RU2063962C1 - METHOD OF SYNTHESIS OF P-NITRO-α-ACETYLAMINO-b-HYDROXYPROPIOPHENONE - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: p-nitro-a-acetylamino-b-hydroxypropiophenone. Yield is 91%. Reagent 1: p-nitro-a-acetylaminoacetophenone. Reagent 2: formalin. Reaction conditions: aqueous-methanolic medium containing isopropanol, in the presence of sodium carbonate at mole ratio p-nitro-b-acetylaminoacetophenone : methanol : isopropanol : water = 1:(4.4581-7.1334):(2.3672-3.7886):(15.07-23.088). Before formalin addition a is added to mixture at amount 0.016 wt.-% of p-nitro-a-acetylaminoacetophenone and process is carried out at 30 C. After sodium carbonate addition temperature of reaction mass is increased by steps to 40-45 C. Synthesized compound is used as an intermediate reagent for synthesis of drugs. EFFECT: improved method of synthesis. 1 tbl

Description

 The alleged invention relates to an improved method for producing n-nitro-a-acetyl-amino-b-hydroxypropiophenone, which is an intermediate in the synthesis of drugs such as synthomycin and levomecitin, and can find application in the pharmaceutical industry.

Closest to the claimed method, i.e. The prototype is a method for producing n-nitro-a-acetyl-amido-b-hydroxypropiophenone by oxymethylation of n-nitro-a-acetamidoacetophenone with formalin in an aqueous mixture of methyl alcohol and methylene chloride in a ratio of 1: 1 at 40 ^o С and pH 7.2- 7.5. The yield of the target product is 95.0, mp 166-168 ^o C. (GDR patent N 37376 from 07.07.64, RZH, 1966, 24 427p).

The disadvantages of this method:
1. The use of a scarce expensive solvent with a low boiling point of -40.1 ^o C. When reproducing this method, the yield of n-nitro-a-acetyl-amino-b-hydroxypropiophenone was 90.0, the product was crystalline. Mp 156.5 157 ^o C. the amount of residual n-nitro-a-acetyl-amino-acetophenone approximately 3.0%
The aim of the proposed invention is to increase the yield, improve the quality, simplify the process of regeneration of solvents, the exclusion from the technology of scarce and expensive solvent.

The novelty of the proposed method is as follows:
1. The oxymethylation reaction is carried out in a mixture of methanol, isopropanol, water with a molar ratio of n-nitro-a-acetyl-aminoacetophenone, methanol, isopropanol, water 1: (4.4581-7.1334): (2,3672-3, 7886 ): (15.07-23.088), preferably 1: (5.3499-6.2395): 2.8412-3.3145): 19.072.

2. The reaction products are pre-treated with bicarbonate soda in an amount of 0.016 by weight of the "ketone" at 25-30 ^o C.

3. The first 30 minutes the reaction is carried out at 38-40 ^o C, the next 30 minutes at 42-45 ^o C.

 The advantages of the proposed method.

1. High quality n-nitro-a-acetyl-amino-b-hydroxypropiophenone. Mp 158-159 ^o C, 159.5-160.5 ^o C, the amount of residual n nitro-a-acetyl-amino-atsophenone 1.5% the amount of paronitrobenzoic acid does not exceed 1.0%
2. Eliminated scarce expensive solvent methylene chloride.

 3. The mother liquors do not contain resinous substances, which simplifies the process of keeping equipment clean.

 4. The process of regeneration of solvents from mother liquors is very simple. The mother liquors are distilled at atmospheric pressure. The GLC method determines the content of methanol, isopropanol and water, the necessary composition is adjusted and the reuse of solvents is carried out. The yield of regenerated methanol 70.26% of isopropyl alcohol 74.8% of the loaded to obtain n-nitroa-acetyl-amino-b-hydroxypropiophenone. The method for producing n-nitro-a-acetyl-amino-b-hydroxypropiophenone has been tested under industrial conditions. Positive results have been obtained.

 Recovery of solvents from mother liquors.

115 ml of water-alcohol mother liquors obtained from the synthesis of "hydroxymethyl" (without adding isopropanol washing), neutralize 0.7 g of carbonate soda to pH 7.5 at a temperature of 40 ^o C for 30 minutes. Analysis of the regenerated alcohols is carried out by GLC. A mixture of alcohols of this composition is suitable for reuse. Then distilled without vacuum for 2 hours, selected distillation to a temperature of 90 ^o C in pairs (the temperature was 80-95 ^o C). Obtain 51.4 g of distillate containing 38.1% methyl alcohol and 40.2 isopropyl alcohol. The yield of regenerated alcohols, counting 70.6 methyl and 74.82 isopropyl from the oxymethylation loaded on the oxymethylation reaction. When the distillation is stopped at a temperature in pairs of 90 ^° C, a vacuum of 0.6 kg / cm _{2 is} connected, at a temperature in pairs of 60-75 ^° C and in a bath of 78-86,0 ^° C, 10.7 g of distillation containing methyl alcohol 8 is taken , 3% isopropyl alcohol 1.0 The yield of regenerated alcohols, taking into account the fraction taken under vacuum, 75.74% methyl and 75.44% isopropyl. During the distillation should be limited to the selection of 1 fraction, because connecting the vacuum gives nothing. When regenerating in an acidic environment, a lot of resin is obtained.

 EXAMPLE 1

To 30 ml (23.76 g, 0.7415 g / mol) of methyl alcohol add 30 ml (23.67 g, 0.3938 g / mol) of isopropyl alcohol, 20 ml (1.1098 g / mol) of water, add 60 g 54.0 n with a content of bp 5.0 (30.8 g 100 0.1386 g / mol) n-nitro-a-acetylamino-acetophenone, add 0.5 g 100% 0.0047 g / mole sodium bicarbonate, stirred for 10 minutes, poured 12.0 ml (13.05 g, 4.82 g 100 0.4345 g / mol) of formalin, heated to 30 ^o C, stirred for 20 minutes, add dropwise 7.0 ml 10 (0.77 g of 100 0.00072 g / mol) of a solution of carbonic soda, while the color of the reaction mass changes from light yellow to brown. For 10 minutes, the reaction mass is heated to 40 ^o C, give exposure at this temperature for 30 minutes, then heated to 42-45 ^o C, give exposure at this temperature for 30 minutes, then the mass is cooled to 15 -8 ^o C, at this temperature is acidified with a solution of sulfuric acid 57.0 in the amount of 1.2 ml to pH = 3.5 (pH meter). The reaction mass is maintained at a temperature of 15-18 ^o C for 1 hour. The precipitated n-nitro-a-acetylamino-b-hydroxy-propiophenone is squeezed out on a Buchner funnel, washed with 15 ml of isopropyl alcohol, 15 ml of water. The product is dried at a temperature of 70 ^o C for 2 hours. 32.0 g of n-nitro-a-acetylamino-b-hydroxypropiophenone are obtained. T. pl. 159.5 160.5 ^o , the content of para-nitro-benzoic acid 0.48 n-nitro-a-acetyl-amino-acetophenone approximately 1.5 The yield is 91.18
105 ml of water-alcohol mother liquors (without the addition of water and alcohol washes) neutralize 0.7 g of carbonic soda to a pH of 7.5 at a temperature of 40 ^o C for 30 minutes. Then distilled without vacuum for 2 hours. Selected distillation to a temperature of 90 ^o C in pairs (mass temperature at the end of the distillation 95 ^o C. Obtain 46.9 g of distillation containing 38.1 methyl alcohol and 40.2 isopropyl alcohol. The yield of regenerated alcohols, counting from the oxymethylation loaded on the reaction 76.16 methyl and 79.63 isopropyl.

EXAMPLE 2
To 35 ml (27.71 g, 0.8648 g / mol) of methyl alcohol add 36 ml (27.61 g, 0.4594 g / mol) of isopropyl alcohol, 20 g of water are sprinkled with 60 g of 54.0- at room temperature with a content of para-nitrobenzoic acid 5.0 (30.6 g 100% 0.1366 g / mol) n-nitro-a-acetyl amino-acetophenone, add 0.5 g 100% 0.0047 g / mol bicarbonate sodium, stirred for 10 minutes, added 12.0 ml (13.05 g, 4.82 g of 100% 0 2, 04345 g / mol form 2-0lin, heated to 30 ^o C, stirred for 20 minutes, added dropwise 7.0 10 ml (0.77 g of 100% 0.0072 g / mol) of a solution of carbonic soda .. Next, as in example 1. Receive 31.3 g of n-nitro-a-acetyl but-b-oksipropiofenona. mp 158-159 ^o C, the content of para-nitrobenzoic acid 0,48 n-nitro-a- acetyl-amino-acetophenone The yield is about 1.5 matochnikov 89.17 Regeneration is carried out analogously to Example 1 The yield of regenerated alcohols, counting from the hydroxymethylation charged to the reaction, is 74.0 methyl and 78.0 isopropyl.

 EXAMPLE 3

To 25 ml (19.8 g, 0.6179 g / mol) of methyl alcohol add 25 ml (19.72 g, 0.3281 g / mol) of isopropyl alcohol, 30 ml (1.6666 g / mol) of water, add 60 g of 54.0 with the content of bp 5.0 (30.8 g 100 0.1386 g / mol) n-nitro-a-acetylamino-acetophenone, add 0.5 g 100% 0.0047 g / mol sodium bicarbonate, mix for 10 minutes, pour 12.0 ml (13.05 g 4.82 g 100 0.4345 g / mol) of formalin, then analogously to Example 1. 31.2 g of n-nitro-a-acetylamino-b-hydroxypropiophenone are obtained. T. pl. 158-159 ^o With the content of para-nitro-benzoic acid of 0.46 n-nitro-a-acetylamino-acetophenone about 1.5 The yield is 91.1
EXAMPLE 4

 To 40 ml (31.68 g, 0.9687 g / mol) of methyl alcohol add 40 ml (31.66 g, 0.5251 g / mol) of ieopropyl alcohol, 10 ml (0.5555 g / mol) of water, add 60 g 84.0% with a content of bp 5.0 (30.8 g 100 0.1386 g / mol) n-nitro-a-acetylamino-acetophenone, add 0.5 g 100% 0.0047 g / mol of sodium bicarbonate, stirred for 10 minutes, poured 12.0 ml (13.05 g of 4.82 g of 100 0.4345 g / mol) of formalin, then analogously to example 1.

31.4 g of n-nitro-a-acetylamino-b-hydroxypropiophenone are obtained, mp. 166.5-159.5 ^o C, the content of n-nitro-benzoic acid 0.34 n-nitro-a-acetylamino-acetophenone about 1.5 The yield is 89.81%
EXAMPLE 5

To 20 ml (15.84 g, 0.4943 g / mol) of methyl alcohol add 20 ml (15.78 g, 0.2625 g / mol) of isopropyl alcohol, 25 ml (1.3888 / mol) of water, add 60 g 54 with a content of para-nitrobenzoic acid 5.0 (30.8 g 100% 0.1386 g / mol) n-nitro-a-acetyl amino-acetophenone, add 0.5 g 100% 0.0047 g / mol bicarbonate sodium, stirred for 10 minutes, poured 120 ml (13.05 g, 4.82 g 100% 0.4345 g / mol) of formalin, then analogously to example 1. Obtain 32 g of n-nitro-a-acetylamino-b-hydroxy- propiophenone. Mp 155-156 ^o With the content of n-nitro-benzoic acid 1.6 n-nitro-a-acetylaminoacetophenone 3.0% The yield is 89.9
EXAMPLE 6

 To 45 ml (35.64 g, 1.1123 g / mol) of methyl alcohol add 45 ml (35.5; 0.5906 g / mol) of isopropyl alcohol, 15 ml (0.8333 g / mol) of water, add 60 g 54.0% with a content of para-nitrobenzoic acid 5.0 (30.8 g 100 0.1386 g / mol) n-nitro-a-acetylamino-acetophenone, add 0.5 g 100% 0.0047 g / mol bicarbonate sodium, stirred for 10 minutes, added 12.0 ml (13.05 g, 4.82 g of 100% 0.4345 g / mol) of formalin, then analogously to example 1.

Obtain 28 g of n-nitro-a-acetylamino-b-hydroxypropiophenone, so pl. 159-160 ^o With the content of n-nitro-benzoic acid of 0.4 n-nitro-a-acetylaminoacetophenone approximately 1.5% The yield is 79.77
EXAMPLE 7 (prototype).

To 35 ml (27.71 g, 0.8648 g / mol) of methyl alcohol add 35 ml (43.85 g, 0.443 g / mol) of dichloroethane, add 60 g 54.0 with a content of para-nitrobenzoic acid 5.0 ( 30.8 g 100 0.1366 g / mol) n-nitro-a-acetyl-amino-acetophenone, stirred for 15 minutes, heated to 30 ^o C, added 12.0 ml (13.05 g, 4.82 g 100 % 0.4345 g / mol) of formalin, 12 ml of a 10.0% (1.32,100% 0.012 g / mol) solution of carbonic soda are added dropwise, while the color of the reaction mixture changes from light yellow to brown. Within 10 minutes, the reaction mass is heated to 38-40 ^o C, give exposure at this temperature for 1 hour, then the mass is cooled to 15-18 ^o C, at this temperature acidification with 57 sulfuric acid solution in an amount of 1.3 ml to pH 3.5 (pH meter). The reaction mass is maintained at a temperature of 15-18 ^o C for 1 hour. The precipitated n-nitro-a-acetylamino-b-hydroxypropiophenone is squeezed out on a Buchner funnel, washed with 15 ml of methyl alcohol, 15 ml of water. The product is dried at a temperature of 70 ^o C for 2 hours.

31.0 g of n-nitro-a-acetylamino-b-hydroxypropiophenone are obtained. Mp 158-160 ^o With the content of para-nitrobenzoic acid 0.5 n-nitro-a-acetyl-amino-acetophenone approximately 1.5 Yield of the target product 86.03% The data are shown in the table. TTT1

Claims (2)

1. The method of producing p-nitro-a-acetylamino-b-hydroxypropiophenone by oxymethylation of p-nitro-a-acetylaminoacetophenone with formalin in an aqueous-methanol medium at an elevated temperature, followed by isolation of the target product, characterized in that the process is carried out in an aqueous methanol medium containing isopropyl alcohol in the presence of Na ₂ CO ₃ at a molar ratio of p-nitro-a-acetylaminoacetophenone: methanol: isopropanol: water, equal to 1: / 4.4581-7.1334 /: / 2.3672-3.7886 /: / 15, 07-23,088 /, moreover, before introducing formalin into the reaction mass, NaHCO ₃ in the amount of 0 is added to it , 016 wt. from p-nitro-a-acetylaminoacetophenone and the process is carried out at 30 ^o C, and after adding Na ₂ CO _{3 the} temperature of the reaction mass is gradually increased to 40-45 ^o C.  2. The method according to claim 1, characterized in that the process is carried out at a molar ratio of p-nitro-a-acetylaminoacetophenone: methanol: isopropanol: water, equal to 1: / 5.3499-6.2395 /: / 2.8412-3 3145 /: 19.079.

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