NO126574B - - Google Patents

Description

Process for the preparation of salts of 4,4'-disulfoxy-diphenyl-(2-pyridyl)-methane.

The present invention relates to a new and advantageous method for the production of salts of h,h'-disulfoxy-diphenyl-(2-pyridyl)-methane. These compounds are known and can be used as laxatives.

It is known in the preparation of k,k*-dihydroxy-diphenyl-(2-pyridyl)-•methane to condense 2-pyridinealdehyde or a reactive derivative thereof, with phenol in the presence of a condensing agent. However, it has been shown that in addition to the desired compound, this method also results in the formation of a high percentage amount (2^-29$) of the undesired isomer 2,V-dihydroxy-diphenyph-(2-pyridyl)-methane. Removal of this requires successive crystallizations from alcohol (at least two crystallizations). The final yield of the pure product is therefore relatively modest.

This unwanted formation of isomers is avoided by the method according to Norwegian interpretation document no. 125,676, where a ring-substituted phenol with one or two halogen atoms with the formula CD below is condensed with pyrrolaldehyde

Furthermore, Norwegian patent no. 115912 describes a method for the production of salts of h, k<-disulfoxy-diphenyl-(2-pyridyl)-methane by starting from k, h'-dihydroxy-diphenyl-(2- pyridyl)-methane.

The present method enables the formation of unwanted isomers to be avoided or reduced to a significant extent so that pure salts of h,h*-disulfoxy-diphenyl-(2-pyridyl)-methane are obtained in good yields.

The present method therefore aims at producing salts of -disulfoxy-diphenyl-(2-pyridyl)-methane. by condensation of 2-pyridinealdehyde or a reactive derivative thereof with a phenol in the presence of a condensing agent, and the method is characterized by the use of a phenol with the formula: where and R2, which may be the same or different, is a halogen or a hydrogen atom, with at least one of the substituents R 1 and R 2 being a halogen atom, to produce a compound with the general formula:

where R-j^ and R2 have the same meaning as stated above, after which the compound of formula II is reacted under anhydrous conditions with chlorosulfonic acid in the presence of an acid binder to produce

a salt of the corresponding sulfuric acid ester with the formula:

where R 1 and R 2 have the same meaning as stated above and Me is an inorganic cation, and the compound thus produced is dehalogenated with Raney nickel in the presence of alkali metal hydroxide.

It should be noted that the formation of the undesired isomers is completely prevented if phenols of the formula (I) are used where R

and R 2 are halogen atoms, in that the positions in the ortho position of the phenolic hydroxyl group are substituted. If only one of these substituents is a halogen atom, this formation takes place, but to a noticeably smaller extent compared to what happens with the unsubstituted phenol, as only one of the 2- and 6-positions can contribute to a side reaction occurring . In the latter case, the reaction product which is obtained in good yield will contain a small amount of the unwanted isomer which, however, can be easily removed by washing with boiling 95% alcohol.

In the compounds of formulas (I), (II) and (III) are preferred

that when R-1 and/or R2 is a halogen atom, that this is a chlorine or bromine atom. Compounds with the formula (I) which can be advantageously used in accordance with the present invention are, e.g. 2-chloro-, 2-bromo-, 2,6-dichloro- and 2,6-dibromophenol. Besides the 2-pyridinal dehyde, its reactive derivatives can also be used, e.g. bisulphite addition derivatives and acetals. Acidic condensing agents are used, e.g. sulfuric acid or phosphoric acid, zinc chloride, aluminum chloride etc. It is preferred to use sulfuric acid.

According to a particularly advantageous embodiment of the present method, 2-pyridinealdehyde is reacted with a phenol of the formula (I), preferably 2-chloro-, 2-bromo-, 2,6-dichloro- or 2,6-dibromo-phenol} in the presence of concentrated sulfuric acid. The phenol with the formula (I) is preferably used in excess, preferably in a ratio of between 1:2.1 and -1:3.5.

The phenol of the formula (I) is slowly added to a homogeneous suspension of 2-pyridinealdehyde in concentrated sulfuric acid at a low temperature, preferably at a temperature of 0 - 5°C. The reaction mixture is kept at this temperature with stirring for 1/2 - 2 hours. The temperature is then allowed to rise spontaneously to 30°C, and the stirring is continued for 1/2 - 2 hours. The conversion is complete by stirring overnight at room temperature. If the phenol with the formula (I) is a 2,6-dihalogen-substituted phenol, the sulfuric acid is preferably added to the mixture of the other two reaction participants. The turnover should then be carried out using moderate heating, preferably at 50°C for 1 hour,

after which the whole thing is left at room temperature for a further 1 hour.

The compound of formula (II) is separated from the reaction mixture by dissolving the reaction mass in an excess of 10% sodium hydroxide followed by precipitation of the compounds by adding 5% hydrochloric acid until the whole becomes neutral, or by direct neutralization of the reaction mixture with a solution of sodium hydroxide or sodium carbonate. The solid product thus obtained is filtered, washed with water, dried, washed carefully with ether and dried. After washing with ether, compounds with the formula (II) are washed where R-^ (or R2) =

H and R2 (or R^) = halogen, also with 95% boiling alcohol to remove the unwanted isomer.

The compounds of formula (II) are new compounds. They are

white solids that are insoluble in water and soluble in sodium hydroxide.

The thus obtained compounds with the formula (II) are reacted

under substantially anhydrous conditions with chlorosulfonic acid in the presence of an acid binder, preferably anhydrous pyridine. An excess of chlorosulfonic acid is preferably used, which is added dropwise to a solution of a compound of the formula (II) in anhydrous pyridine at a temperature of 0 - 5°C. The temperature is then gradually increased to H5 - 80°C, and the reaction mixture is kept at this temperature with stirring for 7 hours, and after standing overnight at room temperature, the reaction mixture is poured slowly into a mixture of ice and sodium hydroxide until the solution becomes alkaline to phenolphthalein. The alkaline solution is then washed with ether, filtered with charcoal, brought to a pH of 7 with 10% hydrochloric acid,

washed with chloroform and, after further adjusting the pH to one

JL. rw \ F w ■ M> value of 7.5 with dilute sodium hydroxide, concentrated to dryness under reduced pressure. The solid residue is washed with ether and taken up with boiling anhydrous alcohol. The undissolved product is separated by filtration, and the alcoholic solution is evaporated to dryness. The raw product obtained by evaporation of the solvent can preferably be used for the subsequent dehalogenation without further purification. If desired, the product can be purified by redissolving in anhydrous alcohol, by filtering with charcoal, and finally by washing with anhydrous ether.

It should be noted that the compounds of formula (III) are new compounds.

The halogen-substituted sulfuric acid ester thus prepared is preferably dehalogenated in crude form or, if desired, in purified form as stated above, x 5% sodium hydroxide solution with Raney nickel by adding this at room temperature and over the course of 3-5 hours, and by stirring overnight at room temperature. Thereby the disodium salt of h, h*-disulfoxy-diphenyl-(2-pyridyl)-methane is obtained, which can be separated from the alkaline solution by adding 10% HC1 until it reaches a pH of 7.5, filtering and evaporating to dryness under reduced pressure, preferably with a thin-layer condenser. The dry residue is taken up with anhydrous alcohol to remove the insoluble salts, and the alcoholic solution is filtered and concentrated until incipient crystallization of the product is obtained.

Example 1

Preparation of the intermediate product 3, 3'-diclar-^.^'-dihydroxy-diphenyl-(2-pyridyl)-methane 75 g (0.7 mol) of 2-pyridinealdehyde was added dropwise over the course of approx. 1 hour was added to a homogeneous mixture prepared between 0 and 10°C from 107 ml of concentrated sulfuric acid and 292.9 g (2.28 mol) of 2-chlorophenol, the temperature being maintained between 0 and 5°C. The mixture was stirred for 1/2 hour at this temperature, which was then spontaneously raised without exceeding 30°C. After stirring for 1/2 hour, the mixture was allowed to stand overnight at room temperature. It was then dissolved under external cooling in a 10% sodium hydroxide solution, filtered with charcoal and neutralized with 5% hydrochloric acid. The produced precipitate, which constituted the crude product, was filtered, washed with water, dried, triturated with ether and again dried. The precipitate weighed 211 g. The isomer 2,^Ldihyd:rox/-3,3'-dichloro-diphenyl-(2-pyridyl)-methane was removed by careful washing with <*>+30 ml of 95% boiling alcohol. 167 g of isomer-free product was obtained in a yield of 69%.

3,3'-Dichloro-N,^^dihydræy-diphenyl-(2-pyridyl)-methane is a white solid that crystallizes from 95% alcohol. Its melting point is 212 - 215°C.

Analysis:

found % : C 62.01, H 3.80, N 3.98, Cl 20.27

for C1gH12Cl2N<0>2

calculated % : C 62.^7, H 3.78, N ^.05, Cl 20.<>>+8

Example 2

Preparation of the intermediate product 3. 3', 5, 5'- tetrachloro-^-.^'- dihydroxy-dif enyl-( 2- pyridyl )- methane 13 ml of concentrated sulfuric acid was added over the course of 15 minutes to a homogeneous mixture of 19 .0<*>+ g (0.1168 mol) of 2,6-dichlorophenol and 5 g (0.0^-67 mol) of 2-pyridinealdehyde. The temperature was kept between 0 and 5°C. - The mixture was stirred at this temperature for 1/2 hour,

and the temperature was then increased to 30°C. The mixture was stirred for a further 2 hours, heated for 1 hour at 50°C and kept for 1 hour at room temperature. The reaction mixture was then neutralized with 330 ml of an 8.5% aqueous solution of sodium carbonate under external cooling and stirred for approx. 1 hour. A product separated out which was filtered, washed, dried, triturated with ether and again dried. It weighed 16.7 g, and the yield was 86%.

3,3',5,5'-tetrachloro-h,h1-dihydroxy-diphenyl-(2-pyridyl)-

methane is a white solid that crystallizes from 95% alcohol, and has a melting point of 231 - 232°C.

Analysis:

found % : C 51.58, H 2.72, N 3.31, Cl 33.99

for Cl8H11CllfN02

calculated % : C 52.08, H 2.67, N.3.38, Cl 3>.17

Example

Preparation of the intermediate product 3. 3' - dibromo-1)-. ^'- dihydroxy- dif enyl -

( 2- pyridyl)- methane

17.1 g of crude product was obtained by starting from 25.6 g (0.1105 mol) of 2-bromophenol, 9 ml of concentrated sulfuric acid, ^.75 g (0.0^2 mol) of 2-pyridinealdehyde and by using the method specified in example 1. The isomer 3,3'-dibromo-2,^-'-dihydroxy-diphenyl-(2-pyridyl)-methane 1 crude product was removed by careful washing with 35 ml of 95%

boiling alcohol. 13.5 g of isomer-free 3,3'-dibromo-N,^'-dihydroxy-diphenyl-(2-pyridyl)-methane were thus obtained in a yield of 70%. The product was a white solid which crystallized from 95% alcohol and had a melting point of 173-175°C.

Analysis:

found % : C <1>*9.88, H 3.11, N 3.9, Br 35.60

for C1gH1^Br2<N0>2

calculated % : C ^9.70, H 3.02, N 3.22, Br 36.72

Example h

Preparation of the intermediate product 3, 3'. 5. 5' - tetrabromo-^ t-. 1!-'-dihydroxy-diphenyl-(2-pyridyl)-methane

1^.68 g (0.0858 mol) of 2-pyridinealdehyde was in the course of 1 hour and

at a temperature of 0 - 5°C added to a suspension of 5<*>+ g (0.21^+5 mol) 2,6-dibromophenol in 37 ml of concentrated sulfuric acid. By proceeding as described in example 2, M+.8 g of 3,3',5,5'-tetrabromo-U-, h1 -dihydroxy-diphenyl-(2-pyridyl)-methane was obtained in a yield of 88% . The product was a white solid which crystallized from 95% alcohol and had a melting point of 223.5 - 225°C.

Analysis:

found % : C 36.57, H 1.91, N 2.30, Br 53.5l

for C1gH11BrlH,N02

calculated %: C 36,<*>+5, H 1,86, N 2,36, Br 53,90

Example 5

a) Disodium- 3. 3' - dichloro- 1*, h * - disulfoxydif enyl-( 2- pyridyl) - methane

5.05 g (0.0^+33 mol) of chlorosulfonic acid was in the course of 10 minutes

added dropwise to a solution of 5 g (0.01M+ mol) of 3,3'-dichloro-^,1*'-dihydroxydif enyl-(2-pyridyl)-methane in 35 ml of anhydrous pyridine. The temperature was kept at 0 - 5°C by means of external cooling. A brown precipitate was obtained. The mixture was gently heated for 7 hours at h5 - 50°C and then allowed to stand overnight at room temperature. The obtained solution was poured into 1^0 ml of water/ice containing 20 ml of 30% sodium hydroxide. The final pH of the solution was above 9. The solution was washed with ether, filtered with charcoal, brought to a pH of 7 with 15% hydrochloric acid, washed with chloroform, its pH adjusted to 7.5, and finally concentrated to dryness under reduced pressure. The obtained solid residue was finely ground with ether, and dried and taken up in 200 ml of boiling anhydrous alcohol. After filtering the soluble part, the alcoholic solution was filtered with charcoal and evaporated under reduced pressure. It'

7.2 g of product were obtained in a yield of 90%. The product can be used for the subsequent reaction without further purification.

However, the crude product can be purified by redissolving in anhydrous alcohol, filtering with charcoal, precipitation from chloroform, decanting the solvent, washing the obtained viscous product with new chloroform and then finally trituration with an anhydrous ether. The product is an ivory white solid with a melting point of 2^-8.5 - 25l°C with cleavage.

Analysis:

found % : C 37.11, H 2.^-2, N 2.1+6, S 10.95, Na 8.11, Cl 12.21

for C1gH11<0g>Cl2NS2Na2

(with ^.1% H 2 O)

calculated % : C 37.6^, H 2.38, N 2.<1>+8, S 11.18, Na 8.02, Cl 12.37

b) Disodium-^, k 1-disulfoxy-diphenyl-(2-pyridyl)-methane

3.7 g of Raney nickel were added to a solution over the course of k hours

of 10 g (0.0182 mol) of impure disodium 3,3'-dichloro-^,^'-disulfoxy-. diphenyl-(2-pyridyl)-methane in 75 ml of 5% sodium hydroxide under vigorous stirring and at room temperature. The mixture was stirred overnight at room temperature, and the undissolved portion was filtered off. The pH of the charcoal-filtered solution was adjusted to 7.5 with 10% hydrochloric acid, and the solution was again filtered and finally evaporated to dryness in a thin-layer concentrator.

The produced, dry residue was taken up for approx. 150 ml of boiling anhydrous alcohol and the alcoholic solution was concentrated to incipient crystallization.

Disodium-^,^'-disulfoxy-diphenyl-(2-pyridyl)-methane was obtained in the form of a white crystalline solid with a melting point of 272-275°C with cleavage.

The yield was 68%.

Analysis:

found % : C <>>+2.31, H 3.21, N 2.76, S 11.90, Na 8.92

for C1gH1^0gN<S>2<Na>2

(with 6.5% H20)

calculated % : C ^1.97, H 3.26, N 2.71, S 12.M+, Na 8.93

Example 6

a) Disodium-3,3'-dibromo-^-^'-disulfoxy-diphenyl-(2-pyridyl)-methane 5.5 g of crude product in a yield of 7h% was obtained by going out

from 5 g (0.01l5'+ mol) 3,3'-dibromo-U-,^'-dihydroxy-dif enyl-(2-pyridyl)-

methane, 35 ml anhydrous pyridine, ^.0^ g (0.03^6 mol) chlorosulfonic acid and by using the method described in example 5a). The product can be purified as described above, or by crystallization from anhydrous alcohol. Disodium 3,3'-dibromo-1*,^'-disulfoxy-diphenyl-(2-pyridyl)-methane is a white crystalline solid with a melting point of 239 - 2<1>+0°C with decomposition .

Analysis:

found % : C 32.66, H 2.17, N 2.08, S 9.51, Na 6.9<*>+, Br 2^,31

for C1gH110gBr2NS2Na2

(with 3.78% H~20)

calculated C 32.50, H 2.09, N 2.10, S 9.6^, Na 6.92, Br 2k.03

b) Disodium-H-,k'-disulfoxy-diphenyl-(2-pyridyl)-methane

The product with a yield of 70% was obtained starting from

11.6 g (0.0182 mol) crude disodium-3,3'-dibromo-^,^'-disulfoxy-diphenyl-(2-pyridyl)-methane, 75 ml of 5% sodium hydroxide and 3.7 g of Raney nickel , and by using the method described in example 5b).

Example 7

a) Disodium- 3. 3' - 5, 5'- tetrachloro- 1*, 1!-' - disulfoxy- dif enyl-(2- pyridyl)- methane

V.21 g (0.0361 mol) of chlorosulfonic acid was added over 10 minutes<1> to 5 g (0.012 mol) of 3,3',5,5'-tetrachloro-**,^'-dihydroxy-diphenyl -(2-pyridyl)-methane in 35 ml of anhydrous pyridine. The temperature was kept between 0 and 5°C by means of external cooling. The mixture was heated for 7 hours at 75 - 80°C and then processed as described in example 5a).

The crude product was separated by evaporation of the alcoholic solution to dryness (yield , and the product can be purified as described in example 5a). Disodium-3,3',5,5'-tetrachloro-^,1*'-disulfoxy-diphenyl-(2-pyridyl)-methane is a pale yellow solid with a melting point of 212 - 220°C with decomposition.

Analysis:

found % : C 33.09, H 1.9^, N 2.09, S 9.73, Na 7.08, Cl 21.5^

for C1<gH>90gCllfNS2Na2

(with 3.9% H20)

calculated % : C 33.5^, H 1.85, N 2.17, S 9.95, Na 7.1^, Cl 22.02

b) Disodium-1*,^'-disulfoxy- diphenyl-(2- pyridyl)-methane

The above product was obtained in a yield of 55% by

start from 11.26 g (0.00182 mol) crude disodium-3,3',5,5'-tetrachloro-^-,^'-disulfoxy-diphenyl-(2-pyridyl)-methane, 75 ml 5% sodium hydroxide and 3.7 g of Raney nickel and by using the method described in example 5b).

Example 8

a) Disodium-3,3',5,5'-tetrabromo-^-,^'-disulfoxy-diphenyl-(2-pyridyl)-methane

Disodium-3,3',5,5'-te tr abromo-^f,V-di sulfoxy-dif enyl-(2-pyridyl)-methane was prepared with a crude product yield of 38%

starting from 5 g (0.008^3 mol) of 3,3',5,5'-tetrabromo-^,^'-dihydroxy-dif enyl-(2-pyridyl)-methane', 35 ml of anhydrous pyridine and 2 .95 g (0.0253 mol) chlorosulfonic acid, and by using the method described in example 7a). The product was a yellow solid with a melting point of 180 - 200°C with decomposition.

Analysis:

found fairy. C 25.88, H 1.61, N 1.6<*>+, S 7.59, Na 5.^, Br 38.01

for C1gH90gBr1+NS2Na2

(with h, 17% H2O)

calculated % : C 26.00, H 1.55 N 1.69, S 7.72, Na 5.53, Br 38.^3

b) Disodium-h,h'-disulfoxy-diphenyl-(2-pyridyl)-methane

The above product was obtained in a yield of 62%

starting from 1^.5 g (0.0182 mol) of crude disodium-3,3',5,5'-tetrabromo-^,^'-disulfoxy-diphenyl-(2-pyridyl)-methane, 75 ml 5% sodium hydroxide and 3.7 g Raney nickel and by using the method described in example 5b).

Claims (1)

Process for the preparation of salts of 'f^-disulfoxy-diphenyl-(2-pyridyl)-methane by condensation of 2-pyridinealdehyde or a reactive derivative thereof with a phenol in the presence of a condensing agent, characterized v q, d that it is used a phenol with the formula: where R-^ and R 2 , which may be the same or different, is a halogen or hydrogen atom, with at least one of the substituents R-^ or R 2 being a halogen atom, to produce a compound of the general formula: where B. 1 and R 2 have the same meaning as stated above, after which the compound of formula (II) is reacted under anhydrous conditions with chlorosulfonic acid in the presence of an acid binder to produce a salt of the corresponding sulfuric acid ester of the formula: where R 1 and R 2 have the same meaning as stated above and Me is an inorganic cation, and the compound thus prepared is dehalogenated with Raney nickel in the presence of alkali metal hydroxide.