HU199402B - Process for producing alpha-azido- and alpha-aminoacyl anilide derivatives - Google Patents

Abstract

Process for the preparation of the compounds of the general Formula (I) and salts thereof <IMAGE> [wherein X<1> is azido or amino and R is hydrogen, C1-4 alkyl or phenyl] which comprises reacting an aniline derivative of the general Formula (II> <IMAGE> [wherein X<2> is chlorine or bromine and R is hydrogen, C1-4 alkyl or phenyl] with alkali metal azide and if desired reducing a thus obtained azide of the general Formula (I) (wherein X<1> is azido and R is as defined above), preferably with a complex alkali hydride or by catalytic hydrogenation, to give the amine of general formula (I) (wherein X<1> is amino and R is as defined above) and if desired converting the obtained product to a salt by reaction with acid.

Description

The present invention relates to a process for the preparation of 2,6-dimethyl-α-amino- or α-azido-acyl anilides.

Throughout this specification, variable substituents always have the following meanings:

R is hydrogen, (C1-C4) -alkyl or phenyl,

X ^{1 is} azido or amino,

X _{2 is} chlorine or bromine.

More particularly, the present invention relates to a process for the preparation of the acetanilide derivatives of the formula I and their salts from a halo anilide of the formula II by reacting a halo anilide of the formula II with an alkali metal azide. The α-azido derivative of formula (IV) is optionally reduced, if desired, by complex alkali hydride or catalytic hydrogenation, and optionally converted to the acid salt.

Among the compounds of formula (I), compounds of formula (III), which are a narrower group of compounds, are known. The other compounds of formula I are novel.

The α-aminoacetanilide derivatives of the formula (III) or their salts are known to be used in the treatment of ventricular tachycardias and arrhythmias and in the treatment of myocardial infarction (Brit. J. Clin. Pharm., 10, 530 (1980); Am. , 1979, 43, 285, several methods for the preparation of these derivatives have been described (U.S. Patent No. 2,400,540, J. Med. Chem. 22, 1979); J. Med. Chem. (1981) 24, 798. ).

In one method, the haloanilide of formula II (Acta Chem. Scand., 8, 1804, 1806) was reacted directly or indirectly with ammonia to form a phthalimide derivative by Gabriel synthesis and then removed by hydrazinolysis to form an amino group. Who.

Disadvantages of forming the amino group as described above: direct ammonolysis can generally only be achieved by low conversion (e.g., 28% for the α-amino-α-methylacetanilide derivative, 10% for the corresponding α-phenyl derivative), and the reaction is undesirable and may be accompanied by formation of amines higher than the primary amine.

The hydrazine toxic compound used for the dephthalylation reaction of the phthalimide intermediate (G.D. Muir, Hazard in the Chemical Laboratory, London, The Chemical Society, 1977, p. 277).

According to the present invention, the haloanilides of formula (II) can be reacted with alkali metal azides of formula (IV), preferably with sodium azide in water or in a mixture of aqueous organic solvents, preferably aqueous methyl, or ethyl, or propyl. alcohol, or in the presence of ethylene glycol half-ethers (methyl or ethyl). The resulting compounds of formula I are formed in good yield (70-90%), pure and free of by-products.

Reduction of the a-azidoacetanilides of formula IV with complex metal hydrides, preferably sodium borohydride, in an alcoholic solution, preferably in ethyl alcohol (T. Sheradsky, Azides as Synthetic Starting Materials, in S. Patai, ed.). The Chemistry of the Functional Group, The Chemistry of the Azido Group, Wiley-Interscience, New York, Chapter 6, p. 331, 1971) or by catalytic hydrogenation in a known manner (M. Freifelder, Catalytic Hydrogenation in Organic Synthesis, Procedures and Commentary, Wiley-Interscience, New York, 1978, p. 138).

The reduction product is the pure α-aminoacetanilide of formula (I).

The formation of α-azido and α-aminoacetanilide derivatives thereof can be accomplished in simple equipment; the progress of the reactions; work-up can be easily monitored by thin layer chromatography.

The process of this invention for the preparation of compounds of formula I is advantageous because

1.) the formation of the amino group optimal for the drug effect can be accomplished simply without atmospheric pressure at atmospheric pressure.

2.) the reactions yield a uniform, pure product with good yield

3.) the starting materials of the compounds are readily available and are not harmful to health.

The invention is illustrated by the following non-limiting examples.

la. example

2.6-Dimethyl-α-azidoacetanilide (I).

formula; R = H, X '= N ₃ )

To a solution of 2.6-Dimethyl-α-chloroacetanilide (5.91 g, 0.03 mol) in acetone (50 ml) was added an aqueous solution (10 ml) of sodium azide (2.93 g, 0.045 mol). The reaction mixture was refluxed at the boiling point of the solvent mixture. The progress of the reaction was monitored by TLC (Kieselgel 60 F 254, 0.2 mm layer, chloroform / ether 1: 1) and worked up by refluxing for 5 hours: the solvent was evaporated in a water bath under vacuum, water (15 mL) and chloroform (25 mL). ), the organic layer was separated and the aqueous portion was extracted with two further portions of chloroform (20 mL). The combined organic solutions were dried over sodium sulfate, filtered, and the filtrate was evaporated in a water bath under vacuum (2666 Pa). The residue was dissolved in ether (50 mL), and the crystalline product from the cooled solution was filtered and dried.

Yield: 4.45 g (72.7%).

Analysis calculated for C ₁₀ H ₂ N ₄ O (mol% = 204.24):

H, 5.92; N, 27.43. Found: C, 58.62; H, 5.88; N, 27.33.

IR (nujol): 3200-3300 (NH), 2090 (N ₃ ), 1650 (CONH) cm ^-1 .

-2HU 199402 Β lb. example

2.6-Dimethyl-α-azidoacetanilide

To a solution of 2.6-dimethyl-α-chloroacetanilide (3.95 g, 0.02 mol) in dimethylformamide (50 ml) was added an aqueous solution (10 ml) of sodium azide (1.95 g, 0.03 mol) and the mixture was stirred at 50-60 ° C. C was held for 4 hours. Meanwhile, the progress of the reaction was monitored by TLC (Kieselgel 60 F 254 in 0.2 mm layer, chloroform / ether 1: 1). The solvents were evaporated under reduced pressure, water (50 mL) was added and the residue was partitioned between chloroform (3 X 50 mL). The organic solution was dried over sodium sulfate, filtered and evaporated (2700 Pa). The residue was dissolved in ether, cooled, and the crystalline precipitated base was filtered, washed with ether / n-hexane (1: 1) and dried. Yield: 2.95 g (72.3%), m.p. 86-88 ° C. The physical constants and spectral values of the product were the same as in la. Example.

2a. example

2.6-Dimethyl-α-azidopropionyl anilide (Formula I; R = CH ₃ , X '= N ₃ )

A solution of sodium azide (2.93 g, 0.045 mol) in water (10 ml) was added to a solution of 2.6-dimethyl-α-bromopropionyl anilide (7.68 g, 0.03 mol) in acetone (100 ml) and the reaction mixture was heated for two days. Meanwhile, the progress of the reaction was monitored by TLC (Kieselgel 60 F 254 in 0.2 mm layer, carbon tetrachloride / ether, 9: 1). The solvent was evaporated under reduced pressure, the residue was dissolved in ether (50 mL) and diluted to crystallization starting with n-hexane (about 10 mL). The product was filtered off from the cooled solution, 5.98 g (91%), mp 78-80 ° C.

Analysis value for C _h H ₁₄ N ₄ O (218.26):

H, 6.47; N, 25.67. Found: C, 60.60; H, 6.70; N, 25.88.

IR (nujol): 3200-3350 (NH), 2100 (N ₃ ), 1650 (COHN) cm ^-1 .

2b. example

2.6-Dimethyl-α-azido-propionyl anilide

From 2.6-dimethyl-α-bromopropionyl anilide (5.12 g, 0.02 mol) in dimethylformamide solution (20 ml), a solution of sodium azide (1.95 g, 0.03 mol) in water (10 ml) was added to lb. The product was prepared as described in Example 1b.

Yield: 3.95 g (90%), m.p. 78-80 ° C.

Physical constants and spectral data for the product are the same as in Table 2a. Example.

2c. example

2.6-Dimethyl-α-azido-propionyl anilide

To a solution of 2.6-dimethyl-α-bromopropionyl anilide (5.12g, 0.02 mol) in ethylene glycol monomethyl ether (30ml) was added an aqueous solution (10ml) of sodium azide (1.95g, 0.03 mol) and the reaction mixture was heated to 60 ° C. held for 6 hours. The mixture was cooled to room temperature, diluted with water (100 mL) and partitioned between chloroform (3 X X 50 mL). The chloroform solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in ether (20 mL) and diluted to crystallization starting with n-hexane: Yield: 3.55 g (81%). The product constants and spectral data were the same as in Table 2a. Example.

3a. example

2.6-Dimethyl-α-azido-α-phenylacetanilide (general formula (I); R = Ph, X '= N ₃ )

2.6-Dimethyl-α-chlorophenylacetanilide (8.21 g,

To a solution of 0.03 mol) in acetone (100 ml) was added an aqueous solution of sodium azide (101) (2.93 g, 0.045 mol) and the reaction mixture was refluxed for two days. The progress of the reaction was monitored by thin layer chromatography (Kiesel 2 gel 60 F 254, 0.2 mm layer, chloroform / ether 16: 1). The product is worked up and crystallized according to la. as described in Example 4a.

Yield: 6.40 g (76%), m.p. 139-140 ° C.

Analysis value for C ₁₆ H ₁₆ N ₄ O (280.35):

Found: C, 68.56; H, 5.75; N, 19.99%. Found: C, 68.43; H, 5.88; N, 20.08%.

IR (Nujol): 3100-3300 (NH), 2070 _(N3),

1635 (CONH) cm -1.

3b. example

2.6-Dimethyl-α-azido-α-phenylacetanilide

2,6-Dimethyl-α-chloro-α-phenylacetanilide (5.46 g

To a solution of 0.02 mol) in dimethylformamide (20 ml) was added a solution of sodium azide (1.95 g, 0.03 mol) in water (10 ml). The reaction mixture is prepared as described in lb. .

Yield 3.0 g (73.5%), m.p. 139-140 ° C.

The physical constants of the product were the same

With the product described in Example 3.a.

4a. example

2,6-Dimethyl-α-aminoacetanilide (I).

formula; R = H, X '= NH ₂ ).

To a suspension of sodium borohydride (1.65 g, 0.044 mol) in dry isopropyl alcohol (100 ml) at 0 ° C with stirring was added 2.6 _50- dimethyl-α-azidoacetanilide (4.08 g, 0.02 mol) in isopropyl alcohol (50 mL) was added. After the addition was complete, the cooling was stopped and the mixture was heated to room temperature for 18 hours, during which time the reaction was checked by TLC (Kiesek ⁵⁵ gel 60 F 254, 0.2 mm layer, chloroform / tetrahydrofuran 1: 3). The solvent was evaporated under reduced pressure while heating from a water bath. To the residue was added dilute hydrochloric acid (10%) and extracted with chloroform (3 X ⁶⁰ X ⁵⁰ mL). The acidic aqueous solution was basified with dilute alkali (10% NaOH or KOH) and partitioned between chloroform (3 X X 50 mL). The chloroform salt solution was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ether (30 mL) and cooled.

the precipitated crystals were filtered and dried. Yield 2.3 (65%), m.p. 81-83 ° C.

Analysis calculated for C ₁₀ H ₁₄ N ₂ O (178.25):

Found: C, 67.39; H, 7.92; N, 15.72%. Found: C, 67.21; H, 8.08; N, 15.59%.

IR (nujol): 3150-3350 (NH, NH ₂ ), 1645 (CONH) cm -1.

The base (1.78 g, 0.01 mol) was dissolved in ethyl alcohol saturated with hydrogen chloride gas (15 mL) warm (about 30-40 ° C), cooled to room temperature and diluted to crystallization with ethyl ether and placed in a refrigerator. The next day, the hydrochloride salt of the product was filtered off, washed with ether and dried. The product (1.98 g, 92%) m.p. 294-296 ° C.

Analysis calculated for C, ₀ H, ₄ N ₂ O ₂ HCl (214.71):

Calculated: C 55.95, H 7.04, N 13.05,

Cl, 16.51%. Found: C, 55.94; H, 7.08; N, 13.18.

C, 16.23%

4b. example

2.6-Dimethyl-α-aminoacetanilides

To a solution of 2.6-dimethyl-α-azidoacetanilide (1.97 g, 0.01 mol) in ethyl alcohol (40 ml) was added ca. 0.7 g of palladium on carbon was added and hydrogen was added to the reaction mixture at room temperature with stirring. The progress of the reaction was monitored by TLC (as in Example 4a), which was complete in about 4 hours. The catalyst was filtered off, the filtrate was evaporated under reduced pressure on a water bath, and the residue was dissolved in chloroform (20 mL) and crystallized by diluting with ether. Yield: 1.87 g (87%), m.p. 81-83 ° C. AC | Reported value ₀ H ₁₄ H ₂ O Calcd analysis (see. Example 4 a.) The measured data was C 67.33, H 7.89, N 15.88%.

4c. example

2.6-Dimethite-α-ammoacetanilides

The catalytic hydrogenation is illustrated in Figure 4b. Example 1b. After filtration of the catalyst, the filtrate was concentrated to ca. Hydrochloric acid gas was added to this ethyl alcohol solution to pH = 3 and then diluted with ether to give the hydrochloride salt of the product directly. Yield 1.95 g (91%), m.p. 295-296 ° C. The assay value for the calculated hydrochloric acid salt (see Example 4a) is:

C 55.98, H7.12, N 12.98%.

5a. example

2.6-Dimethyl-α-aminopropionyl anilide (Formula (I), R = CH ₃ X '= NH ₂ ).

A solution of 2,6-dimethyl-α-azido-propionyl anilide (3.27 g, 0.015 mol) in isopropyl alcohol (30 ml) was added to isopropyl alcohol (1.26 g, 0.033 mol) cooled to 0 ° C. to a suspension of alcohol (30 ml) with stirring.

After cooling was stopped, the mixture was refluxed for 18 hours, while the reaction was monitored by 4 thin-layer chromatography (Kieselgel 60 F 254, 0.2 mm layer, chloroform / tetrahydrofuran 1: 3). 4a. was processed following. Yield: 2.45 g (85%), m.p. 208-209 ° C.

Analysis value for C _h H ₁₆ N ₂ O (192.26):

Found: C 68.72, H 8.39, N 14.57%. Found: C 68.79, H 8.46, N 14.63%.

IR (nujol): 3100-3300 (NH, NH ₂ ), 1650 (CONH) cm ^-1 .

The base (1.92 g, 0.01 mol) was dissolved in ethyl alcohol saturated with hydrogen chloride gas (10 mL) and diluted to crystallization starting with ether. The crystals precipitated in the cooled solution were filtered, washed with ether and dried. The hydrochloride salt of the product was 2.06 g (90%), m.p. 152-154 ° C. Analysis calculated for C ,, H value _I6 O.HC1 N ₂ (228.73) ószszegképletre: C 57.77, H 7.49 N 12.25,

Cl, 15.50%. Found: C, 57.68; H, 7.63; N, 12.28.

Cl 15.53%

IR (Nujol): 3280 (NH), 3000-2800 (Í $ H _3), 1665 (CONH) cm ^-1.

5d. example

2.6-Dimethyl-α-aminopropionyl anilides

2,6-Dimethyl-α-azido-propionyl anilide (2.18 g, 0.01 mol) was added in one portion to cooled to -10 ° C sodium borohydride (0.82 g, 0.022 mol) in ethyl alcohol (20 ml). suspension while stirring. After half an hour, it was allowed to warm to room temperature, and the solvent mixture was refluxed for 14 hours. The solvent was evaporated under reduced pressure, water (15 mL) was added and the residue was partitioned between chloroform (3 x 25 mL). The organic solvent was dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in a small amount of chloroform (5 mL) and diluted with ether until starting crystals formed. From the cooled solution, the crystalline product was filtered off, washed with ether and dried. The physical constants and spectrum data of the base are shown in Figure 5b. were identical. Yield: 1.58 g (82%).

5c. example

2.6-Dimethyl-.alpha.-aminopropionylanild

To a solution of 2,6-dimethyl-α-azido-propionyl anilide (4.36 g, 0.02 mol) in one of the preceding Examples (3a, b) in methanol (100 mL) was added 1.2 g of palladium-on-carbon and 4b. The reaction was hydrogenated as described in Example 1 and chromatographed to monitor the progress of the reaction. The reaction mixture was filtered and the solvent was evaporated under reduced pressure (2666 Pa) to a volume of ca. To 20 ml. The alcoholic solution was acidified to pH 2 by the addition of hydrochloric acid gas, diluted with ether to crystallize and the mixture was cooled. The hydrochloric acid salt of the product was filtered off,

It was washed with ether and dried. Yield 3.3 g (86%). The physical constants and spectral data of the product were identical to those of FIG. product.

5d. example

2.6-Dimethyl-α-amino-propionyl anilide

To a solution of 2,6-dimethyl-α-azidopropionyl anilide (6.54 g, 0.03 mol) in ethyl alcohol (150 ml) was added 1.8 g of palladium on charcoal at room temperature and hydrogenated under agitation. Hydrogenation was followed by thin layer chromatography (Kieselgel 60 F 254, 0.2 mm layer, chloroform / methanol 9: 1). Hydrogenation takes approx. Completed in 6 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure and the residue was dissolved in hydrochloric acid in saturated ethyl alcohol (ca. 20 mL) and warm (ca. 40 ° C). The solution was cooled and diluted with ether to crystallize. The crystalline hydrochloric acid salt was filtered off, washed with ether and dried. Yield: 5.1 g (88.5%). The physical constants and spectral values of the product were identical to those of the product prepared by Method 5a-c.

6a. example

2.6-Dimethyl-.alpha.-amino-.alpha.-phenylacetamide (general formula (I); R = Ph, X '= NH).

A solution of 2,6-dimethyl-α-azido-α-phenylacetanilide (5.60 g, 0.02 mol) in isopropyl alcohol (50 ml) was added sodium borohydride (1.65 g, 0.044 mol) in isopropyl alcohol cooled to 0 ° C. After stirring, the mixture was allowed to warm to room temperature and refluxed for 8 hours at reflux temperature.

The progress of the reaction was monitored by TLC (Kieselgel 60 F 254.0.2 mm, chloroform / methanol (9: 1)). The solvent was evaporated under reduced pressure. .

Yield: 4.18 g (82%), m.p. 123-124 ° C.

Analysis for C value _I6 H ₁₈ N ₂ O (254.35) öszszegképletre:

Found: C, 75.56; H, 7.13; N, 11.01%. Found: C, 75.41; H, 6.99; N, 11.12%.

IR: (nujol): 3360 (NH), 3200-3320 (NH ₂ ), 1680 (CONH) cm ^-1 .

The base (2 -54 g) was dissolved in ethyl alcohol saturated with hydrochloric acid (20 mL) while warm (about 40 ° C), ether was added to the solution at room temperature, cooled, and the crystalline HCl salt was filtered, washed with ether and dried. The product (2.5 g, 86%) mp 254-256 ° C).

Analysis for C ₁₆ H _lg N ₂ O.HCl (290.81):

Calculated: C 66.09, H6.59, N9.63, Found: C 66.12, H 6.67, N 9.72,

Cl 12.33%

6b. example

2.6-Dimethyl-α-amino-α-phenylacetanilides

2.6-Dimethyl-α-azido-α-phenylacetanilide (2.80 g, 0.01 mol) was added to a suspension of sodium borohydride (0.82 g, 0.022 mol) in ethyl alcohol (20 ml) cooled to -10 ° C. After stirring, the mixture was allowed to warm to room temperature and then boiled at reflux for 10 hours. The reaction mixture is prepared as shown in Figure 5b. method as described. Yield 4.06 g (80%). The physical constants and spectral values of the product were the same as in Figure 6a. base.

6c. example

2.6-Dimethyl-α-amino-α-phenylacetanilides

From 2.6-dimethyl-α-azido-α-phenylacetanilide (5.60 g, 0.02 mol), the compound of Example 5c is obtained. The base prepared by catalytic hydrogenation as described in Method 6a, 5.04 g (87%), had the same physical constants as in Example 6a. Example.

6d. example

2.6-Dimethyl-α-amino-α-phenylacetanilides

From 2.6-dimethyl-α-azido-α-phenylacetanilide (5.60 g, 0.02 mole), the product of 5d. method was hydrogenated and worked up. Yield: 5.20 g (89.6%). The physical constants and spectral values of the product were the same as in Figure 6a. hydrochloride salt prepared according to the method of Example 1c.

Claims (3)

1.) Process for the preparation of the acetanilide derivatives of the formula I and their salts - X * is an azido or amino group, R is a hydrogen atom, a C 1-4 alkyl or phenyl group - from a halide anilide of the formula II - X ² is a chlorine or bromine atom, R is as described above, characterized by reacting a haloanilide of formula II, wherein X ² and R are as defined above, with an alkali metal azide; The α-azido derivative, where R is as defined above, is optionally reduced, if desired, with complex alkali hydride or catalytic hydrogenation and, if desired, the product is converted to the acid salt. 2. A process according to claim 1, wherein the haloanilide derivative of formula II, wherein X ² and R are as defined above, is reacted in the presence of an organic solvent. 3. A process according to claim 1 or 2, characterized in that the β-azido derivative of formula IV, wherein R is as defined above, It is reduced by boiling with an alkali hydride complex in an alcoholic solvent or by catalytic hydrogenation at atmospheric pressure at room temperature.