US2671790A

US2671790A - Acylation of aminosulfonic acids

Info

Publication number: US2671790A
Application number: US268925A
Authority: US
Inventors: Long Robert Sidney; Delton W Hein
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1952-01-29
Filing date: 1952-01-29
Publication date: 1954-03-09
Anticipated expiration: 1971-03-09

Description

Patented Mar. 9, 1954 UNITED STATES PATENT OFFICE ACYLATION F AMINOSULFONIC ACIDS corporation of Maine No Drawing. Application January 29, 1952, Serial No. 268,925

18 Claims. 1

This invention relates to the preparation of polyalkoxybenzoyl derivatives of aromatic amino sulfonic acids.

Aromatic amino sulfonic acids are generally acylated by the action of acyl halides in alkaline aqueous medium, the alkali breaking the zwitterion between the amino and sulfonic groups. In the case of polyalkoxybenzoyl halides, however, this process cannot be used because the halides are so sensitive to water that they are decomposed.

In the patents of Scalera and Forster No. 2,573,652, October 30, 1951, and Lecher and Eberhart No. 2,580,234, December 25, 1951, there are described and claimed anhydrous processes which make acylation of the amino sulfonic acids possible. These applications use, among other features, tertiary amines as acid-binding agents. The amines may also constitute reaction liquids and may be used with Or without other solvents. While the anhydrous methods referred to above have made it possible to acylate an aromatic amino sulfonic acid with polyalkoxybenzoyl halides, some problems remained. One of the most serious problems is the extreme difiiculty of removing completely water from the reaction system. Any water present destroys an equivalent amount of the watersensitive polyalkoxybenzoyl halide. Because of the low molecular weight of Water, a very small percentage can result in a serious loss, which is particularly undesirable because of the relatively high cost of the polyalkoxybenzoyl halide. Even in the total absence of water, a considerable excess of the polyalkoxybenzoyl halide was required to drive the acylation to completion within reasonable time; thus, further excesses of the expensiv polyalkoxybenzoyl halide were formerly needed.

The present invention is based on the remarkable discovery that a high yield of polyalkoxybenzoyl amino sulfonic acids may be obtained with only stoichiometrical equivalents of the polyalkoxybenzoyl halide, by acylation in a tertiary base medium not entirely free of water. This accomplishment becomes possible when there is added to the benzoylation reactions an auxiliary agent, a halide of a carboxylic acid of ionization constant between 1 10 and 9x10- The auxiliary acyl halide takes the place of the large excess of polyalkoxybenzoyl in destroying the water and in driving the reaction to completion, but it does not attack the molecule of the amino sulfonic acid. Thus, the reaction is just as complete with only stoichiometrical amounts of the polyalkoxybenzoyl halide as with excesses thereof.

Since the polyalkoxybenzoyl halides are extremely reactive toward water, it is most surprising that the auxiliary acid halide should react preferentially with the water to the exclusion of the polyalkoxybenzoyl halide.

Even more surprising is the fact that a mixture of acylated amino sulfonic acids containing both the polyalkoxybenzoyl residue and the auxiliary acid residue is not obtained. Thisis What would ordinarily be expected. However, such a mixture does not occur, provided the dissociation constant of the auxiliary acyl halide does not exceed 9X10" With acyl halides of still stronger carboxylic acids, some mixed acylation takes place. Why the particular dissociation constant should be critical is not known, as within the range of the present invention are included auxiliary acyl halides of acids having dissociation constants both greater and less than the polyalkoxybenzoyl benzoic acids involved. In addition to the sharp upper limit on dissociation constant, there is a practical lower limit of 1 10 as the acyl halides of acids weaker than this, the reaction does not proceed suitably.

It is possible that a transamidation reaction may take place by the following equation:

OCH:

OHzO-OOONHR R0001 OCH:

The chemical nature of the auxiliary acyl halide appears to play but little part in the present invention, because so long as the acid has the right dissociation constant value, its acyl halide is useful. The following table shows a series of suitable auxiliary acyl halides which are typical.

They are arranged in ascending order of dissociation constants.

Acetic acid 1.86 x 10- Diethylacetic acid 1.89 X Crotonic acid 2.04 X 10- Anisic acid 3.4 x 10- p-t-Butylbenzoic acid 4.0 x 10- p-Methylbenzoic acid 4.3 x 10- Benzoic acid 5.6 x 10* o-Ethoxybenzoic acid 7.0x 10 Because of their cheapness, acetyl chloride and benzoyl chloride are the preferred auxiliary acyl halides. They are so cheap that, for the most part, it is not necessary to recover the acids resulting from their reaction with the water present. However, they are no more efiective than the more expensive acids, but constitute the preferred embodiment of the present invention for economic reasons. While a wide range of auxiliary acyl halides may be used, they must be free from substituents, such as hydroxyl or amino groups, which would cause them to be reactive, either with themselves or with the polyalkoxybenzoyl halide. This is the only restriction on the nature of the auxiliary acyl halide to be used.

The amount of auxiliary acyl halide is not as sharply critical. However, they should normally be used in amounts of at least 0.1 mol per mol reaction medium, but it is an advantage of the invention that the reaction may also be eifected in a reaction medium which contains other organic solvents or diluents which, in some cases, are cheaper than the tertiary amine and, therefore, reduce the manufacturing cost. Typical solvents are monochlorobenzene, mononitrobenzene, dichlorobenzene, methylbutylketone, dibutyl ether and the like. Of course, the other solvents or diluents must be inert.

The exact order in which the acyl halides are used is not important. A very convenient method is to mix the acyl halides in advance. However, they may be used separately. For example. the reaction may be started with a polyalkoxybenzoyl halide, followed by the addition of the auxiliary acyl halide in the necessary amounts. In many cases, this latter procedure is preferable.

Isolation of the product presents no problem and is efiected by ordinary methods. The process of the present invention does not affect this step, except insofar as it eliminates side reactions and therefore makes the separation from the reaction mixture simpler.

The invention will be described in greater detail in conjunction with the specific examples, the parts being by weight unless otherwise specified.

EXAIWPLE 1 Acylation of didmino stilbene disulfonic acid with ZA-dimethoxy benzoyl chloride; auxiliary acid chloride: benzoyl chloride CHaO- of polyalkoxybenzoyl halide and may be increased up to 1 mol per mol of polyalkoxybenzoyl halide. A

Larger amounts are unnecessary.

Among the polyalkoxybenzoyl halides used in the present invention are 2,4-dimethoxybenzoyl halide, 2,4-diethoxybenzoy1 halide, 2,5-dimethoxybenzoyl halide, 2,3-dimethoxybenzoyl halide, 2,4,6-trimethoxybenzoyl halide, 2,4,6-triethoxybenzoy1 halide and the like. Industrially, the most important is the 2,4-dimethoxybenzoyl halide, as it can be used to acylate diaminostilbene sulfonic acids and diaminodibenzothiophenedioxide disulfonic acids to produce valuable fluorescent agents for optical bleaching. It therefore constitutes the preferred embodiment, as far as the polyalkoxybenzoyl halide is concerned.

The reaction of the present invention is applicable to many other aromatic amino sulfonic acids, in which the amine is primary or secondary and, therefore, capable of acylation. Typical examples are sulfonated anilines, such as sulfanilic, orthanilic or metanilic acids, sulfonated naphthylamines, such as naphthionic acid, alphanaphthylamine 6- or 7-sulfonic acid and the like.

As stated above, the process of the present invention is eifected in the presence of a tertiary amine. Typical tertiary amines are the hterocyclic bases, such as pyridine, picolines and lutidines; aliphatic amines, such as triethylamine, dimethylcyclohexylamine; and tertiary aromatic amines, such as dimethylaniline.

The tertiary amine may be-the sole diluent or soin soa H (IJONH CH=OH NIH-4'30 OCH:

l I OCH; OCH:

A mixture of 91.4 parts of 2,4-dimethoxybenzoic acid, parts of benzene and 72.2 parts of thionyl chloride is heated at 50 C. to form the acid chloride, excess thionyl chloride and benzene then being removed by distillation under re-v duced pressure. The resulting solution is added gradually to a mixture of 92.5 parts (pure basis) of 4,4-diaminostilbene-2,2'-disulfonic acid and 490 parts of anhydrous pyridine. After a short period of refluxing, 31.6 parts of benzoyl chloride is added and the reaction completed under reflux.

The mixture is drowned in a solution of 125 parts of sodium chloride and 106 parts of sodium carbonate in 1000 parts of water. After removal of the pyridine by steam distillation, the slurry of product is cooled and filtered, followed by washing with 2% salt solution and drying at 100 C. The yield of pure product is 91-92%.

If the benzoyl chloride is omitted in the above procedure, the yield of product is reduced to about 70%.

EXAMPLE 2 Acylation of diamino stilbene disulfonic acid with 2,4-dimethoacy benzoyl chloride; auxiliary acylating agent: acetyl chloride A mixture of 36.4 parts of 2,4-dimethoxybenzoic acid and 47.6 parts of thionyl chloride in 90 parts of benzene is reacted at 50 'C., excess thionyl chloride then being removed by distillation under reduced pressure. The product is added to a refluxing mixture of parts of pyribasis) of 4,4'-diaminostilbene 2,2 disulfonic acid. After addition is completed, the reaction mixture is refluxed for a short time and there is gradually added 8.65 parts of acetyl chloride. Acylation is completed under reflux and the product is drowned in a solution of 42.5 parts of sodium carbonate and 50 parts of sodium chloride in 400 parts of water. The mixture is freed of pyridine by steam distillation, cooled and filtered. The product is washed with 2% salt solution and dried at 100 C. The yield of pure product is quantitative.

If an equivalent quantity of 2.4-diethoxybenzoic acid is substituted for the 2,4-dimethoxybenzoic acid in the above example, similar results are obtained.

EXAMPLE 3 A'cylation of diamino stilbene disuljonic acid with 2,4-dimethozy benzoyl chloride; auxiliary acylating agent: anisoyl chloride To a mixture of 37.0 parts (pure basis) of 4,4- diaminostilbene-2,2-disulfonic acid and 195 parts of pyridine (water content 0.18%), at the boil, 40.1 parts of 2,4-dimethoxybenzoyl chloride is added as rapidly as possible without causing too rapid refluxing. This is followed after a short period by 20.5 parts of anisoyl chloride. After completion of the reaction, the mixture is drowned in a solution of 50 parts of sodium chloride, 42.5 parts of sodium carbonate in 400 parts of water. After steam distillation to remove the pyridine, the product is cooled, filtered, washed with brine and dried at 100 C. The yield of pure material is approximately 93%.

EXAMPLE 4 Diamino stilbene disulfonic acid and 2,4-dimethoazy benzoyl chloride; auxiliary acylating agent: o-ethomy benzoyl chloride The procedure of Example 3 is followed, except that the anisoyl chloride is replaced by 22.2 parts of o-ethoxybenzoyl chloride. A still higher yield of product is obtained.

EXAMPLE 5 Diamino stilbene disuljonic acid and 2,4-dimethorg benzoyl chloride; auxiliary acylating agent: p-tolugl chloride The acid chloride is prepared in the ordinary manner from 13.6 parts of p-toluic acid and 23.8 parts of thionyl chloride in 23 parts of dry benzene, excess thionyl chloride then being removed by distillation under reduced pressure. The resulting p-toluyl chloride is used in place of the anisoyl chloride, in the procedure of Example 3. An excellent yield of pure bis(2,4-dimethoxy benzamido) stilbene disulfonic acid is obtained.

EXAMPLE 6 A slurry of 37.0 parts (pure basis) of 4,4'-diaminostilbene-2,2'-disulfonic acid in 195 parts of pyridine (water content 0.18%) is heated to the boil. As rapidly as possible without causing too vigorous refluxing, there is added a mixture of 40.1 parts of 2,4-dimethoxybenzoyl chloride, prepared as described in the preceding examples and 16.9 parts of benzoyl chloride. Refluxing is continued briefly until acylation is complete, as shown by the absence of free amino groups in the reaction mixture. The solution is then drowned in 400 parts of water containing 42.5 parts of sodium carbonate and 50 parts of sodium chloride. After removal of the pyridine by steam distillation, the product is cooled, filtered, washed with 2% brine and dried at 100 C. The yield of pure product is EXAMPLE '7 3,7 diaminodibenzothiophenedioxide 2,8 disulfonic acid and 2,4-dimethomybenzoyl chloride; auxiliary acylating agent: benzoyl chloride OCH:

' CHzO .(SCH: To a slurry of 50.4 parts of the monopyridine salt of 3,7-diaminodibenzothiophene dioxide-2,8- disulfonic acid in 200 parts of pyridine is gradually added, at reflux temperature, 40.1 parts of 2,4-dimethoxybenzoyl chloride. After a short additional reflux period, 14.05 parts of benzoylchloride is added. Upon completion of the reaction, the mixture is drowned in a solution of 153 parts of sodium chloride and 122 parts of sodium carbonate in 1070 parts of water. After removal of the pyridine by steam distillation, the product is cooled, filtered, washed with brine and ice water and dried at C. The yield of pureproductis 91 -92%.

If the benzoyl chloride is omitted, the yield of product is substantially reduced.

EXAMPLE 8.

A slurry of 50.4 parts of the monopyridine salt chloride, acylation being completed by heating at C. The reaction mixture is then drowned in a solution of 153 parts of sodium chloride and 122 parts of sodium carbonate in 1000 parts of water. After removal of solvent by steam distillation, the product is cooled, filtered, washed with brine and dried.

' EXAMPLE 9 Sulfanilic acid and 2,4-dimethoxgbeuzoyl chloride; auxiliary acylatiug agent: benzoyl chlo- CHaO A slurry of 38.2 parts of sulfanilic acid in parts of pyridine is heated to the boil and there is added to it 40.1 parts of 2,4-dimethoxybenzoyl chloride. This is followed by 14.1 parts of benzoyl chloride, the reaction being completed under reflux. The mixture is drowned in a solution of 50 parts of sodium chloride and 42.5 parts of sodium carbonate in 400 parts of water. After removal of the pyridine by steam distillation, the

7 product iscooled, salted with-"70 partsof sodium chloride, filtered, washed with 10% salt solution and dried at 110 C.

EXAMPLE 10 Naphthz'onzc acid and ZA-dimethomybenzoyl chloride; auxiliary acylating agent; benzoyl chloride ICONH SOaH CHaO OCH:

EXAMPLE 11 Diamz'nostz'lbenedisulfonic acid and 2,4-dimethomybenzoyl chloride; auxiliary acylating agent: butyryl chloride l The procedure of Example 2 is followed, re-

placing the acetyl chlorideby 10.6 parts of butyryl chloride. Results are similar.

EXAMPLE 12 A slurry of 25.7 parts of 3,7-diaminodibenzothiophene-5,5'-dioxide-2,8-disulfonic acid monopyridine salt in 90 parts of nitrobenzene and 29. parts of triethylamine is prepared. To theslurry with stirring is added 26.3 parts of 2,4-dimethoxybenzoyl chloride prepared from 23.8 parts of 2,4- dimethoxybenzoic acid and 34.4 part of thionyl chloride in the usual manner. The mixture is heated to 135 C. and held at that temperature. for one-half hour. Then 14.1 parts of benzoyl.

chloride is added. After heating until a negative test for free amino groups is obtained, the mixture is drowned in a solution of 61. partsof soda ash and 76 parts of salt in 500 parts, of water and the nitrobenzene and triethylamine are removed by steam distillation. The product is recovered by filtration, washed thoroughly with 2% salt brine and dried at 110 C.

We claim:

1. In a process of producing a polyalkoxybenzamido sulfonic acid by the acylation of an aromatic amino sulfonic acid selected from the group consisting of stilbene amino sulfonic acids, dibenzothiophenedioxide amino sulfonic acids, benzene amino sulfonic acids and naphthalene amino sulfonic acids, in substantially nonaqueous medium comprising a tertiary organic amine, the improvement which comprises using a mixture of a poly (lower-alkoxy) benzoyl halide having at least one alkoxy group ortho to the acyl group and an auxiliary acid halide of a different organic carboxylic acyl, other than a polyalkoxybenzoic acid having at least one alkoxy group ortho to the acyl group, having a dissociation constant in therange of 1 10- to 9X10- said auxiliary acyl halide being free from groups reactive with the other reactants.

2. An improvement according to claim 1 in whichthe poly (lower-alkoxy) benzoyl halide is a 2,4-di(lower-alkoxy) benzoyl chloride.

3. Process according to claim 2 in which the poly (lower-alkoxy) benzoyl halide is 2,4-dimethoxybenzoyl chloride.

4-. Process according to claim 3 in which the auxiliary acyl halide is an aliphatic acid chloride.

5. Process according to claim 4 in which the acyl chloride is acetyl chloride.

6. Process according to claim 1 in which the auxiliary acyl halide is acetyl chloride.

7. Process according to claim 6 in which the tertiary organic amine is a liquid base having a pyridine ring.

8. Process according to claim 1 in which the auxiliary acyl halide is derived from an acid' of the benzoic acid series.

9. An improvement according to claim 8 in which the acyl halide is'benzoyl chloride.

10. Process according to claim 9 in which the tertiary organic amine is a liquid base having a pyridine ring.

11. Process according to claim 10 in which the poly(l0wer-alkoxy)benzoyl halide is a 2,4-di- (lower-alkoxy) benzoyl, chloride.

12; Process according to claim 1 in which the amino sulfonic acid is 4,4'-diaminostibene-2,2- disulfonic acid.

13. Process according toclaim 12 inwhich the.

poly (lower-alkoxy) benzoyl halide is 2,4.-dimethroxybenzoyl chloride.

14. Process according to claim 13 in which the auxiliary acyl chloride is acetylchloride.

15. Process according to claim 1 in which the aminosulfonic acid is 3,7-diaminodibenzothiophenedioxide-2,8-disulfonic acid.

16. Process according to claim 15 in which the poly (lower-alkoxy) benzoyl halide is 2,4-di- (lower-alkoxy) benzoyl chloride.

17. Process according to claim 16 in which the auxiliary acyl halide is an acid chloride of the benzoic acid series.

18. Process according to claim 17 in which the acyl chloride is benzoyl chloride.

ROBERT SIDNEY LONG. DELTON W. HEIN.

References Cited in the fileof this patent UNITED STATES PATENTS Number Name Date 2,156,821 Schneider May 2, 1939 2,468,431 Eberhart et al Apr. 26, 1949 2,497,130 Lubs et al Dec. 14,1950 2,573,652 Scalera et a1 0ct..30, 1951 2,580,234 Lecher et al Dec. 25,1951 2,581,057 Wirth et al. Jan. 1, 1952 2,581,059 Witte Jan. 1, 1952

Claims

1. IN A PROCESS OF PRODUCING A POLYALKOXYBENZAMIDO SULFONIC ACID BY THE ACYLATION OF AN AROMATIC AMINO SULFONIC ACID SELECTED FROM THE GROUP CONSISTING OF STILBENE AMINO SULFONIC ACIDS, DIBENZOTHIOPHENEDIOXIDE AMINO SULFONIC ACIDS, BENZENE AMINO SULFONIC ACIDS AND NAPHTHALENE AMINO SULFONIC ACIDS, IN SUBSTANTIALLY NONAQUEOUS MEDIUM COMPRISING A TERTIARY ORGANIC AMINE, THE IMPROVEMENT WHICH COMPRISES USING A MIXUTRE OF A POLY (LOWER-ALKOXY) BENZOYL HALIDE HAVING AT LEAST ONE ALKOXY GROUP ORTHO TTO THE ACYL GROUP AND AN AUXILIARY ACID HALIDE OF A DIFFERENT ORGANIC CARBOXYLIC ACYL, OTHER THAN A POLYALKOXYBENZOIC ACID HAVING AT LEAST ONE ALKOXY GROUP ORTHO TO THE ACYL GROUP, HAVING A DISSOCIATION CONSTANT IN THE RANGE OF 1X10-5 TO 9X10-5, SAID AUXILIARY ACYL HALIDE BEING FREE FROM GROUPS REACTIVE WITH THE OTHER REACTANTS.