CS201522B2 - Process for preparing benzimidazolcarbamates - Google Patents

Abstract

1307306 Benzimidazole derivatives JANSSEN PHARMACEUTICA NV 29 May 1970 [20 June 1969] 26044/70 Heading C2C Novel benzimidazole derivatives of the formula wherein R is C 1-6 alkyl, C 3-6 cycloalkyl , phenyl, halophenyl, C 1-6 alkylphenyl,. C 1-6 alkoxyphenyl or 2-thienyl, and R 1 is CH 3 or CH 3 CH 2 , and RCO is located at the 5(6)-position, are prepared by reacting compounds of the formula with aminoketones of the Formula V: in the presence of protonic acids. Aminoketones of Formula V above are obtained by hydrogenating the corresponding 4-amino-3-nitropheoyl ketones obtained by ammonolysis of the corresponding 4-halo-3-nitrophenyl ketones resulting from the Friedel- Crafts reaction between the appropriate 3-halo - 4-nitrobenzoyl chloride and compounds of the formula RH, or by nitrating the-corresponding 4-halophenyl ketones resulting from the Friedel- Crafts reaction between the appropriate halobenzene and carbonyl chlorides of the formula RCOCl. Antihelmintic compositions, suitable for the usual routes of administration, contain the above novel benzimidazole derivatives in admixture with suitable carriers.

Description

The present invention relates to a process for the preparation of benzzimidazoicarbamates useful in the treatment of nematode diseases. According to prior methods, alkyl esters of benzimidazole-2-carbamic acids were prepared but were not substituted with acyl at the 5 (6) position.

The object of the present invention is to provide a process for the preparation of novel benzimidazole carbamates, in particular alkyl esters of benzimidazole-2-carbamic acid, which are substituted by acyl. (as described below) in position 5 (6). These esters can be used alone or in combination with other therapeutically active agents in the treatment of helminth diseases and are therefore valuable additives in the fight against helminth infection.

The novel benzimidazole carbamates according to the invention may be structurally represented by the general formula (I).

^R ~ ^c

H (I) wherein R is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, halophenyl wherein halogen is fluorine, bromine or chlorine, alkylphenyl and C 1 -C 6 alkoxyphenyl in the alkyl moiety and 2-th'enyl, R 1 is methyl and ethyl, wherein the - - R - CO - group is in the 5 or 6 position.

Preferred compounds are those wherein R has a meaning other than alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms. Most preferred are those compounds of formula I wherein R is phenyl and R 1 is methyl. These compounds may be designated as alkyl N- (5 (6) -arcyl-2-benzimidazolyl] carbamates and are structurally represented by the following general formula:

H wherein Ar is phenyl, halophenyl, alkylphenyl of 1 to 6 carbon atoms, alkoxyphenyl of 1 to 6 carbon atoms, and 2-thienyl. R 1 is methyl and ethyl; and the Ar-C-substituent is located at the 5 (6) position of the dazoline ring gasoline.

Alkyl and C 1 -C 6 -alkoxy may be straight or branched chain saturated hydrocarbons, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like, and the corresponding alkoxy groups such as methoxy, e.g. ethoxy, propoxy, isoprpoxy, etc .; C 3 -C 6 cycloalkyl may be cytclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and halogen refers to halogen atoms having an atomic mass of less than 80, i.e. fluorine, bromine and chlorine.

Compounds of formula I are prepared according to the method disclosed in U.S. Patent No. 3,010,968 for the preparation of certain other benzimidazole-2-caribamic acid alkyl esters.

A process for the preparation of the benzimidazole carbamates of formula I is characterized by reacting a compound of formula II (//) with a compound of formula III,

Cl-COOR 1, (III) wherein R 1 is as defined above, and then with a compound of formula IV,

f (IV) wherein R is as defined above, and with a protoic acid such as acetic acid.

-In general; the method comprises reacting S-m-ethylisothiourea sulfate of formula II with a suitable alkyl chloroformate of formula

III in the presence of a base, preferably about 25 percent aqueous solution of alkali metal or caustic earth metal, at about pH 8. It further comprises reacting with a suitable acyl-substituted o-phenylenediamine of formula IV, preferably in the form of an acid addition salt. protonic acid to about pH 5-6, for example formic, acetic, propionic and other acids, and preferably in the presence of the corresponding alkali metal salt, for example, formate, acetate, sodium or potassium propionate.

The diajinophenyl ketones of formula IV are obtained by reducing the nitro group of the corresponding ann-ontrophenylketones of formula V. This reaction is readily accomplished by catalytic hydrogenization of a compound of formula V, for example with hydrogen and a catalyst (palladium on charcoal) in a suitable solvent such as lower alkanol. acidified, for example HCl, to increase yields. Conventional treatment with a suitable inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, acetic, oxalic, lactic, fumaric and the like, leads to the corresponding acid addition salts of formula IV. Aminoinitrophenyl ketioles of formula V are obtained from the corresponding halo-ennitrophenyl ketones of formula VI, wherein X is halogen, preferably chlorine or fluorine, by conventional ammonolysis of said ketones, for example by heating compounds of formula VI with lower alkanolic ammonia solution, preferably under pressure in a suitable polar solvent such as sulfolane. Due to the strong electron attraction of the nitro group in the ortho position to the halogen, the amoin-olysis readily converts the halogen group to the amino group. Alternatively, aminonitrophenyl ketones of formula V can be obtained by reacting compound VI with ethyl englycol and ammonium hydroxide at an elevated temperature (about 100-130 ° C). for several hioidines. These reactions can be illustrated in the following scheme:

V (vi)

and)

NH 3 / methanol

(b)

НО — CH2CH2OH methanol

Hz / Pd — C 10%

12.5 N NH 4 OH

(IV>

Some of . The dtaininophenyl ketones of formula IV and the aminomirophenyl ketones of formula V are novel compounds and are important for use in the above syntheses. These new intermediates may be structurally represented by the following general formula:

wherein R 1 is cycloalkyl of 3 to 6 carbon atoms, phenyl, halophenyl, alkylphenyl of 1 to 6 carbon atoms, alkoxyphenyl of 1 to 6 carbon atoms and 2-thienyl, and R 1 is nitro- and amino,

Some of the halonitrophenyl ketones of formula VI are known, for example those wherein R is alkyl of 1 to 6 carbon atoms, phenyl or alkylphenyl of 1 to 6 carbon atoms. Generally, the ketones of formula VI can be prepared under conventional Friedel-Crafts reaction conditions according to the following equation:

AlCt ^

(Friedel-Crafts) or may be prepared by direct nitration of a compound of formula VII, such as by treatment with concentrated or fuming nitric acid at a temperature of -5 to -30 T, which compound of formula VII can be obtained by conventional Frie · del-Crafts reaction the following equations:

O-C-R

[Vlil] (Friedel-Crafts)

Conc. HNO 3 - 20 ° C

O

It has been found that the benzimidazolyl carbamates of the formula I have valuable anthelmintic properties and are particularly useful against various helminthic diseases of the digestive tract of domestic and economically important animals such as dogs, sheep, cattle, chickens and the like. The compounds of formula I are active against a broad spectrum of helminths, for example, Trichostrongylus, O, stertagia, Couma, Htoimonium, Strongyloides, Nematodirus, Bunostomum, Trichuins, Chabertia, Capillaria, Ascaris, Heterakis, Syphacia and the like. Depending on the weight of the animals, daily doses of 0.5 to 40 · mg / kg body weight are generally sufficient to effectively remove contagious organisms from the animal body. Anthelmintic compositions containing an effective amount of a compound of Formula I, either alone or in combination with other active therapeutic ingredients, in admixture with suitable carriers can be readily prepared by conventional pharmaceutical and veterinary techniques for conventional modes of administration.

The compound, methyl N- [5 (6) benzoyl-2-benzimidazolyl] carbamate, has been found to be particularly effective against Syphacia muris, which is related to human mildew, Enterobius vermicularis, by its life cycle. cyclic periodic activity, and deposition of eggs in the rectum region. Adhesive cellophane film is used to induce artificial infection to obtain eggs from the perianal landscape and is administered orally to rats. The animals so infected are housed in individual cages, and food and water are eaten ^; m served at will. Test substances are administered orally by gavage. A sterile saline solution or suspension is prepared in various concentrations corresponding to 40, 10, 2.5, 0.63 and 0.16 mg / kg body weight. The animal receives 1 ml for every 100 g of body weight. Control animals receive the same amount of saline. After 5 days, the animals are sacrificed. Coecum a is isolated from the intestinal tract _; rectum and washed on 100 mesh screens. Saimis, females and immature worms are distinguished and counted. The efficacy compared is expressed as a percentage (%) of the untreated control groups. According to this procedure, methyl N- [5 (6) -benzyl-2-benzimidazoyl] carbamate was found to have 100% efficacy against Syphacia muris in rats given a single oral dose of 0.63 mg / kg body weight. A comparison with the known anthelmintic, parbendazole [methyl 5 (6) -butyl-2-benzimidazole] -Mocarbamate], is shown in the following table:

Single oral dose (mg / kg)

Compound. AND

Compound B

0.16 0% effect 0.31 50% effect 0.63 100% effect 0% effect ¹ 2.5 1000% effect 0% effect 10.0 100% effect 0% effect 40.0 100% effect 100% effect

Compound A = methyl N- (5 (6) -benzoyl-2-benzimidazolyl) carbamate.

Compound M = parbendazole.

The oral LD / 50 = Compound A value is> 80 · mg / kg in sheep and> 40 bg / kg in mice, rats and chickens. The oral LD / 50 of Compound B is> 40 mg / kg in these species.

The following examples illustrate but do not limit the method of the invention. All parts are by weight unless otherwise stated.

Example 1

Hot solution of 53 parts cyclobutylcarbonyl chloride in 45 parts fluorobenzene is added at 60 ^{0 |} C to a mixture of 107 parts aluminum chloride in 270 parts fluorobenzene. Then the mixture is stirred and refluxed for 45 min. The reaction mixture was cooled and poured onto ice. The organic layer was separated and the water was extracted twice with 120 parts of methylene chloride. The combined organic phases were dried, filtered and evaporated. The residue was distilled to give 64 parts of cyclobutyl-p-fluorophenyl ketone; t at 100-102 ° C at a pressure of 266.64 Pa.

Using the same procedure as in Example 1 and using an equivalent amount of cyclopentylcarbonyl chloride instead of cyclobutylcarbonyl chloride, 39 parts of cyclopentyl-p-fluorophenyl ketone are obtained; mp 108-111 ° C at

199.98 to 266.64 Pa.

Example 1 a d 2

150 parts fuming acid nit ^! The reaction mixture is cooled (d = 1.5) and cyclopropyl ketone (39 parts) is added at -10 ° C and -20 ° C. The mixture was then stirred at the same temperature for 40 minutes. The reaction mixture was cooled to -30 ° C and poured onto crushed ice. The precipitated product is filtered off with cooling, washed with cold water and then with a little 2-propanol and after recrystallization from 40 parts of 2-propanol, 34.5 parts (4-chloro, m.p. 80 ° C) are obtained.

Using the same procedure as in Example 2 and using an equivalent amount of a suitable arylcycloalkyl ketone instead of (4-chlorophenyl) cyclopropyl ketone, the following compounds were obtained:

cyclobutyl-4-fluoro-3-nitrophenylnylketone, 51 parts,

m.p. 148-150 ° C at 106.65 Pa, cyclopentyl-4-fluoro-3-nitroellylketone, 37 parts, b.p. 120-160 ° C at 106.65 Pa.

Example 3

To a stirred and cooled (ice bath) suspension of 25 parts of aluminum chloride in 52 díleoh ^fluorine, Benzer was added dropwise a solution of 27.5 parts of 4-3-chlrr níttobenzoylchlotldu in 52 parts flurrbenzeru. The mixture was then stirred overnight at room temperature. The reaction mixture was poured into water and the product was extracted with methyl chloride. The extract was washed successively with sodium bicarbonate solution and passed, dried, filtered and evaporated in vacuo. The solid residue crystallized with 2-propanol to give 25.4 parts of 4-chloro-4'-iflurr-3-nitrobenzophenor, mp 97.9 ° C.

Following the procedure of Example 3 and using an equivalent amount of chlorobenzene or methoxybenzene instead of fluorobenzene, the following ketones are obtained:

4,4‘-Dichloro-3-nitrobenzophenr, m.p. 83.4 ° C,

23.7 parts,

4-Chloro-4'-methoxy-3-nitrobenzofenone, m.p.

105.5 ° C, 17.5 parts.

Example 4

A suspension of 15 parts of aluminum chloride in 60 parts of methylene chloride is cooled in an ice bath and a solution of 25 parts of 4-chloro-3-nitro-benzoyl chloride in 60 parts of methylene chloride is added dropwise; the temperature was kept below 0 ° C. Then, the mixture was stirred at room temperature until the aluminum chloride dissolved. 10 parts of thiophene are then added dropwise at 0 ° C and the mixture is stirred for one hour at room temperature. The reaction mixture was poured onto crushed ice. The organic layer was separated, washed with sodium bicarbonate solution, dried and evaporated. The oily residue solidifies on trituration in 2-propanol. The solid product was filtered off and recrystallized from 2-propanol. The less pure fractions were dissolved in hot benzene, treated with charcoal, filtered, and after addition of petroleum ether to the filtrate the product recrystallized to give 10.1 parts of 4-chloro-3-nitrophenyl-24-phenyl-ketone, m.p. 117.8 ° C.

Example 1 a. D 5

A. A mixture of 5.2 parts of 4-chloro-3-nitrobenzophenone, 5 parts of ammonia, 72 parts of methanol and 13 parts of sulfoflan was heated at 125 ° C overnight in a sealed tube. The reaction mixture was evaporated in vacuo. The semi-solid product is boiled in 100 parts of dilute hydrochloric acid solution. After cooling, the precipitated product was filtered off and dissolved in chloroform. The chloroform phase is dried and evaporated. The residue crystallized from toluene to give 3.4 parts

4-amino-3-nitrobenzophenone, m.p. 141 ° C.

B. A heterogeneous mixture of 261.66 parts of 4-chloro-3-nitrobenzophenone, 3.6 parts of ethylene glycol and 320 parts of 12.5 N ammonium hydroxide solution was heated to 130 ° C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 10 ° C and crystallized. the product is filtered off. It is triturated in 800 parts of methanol, filtered again, washed with 80 parts of fresh methanol and dried at 50 ° C to give 2.31 parts of 4-amino-3-nitrobenzophenone, m.p. 139 ° C.

Example 6

Simes 16 parts of 4'-chloro-3 ^/ '-nitropio) treated under the conditions, 2.8 parts ammonia, 72 -dílů methanolu- and 13 parts of sulfolane was heated in a sealed tube 15 h at 120 ° C. The solvent was evaporated in vacuo and 150 parts of water and concentrated hydrochloric acid solution were added to the residue until acidic. The precipitated product is filtered off, washed successively with water, 2-propanol and ether, and dried at a rate of 10.5 parts. 4'-amino-3'-nitropropiophenone, mp 150 cc.

Following the procedure in Example 6 and using equivalent amounts of the appropriate · 4'-halo-3'-nitrofenylketonu VI -posts 4 ^{<chloro-3'-nitropropiofeno.nu} following compounds are obtained:

4‘-amino-3‘-n-itrobutyrophenone;

b. mp 130 ° C, 13.5 parts; 4‘-amino-3‘-nitrovalerophenone;

mp 118 ° C, 20.5 parts; (4-α-β-3-β-γ-β-β) cyclopropyl ketone;

b. mp 167 ° C, 1.3 parts;

4 - amino-3-mtгofeny1cyklobutylketo ^L n;

mp 156 ^C , 24.3 parts;

4-amino-3-nitrophenylcyclopentyl ketone;

bt 181.8 ° C, 19.7 parts; 4-amino-4'-fluoro ^, 3'-nitro-bi-isophenylene;

b. mp 199 ° C, 17.6 parts;

4'-amino-4'-chloro-3-methoxybenzophenoh;

mp 200.9 ° C, 12.0 parts; 4-amino-4'-пethyl-3-nitro ^and benzofenαn;

mp 145 ° C, 7.0 parts; ^{4-am'nr-4-methoxy-3-'nitr} (beenzoeeIro n;

b. 155.6 c < C, 6.2 parts;

4-amino-3-nitrophenyl-2-ylphenylketone;

b. mp 168.4 ° C, 5.6-part;

Example 1 and -d 7

A mixture of 9.7 parts of 4'-amino-3'-thread: 'opropoene', 160 parts of methanol, 10 parts of concentrated hydrochloric acid solution and 0.5 parts of catalyst - 10% palladium on charcoal - is hydrogenated at atmospheric pressure at room temperature. When the calculated amount of hydrogen is consumed, the hydrogenation is stopped. The catalyst was removed and the filtrate was evaporated. 20 parts of 2-propanol are added to the solid residue, filtered again, washed sequentially with 2-propanol and ether and dried to give 7.2 parts of 3 ‘, 4‘-dia.Minoptoptophene hydrochloride.

Following the procedure in Example 7, and -in using an equivalent amount of the corresponding anťnonitrofrnylketonu vzorce- In -posts am'mo-4'-3'-nitroprO'ptofnnonu -se - d ⁱ obtained following am'nofnhylketony formula IV using any suitable hydrogenation catalyst. In order to obtain the sulphate, sulfuric acid shall be used instead of hydrochloric acid:

3 ‘, 4‘-diaminobutyrophenine hydrochloride;

8.5 part;

3 ‘, 4‘-dl · ammovalerophenone hydrochloride;

4.9 part;

(3,4-diaminophenyl) cyclopropylketone sulfate; mp 180-190 ° C (dec., 6.4 parts;

3,4-palminophenyilcyclobenzyl ketone hydrochloride;

mp 170 ^C , 5.6 parts;

3.4- d ⁱ amtnι <Cfeny1cyklopentylketonhydrochlorid;

b. mp 300 ° C, 7.0 parts;

3.4- · diaimln-both n-zophenoohydrooh lor! d;

b. mp 207 ° C, 7.6 parts;

3.4- diam: no-4 ^< -fluorbe.nzofnhonУydгochlot; d; b. -t. 226-230.5 ° C, 9.1 parts;

3,4-diamino-4‘-chloro-benzophenone hydrochloride; b. 190 ° C (dec., 0.4 part;

3.4- diami. ⁴ not4'-methylbenzophenonehydroyone · ortd;

2.6 parts;

3,4-diamino-4‘-methoxybenzophenone-hydtool;

3.0 parts;

3,4-diadinolphenyl-2-thienylketone hydrochloride,

4.7 parts, bt 160 ^C C.

Example 8

7.8 parts of S-sulfate ^meehylisoth: omočovmy was stirred in 10 parts of water in an ice bath and then added 4.5 parts of methyl chlormrave.nčahu. - Keeping the temperature below 20 °

Celsius is added dropwise over 10 minutes with 17 parts of 25% sodium hydroxide solution (pH ± 8). Then 5.6 parts of acetic acid (pH ± 5) are added. 7 parts of 3,4-diamino-benzophenone hydrochloride in 100 parts of water and then 2.3 parts of sodium acetate are added to the mixture at 20 ° C. The mixture was slowly heated to 85 ° C and stirred at this temperature for 45 minutes. The reaction mixture was cooled and precipitated, and the product was filtered off. It is washed successively with water and ethanol, dried and crystallized from a mixture of acetic acid and methanol to give 5 parts of methyl N- [5 (6) -benzophyllil-2-benzimidazolyl] carbamate; b. t.

288.5 ^C C.

Following the procedure of Example 8 and using an equivalent amount of the corresponding daminophenyl ketone described in Example 7, instead of 3,4-diaminobenzoylphenone hydrochloride, optionally using an equivalent amount of the corresponding alkyl chloroformate instead of methyl chloroformate, the following carbamates are obtained :

methyl N- [5 (6) -acetyl-2-benzimidazolyil] carbamate;

b. mp +300 ° C, 2.9 parts;

methyl N- [5 (6) -propionyl-2-benzimidazolyl] octamate;

mp 279.5 ° C, 8.2 parts;

methyl N- [5 (6) -butyryl-2-benzimidazolyl] carbamate;

bt 27-3 ⁿ C, 3.7 parts;

methyl N- [5 (6) -valeryl-2-benzimidazolyl] carbamate;

b. mp 265 ° C, 4 parts;

methyl N- [5 (6) -cyclopropylcarbonyl-2-benzimidazolyl iicarbamate;

bt 260.5 ^C , 5.5 parts;

methyl N- [5 (6) -cyclobutylcarbonyl] -2-benzimidazolyl] carbamate;

b. mp > 300 ° C, 5.2 parts;

methyl N- [5 (6) - (cyclopentylcarbinyl) -2-benzimidazolyl] carbamate;

b. mp> 30 ° C, 6.2 parts;

methyl N- [5 (6) - (p-fluorobenzoyl) -2-benzimidazolyl] carbamate;

b. mp > 260 ° C, 3.5 parts;

methyl N- [5 (6) - (p-chlorobenzoyl) -2-benzimidazolyl] carbamate;

bt>2'60 ^° C, 1.8 parts;

methyl N- [5 (6) - <p -toluoyl-2-benzimidazolyl] carbamate;

BT 284, ^Q .6 C, 1.1 parts;

methyl N- [5 (6) - (p-methoxybenzoyl) -2-benziimidazolyil] carbamate;

b. mp 289 ° C, 2.7 parts, methyl N- [5 (6) - (2-thenoyl) -2-benziimidazolazolyl] carbamate;

m.p. 288.7 ° C, 2.6 parts;

ethyl N- [5 (6) -benzoyl-2-benzimidazolyl] carbamate;

m.p.> 30 ° C, 2.8 parts.

Example 9

This example illustrates the anthelmintic efficacy of the compounds of formula I. Feces poiovzrostlých or adult sheep infected with various types of worms microscopically zkoluší to identify helminth ova, and determine the number of eggs per gram (EPG] using Mac Masterclvy techniques. ⁺ Every animal The EPG for each worm species is an average of 4 MacMaster census units The average EPG for each species, after an average of 8 censuses, the test compounds are then administered by intubation to the vagina (10 mg / kg) The treated animals are kept in separate units and each animal is tested for 2 weeks EPG data are recorded in the same manner Percentage egg loss is the ratio of the mean EPG value after compound administration divided by the mean EPG value before compound administration and multiplied by 100. se stan In the following table:

+ 1 - 25% Efficacy ++ 26 - 50% Efficacy +++ 51 - 75% Efficacy ++++ 76 - 100% Efficacy ⁺ Gordoin, H. Mel. and Whitlock, Η. V., J.

Coun. seleni, ind. Res. (Austr. J., 12, 50 (1939)).

The compounds in the following table are provided to illustrate the useful properties of all compounds, not to limit the invention.

O £

Φ ω

ω Φ -Ο

Ο p

e o

4- »

СЛ ω rs> 4 W)

4->

ω

Р4 + + 444444 +

+ + 4+

44+

4+

44444+ ++

+ 44 4 + + + + + + I i + I + + + + ¹ 4- ' + + + о + I 1 +. AND 4- + + + + 4- + + 4- i | + 4- + - + + + + + + + о + I 1 + + 4- + + 4- + I I + 1 1 1 + + I 1 + I I I 4- + 1 + I I I

4+ + + +

+ +

+ о + + + +

4—

4+ ~ o + + + +

4 — П

4- 4- o

4- 44-4 + - + о о

+ + + + + + + + 4- i I + + - + + + 4- + + + 4- 4- + I + + - +

о +

+ +

+ о + 44 - + + 44 - + +

+ +

> + о +

+ +

+

44444-4 — Η

4-4-4φ and φ ® φ o + -ι

SSSSSSW

Claims (2)

I will invent the subject A process for the preparation of the benzimidazole carbamates of the general formula I, (II in which R represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, halophenyl, wherein halogen is fluorine, bromine or chloir, alkylphenyl and alkoxyphenyl; 1 to 6 carbon atoms in the alkyl group and 2-thienyl, R is methyl and ethyl, said group. R-CO- is in position 5 or 6, characterized in that reacting a compound of formula II ^{50 liters} of ^H t (H1 with - a compound of formula III), C1-COOO1, (III) wherein R1 is as defined above and then with a compound of formula IV, (IV I wherein R is as defined above) and with a protonic acid such as acetic acid. 2. Method -based -point 1 wherein Z * e is reacted with a proton acid, in the presence of an alkali Koivu ^proton: cal acids.