DD160418A1 - PROCESS FOR PREPARING 17ALPHA SUBSTITUTED GONA-4,9-DIENES - Google Patents

Abstract

The production of 17 alpha-substituted gona-4,9-dienes of the general formula I which are suitable for the treatment of endocrinopathies and for the control of fertility due to their hormonal and anti-hormonal effects, in particular their very strong progestagenic activity, is described. The new process, which avoids significant disadvantages of the known method, is based on 3-methoxy-13 Betta-R-gona-2,5 (10) -diene-17 Betta-clen, which after conversion into the dimethyl ketals with pyridinium chlorochromate in 17 Be oxidized to ketone. These are converted into the 17 Betta spirooxiranes which, by cleavage with nucleophilic reagents and subsequent hydrolysis, give 17 alpha-substituted 17 Betta-hydroxy-13 Betta-R-gon-5 (10) -en-3-ones, which are obtained by bromination / Dehydrobromination be transferred to the compounds I.

Description

213049

Prof. Dr. Kurt Ponsold

Dr. Bernd Menzeribach!

Dr. Michael Huebner j

Dr. Michael Oettel

Dr. Kurt Baraikol-Oettler j

Chem-Ing. Gerhard Teichmüller

Title of Invention j

Process for the preparation of 17Λ-substituted Gona-4 _f ^

Field of application of the invention

The invention relates to a process for the preparation of 17 £ substituted gona-4-, 9-serve the general formula Γ

in the R represents an alkyl radical having 1 to 3 carbon atoms

and X is Cl, Br, P, Nw, SCIT, CN, OH, OR (R a alkyl), |

HH ₂ , a substituted amino group or a nitrogen radical i

heterocycle, which due to their valuable bio- j

logical properties, especially their hormonal and i

antihormonal effects advantageous in pharmaceutical applications;

preparations for the treatment of endocrinopathies and reproductive medicine

production control in humans and agricultural use ''

animals can be used. j

Characteristic of the known technical solutions

Which can be prepared by the present process compounds: are known and have been at the same time with a process for their \ production for the first time in DD-PS 193 348 discloses · j This process starts from 3-methoxy-13ß-R-gona-2,5 (10 ) -dien-17ß «-spiro **! 1,2-oxiranes II from the following scheme into the compounds

213TfW

fertilize I to be transferred:

CHA

The spirooxiranes II which are used as starting materials in this process are prepared in a manner known per se from the totally synthetically readily available 3-methoxy-13β-R-gona-2,5 ( ^/ 10) -diene.-17β-olene V by Oppenauer oxidation and following XSmBBtzvv ?. The thus obtained 17-keto compounds VI with dimethylsulfonium methylide according to DD-PS 80 023 made ·

* 213 (H9

This procedure adheres to various disadvantages which have a particularly unfavorable effect when the process is carried out on an industrial scale. The compounds II, III, V and VI "contain in the ring A an unsaturated Bnoläthergruppierung, which is not only extremely acid-sensitive, but also very easily oxidizable, to produce products with an aromatic A ring * It is therefore forced, in all reactions with these compounds, as well as during their storage »Special precautions to be taken to minimize the formation of undesirable hydrolysis and oxidation products · Often it is necessary to carry out additional purification operations in order to reduce the content of by-products before further reaction ·

Another disadvantage of the process is the fact that for the oxidation of V to VI the generally customary in the art chromic acid oaydation due to the instability of the mentioned Enolethergruppierung not considered and therefore an Oppenauer oxidation (ref. S R Gros, Z Chem · 8, 108 (1968)) · However, this requires a considerable amount of equipment and equipment z. In addition, the work required here at elevated temperature and the steam distillation required for several hours after the reaction has occurred lead to a considerable consumption of energy.

In addition, the aluminum alkanolate used in the Oppenauer oxidation catalyzes the aldol condensation of the excess cyclohexanones to difficult to remove by-products (Lit.: J. Amer Chem. Soc. 62, 3401 (194O) ₉ Chem. Ber. 21t 384 (194-2))

Object of the invention

The aim of the invention is the production of hormones or antihormones acting 174-substituted gona-4,9-serve the above-mentioned general formula I for a new, technological

213049

and economically favorable procedures.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of 17 ^ -substituted Gona-4-, ° / -dienen the general formula I, the main disadvantages of the known procedure, in particular the performance of Oppex »peroxidation and avoids the work with the very oxidation-sensitive intermediates with an enol ether moiety in the ring Δ.

According to the invention this object is achieved by the fact that 3-Metho3jy ^ 13ß-R ^<- gona ~ _2> 5 (10) -diene-17ß- "ole V in known manner by treatment with p- methanol in the presence of catalytic amounts of Toluenesulfonic acid in the dimethyl ketals VH and then this in an organic solvent, preferably chloroform or methylene chloride with pyridinium dinium chlorochromate in the presence of a suitable buffer, preferably an alkali metal acetate at temperatures between 0 and - 20 ⁰ C to the corresponding 3,3-dimethoxy 13ß-R-goni-5 (10) - · en- * 17 * »ones VIII oxidized. These are dissolved after isolation and Reindarstöllimg in dimethylformamide and transferred at room temperature with dimethylsulfonium in the 17ß-spiro-1,2-OxLrane IZ, which then with nuoleophile agents under neutral or alkaline conditions in organic solvents at normal or elevated temperature to 17o - - <JH ₂ X-substituted-3,3-dimethoxy-13β-R-gon-5 (10) -o-17-ols. By treatment with dilute acids in aqueous-organic solvents they become the appropriate 17 <X. Substituted 17β - * [ydroxy-13R-gon-5 (10) -en-3-ones] IV hydrolyzes1 the known per se by bromination and dehydrobromination 1a into the abovementioned 17-substituted gonas. dienes of general formula I

The individual Reaktionsssbbitte the process of the invention are further illustrated by the following scheme:

213049

OH

Vif /.

Q-CH ₃ .

OH

..4 CffJ.Λ

Bas inventive method is advantageously carried out as follows:

The starting materials used for the process according to the invention 3-methoxy-13ß «R-gona-2 _l 5 (10) -diene-17ß- ^li Ole V belong to the prior art and can according to known methods by treatment with methanol in the presence of p-folulfsulfonic acid to the dimethylketals VII

This is dissolved in a halogenated hydrocarbon! preferably in chloroform or methylene chloride and this solution is slowly added dropwise to a cooled to temperatures between 0 and -20 ⁰ C suspension of Pyridiniu ^ chlorochromate in the same solvent to which a suitable buffer substance, preferably sodium acetate or bicarbonate was added · The oxidizing agent is in excess from about 1.2 to 2.0 molar

213049

applies. The suspension is roughened in the temperature range mentioned until it is no longer possible to detect starting material by thin-layer chromatography, which takes up to 6 hours. The work-up is generally carried out by so that it drips into the ether Reaktionsmischttng, filtered off the precipitate by concentration of the filtrate, the 3,3-dimethoxy 13ß-R ~ gon ~ 5 (10) -en-17 wins ^<~ one VIIX However, it is also possible to bind excess oxidizing agent and reduced chromic acid complex by addition of silica gel and, after filtration, to recover the 17-keyones VIIr by concentration as indicated above. The conversion of the thus obtained 17-ketones VIII in the Spirooxlrane IX is carried out with excess dimethyl sulfoniummethylid in dimethylformamide, preferably proceeding so as to add to a suspension of dimethylsulfonium iodide and steroid ketone in this solvent potassium tert-butylate at room temperature. After completion of the addition, stirring is continued for a short time, then the mixture is added to ice water and extracted the oxirane formed with a suitable solvent, preferably methylene chloride or ether. The crude product obtained after evaporation of the solvent is used in the next stage without further purification.

Suitable nucleophilic agents for the cleavage of the spiro-ro- sers IX to the 17oC-CHgX-substituted 3,3-dimethoxy-gon-5 (10) -en-17β-ols include: sodium azide, alkali cyanides, alkali alcoholates, alkali metal hydroxides, The choice of solvent depends on the solubility of the spirooxirane used and the nucleophilic agent used and can be varied within a wide range, such as ethers, dimethyl sulfoxide, ethylene glycol, dimethylformamide and simple alcohols, optionally with the addition of small amounts of water The temperature at which the reaction is carried out can be varied within wide limits and is generally in the range between 20 and 100 ^° C.

The hydrolysis of the thus obtained 17 "i-CHpX-substituted ketals X is generally carried out so that the compounds in a

213049

water-miscible solvent, in particular methanol, ethanol, dioxane or acetone, dissolves or suspends and adds an aqueous solution of an acid. The acids used are above all organic carboxylic acids such as acetic acid, oxalic acid, citric acid or succinic acid, but also dilute mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid or perchloric acid suitable. The isolation and purification of the thus obtained 17 "t -CH ^ -substituted 17β-hydroxy-gon-5 (10) -en-3-one IV is carried out according to the methods customary in chemistry. Their transfer to type I compounds is state of the art.

The process of the present invention is based on the surprising discovery that the readily available 3 '' - dimethoxy-13β-R-gon-5 (10) -en-17β-ols are rapidly and uniformly oxidized in the 17-position by pyridinium chlorochromate »without this provided that certain reaction conditions are met, neither additional oxidation of the A-ring to aromatic products nor hydrolysis of the ketal moiety occurs.

This makes it possible to provide a new process for the preparation of 17cC-substituted gona-4,9-serve the general formula Γ, which has significant advantages over the prior art · This concerns in particular the elimination of the previously carried out apparatus and energy consuming Oppenauer -Oxydation, in spite of careful work, the results in terms of yield and purity are not always reproducible. Furthermore, working with intermediates which have a very hydrolysis- and oxidation-sensitive unsaturated 3-enol ether group in ring A is avoided by the process according to the invention.

The following examples are intended to explain the process according to the invention in more detail without restricting it in any way:

213049

example 1

17 (£ -cyanomethyl-β-hydroxy-i 3β-methyl-gona-4,9 (10) -diene> 3 -one

A) 28.8 g (0.1 mol) of 3-metho: ^ 13ß-methyl-gona ~ 2 _t 5 (10) -diene-17ß- oil ornaments suspended in 500 ml of abs · methanol and 100 mg of p-toluenesulfonic acid added. The mixture is stirred at room temperature until a clear solution has formed and the reaction mixture is then mixed with bicarbonate solution. The precipitated crude product is extracted with ether and the ethereal solution is washed thoroughly with water and dried overnight. Distillation gives a virtually colorless crude product, which is recrystallized from ether / n-hexane. This gives 25 »0 g (79% d. Th ·) 3> 3-dimethoxy-13ß-methyl-gon-5 -ene (10) * 17-ol from the Pp. 110 to 112 ⁰ G, [ck] + ψ 130 ⁰ ·

B) 11.5 g (0.04 mol) of the product shown under A) are dissolved in 50 ml of methylene chloride and this solution within about 45 min. To a stirred and cooled to ca - * 15 ⁰ C suspension of 17 "2 g (0.08 mol) of pyridinium chlorochromate and 7» 0 g of anhydrous sodium acetate in I50 ml of methylene chloride added dropwise After the addition the mixture is stirred for about 4 to 6 hours further, and then dropwise of ether, maintaining the temperature between -3 ⁰ O and -10 ⁰ C. is maintained · After the mixture has warmed to about room temperature, the resulting Niedersohlag is filtered off and thoroughly washed again with ether. After the solvent has been distilled off, 10.3 g (90 % of theory ) of 3 ~ 3 ~ D ~ ^ hoxy * · 13β-methyl-gon-5 (1O> -en-7-one · recrystallization from methanol gives a product of Pp. 1T4 to 116 ° 0, [oCj ψ + 209 °.

0) 32, Og (0 _r 1 mol) of the 3,3-dimethoxy-13β-methyl-gon-5 (10) -o-17-one obtained in the preceding step and 41.0 g (0.2 mol) Trimethylsulfoniumjodid be suspended in 200 ml of dimethylformamide. At room temperature, 45.0 (0.4 mol) of potassium tert-butoxide are added with stirring over about 15 to 20 minutes. The temperature of the Rdaktionslösung is maintained at 20 to 25 ⁰ O. It is then allowed to continue stirring for 20 minutes, then pour the

213049

The resulting spirooxirane is recovered by extraction with ether or methylene chloride. Recrystallization from methanol gives pure 3,3-dimethoxy-13β-methyl-gon-5 (10) -o-17β-spiro-r, 2-oxirane, m.p. . 81 to 83 ⁰ C, [£] ψ + 116 °, yield: 29 to 32 g (90 to 100% d · Th.) ·

D) 40.0 g of JO (12 mol) of 3-dimethoxy-13β-methyl-6-one-5 (10) -11 -17-spiro-1,2-o-3-one are dissolved in 300 ml of ethanol and 30.0 g The mixture is stirred for 2 days at room temperature and the course of the reaction is monitored by thin-layer chromatography. If no unreacted starting material is detectable, the reaction mixture is poured into sis water and the resulting 3,3-7hraethosyl17. Ε-cyanomethyl-13β-methyl-gon-5 (10) -en-i7β-ol recovered by extraction with methylene chloride or ether. · After evaporation of the washed and dried solvent, a pale yellowish oil is obtained. Yield 39 to 4-3 g (90 to 100 % of theory ), which is used without further purification in the next stage.

E) 12.0 g (Oj033 mol) of 3,3-Dimethos3r-17 <^ - cyanomethyl- »13β-methylgon 5 (10) -en-17ß ~ oil from the previous stage are stirred at 30 to 35 ⁰ O bath temperature dissolved in 200 ml of 80% acetone. Then, 8 ml of acetonic sulfuric acid prepared by mixing 1 ml of concentrated sulfuric acid, 3 ml of water and 80 ml of 80% acetone are added to the solution. At constant bath temperature, the mixture is stirred for approximately 30 minutes, then cooled in an ice bath and added dropwise with continuous stirring 800 ml of dilute sodium bicarbonate solution. The resulting precipitate is filtered off with suction, washed several times with distilled water and dried. The crude yield is 9.6 to 10.0 g (9Λ to 97 % d ·Th *). Recrystallization from ethyl acetate gives 17C-cyanomethyl-17β-hydroxy-13β-methyl-gon-5 (10) *-en-3 -one, mp. 172 to 175 ⁰ C, Λ * J ψ + 161 °, yield 7.5 to 8.0 g (73 to 78% d. Th.) ·

P) 31.3 _: e (0 * 1 mol) of the product obtained in the above step

213 (K9

are dissolved in 300 ml of pyridine, cooled to -10 ⁰ C and slowly added dropwise to a solution of 38 _t O g pyridinium perbromide in 300 ml Fyrtdin under vigorous stirring · It is then stirred for 30 min. At 0 to -5 ⁰ G, then 4 hours at room temperature. The mixture is stirred at the end of this tent in 3 1 iced 2N HCl or HgSO ^ stirred, the product precipitates in colorless, finely crystalline form »It is filtered off with suction, washed thoroughly with water and still moist with methanol to methanol · There are obtained 15.0 g (48 % d · Th ·)

g 3- * on from Pp * 209 to 214 ⁰ O, [<A] ψ -306 °

Example 2

17oC -asidomethyl-17β-hydroxy-13β-ethyl-4,9 (10) -dien-3-one

A) 5T2 g COfOIJ mol) 3t>Dimethoxyw> i3ß _"m 0thyl-gon-5 (1O) -EJ * - * 17ß" spiro-1,2-ortran that entspreehend the preceding Example 1 (A - C) were prepared , are suspended in 200 ml of ethylene glycol and heated after addition of 5 »0 g of sodium umazid 6 hours with constant stirring on the boiling water bath. Then the batch is cooled to room temperature and poured it into 1.5 1 of ice water · The precipitated 3,3-Dimetho3cy-17 _<JC "azidomethyl-13ß-methyl-gon-5 (1O) ~ ene" 1? Ss ol is obtained by extraction with ether or methylene chloride · After evaporation of the solvent left a slightly yellowish, viscous 01, which is used in the next step without further purification "yield 3.4 g (61% d- Th.) *

B) Dissolve 3fO g (0.008 mol) of the product obtained in the previous step in 100 ml of 80% acetone and add 2 ml of 5% aqueous acetonic sulfuric acid. The mixture is stirred at 30 ⁰ C for about 30 minutes until the DO no more starting product detect is · The formed 3-Ke ton is precipitated by the addition of bicarbonate solution, filtered off with suction and washed thoroughly with water, ümkristallisation from isopropyl ether gives pure 17oC '-azidomethyl-17.beta. -hydro3>-13β-methyl-goi> -5 (i0) -en-3-one from Pp · 104 to

213049

106 ⁰ C, f <* J ψ + 119 ° »Expander 2.1 g (80 % of theory ) ♦

β) 1> 32 g (0.004 BIoI) of the compound prepared in the preceding step are dissolved in 10 ml of pyridine, cooled to -5 to -10 ⁰ C and treated with a solution of 1.5 g Pyridiniumperbromld in 12 ml of pyridine. The mixture is first stirred for 30 minutes at this temperature, then for 2 to 4 hours at tree temperature and finally poured into the approach in 100 ml of 2 η hydrochloric acid. The precipitated crude product is filtered off with suction, washed thoroughly with water and, while still wet, recrystallized from methanol... O-C-azido-methyl-1,3-hydroxy-1,3-methyl-gona-4,9 (10) -diene-3-one colorless blams of Fp · 204 to 206 ⁰ C, f <* J | ⁵ -250 ° (ca 0.5; _CHCl3), yield: 0.48 g (30% of theory.). *

Example 3

A) 15 »1 g (0.05 mol) of 3-methoxy-13ß ^ ethyl-gona ^ 2 _f 5 (10) -diene-I7B-0I are abs in 500 ml. Suspended methanol and added to 100 mg p * Toluolßulfonsäure added. The mixture is stirred at room temperature until a clear solution has formed, and then the reaction mixture is admixed with bicarbonate solution. The colorless, flaky crude product is filtered off with suction, washed thoroughly with water and dried. Yield 16.0 g (95 % d * Th.). It is used without further purification in the next stage *

B) 5.7 β (0.02 mol) of the product obtained in the preceding stage are dissolved in 40 ml methylene chloride and cooled to ⁰ to about -15 C, vigorously stirred suspension of 8.6 g (0.04 mol) Pyridiniumohlorochromat and 4.0 g of anhydrous Natrlumacetat added dropwise in 100 ml of methylene chloride. After completion of the addition, stirring is continued for about 6 hours and then added ether, the temperature between -O ⁰ C and -10 ⁰ C is maintained. After the reaction has warmed to room temperature, the resulting precipitate is filtered off and washed thoroughly with ether. Distillation of the solvent gives 5.2 g (78 % of theory ) of a colorless, slowly crystallizing oil. Recrystallization from hexane gives needles of mp 83 ° to 87 ° σ, Cd] ψ

2130U

+ 163 ° (cs 0.5, GHCl ₃ ), yield: 4.5 g (69 % of theory) .

C) 3 '3 g (0.01 MoI) of obtained in the prefixing stage 3> 3-dimethoxy ^ 13ß ~ € thyl ~ gon-5 (10) -en-17-one and 4 _t 1 g (0.02 Mol) trimethylsulfonium;) or are suspended in 200 ml of dimethylformamide. Stirring at room temperature ^ t? g (0.04 mol) of potassium tert-butoxide added. The mixture is then allowed to stir for a further 20 minutes, then the mixture is poured into ice-water and the spiroepoxld formed is extracted by extraction with methylene chloride. After the usual work-up of the extracts, a colorless oil is obtained , which can be used without further purification in the next stage. Yield: 3.0 g (90 % of theory ).

D) 3 »5 g (0.01 mol) of 3,> Dimethoxy-13B-ethyl-gon-5 (10) -en-17ßspiro ~ 1,2-oxirane from the previous stage are suspended in 100 ml of ethylene glycol and after addition The mixture is then heated to room temperature and poured into about 1 1 of ice water · The precipitated. 3, 3 "dimetho: xy-17" 1-azidomethyl-13β-ethyl ** gono-5 (10) -o-17β-ol is obtained by extraction with methylene chloride. After evaporation of the solvent an almost colorless, slowly crystallizing one remains oil, which is used without further purification in the next stage. Yield: 3.0 g (76.5 % of theory ) ♦

E) 3 * 0 g (0 * 0075 mol) of the crude 3,3-dimethoxy-17-azidomethyl-13β-ethyl <-gon ·· 5 (10) -175β-ol obtained in the preceding step are dissolved in Dissolved 100 ml of 80% acetone acetone and 2 ml of a 5% aqueous ace tonic sulfuric acid ztigefügt. The mixture is stirred at room temperature until starting material is no longer detectable in the thin-layer chromatogram, which takes about 30 to 120 minutes. The mixture is stirred in dilute sodium bicarbonate solution sucks the colorless, flaky crude product and washed thoroughly with water. Recrystallization from acetonitrile gives 17c-azidomethyl-.beta.-yydroxy-.beta.-ethyl.

213049

gon-5 (10) -en-3-one in the form of colorless prisms of pp. 120 to 122 ⁰ C, i <k1 ψ + 115 °. Yield: 1.9 g (73 % of theory ).

3 | g 1 (Q _t OO9 mol) of 6-azidomethyl "-17ß-hydrox7 ** 13ß ^ thyl-gon-5 (10) -ene""3-one" grounded in 50 ml of pyridine dissolved the above-described 17 ^ and cooled to 0 ⁰ C. To this solution is slowly added dropwise 1.58 g of bromine, which is dissolved in 10 ml of methanol. The mixture is stirred at 0 ^° C. for 30 minutes, then at room temperature for 3 to 4 hours, and finally the solution is poured into about 1000 ml of ice-cold 2N-saline The colorless, flaky crude product is filtered off with suction, washed thoroughly with water and dried dissolve it in a little chloroform in the boiling heat, filtered and, after cooling, add to the same or double the amount of methanol. 17 C-Azidomethyl-17β-hydroxy-13β-ethyl-gona-4,9 (10) diene-3 - ^ n kristallisieaet in small prisms, mp 223-226 ⁰ C, [<* »] ψ • 224 ° (c = 0.5 Fyridin s) $ yield 2.26 g (73% of theory.). ·..

Claims (3)

213049 Invention Inquiry 1 · Process for the preparation of 17dC-substituted gona-4,9-serve of the general formula I. in the H represents an alkyl radical having 1 to 3 carbon atoms and X is Cl, Br, F, N _3, SCN, CN, OH ^ OR ^# (B * - = alkyl), NH _2, a substituted amino group or a nitrogen-containing heterocycle , characterized in that 3-Metho33r-13ß-R-gona-2,5 (10) -diene-17ß-ole in a conventional manner in the 3,3-dimethyl ketals, these in a suitable organic solvent in the presence of a buffer substance with pyridinium chlorochromate to the 3,3-Dimethoa be ~ 13ß ~ R-gon · * 5 (10) -en-17-ones oxidized, these converted with dimethylsulfonium methylide in the 17ß-Spiro-1,2-OAD.rane , This reacts with nucleophilic agents in a suitable organic solvent at normal or elevated temperature to the 17 ^ -substituted 3 »3-dimethoxy ~ 13ß ** H-gon-5 (10) -en-17ß-ols, this then by treatment with dilute acids in aqueous-organic solvents to the 17 <*. Substituted 17ß-Hydrozy-13ß-E-gon-5 (10) -en-3-ones hydrolyzed and these in a conventional manner by bromination and dehydrobromination in the 17 d. substituted gona-4,9-dienes of general formula I 2 · Process for the Preparation of 17-Substituted Gona-4.9 * * characterized in that the oxidation of the 3i-dimethyl-13β-R-gon-5 (10) -en-17-ols with pyridinium chlorochromate in a suitable organic solvent, preferably chloroform or methylene chloride in the presence of a buffer substance, preferably sodium acetate or sodium bicarbonate, at temperatures between ⁰ ° C. and ** ² ° C. 213049 3 · Process for the preparation of substituted gona-4,9-, characterized in that the reaction of the 3i-3-dimethoxy-13β-R-gon-5 (10) -en-17 -> ne to the Enclosing 17ß- »spiroepoxides with Dimethylsulfoniunmethylid in dimethyl · · · formamide takes place. ') Process for the preparation of i7flC-substituted gonaquine, characterized in that the cleavage of the 3,3-dimetho-13β-E-gon-5 (10) -17-β-spiro 1,2-03d.rane with hydrophilic agents is carried out under neutral or alkaline conditions and that the solvent used is preferably a water-miscible organic solvent. j * Process for the preparation of 17cC-substituted gona-4,9-dienes, characterized in that the hydrolysis of the 17öC-substituted 3,3-dimethoxy-i3β-R-gon-5 (10) -en- * 17ßole in a hydrous organic solvent, preferably aliphatic alcohols, dioxane, acetone or dimethylformamide and as acids organic carbonic acids such as acetic acid, oxalic acid, citric acid or succinic acid or a dilute mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or perchloric acid used ·