleavage. The title compounds and their salts are of interest as pharmaceuticals, particularly for normalizing serum lipid levels. {* 1,1-disubstituted * 3-hydroxy-pyrazole; 1-substituted 3-hydroxy-pyrazole; 4-pyrazolin-3-one; dichloroacetic; Dichloressigsaeureester; Alcohol; anhydrous base; Halogenation without ether cleavage; pharmaceuticals; Serum lipid levels}

Description

Field of application of the invention

The invention relates to a process for preparing the hitherto unknown 1,1'-disubstituted a, a'-bis [pyrazolyloxy- (3)] acetic acids of the general formula I and their salts with physiologically tolerable inorganic or organic bases,

Cook*

wherein in the general formula I

R ¹ benzyl, with 1 to 2 alkyl groups containing 1 to 3C atoms, with 1 to 2 halogen atoms or with 1 to 2 methoxy groups in the phenyl radical substituted benzyl, phenyl or with 1 to 2 alkyl groups containing 1 to 3C atoms, with 1 to 2 halogen atoms or phenyl substituted with 1 to 2 methoxy groups, R ^{2 is} hydrogen, methyl, chlorine or bromine and

R ^{3 is} hydrogen or alkyl having 1 to 6C atoms.

The new 1,1'-disubstituteda, a'-bis- [pyrazolyloxy- (3)] acetic acids of the general formula I and their salts are of interest as pharmaceuticals, in particular for the normalization of the serum lipid level.

Characteristic of the known state of the art

The claimed according to the invention 1,1'-disubstituted a, a'-bis [pyrazolyloxy- (3)] acetic acids of the general formula I are a hitherto completely unknown chemical class of compounds. Also methods for their preparation or methods for preparing comparable N-heterocyclic substituted dihydroxyacetic acids have been unknown.

Object of the invention

The aim of the invention is to produce the hitherto unknown 1,1'-disubstituted α, α'-bis- [pyrazolyloxy- (3)] acetic acids of general formula I in a technically feasible synthetic routes as active ingredients with a defined chemical structure.

Explanation of the essence of the invention

The object of the invention is to develop a process for the preparation of novel 1,1'-disubstituted α, α'-bis- [pyrazolyloxy- (3)] acetic acids, which is to proceed under simple reaction conditions.

This object is achieved according to the invention by a tautomer mixture of a 1-substituted-3-hydroxy-pyrazole of the general formula II and a 1-substituted 4-pyrazolin-3-one of the general formula III,

wherein in II and III R ¹ and R ^{2 have} the same meanings as in the general formula I, in the presence of an anhydrous base with a dichloroacetic acid ester of the general formula IV in which R ^{3 is} alkyl having 1 to 6 carbon atoms, or one Dichloroacetic acid of the formula IV in which R ^{3 is} hydrogen,

with the addition of catalytic amounts of a Alkalibromids or iodide in a suitable alcohol as the reaction medium in the temperature range of 85 to 160 ⁰ C with exclusion of water, then distilled off the alcohol, the residue using a Dichloressigsäureesters IV (R ³ = alkyl having 1 to 6C atoms ) is saponified as by-product by heating with aqueous or methanolic aqueous sodium hydroxide solution for 5 to 15 minutes or, when using dichloroacetic acid IV (R ³ = H) as starting material in water, the first aqueous solution of the sodium salt of a carboxylic acid, optionally after distilling off methanol of the general formula I (R ³ = H) optionally extracted with an indifferent, water-immiscible solvent, by acidification of the aqueous phase, the carboxylic acid of general formula I (R ³ = H) precipitates, these by reprecipitation from an aqueous sodium or Potassium bicarbonate solution and recrystallize optionally, when in IR ² = H, chlorinated or brominated in a chlorinated hydrocarbon in the temperature range of -12 ° C to + 12 ° C with the addition of a hydrogen halide acceptor in the 4,4-position or with the equimolar amount an alkali alcoholate or an i-deoxy-methylamino-sugar alcohol in a lower alcohol in a crystalline salt.

The anhydrous base according to the invention is produced by dissolving at 100 to 130 ⁰ C predried 'Tautomerengemisch, preferably 2.0 mol, the general formulas II and III in dry reaction apparatus in an appropriate for the reaction of the invention anhydrous alcohol, the 1.8 to 3,6mol sodium alcoholate dissolved, or that one of the tautomeric mixture of the general formulas II and III dissolves in a methanolic sodium or potassium hydroxide solution containing 1 mol of NaOH or KOH, then distilled off methanol and water, the resulting salt dries , in an alcohol suitable for the reaction according to the invention dissolves and optionally removed residual water by azeotropic distillation.

Preferably, from 1.05 to 1.25 mol of dichloroacetic acid methyl or ethyl ester and from 2.2 to 2.5 mol of anhydrous base are used per 2.0 mol of tautomeric mixture of the general formulas II and III.

According to the invention, the dichloroacetic acid ester IV used (R ³ = alkyl having 1 to 6 carbon atoms) or the dichloroacetic acid IV used (R ³ = H) can be added to the reaction solution in one portion or in several portions as such or diluted with the reaction medium become.

According to the invention, when using a dichloroacetic acid ester IV (R ³ = alkyl having 1 to 6 C atoms) as starting material, the residue remaining after distilling off the alcohol used as the reaction medium, which ester according to the invention of 1,1'-disubstituted a, a'-bis- [pyrazolyloxy- (3)] acetic acid of general formula I (R ³ = alkyl having 1 to 6C atoms), before the saponification according to the invention in a water-immiscible organic solvent, preferably in dichloromethane, are taken up and the organic phase for the purpose of separation less Shares of unreacted Tautomerengemisch Il and III, which is well soluble according to the invention in aqueous sodium or potassium hydroxide solution, however, is insoluble in aqueous sodium bicarbonate solution, with 1 to 2 normal sodium hydroxide solution and then shaken with water. The remaining after distilling off the dichloromethane ester mixture of the general formula I (R ³ = alkyl having 1 to 6 carbon atoms) according to the invention further processed by brief saponification with aqueous or aqueous-methanolic sodium hydroxide solution.

According to the invention, the extraction of the aqueous solutions of alkali salts of the carboxylic acids of the general formula I {R ³ = H) obtained according to the invention is suitable as an indifferent, water-immiscible solvent, preferably dichloromethane or ethyl acetate. This applies according to the invention both for the inventive first aqueous solution of the sodium salt of a carboxylic acid of general formula I (R ³ = H) and for the purpose of fine cleaning by dropping from aqueous alkali metal bicarbonate solution according to the invention prepared aqueous solution of an alkali metal salt of a carboxylic acid of general formula I ( R ³ = H).

According to the invention, 1,1'-disubstituted a, α'-bis- [pyrazolyloxy- (3)] acetic acids of general formula I with R ² = Cl or Br can be prepared either by tautomer mixtures of 4-halo-substituted 3-hydroxy pyrazoles II and 4-pyrazolin-3-ones III (R ² = Cl or Br) with dichloroacetic acid esters or with dichloroacetic acid, or by reacting 1,1'-disubstituted a, a'-bis- [pyrazolyloxy- (3)] acetic acids of general formula I with R ² = H halogenated under the mild conditions according to the invention, ie, with cooling 2 mol sulfuryl chloride or with 2mol bromine (2Br ₂ ) proimol I (R ² = H) at -12 ° C to +12 ⁰ C. , preferably in dichloromethane, with the addition of a hydrogen halide acceptor, preferably with the addition of calcium carbonate. According to the invention, it is expedient to use the halogenating agent, for. As SO ₂ Cl ₂ or Br ₂ , to dilute with dichloromethane.

When applying more severe acidic conditions in the halogenation than the conditions according to the invention, an undesired ether cleavage takes place, with tautomer mixtures of 1-substituted 3-hydroxy-pyrazoles II and 4-pyrazolin-3-ones III being formed from the compounds of general formula I. By means of this ether cleavage it can be demonstrated that the chlorination or bromination according to the invention of the novel carboxylic acids of the general formula I (R ² = H) takes place in the 4,4'-position: In the ether cleavage, tautomer mixtures of II (R ² = Cl or Br) and III (R ² = Cl or Br), the structure of which is proved ^ -NMR spectroscopically.

The inventive novel structure I of 1,1'-disubstituted a, a'-bis [pyrazolyloxy (3)] acetic acids is clearly demonstrated by elemental analyzes and 'H-NMR spectroscopic parameters (see below). In principle, the tautomer mixtures used as starting materials according to the invention can be prepared from 1-substituted 3-hydroxy-pyrazoles II and 4-pyrazolin-3-ones IM with dichloroacetic acid or esters IV thereof at the 3-hydroxy function (of II) or on the 2- (3-hydroxy) pyrazoles. NH) function (of III) or of the 4 (CH) function (of Il and III, R ² = H), whereby six differently structured isomeric compounds, namely three identical bis-substituted and three mixed bis-substituted, can arise. Under the process conditions of the invention, however, only one of these six isomers is recovered, namely only with the general formula I.

The compounds of general formula I according to the invention are clearly symmetrical. Corresponding to the formula I show ^ -NMR spectra of the novel compounds I of the invention (R ¹ = aralkyl, R ² = H) of the protons (H-4) [(H-5), (H-4 ')] ( H-5 ') only one AX system (4H) with the characteristic H, H coupling constant J45MV) = 2.45 ± 0.05 Hz. For compounds which differ from a possible substitution on the 2 - Derive (NH) function of III (R ¹ = aralkyl, R ² = H), a significantly higher Η, Η coupling constant, namely J45 <4-5 '> = 3.55 ± 0.05Hz, is expected (See H. Dorn, J. Prakt. Chem., 315, 390 [1973]), which are not found for the compounds I according to the invention. According to the structure I of the invention, compounds of general formula I (R ¹ = aryl, R ² = H), according to one of the 1,1'-bis-aryl-substitution somewhat elevated Η, Η coupling constant Ü46 (4-5 ·) = 2,70 ± 0,05Hz. In a basically also possible substitution of the 4- (CH) function (of II and III, R ² = H) are in the ¹ H-NMR spectra for the compounds of general formula I (R ² = H) according to the invention characteristic AX systems (4 H) are not expected.

embodiments

example 1

87.1 g (0.5 mol) predried 1-benzyl-3-hydroxy-pyrazole and 83 mg (0.5 mmol) of potassium iodide in 500 ml of anhydrous 1. In a dry reaction apparatus with reflux condenser, mechanical stirrer and two feed vessels with pressure compensation normal solution of sodium n-butoxide in n-butanol with stirring and heating to 40 ° C dissolved. With stirring and further heating to 55 to 65 ° C is allowed to run in 30 minutes, the mixture of 35.8 g (0.25 mol) of dichloroacetic acid methyl ester and 40 ml of anhydrous n-butanol, then heated for 5 hours under reflux and stirring to boiling, then reduced Temperature of the reaction mixture again at 55 to 65 ° C and the first half of up to 125 ml of an anhydrous 1 normal solution of sodium n-butoxide in n-butanol run. The first half of a mixture of 7.2 to 9.0 g (0.05 to 0.063 mol) of dichloroacetic acid methyl ester and 10 to 15 ml of anhydrous n-butanol is then allowed to run in under stirring for 15 minutes, then heated to boiling for 45 minutes with stirring repeat this

Operations with the second half of the sodium n-butylate solution and the second half of the dichloroacetic acid methyl ester solution. The mixture is then distilled off, finally under reduced pressure, the solvent. To the residue are added 500 ml of 1 normal aqueous sodium hydroxide solution, heated to boiling for 5 minutes, the first solution of the sodium salt of the carboxylic acid I (R ¹ = CH ₂ -Ph, R ² = R ³ = H) Norit (activated carbon), heated for a further 5 minutes, filtered and added to the cooled filtrate 2 to 4 η hydrochloric acid to pH 4.5 to 5.5. The precipitated carboxylic acid I is separated from the aqueous mother liquor and sets 400 ml of water from 30 to 35 ° C and gradually 42 g of sodium bicarbonate to. The resulting solution of the sodium salt of the carboxylic acid I is filtered, optionally after a second treatment with Norit (activated carbon). It can be extracted with 100 to 120 ml of ethyl acetate in 2 portions. By acidification of the aqueous sodium salt solution with hydrochloric acid to pH 4.5 to 5.5 is in a yield of 76 to 85% of theory a, a'-bis [1-benzyl-pyrazolyloxy- (3)] acetic acid which can be recrystallized from i-propanol, n-butanol or ethyl acetate, mp 122-124 ° C. Instead of Dichloressigsäuremethylester can be used analogously (without saponification) dichloroacetic acid, the yields are lower by 3 to 5%. An almost identical yield of I is also achieved when using n-propanol as the reaction medium, whereas ethanol, i-propanol and tert. Butanol unfavorable and the dipolar-aprotic solvents acetone, acetonitrile and dimethylformamide unsuitable snd.

C22H20 N ₄ O ₄ (404.4) H 4,98 N 13,85 calc .: C 65,33 H 4.95 N 13,72 Found .: C 65.31

¹ H-NMR (60 MHz, based on TMS int.) In CDCl ₃ (in [CD ₃ J ₂ CO): δ (CH ₂ -Ph) = 5.10 [5.14] s, 4H, δ (H) 4) = 5.80 [5.79] d, 2H, δ (H-6) = 6.47 [6.67] s, 1 H, δ (H-5) = 7.13 [7.49] d, 2H, δ (CO ₂ H) = 9.97 [6,18] s, 1 H, D ₂ O is replaced, ppm J ₄₅₁₄ V) = 2.45 [2.40] ± 0.05 Hz.

Example 2

Dissolve 17.42 g (100 mmol) of 1-benzyl-3-hydroxy-pyrazole in 200 ml of 0.5 nm methanolic potassium hydroxide, prepared by dissolving KOH in methanol, assaying by titration with 0.1 η HCl (phenolphthalein ), and then distilled the methanol and water, finally in vacuo. 300 ml of n-butanol and 50 mg (0.3 mmol) of potassium iodide are then added to the remaining salt and 80 ml are distilled off via a short body column (boiling point constant 117.5 ° C.) The mixture is then left under constant stirring with exclusion of water slowly distilling off n-butanol over the column in 30 minutes, the mixture of 7.15g (50mmol) dichloroacetate and 50ml n-butanol run and heated for 5 hours with stirring and slowly distilling off a portion of n-butanol through the column to boiling. The n-butanol is then distilled off, finally under reduced pressure, the residue is dissolved in 200 to 250 ml of dichloromethane and the solution is extracted with 50 ml of 0.3N sodium hydroxide solution and then with water. Acidification of the aqueous phase gives 4 to 8%. The oil remaining after distilling off the dichloromethane is an ester mixture of the formula I. ¹ H-NMR in CDCl ₃ : δ (CH ₂ -Ph ) = 5.07s, 4H, δ (H-4) = 5.79d, 2H, δ (H-6) = 6.63s, 1H, δ (H-5) = 7.14d, 2Hppm, J _{45 (} 4v) = 2.45 ± 0.05Hz.

The oil is dissolved in 35 ml of methanol, 60 ml in sodium hydroxide solution, heated for 3 to 5 minutes to boiling, distilled off the methanol and the volume is brought to 100 ml with water. The first solution of the sodium salt of the carboxylic acid I (R ¹ = CH ₂ -Ph, R ² = R ³ = H) thus obtained is further processed analogously to Example 1. It is obtained with 75 to 84% d. Th. Yield a, a'-bis [1-benzyl-pyrazolyloxy- (3)] acetic acid, mp 122-124 ° C.

Example 3

From Example 1 or Example 2, 1- (4-isopropylbenzyl) -3-hydroxy-pyrazole and methyl dichloroacetate are prepared from α, α'-bis [1- (4-isopropylbenzyl) -pyrazolyloxy- (3)] acetic acid (recrystallized from carbon tetrachloride) ago, mp. 109-110 ⁰ C.

C ₂ sH ₃ 2N ₄ O ₄ (488.6) H 6,60 N 11,47 calc .: C 68,83 H 6,48 N 11.39 Found .: C 68.78

¹ H-NMR in CDCl ₃ : δ (Me ₂ ) = 1.13 / 1.25 d, 12H, δ (CHMe ₂ ) = 2.87 h, 2H, δ (CH ₂ -Ar) = 5.07s, 4H, δ (H-4) = 5.8Od, 2H, δ (H-6) = 6.48s. 1 H, δ (H-5) = 7.11 d, 2H, δ (CO ₂ H) = 11.23s, 1 H, exchanges with D ₂ O, ppm, J _45M v) = 2.45 ± 0 , 05Hz.

Example 4

From Example 1 or Example 2 is prepared from 1- (4-chlorobenzyl-3-hydroxy-pyrazole and dichloroacetic acid methyl ester, the aa'-bis [1- (4-chloro-benzyl) -pyrazolyloxy- (3)] acetic acid forth, m.p. . 134 to 135, ⁰ C (recrystallized ausToluen).

C ₂₂ H ₁₈ CI ₂ N ₄ O ₄ (473.3) H 3,83 N 11,84 calc .: C 55.83 H 3.76 N 11,64 Found .: C 55.79

¹ H-NMR in CDCl ₃ On (CD ₃ J ₂ CO): δ (CH ₂ -Ar) = 5.07 [5.20] s, 4H δ (H-4) = 5.81 [5.82] d, 2H δ (H-6) = 6.47 [6; 68] s, 1 H, δ (H-5) = 7.15 [7.58] d, 2 H, 0 (CO ₂ H) 10.33s, 1 H, exchanges with D ₂ O, ppm, J _{45 (4V} ) = 2.50 [2.45] ± 0.05Hz.

Example 5

Analogously to Example 1 or Example 2 is prepared from 3-hydroxy-1-phenyl-pyrazole and Dichloressigsäuremethylester the α, α'-bis [1-phenyl-pyrazolyloxy- (3)] acetic acid forth, mp. 147 ° C (from toluene recrystallized).

C ₂₀ Hi ₆ N ₄ O ₄ (376.4)

Calc .: C 63.83 H 4.29 N 14.89

Found: C64.04 H4.38 N 14.75

¹ H-NMR in (CD ₃ I ₂ CO: δ (H-4) = 6.14d, 2H, δ (CO ₂ H) = 6.61 s, 1 H, δ (H-6) = 7.10 s , 1 H, δ (H-5) = 8,19d, 2H ppm, = 2,70 ± 0,05Hz

Example 6

The suspension of 25.1 g (62 mmol) of α, α'-bis [1-benzyl-pyrazolyloxy- (3)] acetic acid and 12.5 g of calcium carbonate in 300 ml of dichloromethane is cooled to -5 ° C to -7 ° C and then, while stirring and cooling in 2 hours, the solution of 16.9 g (125 mmol) of sulfuryl chloride in 120 ml of dichloromethane is added, keeping the internal temperature at - 5 ⁰ C to +2 ⁰ C is maintained thereafter at this temperature for a further 2 Stirred for hours. The dichloromethane solution is then extracted repeatedly with water, the phases are separated and the dichloromethane is distilled off from the organic phase (can be reused). The residue is dissolved at 30 to 35 ⁰ C in aqueous sodium bicarbonate solution, filtered and precipitated with hydrochloric acid to pH 4.5 to 5.5, the a, a'-bis [1-benzyl-4-chloro-pyrazolyloxy (3)] acetic acid, mp 129 to 130 ⁰ C (recrystallized from toluene).

C ₂₂ H I ₈ CI ₂ N ₄ O ₄ (473.3) H 3,83 N 11,84 calc .: C 55.83 H 3,83 N 11,80 Found .: C 55.79

Example 7

The suspension of 8.09 g (20 mmol) of α, α'-bis- [1-benzyl-pyrazolyloxy- (3)] acetic acid and 4 g of calcium carbonate in 70 ml of dichloromethane is cooled to -5 ° C to -7 ° C and then added while stirring and cooling within 2 hours, the solution of 6.4 g (40 mmol) of bromine in 40 ml of dichloromethane, wherein the internal temperature is maintained at -5 ° C to + 2 ° C. The procedure is analogous to Example 6 and receives the a, a'-bis [1-benzyl-4-bromo-pyrazolyloxy- (3) acetic acid, mp 129 to 130 ⁰ C (recrystallized from benzene). The yields of chlorination and bromination are over 80% d. Th.

C ₂₂ H _ls Br ₂ N ₄ O ₄ (562.2) H 3,22 N 9.96 calc .: C 47.00 H 3,20 N 9.83 Found .: C 47.43

Example 8

703 mg (1.25 mmol) of α, α'-bis- [1-benzyl-4-bromo-pyrazolyloxy (3)] acetic acid are refluxed with 5 ml of 48% hydrobromic acid and 5 ml of acetic acid for 30 to 40 minutes , cools and adds 60ml ice-water. The precipitated product is recrystallized from n-propanol. 1-benzyl-4-bromo-3-hydroxy-pyrazole, m.p. obtained 582mg (92 d. Th.). 163-164 ⁰ C.

'H-NMR in CDCl ₃ : δ (CH ₂ -Ph) = 504s, 2H, δ (H-5) = 7.12 s, 1H, ppm. The product is according to Schmp. And ¹ H-NMR spectrum identical to that obtained by bromination of 1-benzyl-3-hydroxy-pyrazole according to conventional methods.

710 mg (1.5 mmol) of α, α'-bis [1-benzyl-4-chloro-pyrazolyloxy (3)] acetic acid are refluxed with 6.5 ml of 38% hydrochloric acid and 6.5 ml of acetic acid for 60 minutes , cool and add 75 ml of ice-water. The precipitated product is recrystallized from ethanol. 588mg i-BenzyM-chloro-S-hydroxy-pyrazole, m.p. obtained (94% of theory..) 176 ⁰ C ¹ H-NMRInCDCI ₃ (Jn (CD _{3) 2} SO). Δ (CH ₂ -Ph) = 5.05 [5.03] s, 2H, δ (H-5) = 7.13 [7.68] s, 1 H ppm.

The product is identical to that obtained by chlorinating 1-benzyl-3-hydroxy-pyrazole by conventional methods according to mp and ¹ H-NMR spectrum.

Example 9

1-Benzyl-3-hydroxy-4-methyl-pyrazole and methyl dichloroacetate are prepared analogously to Example 1, the α, a'-bis [1-benzyl-4-methyl-pyrazolyloxy (3)] acetic acid. The carboxylic acid I precipitated from aqueous sodium bicarbonate solution according to Example 1 is dissolved in diethyl ether, dichloromethane or ethyl acetate, the solution is dried with sodium sulfate, filtered and the solvent is removed under exclusion of water. The residue obtained is dissolved in 400 to 450 ml of anhydrous ethanol, equates to the acid I equimolar amount of 1-deoxy-1-methylamino-D-galactitol (mp 134 to 135 ° C, molecular weight 195.2) and heated until a homogeneous solution arises. Upon cooling, the 1-deoxy-i-methylamino-D-galactitol salt of a, a'-bis [1-benzyl-4-methyl-pyrazolyloxy- (3)] acetic acid, m.p. 110-111 ° C.

C ₃₁ H ₄₁ N ₅ O ₉ (627.7) H 6,58 calc .: C 59,31 H 6,60 Found .: C 59.39

N 11.08.

Claims (9)

1. A process for the preparation of novel l, 1'-disubstituted a, a'-bis [pyrazolyloxy- (3)] acetic acids of general formula I, .1 in the R ^{1 is} benzyl, having 1 to 2 alkyl groups which contain 1 to 3C atoms, with 1 to 2 halogen atoms or with 1 to 2 methoxy groups in the phenyl radical substituted benzyl, phenyl or with 1 to 2 alkyl groups containing 1 to 3C atoms, with 1 to 2 halogen atoms or with 1 to 2 methoxy substituted phenyl, R ^{2 is} hydrogen, methyl, chlorine or bromine and R ^{3 is} hydrogen or alkyl having 1 to 6C atoms mean. and their salts with physiologically compatible inorganic or organic bases, characterized in that a tautomer mixture of a 1-substituted 3-hydroxy-pyrazole of the general formula II and a 1-substituted 4-pyrazolin-3-one of the general formula III, c " wherein in II and III, R ¹ and R ^{2 have} the same meanings as in the general formula I, in the presence of an anhydrous base with a dichloroacetic ester of the general formula IV in which R ^{3 is} alkyl of 1 to 6C atoms, or a dichloroacetic acid of the general formula IV in which R ^{3 is} hydrogen, with addition of catalytic amounts of an alkali bromide or iodide in a suitable alcohol as the reaction medium in the temperature range of 85 to 160 ⁰ C with exclusion of water, then distilled off the alcohol, the residue at Use of a dichloroacetic acid ester IV (R ³ = alkyl having 1 to 6C atoms) saponified as by-product by heating with aqueous or methanolic aqueous sodium hydroxide solution for 5 to 15 minutes or, when using dichloroacetic acid IV (R ³ = H) as starting material in water, the , optionally after distilling off methanol, obtained first aqueous solution of the sodium salt of a carboxylic acid of general formula I (R ³ = H) optionally with an indifferent, water-immiscible solvent, by acidification of the aqueous phase, the carboxylic acid of general formula I (R. ³ = H) fails, this by Umfal len from an aqueous sodium or potassium bicarbonate solution and recrystallization, they optionally, when in IR ² = H, in a chlorinated hydrocarbon in the temperature range from - 12 ° C to + 12 ° C with the addition of a hydrogen halide acceptor in der4, Chlorinated or brominated 4'-position or converted with the equimolar amount of an alkali metal alkoxide or a 1-deoxy-imethylamino-sugar alcohol in a lower alcohol in a crystalline salt. 2. The method according to claim 1, characterized in that 2.0 mol of tautomeric mixture of a 1-substituted 3-hydroxypyrazole (II) and a 1-substituted 4-pyrazolin-3-one (III) in the presence of 1.8 to 3.6 mol of a anhydrous base with 0.9 to 1.3 mol of a Dichloressigsäureesters (IV, R ³ = alkyl having 1 to 6C atoms) or a dichloroacetic acid (IV, R ³ = H) are reacted with addition of an alkali metal bromide or iodide. 3. The method according to claim 1 and 2, characterized in that the anhydrous base is produced by dissolving at 100 to 130 ^c C pre-dried tautomeric mixture of the general formulas II and IM in dry reaction temperatures in an appropriate for the reaction of the invention anhydrous alcohol, containing 1.8 to 3.6 moles of sodium alcoholate, or dissolving 1 mole of a tautomeric mixture of the general formulas II and III in a methanolic solution of sodium or potassium hydroxide containing 1 mole of NaOH or KOH, then distilling off methanol and water , The resulting salt is dried overnight, dissolved in an appropriate for the reaction of the invention alcohol and optionally removed residual water by azeotropic distillation. 4. The method according to claim 1 to 3, characterized in that preferably used per 2.0 mol Tautomerengemisch of the general formulas II and III 1.15 to 1.25mol Dichloressigsäuremethylester or ethyl ester and 2.2 to 2.5 moles of anhydrous base. 5. The method according to claim 1 to 4, characterized in that the dichloroacetic ester IV used (R ³ = alkyl having 1 to 6C atoms) or the dichloroacetic acid IV used (R ³ = H) in one portion or in several partial portions as such (r) or diluted with the reaction medium to be added to the reaction solution. 6. The method according to claim 1 to 5, characterized in that the reaction medium is anhydrous aliphatic alcohols having 3 to 6C atoms and methyl and ethyl glycol, preferably n-propanol and n-butanol, are used. 7. The method according to claim 1 to 6, characterized in that when using a Dichloressigsäureesters IV (R ³ = alkyl having 1 to 6C atoms) as the starting material of the residue remaining after distilling off the alcohol used as the reaction medium residue, which according to the invention Estervon 1,1 'Disubstituted a, a'-bis- [pyrazolyloxy- (3)] acetic acids of general formula I (R ³ = alkyl having 1 to 6C atoms), before saponification in a water-immiscible organic solvent, preferably in Dichloromethane, recorded and the organic phase for the purpose of separating small amounts of unreacted Tautomerengemisch Il and III, which is readily soluble according to the invention in aqueous sodium or potassium hydroxide solution, however, insoluble in aqueous sodium bicarbonate solution, with 1 to 2 normal aqueous sodium hydroxide solution and then shaken with water can be and that after distilling off the dichloromethane remaining ester mixture of the general in which formula I (R ³ = alkyl having 1 to 6 carbon atoms) according to claim 1 is further processed. 8. The method according to claim 1 to 7, characterized in that for the extraction of the aqueous solutions of alkali metal salts of the carboxylic acids of general formula I (R ³ = H) as indifferent, water-immiscible solvent, preferably dichloromethane or ethyl acetate, is suitable. 9. The method according to claim 1 to 8, characterized in that the chlorination or bromination of a compound of general formula I with R ² = H is preferably carried out in dichloromethane and preferably with the addition of calcium carbonate as a hydrogen halide acceptor.