GB1589673A - Anthraquinone colourants - Google Patents

Description

(54) IMPROVEMENTS IN AND RELATING TO ANTHRAQUINONE COLORANTS (71) We, DYNAPOL, a Corporation of the State of California, 1454, Page Mill Road, Palo Alto, California 94304, United States of America do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to anthraquinone intermediates, and has particular reference to intermediates for a family of red colourants for use as dietary additives.

In our copending British Patent Application No: 50547/77 (Serial No. 1589672) there is described and claimed, a polymeric colourant having the formula:

wherein R, and R2 are independently selected from hydrogen, halogen of atomic number 9 through 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitro, and sulfonate; R3 is hydrogen or a lower alkyl of 1 to 4 carbon atoms or a lower alkyl sulfonate of 1 to 4 carbon atoms, B is an organic polymeric backbone attached to N by a covalent bond and characterized as having no crosslinks and containing only covalent bonds stable under the acidic, basic and enzymatic conditions of the mammalian gastrointestinal tract; and n is a number from 10 to 4000.

The intermediates of this invention are useful in the preparation of these polymeric colourants.

According to the present invention therefore there is provided a method for the production of an anthraquinone of the formula 1

where R1 and R2 are independently selected from hydrogen, halogen of atomic number 9 through 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitro and a sulfonate salt, and wherein X is a halogen of atomic number 17 to 53 inclusive.

which comprises the steps of: a) reacting 1-amino-2-methyl-4-halo anthraquinone with a benzyl carboxylic acid chloride in a reaction solvent and b) cyclizing the resultant product with a base to form the anthraquinone of formula 1.

According to another aspect of the invention there is provided a compound of the formula 1.

wherein Rl and R2 are independently selected from hydrogen, halogen, of atomic number 9 to 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitros, and a sulfonate salt and wherein X is a halogen of atomic number 17 through 53 inclusive.

The positions of the pendant nonfused aromatic ring to which Rl and R2 are covalently bonded carry hydrogens. R1 and R2 preferably are separately attached to the ring at the 2, 4 or 6 positions. Preferably, R1 is hydrogen and R2 is selected from the class of substituents set forth hereinabove. More preferably, R, is hydrogen and R2 is hydrogen, chloro or methoxy.

In a most preferred colour R, and R2 are both hydrogen. This is an excellent red.

Surprisingly, the presence of the diverse range of other R1 and R2 substituents, varying from strongly electron withdrawing nitro groups to strongly electron donating alkoxy groups make only minor differences in the shade of these colours. A group of preferred colours having a single nonhydrogen substituent on the nonfused ring is shown in Table I.

TABLE 1 Substituent Ring Position Cl 2 or 4 Br 2 or 4 S03- M+ 4 NO2 2 or 4 -O-CH3 2 or 4 -OC2H5 2 or 4 The colors of this invention may be prepared by the following two routes. These routes are presented as exemplary methods and are not to be construed as limiting the scope of this invention.

The first route begins with 1-amino-2-methyl-4-bromo-anthraquinone, a material marketed by Sandoz Color and Chemical under the tradename AMBAX, or made as in Example I.

This material is reacted with a benzyl carboxylic acid chloride.

corresponding to the nonfused pendant aromatic ring desired in the colorant as follows:

This reaction is carried out in liquid phase in a reaction solvent. Suitable solvents include aprotic organic liquids especially cyclic and acyclic olefinically saturated aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, heptane, C6-C9 hydrocarbon mixed solvents, cyclic and acyclic ethers such as dimethoxyethane, 1,4-dioxane or diglyme. This reaction is carried out at elevated temperatures such as from 50"C to 1500C with temperatures of from 75"C to 1300C being preferred. In our work the atmospheric reflux temperature of the solvent has been used. The reaction could be carried out under pressure to obtain higher temperatures if desired. Reaction time is inversely proportional to temperature. Reaction times of from a few (3-5) minutes to 24 hours generally are employed. The following examples will aid in selecting times and temperatures. At 50-80"C, times of 10-24 hours are usually adequate. At 110-115"C, the reaction appears complete in 20-30 minutes with times of from 20 minutes to three hours being used; at 1500C, 3 to 5 minutes are adequate. Generally, a slight molar excess of the acid halide is employed since it is the less expensive reactant. AMBAX/acid halide ratios of 1:1 to 1:2.0 are generally preferred with ratio of 1:1.1 to 1:1.3 being most preferred.

This AMBAX addition product is then cyclized with base.

The base employed is not critical, any strong inorganic base such as NaOH or KOH will work. From 0.5 to 2 equivalents (basis colorant) of base may be used. This step is generally carried out at elevated temperatures such as 90"C to 250"C with temperatures of 90"C to 200"C being preferred. This step can immediately follow the acid halide addition step by adding to the crude halide addition product and heating for from five minutes to 24 hours.

At 80"C 24 hours is a good reaction time, at 110-1200C, 15 minutes to one hour are employed. At 175-200"C, five minutes are employed. Otherwise, the halide addition product can be isolated by evaporation of solvent and crystallization and dissolved in fresh inert aprotic solvent such as those used for the addition and then treated with base. This more complicated method offers some yield advantages. Both methods yield the intermediate

wherein Rl and R2 are as already defined. It will be appreciated that the Br substituent is present principally because the AMBAX starting material is a bromo compound. Other halo leaving groups (i.e., Cl-, I-) are essentially equivalent. The examples which follow will show the preparation of such equivalent materials. This intermediate may be further reacted at this stage to introduce or change the R1 and R2 substituents. Particularly, sulfonate R,'s or R2,s may be introduced at this stage by liquid phase contact with 100% H2SO4 at 80-150"C for 0.5 to 2 hours, or by treatment with 15-30% oleum at room temperature (18"C) to 500C for 0.5 to 5 hours.

Following is a description by way of example only of methods of carrying the invention into effect.

Example I Preparation of

wherein R1 and R2 are hydrogen.

A. 1-amino-2-methylanthraquinone (300 g) is slurried with 1500 ml of acetic acid in a 5-liter flask. The temperature is raised to 40"C. Neat bromine (405 g) is added over 2.5 hours with stirring at 40-50"C. The mixture is stirred for 20 additional minutes and filtered.

The solids so recovered are washed with acetic acid and water and sucked dry with an aspirator and transferred to a reaction flask along with 150 g of NaHSO3 and 1.5 liters of water. The mixture is gradually heated to 90"C (over two hours) with stirring to give 1-amino-2-methyl-4-bromoanthraquinone as a solid which is recovered from the reaction mixture by filtration in 90% yield, rinsed with water and dried overnight at 1550C and 1 mm Hg absolute vacuum.

It will be appreciated that chlorine or iodine could be substituted for bromine in this reaction if desired.

B.

Br 000 0 REFLUX 0 refIux' O C < C6Hs CH3 O Br O NH2 Br ;Ȯ01cH3 H O Wt used 15.8 g 8.5 g 21.7 g (theory) Moles used 0.050 0.055 Ratio 1.0 1.1 A 250 ml flask equipped with overhead stirrer, water-cooled condenser, an Ar inlet is charged with the bromoanthraquinone of part A and 120 ml of toluene. To the red slurry is added the phenylacetyl and the mixture is heated to reflux. The reaction is followed by thin-layer chromatography. After one hour most of the starting material is gone. After three hours, the reaction appears to be over, although some starting material still remains.

After 3.5 hours total refluxing, the reaction is cooled to ca. 800 and filtered. The dark yellow filtrate is concentrated to ca. 30 ml on a rotory evaporator and cooled. A large amount of dark solid forms which is isolated and washed with ether until a yellow (dark) solid is obtained. The solid is oven dried at 70 , < 1 mm, for four hours to afford 12.5 g (57.6%) of yellow-green solid product.

Wt used 4.56 g 0.45. g 4.37 g (theory) Moles used 10.5 mmole 8.0 mg - f.w.

A 100 ml 3-necked flask is equipped with water-cooled condenser, overhead stirrer, thermowell, and an argon inlet. The flask is charged with the phenylacetyl product of Part B, and 30 ml methyl Cellosolve (Registered Trade Mark). The contents are heated to 122" and the KOH in 0.6 ml H2O is added dropwise over one minute. The reaction is stirred at 1200 for one hour.

The reaction mixture is cooled to about 5"C. Isolation of a solid precipitate, followed by washing, affords 1.71 g (39.1%) of bright, shining gold solid.

The dark, yellow filtrate is concentrated via rotary evaporator to dryness and the dark solid is recrystallized fyom 170 ml of acetic acid to afford 2.3 g (52.6%) of a dull, golden colored powder. Total yield is 4.01 g (91.8%).

Example 11 Preparation of

Wt. used 17.06 g 11.90 g 18.9 g (theory) Moles used 0.100 0.100 A 50 ml flask is charged with the organic acid and the SOCK2. A single boiling chip is added and the flask fitted with air condenser and drying tube. Heating in a 45" oil bath is begun. The reaction is cooled after 23 hours.

To the solution is added 5 ml of benzene. Volatile material is pumped off at room temperature of 0.5 mm Hg. The product is then distilled through a short path vacuum distillation apparatus as a water white product, b.p. 63-64 at 0.10 mm Hg. The yield of distilled product is 12.3 g (65%).

B.

o Br totuene coci ;2ct rettux o H3 &commat;~ NH2 O NH2

Wt. used 15.8 g 10.87 g 120 ml 23.4 g (theory) Moles used 0.050 0.0575 Ratio 1.0 1.15 The procedure of Example I is repeated using the above materials to afford the above product.

5 10 15 20 25 30 35 40 45 50 55 60

Wt. used 9.85 g 0.88 g 9.46 g (theory) Moles used 0.021 0.0157 g Ratio 1.0 0.75 This product and 60 ml of Cellosolve are added to a 250 ml flask. The slurry is heated to 123". The KOH is dissolved in 1.0 ml H2O and added over one minute. The reaction is cooled after heating at 115 for 35 minutes. The mixture is allowed to cool slowly to room temperature and then cooled to 5"C. A solid precipitate is isolated and washed to afford 3.32 g of glittering, brownish/golden crystals.

The dark filtrate is concentrated to dryness and the resultant dark solid recrystallized from 675 ml boiling acetic acid. The greenish-yellow needles are isolated and washed.

Drying at 85 , < mm for four hours affords 3.8 g of a golden solid.

Example III If the preparation of Example II is repeated using the chloro or iodo anthraquinones in place of the bromo anthraquinone shown in Example I, the corresponding chloro or iodo products result.

Similarly, use of the 2,4-dichloro, the 2-chloro, the bromo or the iodo equivalents of the 4-chloro acid in place of the 4-chloro acid in Example II results in the 2,4-dichloro, the 2-chloro, the bromo or the iodo-substituted products respectively.

Example IV Preparation of

The product of Example I,

0.6 g and 4.4 g of 20% oleum are stirred together at room temperature. After one-half hour, it appears that reaction has occurred. The stirring is continued for a total of five hours. The reaction mixture is poured over ice and water and a solid precipitate forms and is collected. The solid is dissolved in a liter of 2 M NH40H, filtered and the solution is evaporated to dryness. The solid which results is extracted with methanol. The methanol is evaporated to afford 0.775 g of the desired sulfonate product.

Example V

A 5hers. C R.T.

){2NHo2' Shrs. tR.

coc' Wt. Used 18.11 g 12.0 19.9 (theory) Moles Used .100 .101 The reagents are weighed into a flask and allowed to stand at room temperature ( - 21 ) overnight. A stirring bar is added and the reaction driven to completion by warming at 35 until no solid is visible (five additional hours). To the red solution is added 5 mls benzene and the volatile material is removed with vacuum.

B. The 2-nitro acid chloride of Part A is reacted with AMBAX and the ring is closed to give the product

The general reactions of Example I are used. The reaction of this acid chloride with AMBAX is more facile and requires only three hours at reflux.

Example V1 This example illustrates an alternative preparation of the compound of this invention.

o Br 0 Br O Br O Br oo CH3 0 2 100-1130 O NH2 COCI < NH Wt. used 1.897 kg 1.113 kg 370 g Moles used 6.0 7.2 Ratio 1.0 1.2 A 22-liter resin kettle is charged with the anthraquinone and 13.8 liter of diglyme. The reactor is fitted with a 4-necked head which is equipped with overhead stirrer, thermocouple, argon outlet/reflux condenser, and an argon inlet to sweep the system. The reaction mixture is then heated to 111-113 and the acid chloride is added quickly. After 30 minutes at 111-113 , a pH probe is inserted into the reaction mixture in place of the argon inlet. A solution of 370 g of potassium hydroxide in 346 ml of water is then carefully added portionwise while the pH of the system is monitored. By the end of the hydroxide addition, the pH meter should give a reading of ca. 10.3. Product soon begins to drop out and after a total reaction time of 90 minutes (including 30 minute acetylation time) the heating mantle is turned off.

Next the system is cooled refluxively by gradually reducing the internal pressure using a water aspirator. When the pressure reaches 27-inch Hg of vacuum, the internal temperature is 55 . The vacuum is released and 3 liter of methanol are added. The resultant slurry is then filtered via a ceramic filtering crock and sucked dry. The filter cake is washed with one 4-liter portion of methanol, sucked dry at a large water aspirator, and finally vacuum oven dried overnight at 80 , 0.4 mm Hg. The yield of yellow-green product is 1.904 kg (76%).

WHAT WE CLAIM IS: 1. A method for the production of an anthraquinone of the formula 1

wherein Rl and R2 are independently selected from hydrogen, halogen of atomic number 9 to 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitro, and a sulfonate salt, and wherein X is a halogen of atomic number 17 to 53 inclusive, which comprises the steps of: a) reacting 1-amino-2-methyl-4-halo anthraquinone with a benzyl carboxylic acid chloride in a reaction solvent and b) cyclizing the resultant product with a base to form the anthraquinone of formula 1.

2. A method according to claim 1 wherein the solvent is an aprotic organic liquid.

3. A method according to claim 2 wherein the aprotic liquid is selected from a cyclic or acylic olefinically saturated aromatic or aliphatic hydrocarbon, or a cyclic or acylic ether.

4. A method according to any one of claims 1 to 3 wherein step (a) is effected at a temperature in the range 50 to 1500C.

5. A method according to claim 4 wherein the temperature selected is the atmospheric reflux temperature of the solvent selected.

6. A method according to any one of claims 1 to 5 wherein the molar ratio of the 1-amino-2-methyl-4-halo anthraquinone to the benzyl carboxylic acid chloride is in the range of 1:1 to 1:2 respectively.

7. A method according to any of the preceding claims wherein the base of the step (b) is a strong inorganic base.

8. A method according to any preceding claim wherein the step (b) is effected at a temperature of 90"C to 250"C.

9. A method according to any preceding claim wherein the product resultant from step (a) is isolated prior to utilization in step (b).

10. A method according to any preceding claim wherein X is bromo-.

11. A method according to any preceding claim wherein R, or R2 are introduced into the molecule after step (b).

12. A method according to any one of the preceding claims and substantially as hereinbefore set forth.

13. A compound of the formula I

wherein R1 and R2 are independently selected from hydrogen, halogen of atomic number 9 to 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitros, and a sulfonate salt and wherein X is a halogen of atomic number 17 through 53 inclusive.

14. A compound according to claim 13 wherein X is bromo-.

15. A compound according to either of claims 13 or 14 wherein R, or R2 are both hydrogen.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (18)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   4-liter portion of methanol, sucked dry at a large water aspirator, and finally vacuum oven dried overnight at 80 , 0.4 mm Hg. The yield of yellow-green product is 1.904 kg (76%).

   WHAT WE CLAIM IS: 1. A method for the production of an anthraquinone of the formula 1

   wherein Rl and R2 are independently selected from hydrogen, halogen of atomic number 9 to 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitro, and a sulfonate salt, and wherein X is a halogen of atomic number 17 to 53 inclusive, which comprises the steps of: a) reacting 1-amino-2-methyl-4-halo anthraquinone with a benzyl carboxylic acid chloride in a reaction solvent and b) cyclizing the resultant product with a base to form the anthraquinone of formula 1.
2. 2. A method according to claim 1 wherein the solvent is an aprotic organic liquid.
3. 3. A method according to claim 2 wherein the aprotic liquid is selected from a cyclic or acylic olefinically saturated aromatic or aliphatic hydrocarbon, or a cyclic or acylic ether.
4. 4. A method according to any one of claims 1 to 3 wherein step (a) is effected at a temperature in the range 50 to 1500C.
5. 5. A method according to claim 4 wherein the temperature selected is the atmospheric reflux temperature of the solvent selected.
6. 6. A method according to any one of claims 1 to 5 wherein the molar ratio of the 1-amino-2-methyl-4-halo anthraquinone to the benzyl carboxylic acid chloride is in the range of 1:1 to 1:2 respectively.
7. 7. A method according to any of the preceding claims wherein the base of the step (b) is a strong inorganic base.
8. 8. A method according to any preceding claim wherein the step (b) is effected at a temperature of 90"C to 250"C.
9. 9. A method according to any preceding claim wherein the product resultant from step (a) is isolated prior to utilization in step (b).
10. 10. A method according to any preceding claim wherein X is bromo-.
11. 11. A method according to any preceding claim wherein R, or R2 are introduced into the molecule after step (b).
12. 12. A method according to any one of the preceding claims and substantially as hereinbefore set forth.
13. 13. A compound of the formula I

    wherein R1 and R2 are independently selected from hydrogen, halogen of atomic number 9 to 53 inclusive, lower alkyls and lower alkoxies of from 1 to 3 carbon atoms, nitros, and a sulfonate salt and wherein X is a halogen of atomic number 17 through 53 inclusive.
14. 14. A compound according to claim 13 wherein X is bromo-.
15. 15. A compound according to either of claims 13 or 14 wherein R, or R2 are both hydrogen.
16. 16. A compound according to any of claims 13 to 15 wherein Rl and R2 are attached at

    the 2, 4 or 6 positions.
17. 17. A compound according to any one of claims 13, 14 or 16 wherein R is hydrogen and R2 is hydrogen, chlorine or methoxy.
18. 18. An anthraquinone according to claim 13 and substantially as hereinbefore set forth with reference to the foregoing Examples.