Method for obtaining 1-oxyethyl-2-methyl-5- nitroimidazole

专利摘要:
Process for the preparation of hydroxyalkylating agents of general formula: …<IMAGE>… in which R denotes an alkyl radical, n is equal to 2 or 3, R1 denotes a hydrogen atom or an alkyl radical and R2 denotes an alkyl radical, optionally substituted phenyl or …<IMAGE>… the new agents thus obtained and their use. …<??>The agents of general formula (I) are useful in particular for preparing 1-hydroxyalkylimidazoles.
公开号:SU1657058A3
申请号:SU894613235
申请日:1989-01-13
公开日:1991-06-15
发明作者:Массонно Вивиан；Мюльхаузер Мишель；Бюфорн Альбер
申请人:Рон-Пуленк Санте (Фирма)；
IPC主号:

专利说明:

The invention relates to an improved process for the preparation of 1-hydroxyethyl-2-methyl-5-β-nitro-imidazole derivatives having biological activity that allows the use of compounds in therapy.
The purpose of the invention is to increase the yield of the target product.
The goal is achieved by the interaction of a compound of the formula
02N
CH3
where X is acyloxymethyl, with a compound of the formula
R, -CO-0-CH4CH4-0-50y-K “.
where R is Cx-Cf-alkyl;
R - C / -C4 alkyl or radical
-0-CHeCH2-OCOR4, where R / is alkyl C, -Sf at 80-90 ° C, followed by hydrolysis of the resulting product with water or alcoholysis with an alcohol selected from methanol and ethanol, at a temperature from 80 C to the boiling point of the reaction mixture and the selection of the obtained product.
WITH
N
WITH
with with
Example 1. In a distillation apparatus, the receiver of which is immersed in an acetone-dry ice bath, 292.3 g of glycol diacetate (2 mol) and 50.4 g of dimethyl sulfate (0.4 mol) are introduced.
The apparatus creates a pressure of 200 mm Hg. Art. (26.6 kPa), then the reaction mixture is heated for 5 hours to. During heating, 60 from 5 methyl acetate is distilled off. The reaction mixture is cooled to approximately 100 ° C, then distilled off, under a reduced pressure of 1 mm Hg. Art. (0.13 kPa), 206 cm glycol diacetate (bath temperature 110 С, vapor temperature 65 ° С).
Di- (2-acetoxy-ethyl) -sulfate in the form of a light yellow oil is recovered in the kettle.
Di (2-acetoxy-ethyl) sulphate is characterized by: infrared spectrum, in which the main characteristic absorption bands, expressed
ten
The degree of conversion of 1-acetoxime, tyl-2-methyl-4-nitro-imidazole is 81%.
 "
The yield of metronidazole is 71.5% with respect to the 1-a toxymethyl-2-methyl-4-nitro-imidazo used and 881 with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-dazole.
Example 3. In a flask equipped with a magnetic stirrer, 15.7.9 g of 1-acetoxymethyl-2-methide-4-nor are introduced.
Ro-imidazole (0.04 mol) and 10.8 g of di (2-acetoxy-ethyl) sulphate (0.04 mol). Heat the reaction mixture to 80 ° C for 4 hours. Then
c, 1740 (C-0 acetate); 20 add 20 cm of methanol and heating- 1395 - 1195 (C-0-SO-O-C) and 1245 (C-0): proton nuclear magnetic resonance spectrum (360 MHz; SESN;
ppm
4.45 (t);
chemical displacements of 4.31 (t) and (2S).
In a flask equipped with a magnetic stirrer, 2.7 g of di (2-acetoxy-α-ethyl) sulfate (0.01 mol) and 1.99 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole are introduced (0.01 mol). The reaction mixture is heated to within 5 hours. Then 5 cm-water is added and heating is continued to 80 ° C for 3 hours.
After cooling, the mixture is analyzed by high-performance liquid chromatography (HPLC) and 1.10 g of metronidazole and 0.288 g of 2-methyl-4 (or 5) -nitro-imidazole are detected.
The 1-ace conversion rate of methyl-2-methyl-4-nitroimidazole is 77.3%.
during reflux for 4 hours. After cooling to 20CC, the pH is adjusted to 11.7 by addition of 5.5 cmE of concentrated sodium alkali (d 1.33). The precipitate that forms is filtered off and washed twice with 3 cm of methanol.
After drying, 4.61 g of about 30 products are obtained in which a mixture of imidazole derivatives is formed from 98.6% of a meter of nidazole and 0.6% of 2-methyl-4 (or 5) -nitro-imidazole (HPLC) with internal ethanol).
35
40
Analysis of the obtained product by HPLC with external ethanol shows that it contains 2.85 g of metronid ash and 0.014 g of 2-methyl-4 (or 5) -ni-imidazole.
 The yield of metronidazole is 64.2% relative to the starting 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
Example 2. In a flask equipped with a stirrer, 10.8 g of di (2-acetoxy-ethyl) sulphate (0.04 mol) obtained under the conditions of example 1 and 7.96 g of 1-acetoximethyl-2 are introduced. -methyl-4-nntro-imidazole (0.04 mol). The reaction mixture is heated at 80 ° C for 4 hours. Then 20 cm of methanol is added and heated under reflux for 4 hours. Analysis of the resulting solution by HPLC using external ethanol shows that it contains 4.89 g of metronidazole and 0.95 g of 2- methyl 4 (or 5) - nitroimidazole.
The degree of conversion of 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 81%.
 "
The yield of metronidazole is 71.5% with respect to the 1-acetoxymethyl-2-methyl-4-nitro-imidazole used and 881 with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
Example 3. In a flask equipped with a magnetic stirrer, 15.7.96 g of 1-acetoxymethyl-2-methid-4-nitro-imidazole (0.04 mol) and 10.8 g of di (2-acetoxy-ethyl) are introduced. sulfate (0.04 mol). Heat the reaction mixture to 80 ° C for 4 hours. Then
20 add 20 cm of methanol and heat
add 20 cm of methanol and heat
After cooling to 20CC, the pH is adjusted to 11.7 by addition of 5.5 cm of concentrated alkali sodium (d 1.33). The precipitate that forms is filtered off and washed twice with 3 cm of methanol.
After drying, 4.61 g of product is obtained in which the mixture of imidazole derivatives is formed from 98.6% of metronidazole and 0.6% of 2-methyl-4 (or 5) -nitro-imidazole (HPLC) with internal ethanol).
0
0
five
five
Analysis of the obtained product by the method of HPLC with external ethanol shows that it contains 2.85 g of metronidazole and 0.014 g of 2-methyl-4 (or 5) -nitro-imidazole.
Analysis of the filtrate by the method of HPLC with external ethanol shows that it contains 2.15 metronidazole and 0.93 g of 2-methyl-4 (or 5) -nitro-imidazole.
The conversion of 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 81.4%.
The yield of metronidazole is 90% relative to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
Example 4. In a distillation apparatus, the receiver of which is immersed in an acetone-dry ice bath, 23.4 g of glycol diacetate are added (0.16 mol and 7.84 g of concentrated sulfuric acid (d = 1.83) (0.08 mol ).
The pressure in the apparatus is 15 mm Hg. Art. (2 kPa). Then the reaction mixture is heated to 100 ° C for 3 hours, distilled 8 g of acetic acid.
In the kettle, di (2-acetoxy-ethyl) sulphate is obtained in the form of a yellow oil.
In a flask equipped with a magnetic stirrer, 7 g of di (2-acetoxy-α-ethyl) sulfate obtained above and 5.1 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole (0.026 mol) are introduced. Heat the reaction mixture to 80 ° C for 6 hours. Then add 13 cm of water and continue heating for 4 hours to.
The resulting solution is analyzed by HPLC with an external standard and 2.39 g of metronidazole and 1.03 g of 2-methyl-4 (or 5) -nitro imidazole are detected.
The conversion of 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 68%.
The yield of metronidazole is 54.5% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 79% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
Example 5. In a flask equipped with a magnetic stirrer, 6 g of di (2-acetoxy-ethyl) sulfate obtained under the conditions of Example 4 and 4.38 g of 1-acetoxymethyl-2-methyl-4-nitro- imidazole (0,022 mol). Heat the reaction mixture for 6 hours to 80 ° C, then add 11 cm of methanol and continue heating under reflux for 4 hours.
The resulting solution was analyzed by the method of HPLC with external ethanol, 2.47 g of metronidazole and 0.82 g of 2-methyl-4 (or 5) -nitro-nmidazole.
The conversion of 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 71%.
The yield of metronidazole is 65.6% with respect to the starting 1-acetoxyketyl-2-methyl-4-nitro-imidazole and 93% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitro-imidazole.
Example 6. In a distillation apparatus, the receiver of which is immersed in a bath of acetone — dry ice, 9 g of glycol is introduced.
acetate (0.0b2 mol) and 6 g methanesulfonic acid (0.062 mol). The apparatus creates a pressure of 16 mm Hg. Art. (2 kPa), then the reaction medium is heated to 1 1 O ° C for 4 h. During heating, 2.81 g of acetic acid is distilled off.
A light-yellow oil containing 80 wt.% Is recovered in the kettle. % acetoxyethyleneglycol.
Acetoxyethylene glycol mesilate is distinguished by: an infrared spectrum, in which the main characteristic absorption bands, expressed in, are 1740 (acetate), 1360 () and 1180 (50g-0); nuclear proton magnetic resonance spectrum (360 MHz;, chemical substitutions in ppm): 4.36 (t), 4.26 (t), 3.07 (S) and 2 (S).
In a flask equipped with a magnetic stirrer, 2.5 g of acetoxyethylene glycol mesylate prepared above are introduced.
25 and 1.427 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole (0.072 mol). The reaction mixture is heated to 6 hours. Then 20 cm of ethanol is added and the mixture is heated under reflux.
30 for 1 hour
Analysis of the resulting solution by high-performance liquid chromatography with external ethanol shows that it contains 0.932 g
metronidazole and 0,120 g 2-methyl-4
(or 5) -nitro-imidazole.
The conversion of 1-acetoxn-methyl-2-methyl-4-nitroimnazole is 87%.
The yield of metronidazole is 77% with respect to the starting 1-acetoxymethyl-2-methyl-4-nitro-imidazole and 89% with respect to the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.
Example 7. In a flask equipped with a magnetic stirrer, 2.5 g of acetoxyethylene glycol mesylate (prepared according to Example 6) and 1.405 g of 1-acetoxymethyl-2-methyl-4-nitro-imidazole (0.0071 mol) are introduced. The reaction mixture is heated to 6 hours. Then, 20 cm of water is added and heated to 80 ° C for 1 hour.
Analysis of the resulting solution by HPLC with an external standard shows that it contains 0.907 g of metronidazole and 0.112 g of 2-methyl-4 (or 5) -nitro-imidazole. Degree of transformation
Neither 1-acetoxymethyl-2-methyl-4-nitro-imidazole is 88%.
The yield of metronidazole is 74% with respect to the starting 1-acetoxy-2-methoxy-4-nitro-imidazole and 85% with respect to the converted 2-acetoxymethyl-4-nitro-imidaeol.
Example 8. In a flask equipped with a stirrer, 5.4 g of di (2-acetoxyethyl) sulfate and 1.85 g of 1-acetoxymethyl-4-nitro-imidazole are introduced. 30 cm of quilol are added, then the mixture is heated to 80 ° C for 6 hours. Then 30 cm of water are added, then the reaction mixture is heated under reflux for 4 hours.
Analysis of the aqueous phase by high-performance liquid chromatography with external ethanol shows that the degree of conversion of 1-acetoxymethyl-4-nitroimidazole is 88%, the yield of 1-hydroxyethyl-5-nitro imazole is 97% with respect to 1-acetoxymethyl-4-nitro-imidazole converted.

权利要求:
Claims (2)
[1]
Invention Formula
The method of obtaining 1-hydroxyethyl-2-30-methyl-5-nitroimidazole formula
N02
N-YN CH2CH2OH
0
five
0
0
five
. CH3
on the basis of 4-nitroimidazole derivative, characterized in that, in order to increase the yield of the target product, the compound form, MoulyOn, is used as 4-nitro-imidazole
-)
RYN-X CH3
where X is acyloxymethyl, and is reacted with a compound of the general formula:
R —CO — OCHeCH —O — SOe — Rfc,
where R {- Cj - Sdgalkil;
N-
[2]
2.- C-C4 alkyl or radical
-0-CH CHU-OCOR, where R C -Sf-alkyl,
is heated at a temperature of 80-90 ° C, then the resulting product is hydrolyzed with water or alcoholized with an alcohol selected from methanol and ethanol, at a temperature of from 80 ° C to the boiling point of the reaction mixture, and the resulting product is isolated.

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