IE46298B1 - Process for making 2-amino-4-hydroxyquinolines - Google Patents

Abstract

The invention relates to the preparation of 2-amino-4-hydroxyquinoleines. [FR2377384A1]

Description

This invention relates to a process for production of 2 - amino - 4 - hydroxyquinolines. More particularly, it relates to the reaction of an isatoic anhydride with malononitrile in the presence of a base to produce as intermediate a 2 - amino - a,a - dicyanoacetophenone and a 2 - amino - 3 - cyano - 4 - hydroxyquinoline, followed by hydrolysis and decarboxylation of said intermediates under acid or base conditions.

The synthesis of 2 - amino - 4 - hydroxyquinolines via the fusion of ethyl cyanoacetate with an anilinium benzenesulfonate or p-toluenesulfonate is described by Hardman et al, J. Chem. Soc., 3878 (1954). Gabriel, Ber., 51 1500 (1918)/reports preparation of 2 - amino - 4 hydroxyquinoline by reduction of ethyl a - cyano - a 15 (o - nitrobenzoyl)acetate and by hydrolysis of a cyano -a - (o - phthalimidobenzoyl)acetate. These methods, however, are characterized by relatively low yields, poor availability of necessary reactants and, in the case of the fusion procedure described above, limitation as to the amount of product which can be made in a single preparation.

For convenience, isatoic anhydride, the trivial but widely used and recognized name for 2H - 3,1 benzoxazine - 2,4 - (IH) - dione, is used throughout this document. -- 3 The reactions of N-alkyl isatoic anhydrides with malonic acid esters to produce N-alkylquinolinediones is reported by Coppola, et al, J. Org. Chem. 41, 825 (1976). The replacement of malonic esters by compounds having an active methylene group and an electrophilic group capable of reacting with the liberated anilino nitrogen, for example, carbanions of the appropriate nitroacetate, phosphonoacetate, phosphonoacetonitrile or β-ketosulfone, permits introduction of nitrogen, phosphorus or sulfur substituents in the 3-position of the quinoline system.

Coppola, et al, (loc. cit), also describe the reaction of N - (3 - chloropropyl)isatoic anhydride and of N - (2 - propynyl)isatoic anhydride with the sodium salt of malononitrile to produce 2,3,4,6 - tetrahydro 6 - oxo - IH - pyrimido/I,2 -_a7guinoline - 5 carbonitrile and 1,2,3,5 - tetrahydro - 2 - methylene 5 - oxoimidazo/1,2 -_a7quinoline - 4 - carbonitrile, respectively.

It has now been found that 2 - amino - 4 hydroxyquinolines can be conveniently prepared by a process which comprises the steps of (a) reacting an isatoic anhydride with malonitrile in a reaction-inert solvent under basic conditions and (b) then treating the reaction product of step (a) thus produced with acid or base.

The process is of general applicability to the synthesis of 2 - amino - 4 - hydroxyquinolines. Particular interest, however, resides in the 2 - amino - 4 hydroxyquinolines having the formula and acid addition salts thereof, wherein each of R^, Rg and Rg is hydrogen, alkyl having from 1 to 5 carbon atoms, alkoxy having from 1 to 5 carbon atoms, fluoro, chloro, bromo, methylthio or methylsulfinyl; with the proviso that no more than two of R·^, R2 and Rg are bulky groups; i.e., branched chain alkyl or branched chain alkoxy, and when two of said R^, Rg and Rg are bulky groups they are located on non-adjacent positions or R^ and Rg when taken together are 1,3-butadienyl or alkylenedioxy of 1 to 2 carbon atoms; because of their use as intermediates for production of 1 - oxo - IH - 6 - alkoxypyrimido/T) 2 -_a7~ quinoline - 2 - carboxylic acids and esters which are of value as antiallergy agents. These latter compounds, their preparation and use are described in Belgian Patent 827,407, granted October 1, 1975.

Accordingly, the present invention provides a process for production of 2 - amino - 4 - hydroxy20 quinolines having the formula or an acid addition salt thereof wherein each of R^, R2 and R3 is hydrogen, alkyl having from 1 to 5 carbon atoms, alkoxy having from 1 to 5 carbon atoms, chloro, bromo, fluoro, hydroxy, methylthio or methylsulfinyl; or R-£ and R2 when taken together are attached to adjacent ring carbon atoms and are 1,3-butadienyl or alkylenedioxy having from 1 to 2 carbon atoms; which comprises the steps of: (a) reacting an isatoic anhydride having the wherein R^, R2 and R3 are as defined above, in a reaction-inert solvent with malonitrile in the presence of a base, and (b) treating the reaction product of step (a) with strong acid or strong base at a temperature of from 80°C to 150°C.

A preferred embodiment of the invention is when 20 the process is carried out for the production of compounds of formula (I) above wherein each of R. and Rg is hydrogen.

Suitable solvents for step (a) are the following and mixtures thereof: N,N - dimethylformamide, N,N dimethylacetamide, dimethylsulfoxide, 2,4 - dimethyl5 tetrahydrothiophene 1,1 - dioxide, hexamethylphosphoramide, cyclic and acyclic ethers, alkanols especially those having up to ten carbon atoms, crown ethers (macrocyclic polyethers) such as those described by Pedersen in J. Am. Chem. Soc., 89, 7017 (1967) and by Pedersen et al in Angew. Chem. Internat. Edit. 11, 16 (1972), and aromatic hydrocarbons such as benzene, xylene and toluene.

As illustrated herein, not all the reactants need be soluble in the particular solvent used. It is sufficient if either the isatoic anhydride reactant or the molononitrile be soluble in the solvent used, and that the reactants and products not enter into reaction with the solvent, except as noted below, under the reaction conditions used. The exception refers to possible reaction of the base with the solvent.

Bases suitable for the reaction of step (a) comprise a wide variety of bases of organic and inorganic nature which can be used. Representative organic bases are trialkylamines, especially those having from three to twelve carbon atoms? N - methylmorpholine and N,N dimethylaniline. Representative inorganic bases are alkali metal amides, alkoxides, hydrides and hydroxides, especially those of sodium and potassium? triphenylmethyl sodium; and metallic sodium and potassium.

As the man skilled in the art will recognize, some of the useful bases enumerated above, particularly those of inorganic nature, will react with certain solvents. Metallic sodium or potassium, for example, will react with alkanols? and alkali metal hydroxides will react with crown ethers. Thus, depending upon the 46398 - 7 extent of its reaction with the solvent, the base added to the reaction may or may not be the base which actually expedites the reaction. However, included within the bases suitable for the reaction of step (a) are those formed by reaction of the added base with the solvent.

The reaction of step (a) is preferably conducted at a temperature of from 20°C to 150°C. The favored temperature is from 50°C to 100°C, especially from 50°C to 60°C.

The products of the reaction of step (a) are 2 amino - α,a - dicyano - aoetophones (formula III) and - amino - 3 - cyano - 4 - hydroxyquinolines (formula .which IV). It appears that formula III compounds/are produced first, under the conditions of the reaction, undergo partial cyclization to formula IV compounds.

The formation of a mixture of compounds of formulae III and IV in step (a) is immaterial to the overall process of this invention since, under the conditions of step (b), they are each converted to 4hydroxyquinolines (formula I). Separation of the compounds is not necessary. For reasons of convenience and economy, it is preferred to use the reaction product of step (a) without purification in step (b). They are recovered by acidifying the reaction mixture, - 8 for example by pouring the reaction mixture into cold dilute hydrochloric acid. The resulting precipitate, a mixture of the above-named products, is then treated with acid or base, step (b), to produce the desired 2 - amino - 4 - hydroxyquinolines.

In step (b), the reaction product of step (a) is treated with a strong acid or a strong base at a temperature ranging from 80°C to 150°C. Higher temperatures appear to offer no advantage and may even reduce the yield of the desired product as a result of degradation reactions. At lower temperatures the reaction is so slow as to be of no practical use.

The choice of acid or base conditions to convert the reaction product of step (a) to the desired 2 amino - 4 - hydroxyquinoline is dependent upon the value of the R^, R2 and Rg substituents. When R^, R2 or Rg is a group which would undergo reaction with acid e.g., an ether group, and retention of said group in its original form is desired, then a base is used in step (b) to achieve the aforesaid conversion. If hydrolysis of the ether group is desired, then, of course, an acid, e.g. HBr, can be used to accomplish the conversion of the step (a) reaction product to a 2 - amino - 4 - hydroxyquinoline and hydrolysis of the ether group in a single step.

The isolated reaction product of step (a) is suspended in a strong acid or strong base and the resulting mixture heated to a temperature of from 80°C to 150°C. Suitable strong acids are hydrobromic acid, hydrobromic acid-acetic acid, sulfuric acid and hydrochloric dcid. When using hydrochloric acid, the reaction is carried out under pressure as, for example, in a glass bomb. The favored acid is hydrobromic acid, especially 48%, hydrobromic acid, since it affords good yields of the desired 2 - amino - 4 - hydroxyquinolines - 9 in a readily isolable form, i.e., as the hydrobromide salts.

The products resulting from acid treatment of step (a) reaction products are isolated in the form of their acid addition salts corresponding to the acid used by chilling the reaction mixture, or by evaporation.

They are converted to their base form by neutralization of an aqueous solution (or suspension) of the acid with base. The 2 - amino - 4 - hydroxyquinoline products generally precipitate and are recovered by filtration.

If precipitation of the 2 - amino - 4 - hydroxyquinoline product does not occur, it is recovered by evaporation or by addition of a water-miscible organic solvent to precipitate it from the solution.

As noted above, conversion of the reaction product of step (a) to a 2 - amino - 4 - hydroxyquinoline can also be accomplished by treatment with a strong base. Suitable strong bases are the alkali metal hydroxides, especially aqueous solutions of sodium or potassium hydroxide of 6N or higher concentration, since they afford satisfactory yields of desired 2 - amino - 4 hydroxyquinolines. The products are recovered by neutralization of the alkaline reaction mixture to precipitate the free 2 - amino - 4 - hydroxyquinoline.

Many of the required isatoic anhydride reactants are available commercially. Those which are not, are conveniently synthesized from the appropriate anthranilic acid and phosgene according to the procedure reported by Wagner et al., Ora· Syn., Coll. Vol. Ill, 488 (1955). The requisite anthranilic acids, if not known compounds, are obtainable by methods known to those skilled in the art.

The 2 - amino - 4 - hydroxyquinolines are valuable intermediates for production of 1 - oxo - IH - 6 alkoxypyrimido/T, 2 ^a/quinoline - 2 - carboxylic acids - 10 and its esters which are useful as antiallergy agents and have the formula wherein R^, Rg and Rg are as defined above; R^ is hydrogen or alkyl; and Rg is alkoxy having from 1 to 5 carbon atoms.

Compounds of formula II are prepared from 2 amino - 4 - hydroxyquinolines by the reaction sequence comprising conversion of the appropriate 2 - amino - 4 10 hydroxyquinoline to a 2 - amino - 4 - alkoxyquinoline by reaction with a lower alkyl ester of an arylsulfonic acid or by reaction, as their sodium salts, with a lower alkyl halide. The thus-produced 2 -amino - 4 alkoxyquinolines are then condensed with a dialkyl ethoxymethylenemalonate in a reaction-inert solvent at from 80°C to 125°C., to give a dialkyl 4 - alkoxy - 2 quinolylaminomethylenemalonate which is then cyclized by heating from 175°C. to 25O°C. in a reaction-inert solvent such as a mixture of diphenyl ether and diphenyl, especially that which contains 26.5% diphenyl and 73.5% diphenyl ether and is sold under name Dowtherm A (a registered Trade Mark of) Dow Chemical Co., Midland, Michigan). - 11 The thus-produced alkyl 1 - oxo - IH - 6 alkoxypyrimido/Γ, 2 -_a7quinoline - 2 - carboxylates are then hydrolyzed to the corresponding acids, for example, by heating an aqueous mixture of the appropriate ester with hydrochloric acid at from 50°C to 100°C until hydrolysis is complete. The acids are recovered by filtration if they precipitate upon cooling the reaction mixture, or by evaporation of the reaction mixture.

EXAMPLE 1 2-Amino-4-hydroxyquinoline A solution of isatoic anhydride (49.8 g., 0.3 mole) in 300 ml of dimethylformamide is added, during 30 minutes, to a warm (50°-60°C) solution of malononitrile (21,8 g 0.33 mole) and triethylamine (33.4 g 0.33 mole) in 100 ml of Ν,Ν-diethylformamide. Brisk evolution of carbon dioxide is observed. The reaction mixture is maintained at 50°-60°C for 30 minutes after addition of the anhydride is completed and is then poured into 2500 ml of ice-cold 0.2 N hydrochloric acid. The precipitate which forms is isolated by filtration and dried. It is then suspended in 48% hydrobromic acid (1500 ml) and the mixture refluxed for 20 hours. The resulting clear solution is chilled in an ice bath and the precipitate which forms collected by filtration. It is then dissolved in warm water and, after filtering to remove a small amount of insoluble material, the solution is made alkaline with ammonium hydroxide. The resulting precipitate is filtered, washed with water and isopropanol, and dried to give 41.2 g (86%) of product; m.p. 298°-3OO°C, dec. An analytical sample is recrystailized from methanol-water, m.p. 300°C, dec. Analysis: Calc'd for Ο9ΗθΝ2Ο: C, 67.47,- H, 5.03,- N, 17.49. 43298 - 12 Found: C, 67.23; H, 5.12; N, 17.50.

MS: m/e=160 (m+) Repetition of this reaction but replacing triethyl amine with N-methylmorpholine, N,N-dimethylaniline, tri-n-butylamine, N-decyl dimethylamine, N-hexyl dimethylamine, sodamide, triphenylmethyl sodium, sodium hydride, potassium ethoxide, metallic sodium, or potassium hydroxide, affords the same product.

EXAMPLE 2 2-Amino-4-hydroxy-6-methylquinoline A solution of 5-methyl isatoic anhydride (19.5 g, 0.11 mole) in 150 ml of Ν,Ν-dimethylformamide is added, during 15 minutes, to a warm (55°-6O°C) solution of malononitrile (7.9 g, 0.12 mole) and triethylamine (12.1 g, 0,12 mole) in Ν,Ν-dimethylformamide (100 ml). Carbon dioxide is evolved and the reaction mixture is stirred for 30 minutes after addition of the anhydride is complete without further heating. The resulting clear, dark solution is poured into ice-cold 0.2N hydrochloric acid (1220 ml). The solid which separates is isolated by filtration and dried (19.5 g). A portion of said solid (9.5 g) is then suspended in 48% hydrobromic acid (250 ml-acetic acid (50 ml) and the mixture refluxed for 20 hours. The clear solution that results is chilled in an ice bath and the precipitate which forms is collected by filtration.· It is dissolved in ethanol-water (200 ml of 1:1) and, after filtering to remove a small amount of insoluble material, the filtrate made alkaline with ammonium hydroxide. Crushed ice is added and the solid which precipitates is filtered and dried: 6.2 g (73%); m.p. 343°C (dec).

An analytical sample is prepared by recrystallization from methanol-water. 6 2 3 S - 13 Analysis: Calc'd for cioH1ON2O: C, 68.94; H, 5.79; N, 16.08.

Found: C, 68.75; H, 5.84; N, 16.06.

EXAMPLE 3 2-Amino-6-chloro-4-hydroxyquinoline Following the procedure of Example 2,5-chloroisatoic anhydride (19.8 g. 0.1 mole), malonontrile (7.3 g, 0.11 mole) and triethylamine (11.1 g, Oil mole) are reacted together in Ν,Ν-dimethylformamide (200 ml) to give 20 g of product. Five grams of said product are refluxed for 22 hours in 48% hydrobromic acid (175 ml) to give 4.2 g (86%) yield of title product; m.p. 356°C (dec).

Analysis: Calc'd for CgH^ClNgO: C, 55.54; H, 3.63; N, 14.40 Found: C, 55.17; H, 3.68; N, . 14.26.

Repetition of this procedure but using 12N sulfuric acid in place of hydrobromic acid affords the same product.

EXAMPLE 4 2-Amino-6-methoxy-4-hydroxyquinoline To a solution of malononitrile (6.0 g, 0.91 mole) and triethylamine (9.2 g, 0.091 mole) in N,N-dimethylformamide (50 ml) at 55°-60°C. is added rapidly, and with stirring, a solution of 5-methoxy isatoic anhydride in Ν,Ν-dimethylformamide (100 ml). The reaction mixture is maintained at 55°-6O°C. during addition. Carbon dioxide is evolved and the reaction mixture is stirred - 14 for a half-hour following completion of addition without application of further heating. The clear solution is poured into 0.2N of cold hydrochloric acid (1015 ml) and the resulting precipitate separated by filtration and dried; 16.5 g; m.p. >37O°C.

A portion of said product (1.08 g) is added to 6N potassium hydroxide solution (20 ml) and the mixture heated to reflux for about 18 hours. The clear, dark solution formed is cooled and acidified with acetic acid.

The dark brown solid which precipitates is filtered, taken up in ethanol-water (1:2, 30 ml) and the solution made alkaline with ammonium hydroxide. The resulting solid is filtered and dried. Yield = 710 mg (69%); m.p. 298°-3OO°C.

MS: m/e=190 (m+) Analysis: Calc'd Pound:for C10H10N2 C, 63.14; °2: H, 5.30; N, 14.73. 20- C, 62.85; H, 5.23: N, 14.56. EXAMPLE 5 The procedure of Examples 1 and 4 are repeated but using the appropriate anthranilic acid as reactant to give the following compounds. When any of E^, R2or Rj is alkoxy, the procedure of Example 4 is used.

R1R2R3 7-0CH3 H H 6-OCH3 7-OCH3 H 6-OC2H5 H H 6-F H H H 7-F H H I 7-C1 H 1 6,7-CH==CH - - ch=“—-ca H 5-CH3 H 8-OCH3 H H 8-OCH3 H H 8-C1 6-CH3 H 8-CH3 6-i-C3H7 H H 6,7—0 - ch2 0 H H 7,8-0 —CH2 - — 0 — 5-Br H H H H 8-Br fi 6-n-C4Hg H H 6-sec-C4Hg H H 6-t-C4H9 H 5-Cl H H H H8-C2H5 H6~C2H5 H H 6-OH H fi H 7-OH 5-OH H H 5-OCH3 H 8-OCH3 5-CH3 H 7-CH3 6 2 9 8 R1R2R3 5,6 — 0 - ch2 0 H 6-0—i-C3H? 7-0-i-C3H7 H 6-OH H 8-0H 5 ‘ 6-F 7-F H 6-OC2H5 7-OC2h5 H 6-t-C4Hg 8-t-C4Hg H H 7-Br 8-Br H 7-C1 8-0H 10 6,7*—0 — - CH2-CHg- 0- H 5-OCHg H 7-OCHg 5-OC2H5 H 8-OC2H5 H 6-i-CgH7 8-r-CgHg H 6-SCHg H 15 H 6-SOCHg H H H 7-SCHg 6-0 - n —C^Hg 7-0—n-C^Hg H H 6-0—n-C3H7 7-Br 5-Cl 6-0—n-C3H7 8-C1 20 5-Br 6-SCHg 7-Br H H 7-n-C4Hg 5-Cl 6-0—n-C3H7 7-C1 H 6-SCHg 7-C1 H 6-SOCHg 7-C1 25 H 6-Cl 7-SCHg H 6-Cl 7-SOCHg H 6-SCHg 7-soch3 H 6-SCHg 7-SCH3 R1R2R3 H 6-SOCHg 7-SOCH 6-OCHg 7-OCHg 8-OCHg 5-OCHg 6-OCHg 7-OCHg 5-C1 7-C1 H 6-Cl 7-Cl H 5-C1 6-Br H Η 7,8-CH= CH - CH== CH EXAMPLE 6 2-Amino-4-hydroxyquinoline The procedure of Example 1 is repeated on onetenth the scale described therein and using concentrated hydrochloric acid in a sealed tube in place of 48% hydrobromic acid. The hydrochloric acid treatment is conducted at 125°C. The product is identical to that of Example 1.

Claims (5)

1. CLAIM S.·,1. A process for production of 2 - amino - 4 hydroxyquinolines having the formula 5 or an acid addition salt thereof wherein each of R^, R 2 and Rg is hydrogen, alkyl having from 1 to 5 carbon atoms, alkoxy having from 1 to 5 carbon atoms, chloro, bromo, fluoro, hydroxy, methylthio or fflethylsulfinyl; or Rj and Rg when taken together are attached to 10 adjacent ring carbon atoms and are 1,3-butadienyl or alkylenedioxy having from 1 to 2 carbon atoms; which comprises the steps of (a) reacting an isatoic anhydride having the formula wherein R^, Rg and Rg are as defined above, in a reaction inert solvent with malonontrile in the presence of a base, and - 19 (b) treating the reaction product of step (a) with strong acid or strong base at a temperature of from 80°C to 15O°C.

2. A process as claimed in Claim 1 wherein the 5 temperature of step (a) is from 20°C to 150°C.

3. The process as claimed in either Claim 1 or Claim 2 wherein each of R^ and R 2 is hydrogen.

4. A process as claimed in any one of Claims 1 10 to 3, and substantially as described in any one of Examples 1 to 6.

5. 2 - Amino - 4 - hydroxyquinolines produced by the process of any one of Claims 1 to 4.