PT85478B - PROCESS FOR THE PREPARATION OF PYRIMIDINE DERIVATIVES - Google Patents

Description

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in which X has the above-mentioned meanings, with an acid anhydride of the general formula (III)

(Ib), (Ib), (Ic) and (Id), respectively, are thus obtained. They are valuable intermediate products for the preparation of the compounds of the general formulas (Ia). the preparation of β-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidine-pyrimidine (minoxidil) having blood pressure and hair growth stimulating properties. The present invention relates to novel pyrimidine derivatives of the general formulas (Ia), (Ib) and (Ic)

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what are they? 5

R is an alkenyl group having 1 to 6 carbon atoms or an aryl group optionally substituted by halo; and X represents a chlorine or bromine atom or an arylsulfonyloxy group which optionally has one or more substituents. The invention further relates to the preparation of the novel pyrimidine derivatives of the general formulas (Ia), (Ib) and (Ic) as well as the known pyrimidine derivatives of the general formula (Id)

in which the significances of the symbol X are the same as indicated above.

According to the present invention, the pure compounds of the general formulas (Ia), (Ib), (Ic) and (Id) and mixtures thereof are respectively prepared by reacting a 2,3-diaminopyrimidine derivative of the formula general (II)

The meanings of the symbol X are the same as above, with acid anhydride of the general formula (III)

R

(III) in which the meanings of R are the same as those mentioned above in the presence of water and hydrogen peroxide and separating the product mixture or the pure compounds of general formulas (Ia), (Ib), ( Ic) and (Id), respectively.

The novel compounds of the general formulas (la), (Ib) and (Ic) and the known compounds of the general formula (Id) are valuable intermediates for the preparation of 5-amino-1,2-dihydro- hydroxy-2-imino-4-piperidine-pyrimidine (L-i-noxidyl) with blood pressure lowering and hair growth stimulating properties.

According to the process of the present invention, the compounds of the general formulas (Ia), (Ib), (Ic) and (Id) are prepared from derivatives of general formula (II) (the meanings of R and X being of these formulas the same as mentioned above). Compounds of general formula (II) are known; for example, those containing a. chloro or bromo atom having X-meanings are described in the specification of U.S. Patent 3,464,464 and those containing an arylsulfonyloxy group are described in the specification of

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7 and 177Â ° C.

Patent Ηungara 2Τ2.

The compounds of the general formula (Id) wherein X is chlorine or bromine are known from the abovementioned disclosure of the above-mentioned U.S. Patent 272,364,364 and those in which X the arylsulfonyloxy group are known from Hungarian Patent 272,177,601. Other compounds, i.e. the compounds of general formulas (la), (ib), and (ic) which may be prepared by the process according to the present invention. invention are novel. The term " arylsulfonyloxy which optionally has one or more substituents " in the definition of the substituent X in the general formulas (la), (Ib), (Ic), (Id) and (II) preferably denotes a phenylsulfonyloxy group substituted on the phenyl ring by 1 to 3 lower alkyl groups, preferably methyl groups. Preferred representative examples of such groups are the tosyloxy group and the mesitylene sulfonyloxy group. X, more preferably, represents a chlorine atom. (Ib), (Ic), (Id) and (III) The substituent R as an alkyl group of up to 6 carbon atoms may mean any straight or branched chain hydrocarbyl group having 1 to 5 atoms of for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-2-hexyl and isohexyl, up to 4 carbon atoms, and most preferably the methyl radical. Aryl groups also included in the signification of P may be any aryl group having 6 to 12 carbon atoms, preferably 1 to 4, the phenyl group which may be substituted by one or more halogen atoms, preferably the chlorine atom . The invention has as its object the preparation of the compounds from simple chemicals, readily available on the market and in a high yield, respectively.

//. from which the I-inoxydil, an active ingredient of pharmaceutical compositions, in substantially greater yields than has hitherto been obtained can be readily prepared.

According to the above-mentioned patent specification, the known compounds of the general formula (Id) are prepared by oxidizing the corresponding 2,6-diazino-pyrimidine derivatives of the general formula (II) with m-chloro-per- -benzoic acid in the case of the 4-chloro compounds in a yield of 44 and, in the case of the 4-tosyl compounds, in a yield of 55%. In addition to the low yields, the known processes have other drawbacks such as the need to use large volumes of reagents and also the fact that the oxidizing agent is a labile compound which is difficult to handle and is not easily commercially available. The Applicant has now discovered that the abovementioned drawbacks are eliminated if the compounds of the general formula (II) are reacted in the presence of hydrogen peroxide with an appropriate acid anhydride of the general formula (III) instead of reacting with (Ib) and (Ic), by way of which the 6-chloro-perbenzoic acid derivatives of formula (I) amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidine-pyrimidine having therapeutic effect essentially more preferably than employing the syntheses hitherto known.

In accordance with the present invention, the starting material of the general formula (II) (wherein X is the same as mentioned above) is preferably dissolved together with the hydrogen peroxide, containing water in the required volume and in a variable amount, in a solvent which is inert with respect to the oxidation reaction, for example in alcohols, ethers, esters or solvents η I BAD ORIGINAL '

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of the ketone type, and then adding the appropriate acid anhydride of the formula (III) (wherein R has the above-mentioned meanings) to the solution at a temperature of from 40 ° C to 9 ° C. In the course of the process, from the two reactants, percarboxylic acid is obtained which oxidizes the starting material of the general formula (II). The oxidation results in the formation of the Î ± -oxide derivatives of the general formulas (Ia), (Ib), (Ic) and (Id).

The compounds of the general formulas (Ia) and (Ib) are monoacyl derivatives with the difference that in the first group of derivatives the acyl group is on the oxygen atom attached to the nitrogen atom in the 1-position and, in the second group of derivatives , is in the amino group of the 2-position. The N-acyl derivatives of the general formula (Ib) are converted into the O-acyl derivatives of the general formula (la) even under extremely mild conditions, then when dissolved, or under the effect of slight heating or traces of acid or base or water. The X-oxide derivative of the general formula (Ic) is an acyl compound in which one of the acyl groups is attached to the oxygen atom attached to the nitrogen atom in the 1-position and the other is attached to the amino group in the 6-position. As as mentioned above, the X-oxide derivative of the general formula (Id) is a known compound which is very easily formed from the above-mentioned M-oxides of the general formulas (Ia), (Ib) and (Ic) under bond alkaline effect. Conversely, the compounds of the general formulas (Ia), (Ib) and (Ic) are obtained from the compounds of the general formula (Id) by reaction with a small amount of anhydride. j The course of the practical realization of the process, s.

(Ic) and (Id) is a function of the experimental conditions. The ratio of the products is first influenced by the method of processing the reaction mixture, by the type of the product

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and by the molar ratio of the reagents used,

If the reaction mixture is worked up after the reaction is carried out employing the treatment with aqueous alkaline solution, the acyl compounds of the general formulas (la), (Ib) and (Ic) are first formed are quantitatively transformed into compounds of the general formula ) and only this latter compound can be isolated. If, in the course of processing, the reaction mixture is not subjected to such treatment, the compounds of general formulas (Ia), (Ib) and (Ic) which can be isolated are obtained. It is also possible to proceed in such a way that the crystallized part of the compounds of the general formulas (Ia), (Ib), (ic) and (id) is first separated and then, after being alkalized, the compound of the general formula (Id) thus obtained is isolated from the mother liquor. The process according to the present invention has a special dependence on the solvent employed. The pyrimidine derivative of the general formula (II) used as the starting material is very sparingly soluble in most organic solvents. However, it has surprisingly been found that the compound of the general formula (II) is solubilized under the effect of slight heating carried out in the presence of water at 2 ° C moles of water relative to 1 mole of the compound of the formula In the course of carrying out the process, the water required for dissolution is added to the reaction mixture preferably together with the hydrogen peroxide. The proportion of the compounds in the oxidation product carried out in In an analogous manner, but in the case of different solvents, the compound of the general formulas (Ia) and (Ib) is obtained in the presence of a compound of formula The C-acyl compound of the general formula (Ia) may be prepared in the presence of tetrahydrofuran.

(Et), a prevailing amount of the compound of general formula (la) is obtained together with a minimum amount of the compound of general formula (Ic). If X is tosyl, the compound of formula (Ia) is formed in ethanol and the compound of general formula (Ib) can not be isolated.

By increasing the amount of acid anhydride used for the reaction in the same solvent, the diacyl compound of the general formula (Ic) is obtained, surprisingly even if the reaction is carried out in an aqueous medium. The quality of the R group does not influence the proportion of products.

As mentioned above, the common drawbacks of known processes for the preparation of the known compounds of the general formula (Id) and the other analogous compounds are a relatively small yield, the need to use large volumes and the labile character of the oxidizing agent applied. The process according to the present invention does not exhibit these drawbacks. The yields are higher, the oxidizing agent is readily obtained, formed from simple chemicals during the reaction and the need for the reaction volume is essentially lower than in the case of the known processes. From the partially novel compounds of the present invention, β-amino-1,2-dihydroxy-2-imino-4-piperidinopyrimidine (linoxidyl) can be prepared which has antihypertensive drugs in essentially greater yield than using the known methods. The conversion of the compounds to be prepared by the process of the present invention into Xinoxydil is carried out by reacting with piperidine and hydrolyzing the compound thus obtained. of the process according to the operative method described in co-deposited patent application Ser.

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with the present request. While the best known process according to Hungarian Patent 177 601 has only a yield of about 20-21 if the process according to the present invention is employed, it is possible to obtain the product I. Tinoxidil in a total yield of about of 49-50 f in relation to the starting material of the general formula (II). In connection with the processes known in the prior art, this may be regarded as an essential and unexpected improvement. A possible reason for the higher yields that can be achieved by the process according to the present invention is that the oxidizing agent simultaneously forms protecting acyl groups of the sensitive substituents of the compound to be produced. This phenomenon protects the molecules against excessive oxidation.

Further details of the present invention are explained by way of the following non-limiting Examples.

Example 1

Preparation of 2-acetamido-4-chloro-6-amino-pyrimidine-1-oxide and Î ± -amino-11-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine (0.035 mole) of 2,6-diamino-4-chloroerythyridine in 70 milliliters of anhydrous ethyl alcohol was added. 7 milliliters of 70% aqueous hydrogen peroxide and 14 milliliters of acetic anhydride are added dropwise while stirring at 4 ° C for 0.5 hour. The reaction mixture was stirred at 0 ° C for a further two hours, then cooled and the flocculent crystals were separated, washed with ethanol and dried. There are thus obtained 2.67 grams (38%) of 2-acetamido-4-chloro-6-amino-pyrimidine-1-oxide. GOOD ORIGINAL 'ϋ

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Infrared spectrum (cm " 1) (ICBr): 3400, 1690, 1540, 1510.

The water is evaporated in vacuo, 20 milliliters of water is added to the residue and the mixture is stored in a refrigerator overnight. The crystals are filtered, washed with water and dried. 1.7 grams (24%) of 6-amino-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine is thus obtained.

Infrared spectrum (cm-1) (KIBr): 3420, 1730, 1650, 1570, 1550,

Ultraviolet spectrum (nm) (StOH): 247, 275, 325.

Nuclear magnetic resonance spectrum (CDCl3 + TFA-d) & 2 AI (s, 3H), 7.98 (s, 1H).

Example 2

Preparation of 6-amino-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine

5 grams (0.035 mol) of 2,5-diamino-4-chloro-pyrimidine are dropped into 50 milliliters of anhydrous tetrahydrofuran. While stirring, 7 milliliters of a 70% aqueous solution of hydrogen peroxide and 15 milliliters of acetic anhydride are added dropwise at a temperature of 40 ° C for half an hour. The reaction mixture is stirred at 5Â ° C for a further two hours. After the tetrahydrofuran is evaporated, 50 milliliters of water are added to the residue and then kept in a refrigerator overnight. So 4.00 grams (57%) of the desired compound is separated. Further 0.77 grams (11æF) of this compound is obtained by filtering the product obtained in a second separation.

The infrared, ultraviolet and nuclear magnetic resonance spectra correspond to those of the i-

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obtained in the previous example.

Example 3

Preparation of 6-acetamido-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine and 6-amino-1,2-dihydro-1-acetoxy-3-imino 2-chloro-pyrimidine 170 ml of tert -butanol are mixed with 17.28 g (0.12 mole) of 2,2-diamino-4-chloro-pyrimidine while stirring at 50 ° C. 0; then 17 ml of 30% aqueous solution of hydrogen peroxide is added. To the solution thus obtained is added dropwise 35 ml of acetic anhydride at a temperature of 55 to 60 ° C for one hour. The reaction mixture is stirred at this temperature for an additional hour, then cooled to 152 ° C and allowed to stand for two hours. The crystals which separated were washed, washed twice with 20 ml of water each time and twice with 20 ml of ethanol each time and then dried.

There is thus obtained 15 g (52%) of the desired product consisting of 30 of the above diacetyl compound and 70% of the above-mentioned monoacyl compound. 5 g of sodium peroxide dissolved in 12 ml of water and then 17 ml of mother liquor are added and the mixture is stirred at room temperature for 0.5 hour. Then it is distilled in vacuo to half its volume and neutralized with a 40% aqueous sodium hydroxide solution until pK 6. The reaction mixture is allowed to stand in the refrigerator overnight, washed, washed three times with 20 ml of water each time and dried. In this manner, 2.4 g (10% yield) of the desired monoacyl compound is obtained.

The data of the infrared, ultraviolet and nuclear magnetic resonance spectra of

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/ £ t 1 " no-acetyl compounds correspond to those indicated in Example 1. Characteristics of the desired diacetyl compound:

Infrared spectrum (cm-1) (KBr): 1720, 1590, 1500, 1570.

Example 4

Preparation of 6-Acetamido-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine 3.2 g (0.02 mole) of 6-amino- 1,2-dihydro-1-hydroxy-2-imino-4-chloro-pyrimidine with 30 ml of acetic anhydride for one hour and then 200 ml of ether are added to the reaction mixture. The formed white crystals are filtered, washed with ether and dried.

There is thus obtained 3.9 g (80%) of the desired compound. The physical parameters of the product correspond to those mentioned in Example 3.

Example 5

Preparation of 6-amino-1,2-dihydro-1-hydroxy-2-imino-1-chloro-pyrimidine

1.5 g (10 mmol) of 2,6-diamino-4-chloro-pyrimidine are dissolved in 20 ml of anhydrous tetrahydrofuran. Under stirring and heating to reflux a mixture of 10 ml of acetic acid and 2 ml of a 70% aqueous solution of hydrogen peroxide is added. The reaction mixture is boiled, evaporated in vacuo to a third of its volume and a solution of sodium hydroxide at 40 DEG C.

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to the residue until a pH of 8 is reached. The mixture is allowed to sit in a refrigerator overnight. The crystals are washed, washed with water and dried. Yielding in this way 1.0 g (63%) of the desired compound is obtained.

Infrared spectrum (cm-1) (KBr): 3400, 3310, 1550, 1630.

Ultraviolet spectrum (nm) (IleOH) Î': 230, 294.

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Example 6

Preparation of 6-Aminino-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine and 5-acetanido-1,2-dihydro-1-acetoxy- 4-chloro-pyrimidine

In 150 ml of water, 2.32 g (0.03 mol) of 2,2-diamino-4-chloro-pyrimidine and 9.6 ml of a 30% aqueous solution are dissolved at 60 ° C. of hydrogen peroxide. While mixing, 18 ml of acetic anhydride is dropped dropwise over the solution at 55 to 60 ° C for 40 minutes. The reaction mixture is stirred at this temperature for an additional 1.5 hours and then cooled to 15 ° C. After two hours, the precipitate is filtered, washed with water and dried.

1.45 g (20%) of o-acetamido-1,2-dihydro-1-acyloxy-2-imino-4-chloro-pyrimidine are thus obtained.

The mother liquor is eutralized to pH 5 with an aqueous solution of sediment hydroxide at 40 > and allowed to stand in a refrigerator for a daughter-in-law. The crystals thus formed are washed, washed with water and dried. In this manner 1.2 g (20%) of δ-amino-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine are obtained. p, original AD

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(i.e.

The physical parameters of the products obtained are the same as those of the corresponding products of Examples 1 and 3.

Example 7

Preparation of 6-acetamido-1,2-dihydro-1-acetoxy-2-n-4-p-toluenesulfonyloxy-pyrimidine

84 g (0.3 mol) of 2,6-diamino-4-tolyloxypyrimidine are added to 1200 ml of anhydrous tetrahydrofuran. At room temperature 40 ml of a 70% aqueous hydrogen peroxide solution are added dropwise while stirring, whereupon the material dissolves. While stirring, 200 ml of acetic anhydride are added to the α-tosyl solution for one hour. After the mixture is added, it is stirred at 0Â ° C for a further two hours. The solvent is then evaporated to the residue in vacuo " and the residue is allowed to stand in a freezer overnight. The material which separated was washed, washed with tetrahydrofuran and dried. Proceeding in this way, 77 g (68%) of the desired compound are obtained.

Melting point: 19 ° to 200 ° C

Infrared spectrum (cm-1) (EBr): 1720, 169C 1600, 1580, 1500.

Ultraviolet (nm) spectrum (EtOH) νmax: 252, 285, 321. Nuclear magnetic resonance spectrum (Î »C 17 17 + + TEA-d) Î': 2.38 (s, 3H); 2.48 (s, 3H); 2.55 (s, 3H); 7.42 (s, 1H); 7.46 and 7.98 (dd, 4H).

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Example 8

Preparation of 6-amino-1,2-dihydro-1-acetoxy-2-

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-imino-4-.beta.-toluenesulphonyloxy-pyrimidine

2,6-Diamino-4-tosyloxy-pyrimidine (2.00 g, 0.001 mole) is added to 70 ml of ethanol. To the suspension thus obtained, 5 ml of an aqueous solution of hydrogen peroxide at 70 ° C. at 4 ° C. and then 3 ml of acetic anhydride are added. The suspension is homogenized by heating at 50 ° C and the solution becomes opalescent upon standing. By conroding the reaction by thin layer chromatography, the reaction is complete and the desired compound is accompanied by some diacetyl compound. Filtration of the reaction mixture removes 0.35 g of a solid material. If the ethyl alcohol is distilled off and if the residue is allowed to stand in a refrigerator, product separation can not be observed. Decanting the water and dissolving the residue in ethanol affords a crystalline product. Proceeding in this manner, 1.95 g (54%) of the desired compound is obtained.

Infrared spectrum (cm-1) (14Br): 3440, 1720, 1560, 1650, 1600.

Ultraviolet spectrum (nm) (EtC-H) νmax: 244, 260, sh, 322.

 € ƒâ € ƒâ € ƒNH Nuclear Magnetic Resonance Spectrum (CDClâ,ƒ + TFA-d) Î': 2.44 (s, 3H), 5.50 (s, 3H), 7.53 (s, 8.00 (dd, 4H).

Example 9

Preparation of 5-amino-1,2-dihydro-1-proionionyl-2-imino-4-chloro-pyrimidine at 4 ° C, 8.54 g (8.55 g, o-dianino-4-chloro-pyrimidine in the mixture consisting of

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of an aqueous solution of hydrogen peroxide at 70 ° C, then the temperature is raised to 50 ° C, 18 ml of propionic acid are added dropwise to the mixture the reaction is stirred in such a way that the temperature is kept at 50 ± 2 ° C. The reaction mixture is then stirred at this temperature for two hours and air is refluxed to room temperature. After two hours, the separated product is filtered, washed with ethanol and then dried.

6.34 g (49%) of 6-amino-1,2-dihydro-1-propionyloxy-2-imino-4-chloro-pyrimidine are obtained. After being allowed to stand for a further night, another 0.6 g (4%) of the desired product is separated from the mother liquor.

Infrared spectrometer (nmr) (XBr): 1750 (C = 0) Protonic nuclear magnetic resonance spectrum (D2 SO-d6): 1.16 (t, 3H, CH3), 2.55 ( Q, 2H, CH2), 7.60 (s, 1H, C5 -H), 7.52 (broad, 1H, NH =).

Example 10

Preparation of 5-amino-1,2-dihydro-1-acetoxy-2-amino-4-chloropyrimidine and 6-acetamido-1,2-dihydro-1-acetoxy-2-imino -4-chloro-pyrimidine

Dissolve 2,6-diamino-4-chloro-pyrimidine (4.32 g, 0.03 mole) in the mixture consisting of 43 ml of ethyl acetate and 3 ml of a 70% aqueous solution of hydrogen. At a temperature in the range of 55-50Â ° C, 12 ml of acetic anhydride is added over one and a half hours. The reaction mixture is stirred at this temperature for another half hour, then cooled and allowed to stand in a refrigerator overnight. The crystals formed are collected by filtration, washed with ethyl acetate and then dried,

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r fall. 1.80 g (25 μl of 5-acetamido-1,2-dihydro-1-acetoxy-2-imino-4-chloro-piperidine is thus obtained.

The mother liquor containing ethyl acetate is extracted with 40 ml of 10% aqueous sodium hydroxide solution and then twice with 40 ml of water each time. The ethyl acetate-containing fraction is evaporated to half volume, the precipitate is filtered and washed with water. 1.25 g (20%) of 5-amino-1,2-dihydro-1-acetoxy-2-imino-4-chloro-pyrimidine are thus obtained. From the combined alkaline and aqueous phases, a further 0.5 g (10%) of the desired product is isolated on the following day.

Example 11

Preparation of 6-acetamido-1-acetoxy-2-imino-4-methylsulfonyloxy-1,2-dihydro-pyrimidine

45.5 g (0.15 mole) of 2,4-diamino-4-methylenesulfonyloxy-omyrimidine are suspended in 500 ml of tetrahydrofuran in a 1000 ml round bottom flask equipped with a blender, reflux condenser and a charge funnel. While stirring, 20 ml (27.2 g) of an aqueous solution of 70% strength hydrogen peroxide are added, after which the solid material dissolves. The solution is then heated in an oil bath and IC50 ml (108.1 g, 1.05 mole) of acetic anhydride at 40 ° C is added dropwise in such a manner that the temperature of the mixture do not exceed 0 ° C. The reaction mixture is then stirred at 50 ° C for another hour. The tetrahydrofuran is then evaporated in vacuo at 5 ° C and the residue is cooled in a refrigerator. The material is separated and washed with tetrahydrofuran. ! • Drying out, we get 34, δ rc: · (53.5 Γ *) d

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Claims (3)

21 21 w 5-Acetaride-1-acetoxy-2-imino-4-mesitylenesulfonyloxy-1-pyrimidine with the white crystalline material. Melting point: 162-153 ° C (decomposition). The product is chromatographically uniform. Elemental analysis for the formula: Calculated: C = 49.99%, H = 4.94%, N = 13.72%; S = 7.85; Found: C = 49.94. ** - 4.94 (m, 1), 13.95 (s, 7.76%). Infrared spectroscopy (cm-1) (ICBr): 3400, 1720, 1595, 1580, 1200, 1175, 1050. Nuclear magnetic resonance (Dβâ,ƒ) ν: 2.10; 2.25; 2.35 (3H, s); 2.6 (SH, 2, 21.6'-Cl-j) ϊ s-5-)); 6.85 (2H, s, 3.55 (2H, s). KlIVIlITy ^ CES 12- Process for the preparation of novel cis- (Ia), s / oa (I) and / or (Ic) derivatives 1 22 i i in which R3 represents a C1-4 alkyl group. 1 to 5 carbon atoms or an aryl group optionally substituted by halogen; and X represents a chlorine or bromine atom and an arylsulfonyloxy group optionally having one or more substituents characterized in that: p, < RTI ID = 0.0 > 2. A 2,6-diaryloxypyrimidine derivative of general formula (II) > in which X has the same meanings as indicated above, with an acid anhydride of the general formula (III) (III) in which R has the same meanings as mentioned above, in the presence of water and hydrogen peroxide; the pure product mixture of the general formulas (Ia), (Ib), (Ic) and (Id), respectively, are separated. 22. A process according to claim 1, wherein 2 to 20 moles of water is used per mole of the compound of the general formula (II), wherein X is as defined in claim 1. August, 1937, the Official Entity of Industrial Property, López de Emilio de Silvo Carvalho * * * * * * * * * Raa Castilho. 2Ci 2. " eSq. lelef. 65 13 3U - LLír.OA ORIGINAL BAD