The method of obtaining (nitroxymethyl)phenyl esters of salicylic acid derivatives

 

(57) Abstract:

The invention relates to a method for producing (nitroxymethyl)phenyl esters of derivatives of salicylic acid of the formula (I)

where R1means OCOR3group, where R3means methyl, ethyl or a linear or branched C3-C5alkyl;R2means hydrogen. The method includes the following stages: a) reaction of a halide derivative of salicylic acid with hydroxybenzylated alcohol in the presence of a base in an organic solvent; (b) nitration of the resulting product in anhydrous conditions in an inert organic solvent having a boiling point lower than 200 C at atmospheric pressure, a mixture of nitric acid with an excellent inorganic acid or organic acid, or an anhydride of one or two organic acids; (C) isolation of the final product. The technical result - the reduction process, the reduction of side reactions, increase product yield. 5 C.p. f-crystals, 1 table.

The present invention relates to a method for producing (nitroxymethyl)phenyl esters of derivatives of salicylic acid.

From prior art it is known that (nitroxymethyl)phenyl esters derived salicyl the chloride acetylsalicylic acid (nitroxymethyl)phenol. (Nitroxymethyl)phenol obtained by synthesis, comprising the following stages:

reaction of phenol with NVG in an organic solvent to obtain (methyl bromide)phenol and

- reaction (methyl bromide)phenol in an organic solvent with AgNO3education (nitroxymethyl)phenol.

The method based on the reaction between (nitroxymethyl)phenol and acylchlorides acetylsalicylic acid has the following disadvantages:

- (methyl bromide)phenol obtained in the first stage of the synthesis, is chemically unstable and irritating connection;

- Niteroi agent used in the reaction with (methyl bromide)phenol, is a very expensive reagent;

(nitroxymethyl)phenol is an unstable compound, which can easily decompose uncontrolled way, and it must be purified before reaction with the chloride of acetylsalicylic acid, which further increases production costs and requires additional equipment for production use.

Therefore, the synthesis of the mentioned derivatives through the use of intermediate (nitroxymethyl)phenol is difficult and expensive when carrying out on an industrial scale.

In international announced the m nitration by AgNO3(hydroxymethyl)phenyl esters of acetylsalicylic acid, obtained by the reaction of acid chloride with hydroxybenzaldehyde and recovery of the aldehyde groups to primary alcohol. This process as described above, uses as nitriloside agent is silver nitrate and, therefore, is not very advantageous from the industrial point of view. In addition, the overall yield of this method is not too high.

When using the experience of the prior art can be obtained nitrosopropane salicylic acid of the formula (I) reaction (hydroxymethyl)phenyl ester of acetylsalicylic acid with nitriloside reagents based on nitric acid. However, in the reaction conditions of the prior art nitric acid causes adverse reactions, such as, for example, nitration of aromatic substrates (see "Nitration: Methods and Mechanism", 1984, VCH ed., page 269) and the oxidation of primary alcohols to aldehydes (see "Industrial and Laboratory nitration", 1976, ACS publ., p. 156).

Therefore, these methods of the prior art also unable to solve the problem of getting on an industrial scale nitrosopropane salicylic acid, as defined above.

Felt potreby would be cheaper, than methods of the prior art, in relation to and used nitriloside agent and outputs, and mostly without the disadvantages of the prior art.

The object of the present invention is a method of obtaining (nitroxymethyl)phenyl esters of derivatives of salicylic acid, and the compounds have the following formula (I):

where R1means R3group, where R3means methyl, ethyl or a linear or branched C3-C5alkyl, or a residue of a saturated heterocyclic ring having 5 or 6 atoms containing heteroatoms, independently selected from O and N;

R2means hydrogen, halogen, linear or branched when possible, WITH1-C4alkyl, linear or branched when possible, C1-C4alkoxy; linear or branched, when possible, C1-C4perfluoroalkyl, for example, trifluoromethyl; mono - or di-(C1-C4)alkylamino;

Preferably (I) R1is acetoxy and is in the ortho-position relative to the carboxyl group, R2means hydrogen; oxygen of the ester group linked to the aromatic ring, substituted (nitroxy)methylene the a-position; the said method comprises the following stages:

a) reaction of a halide derivative of salicylic acid of the formula (I-A):

where Hal=CL, Br and R1and R2have the above meanings, with hydroxybenzylated alcohol in the presence of a base in an organic solvent or in a mixture of water with a miscible or not miscible with water with an organic solvent to obtain the compound (I-B) having the following formula (I-B):

where R1and R2such as defined above;

b) nitration of the compound (I-In) in anhydrous conditions in an inert organic solvent through a mixture formed of fuming nitric acid with an inorganic acid other than nitric acid, or with organic acid, or anhydride with one or two organic acids, obtaining nitrosopropane formula (I).

c) isolation of the final product by adding water to the organic phase, phase separation, drying and evaporating the organic phase.

At the stage of (a) the base can be an inorganic base, such as, for example, hydroxides, oxides, carbonates and bicarbonates of alkali metals (sodium, potassium, lithium); or an organic base, nephrolithiasis, such as triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo etc.

The organic solvent used in stage a) can be an organic solvent miscible with water, such as C1-C4aliphatic alcohols, e.g. methanol, ethanol, isopropanol, n-butanol; or an organic solvent not miscible with water, for example, aromatic hydrocarbons such as toluene and xylene, chlorinated organic solvents, such as methylene chloride, chlorobenzene, other solvents that can be used are aliphatic esters, for example, C1-C4acids with C1-C5alcohols, such as, for example, ethyl acetate and butyl acetate and so on; aliphatic and cycloaliphatic ketones, such as C3-C12for example, acetone, ketone, cyclohexanone, etc.

At the stage of (a) the reaction is carried out at a temperature in the range from -20 to +50C, preferably 0-20C, when used with respect to the moles of hydroxybenzylated alcohol in the reaction amount in moles of acid halide (I-A) in a ratio of between 1 and 2, preferably between 1.2 and 1.5, and the amount in moles of base is between 0.1 and 2, preferably IU the Oia takes place in an aqueous solvent or in a mixture of water with water-soluble organic solvent, the addition of an organic solvent that is not miscible with water such as ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried, evaporated and the product isolated. If necessary, the compound can be purified by crystallization from solvents such as, for example, n-hexane, n-heptane, ligroin, toluene, methanol, isopropanol, Diisopropylamine, etc. or mixtures thereof. Typically, the output is more than 80%.

At the stage b) nitration reaction is carried out at a temperature in the range of 20 and +40C, preferably from 0 to 20C; used amount in moles of nitric acid is in a ratio of between 1 and 6, preferably 1 and 3 relative to the moles of hydroxyether (I-B); the amount in moles of an organic or inorganic acid other than nitric acid, or anhydride, as defined above, is in a ratio of between 0.5 and 6, preferably between 1 and 3 relative to the moles of the compound (I-B).

Inorganic acid other than nitric acid is, for example, sulfuric acid; an organic acid is, for example, methanesulfonic acid, triftormetilfullerenov acid, triperoxonane acid, trichloroacetic acid, acetic acid, and the anhydride is cusnum anhydride, trichloroacetic anhydride, etc. or a mixture of anhydrides, such as, for example, triperoxonane-triftormetilfullerenov anhydride, etc.

The inert organic solvent used in stage b) is a solvent that has a boiling point lower than 200C at atmospheric pressure, and may be chlorinated solvent, such as dichloromethane; or nitroalkanes, such as, for example, nitromethane, or an aliphatic or cycloaliphatic ether, such as, for example, methyltretbutylether, tetrahydrofuran, etc.; complex ester, such as ethyl acetate; or an aliphatic or aromatic nitrile, such as acetonitrile, benzonitrile.

The amount of solvent is not critical, as a rule, the volume exceeds 1 to 20 times the amount by weight of hydroxyether (I-B) in the reaction.

When nitration at the stage b) is carried out in the presence of organic anhydride, as defined above, the anhydride is preferably first mixed with hydroxyether (I-B) and then the resulting mixture was added to a solution of nitric acid in an inert organic solvent.

Preferably used an organic anhydride is acetic anhydride.

N is, for example, n-hexane, n-heptane, naphtha, methanol, isopropanol or mixtures thereof.

The following examples describe the invention without limiting its scope.

Example 1A

Obtaining 3-hydroxymethylene ether 2-acetoxybenzoic acid (compound I-B) in a mixture of water and organic solvent.

3-hydroxymethylene (25,25 g of 0.2 mole) is dissolved in 5% sodium hydroxide solution (160 ml). To the thus obtained solution was added a solution of chloride of acetylsalicylic acid (40,4 g of 0.2 mol) in dichloromethane (50 ml) at room temperature under stirring. The mixture is left at room temperature under stirring for 2 hours and then extracted with dichloromethane (2100 ml). Separate the organic phase was dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from a mixture of ethyl acetate and hexane. Get 3-hydroxymethylene ether 2-acetoxybenzoic acid (45,8 g to 0.16 moles, yield 80%).

The pace. pl.: 79-81C.

1H-NMR (CDCl3)(M. D.): to 2.29 (s, 3H); 4,71 (s, 2H), 7,07 to 8.2 (m, aromatics, 8H).

Example 1b

Obtaining 3-hydroxymethylene ether 2-acetoxybenzoic acid (compound I-B) in an organic solvent not miscible with water, 3-hydroxymethyl the solution was added a solution of chloride of acetylsalicylic acid (16 g, of 0.08 mol) in toluene (50 ml) at a temperature of 5-10C. with stirring. The mixture of support at a temperature in the above range, stirring for 2 hours, then poured into water and then extracted with dichloromethane (2100 ml). The organic phase is separated, washed successively with 25% wt./about the potassium carbonate solution, water, 3% hydrochloric acid solution and finally again with water, then dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from isopropanol. Get 3-hydroxymethylene ether 2-acetoxybenzoic acid (45,8 g 0,16 mol, yield 80%).

The pace. pl.: 79-81C.

1H-NMR (CDCl3)(M. D.): to 2.29 (s, 3H); 4,71 (s, 2H), 7,07 to 8.2 (m, aromatics, 8H).

Example 1C

Obtaining 3-hydroxymethylene ether 2-acetoxybenzoic acid (compound I-B) in an organic solvent, miscible with water, 3-hydroxymethylene (10 g, of 0.08 mol) dissolved in acetone (50 ml). In the resulting solution was suspended powder potassium carbonate (22,2 g of 0.16 mol). To the suspension is added a solution of chloride of acetylsalicylic acid (16 g, of 0.08 mol) in acetone (50 ml) at a temperature of 5-10C. with stirring. The mixture of support at a temperature in the above interval with stirring tegenlicht 3-hydroxymethylene ether 2-acetoxybenzoic acid (21,0 g, of 0.07 mol, yield 91%).

The pace. bed: 79-81s with.

1H-NMR (CDCl3)(M. D.): to 2.29 (s, 3H); 4,71 (s, 2H), 7,07 to 8.2 (m, aromatics, 8H).

Example 2

Obtaining 3-nitroxyethyl ether 2-acetoxybenzoic acid nitration fuming nitric acid in the presence of sulfuric acid 3-hydroxymethylene ether 2-acetoxybenzoic acid.

A solution of fuming nitric acid (to 3.92 g, 62.2 mmole, 3 mol relative to the moles of hydroxyether I-B) and 96% sulfuric acid (6,10 g, 62.2 mmole, 3 mol relative to the moles of hydroxyether I-B) in dichloromethane (25 ml) cooled to 0C and added dropwise within 1 hour with stirring and in a nitrogen atmosphere to a solution of 3-hydroxymethylene ether 2 acetoxybenzoic acid (6 g, 20,7 mole) in 25 ml dichloromethane. The mixture was then diluted with dichloromethane (50 ml) and poured into water and ice (100 g). The organic phase is separated, washed with water, dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from isopropanol, getting the 3-nitroxyethyl ether 2-acetoxybenzoic acid (5.6 g, 17 mmol, yield 82%).

The pace. pl.:61-62C.

1H-NMR (CDCl3)(M. D.): 2,31 (s, 3H); 5,44 (s, 2H), 7,16 is 8.22 (m, aromatics, 8H).

Examples 2a-2f

Example 2 is repeated, changing the amount of mol is-acetoxybenzoic acid (I-B). The table shows the molar ratio of the used reagents with respect to the compound (I-B) and the relative percentages between 3-nitroxyethyl ether 2-acetoxybenzoic acid (I) 3-(formyl)phenyl ether 2-acetoxybenzoic acid (I-B1), taking into account, when present, also the original compound (I-B).

The table shows that the highest yield obtained using a molar ratio of nitric acid/compound (I-B), is equal to 3, and the ratio of sulfuric acid/compound (I-B), equal to 1.5.

Example 3

Obtaining 3-nitroxyethyl ether 2-acetoxybenzoic acid nitration fuming nitric acid, in the presence of acetic anhydride, 3-hydroxymethylene ether 2-acetoxybenzoic acid.

A solution of fuming nitric acid (1.44 g, 22.8 mmol), acetic anhydride (2,33 g, 22.8 mmol) in dichloromethane (25 ml) cooled to 0C. and with stirring for 1 hour in a nitrogen atmosphere to a solution of 3-hydroxymethylene ether 2-acetoxybenzoic acid (6 g, 20.7 mmol) in 25 ml dichloromethane. The mixture is heated to 20C for one hour and then diluted with dichloromethane (50 ml) and poured into water and ice (100 g). Separate the organic phase, washed with water, the obtained 3-nitroxyethyl ether 2-acetoxybenzoic acid (5.6 g, 17 mmol, yield 82%).

Example 4

Obtaining 3-nitroxyethyl ether 2-acetoxybenzoic acid nitration fuming nitric acid, in the presence of acetic anhydride, 3-hydroxymethylene ether 2-acetoxybenzoic acid (acetic anhydride is mixed with hydroxyether).

A solution of fuming nitric acid (1.44 g, 22.8 mmol) in dichloromethane (25 ml) cooled to 0C and added dropwise within 1 hour with stirring and in a nitrogen atmosphere to a solution of 3-hydroxymethylene ether 2-acetoxybenzoic acid (6 g, 20.7 mmol) and acetic anhydride (2,33 g, 22.8 mmol) in 25 ml dichloromethane. The mixture is heated to 20C for 1 hour and then diluted with dichloromethane (50 ml) and poured into water and ice (100 g). Separate the organic phase, washed with water, dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from isopropanol and get 3-nitroxyethyl ether 2-acetoxybenzoic acid (6.42 per g, 19.5 mmol, yield 94%).

Example 5

Obtaining 3-nitroxyethyl ether 2-acetoxybenzoic acid nitration fuming nitric acid in the presence methanesulfonic acid 3-hydroxymethylene ether 2-acetoxybenzoic acid.

A solution of fuming nitric acid is between 1 hour under stirring in nitrogen atmosphere to a solution of 3-hydroxymethylene ether 2-acetoxybenzoic acid (6 g, 20.7 mmol) in 25 ml dichloromethane. The mixture is diluted with dichloromethane (50 ml) and poured into water and ice (100 g). Separate the organic phase, washed with water, dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from isopropanol and get 3-nitroxyethyl ether 2-acetoxybenzoic acid (2,73 g, 8,29 mmol, yield 40%).

Example 6

Obtaining 3-nitroxyethyl ether 2-acetoxybenzoic acid nitration fuming nitric acid, in the presence of acetic anhydride, 3-hydroxymethylene ether 2-acetoxybenzoic acid (acetic anhydride is mixed with hydroxyether).

A solution of fuming nitric acid (990 mg, 15.2 mmol), acetic anhydride (1.55 g, 15.2 mmole) in dichloromethane (25 ml) cooled to 0C and added dropwise over 1 hour under stirring in nitrogen atmosphere to a solution of 3-hydroxymethylene ether 2-acetoxybenzoic acid (4 g, 13.8 mmol) in 25 ml dichloromethane. The mixture is heated to 20C for 1 hour and then diluted with dichloromethane (50 ml) and poured into water and ice (100 g). Separate the organic phase, washed with water, dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is crystallized from isopropanol and get 3-nitroxymethyl LASS="ptx2">

where R1means R3group, where R3means methyl, ethyl or a linear or branched C3-C5alkyl;

R2means hydrogen;

preferably (I) R1is acetoxy and is orthopaedie relative to the carboxyl group, R2means hydrogen; oxygen of the ester group linked to the aromatic ring, substituted (nitroxy)methylene group, in the ortho-, meta - or para-position relative to (nitroxy)methylene group;

preferably this meta-position;

moreover, the above method includes the following stages: a) reaction of a halide derivative of salicylic acid of the formula (I-A)

where Hal = C1, Br and R1and R2have the above values,

with hydroxybenzylated alcohol in the presence of a base in an organic solvent or in a mixture with water miscible or water-immiscible organic solvent to obtain the compound (I-B) having the following formula:

where R1and R2have the above meanings;

b) nitration of the compound (I-B) in anhydrous conditions in an inert organic solvent which has a boiling point of the organic acid, other than nitric acid, or with organic acid, or anhydride with one or two organic acids, obtaining nitrosopropane formula (I), and the molar ratio of nitric acid to the compound (I-B) is between 1 and 6 and the molar ratio of inorganic acid other than nitric acid, or organic acid or an organic anhydride, defined above, to the compound (I-B) is between 0.5 and 6;

(C) the allocation of the final product by adding water to the organic phase, phase separation, drying and evaporating the organic phase.

2. The method according to p. 1, where at the stage of (a) organic solvents are C1-C4aliphatic alcohols; aromatic hydrocarbons, aliphatic esters, chlorinated organic solvents, aliphatic and cycloaliphatic ketones.

3. The method according to one of the p. 1 or 2, where in stage a) the reaction is carried out at a temperature in the range from -20 to +50C, when used in relation to the moles of hydroxybenzylated alcohol in the reaction amount in moles, respectively, of the acid halide (I-A) in a ratio of between 1 and 2, preferably between 1.2 and 1.5, and the amount in moles of base is between 0.1 and 2, presale -20 to +40C, and the number of moles of nitric acid is in a ratio of between 1 and 3, relative to the moles of the compound (I-B), and the amount in moles of inorganic acid other than nitric acid, or organic acid or an organic anhydride, as defined above, is in a ratio of between 1 and 3, relative to the moles of the compound (I-B).

5. The method according to p. 4, wherein the nitration is carried out in the presence of the anhydride, which is pre-mixed with hydroxyether (I-B), and the resulting mixture was added to a solution of nitric acid in an inert organic solvent.

6. The method according to p. 5, where the anhydride is acetic anhydride.

 

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