Synthesis method of (Z)-2-methoxyimino-2-furyl ammonium acetate

Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of (Z)-2-methoxyimino-2-furyl ammonium acetate, which comprises the following steps: 1) carrying out oxidative esterification reaction on a compound (I) and potassium alkyl xanthate to generate a compound (II); 2) carrying out hydrolysis reaction on the compound (II) and alkali to generate a compound (III); 3) performing oximation reaction on the compound (III) and methoxyl ammonium salt to obtain a compound (IV), and 4) performing salt forming reaction on the compound (IV) and ammonia to generate a compound V. According to the method, the reaction operation is simple and reliable, the yield is high, the high-purity (Z)-2-methoxyl imino-2-furyl ammonium acetate is obtained, and remarkable economic benefits and environmental protection benefits are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt. Background Art

[0002] Among the second-generation cephalosporin antibiotics, cefuroxime is the most produced and applied antibiotic, which has a huge consumer market and good development prospects. Therefore, as an indispensable intermediate in the preparation of cefuroxime, the synthesis method of (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt has become the focus of researchers in this field.

[0003] At present, most methods at home and abroad use oximation reaction of acetofuran with nitrous acid, and then react with methoxyamine to convert it into ammonium salt. Most methods have the following disadvantages: 1. The process is cumbersome, the amount of oxidant is too large, the operation is difficult to control, and the overall yield of the reaction is low. 2. The use of metal salts causes environmental pollution, and a large amount of nitric oxide and nitrogen dioxide gas is released during the reaction process, which has a great adverse effect on the occupational health of operators and the environment. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing (Z)-2-methoxyimino-2-furanyl acetate ammonium salt.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for synthesizing (Z)-2-methoxyimino-2-furanyl acetate ammonium salt comprises the following steps: S1. Compound I furfural and alkyl xanthate potassium are reacted in DMSO and H 2 O in the solvent to produce compound II 2-oxofuranoyl acetate;

[0007] S2. hydrolyzing compound II 2-oxofuranyl acetate with a base to generate compound III furanone acid;

[0008] S3. Compound III furanone acid is subjected to oximation reaction with methoxyammonium salt to obtain compound IV methoxyiminofuranacetic acid;

[0009] S4. Compound IV methoxyiminofuranacetic acid is reacted with ammonia to form a salt to produce compound V furan ammonium salt; the synthetic route of the entire reaction is as follows:

[0010] Wherein, R in the formula is an alkyl group, preferably a methyl group.

[0011] Furthermore, in the oxidative esterification reaction of step S1, the reaction solvent is DMSO / H 2The mass ratio of O is 1:1 to 1:3; the amount of potassium alkyl xanthate used is 1 to 5 molar equivalents relative to furfural; the reaction temperature is 30 to 120° C.; and the reaction time is 8 to 16 hours.

[0012] Furthermore, in the hydrolysis reaction of step S2, the amount of water used is 27 to 40 molar equivalents relative to 2-oxofuranoacetic acid ester; the pH is adjusted to 0.1 to 3 with hydrochloric acid; and the reaction time is 4 to 10 hours.

[0013] Furthermore, in the oximation reaction of step S3, compound (III) furanone acid is first dissolved in an organic solvent, and the amount of the organic solvent used is 15 to 35 molar equivalents relative to furanone acid; the amount of methoxyamine hydrochloride used is 1.0 to 2.0 molar equivalents relative to furanone acid; and the reaction time is 5 to 12 hours.

[0014] Furthermore, in the salt-forming reaction of step S4, compound IV furanone acid is dissolved in an organic solvent, and the amount of the organic solvent dichloromethane used is 15 to 35 molar equivalents relative to furanone acid; the reaction temperature is -20 to 10° C.; and the reaction time is 0.1 to 1.0 h.

[0015] The invention has the advantages that the reaction operation is simple and reliable, the reaction route is short, it is green and environmentally friendly, the yield is high, the post-treatment is easy, and high-purity (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is a liquid chromatogram of (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0017] Example 1

[0018] A method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt comprises the following steps:

[0019] The first step: Synthesis of compound Ⅱ 2-oxofuranylacetate

[0020] Add 5.5 g (0.05 mol) of furfural, 21.9 g (0.15 mol) of potassium alkyl xanthate, and 50.6 g (0.2 mol) of iodine into a flask, then add 20 ml of DMSO / H2O (1:2), stir and react at 80°C for 12 h, extract, dry, filter and concentrate to obtain 5.1 g of 2-oxofuranyl acetate with a yield of 93%.

[0021] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of potassium alkyl xanthate, reaction time, reaction solvent, etc. in the first step of Example 1 were changed. The reaction results are shown in Table 1.

[0022] Table 1: Comparison of product yields under different conditions

[0023]

[0024] Step 2: Synthesis of Compound III Furanone Acid

[0025] Add 4.6 g (0.03 mol) of compound II 2-oxofuranyl acetate and 15 g (0.8 mol) of water into a flask, adjust the pH value to 10 with concentrated alkaline water, react at room temperature with stirring for 6 h, add hydrochloric acid to adjust the pH value to 1, add ethyl acetate to extract, dry, filter and concentrate to obtain 3.9 g of product furanone acid with a yield of 85%.

[0026] In order to compare the product yields under different reaction conditions, the reaction conditions such as the amount of water used, the pH adjusted with hydrochloric acid, and the reaction time in the second step of Example 1 were changed. The reaction results are shown in Table 2.

[0027] Table 2: Comparison of product yields under different conditions

[0028] Serial number Water consumption Hydrochloric acid to adjust pH Reaction time Yield (%) Second step reaction 27 molar equivalent 1 6 85 Comparison 1 40 molar equivalent 1 6 65 Comparison 2 20 molar equivalent 1 6 72 Contrast 3 27 molar equivalent 3 6 76 Contrast 4 27 molar equivalent 0.1 6 78 Contrast 5 27 molar equivalent 1 4 74 Contrast 6 27 molar equivalent 1 10 81

[0029] Step 3 Synthesis of Compound IV

[0030] Add 2.8 g (0.02 mol) of compound III furanone acid and 5.5 g (0.04 mol) of potassium carbonate into a flask, then add 40 g (0.5 mol) of dichloromethane. Keep the temperature of the reaction solution at 0°C, then slowly add 2.5 g (0.03 mol) of methoxyamine hydrochloride. Stir the reaction at 0°C for 8 h. After the reaction is completed, extract, filter and dry to obtain 2.5 g of compound IV methoxyiminofuranacetic acid with a yield of 89%.

[0031] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of potassium carbonate, amount of dichloromethane, amount of methoxyamine hydrochloride, reaction time, etc. in the third step of Example 1 were changed, and the reaction results are shown in Table 3.

[0032] Table 3: Comparison of product yields under different conditions

[0033]

[0034] Step 4 Synthesis of Compound Ⅴ

[0035] Add 1.7 g (0.01 mol) of compound VI methoxyiminofuranacetic acid into a flask, add 20 g (0.25 mol) of dichloromethane, slowly drop a saturated solution of ammonia in ethanol (saturated solution of ammonia in ethanol at -5°C) into the above solution to adjust the pH to 8, keep stirring at 0°C for 30 min, filter with suction to obtain a light yellow solid, and wash the filter cake with 30 ml of a mixed solution with a volume ratio of dichloromethane: ethanol = 6:1 to obtain a white powdery solid, i.e. 1.3 g of furan ammonium salt, with a yield of 78%.

[0036] In order to compare the product yields under different reaction conditions, the reaction conditions such as temperature, amount of reaction solvent, reaction time, etc. in the fourth step of Example 1 were changed. The reaction results are shown in Table 4.

[0037] Table 4: Comparison of product yields under different conditions

[0038] Serial number Temperature(℃) Reaction solvent dosage Time (h) Yield (%) The fourth step reaction 0 25 molar equivalent 0.5 78 Comparison 1 10 25 molar equivalent 0.5 58 Comparison 2 -20 25 molar equivalent 0.5 60 Contrast 3 0 35 molar equivalent 0.5 69 Contrast 4 0 15 molar equivalent 0.5 66 Contrast 5 0 25 molar equivalent 1.0 75 Contrast 6 0 25 molar equivalent 0.1 18

Claims

1. A method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt, characterized in that: The following steps are involved: S1. Compound I furfural and potassium alkyl xanthate are subjected to oxidative esterification reaction in a solvent of DMSO and H2O to generate compound II 2-oxofuranyl acetate; S2. hydrolyzing compound II 2-oxofuranyl acetate with a base to generate compound III furanone acid; S3. Compound III furanone acid is subjected to oximation reaction with methoxyammonium salt to obtain compound IV methoxyiminofuranacetic acid; S4. Compound IV methoxyiminofuranacetic acid is reacted with ammonia to form a salt to produce compound V furan ammonium salt; the synthetic route of the entire reaction is as follows: Wherein, R is an alkyl group.

2. The method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt according to claim 1, characterized in that: In the oxidative esterification reaction of step S1, the mass ratio of the reaction solvent DMSO / H2O is 1:1-1:3; the amount of potassium alkyl xanthate used is 1-5 molar equivalents relative to furfural; the reaction temperature is 30-120°C; and the reaction is carried out for 8-16 hours.

3. The method for synthesizing the (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt according to claim 1, characterized in that: In the hydrolysis reaction of step S2, the amount of water used is 27 to 40 molar equivalents relative to 2-oxofuranyl acetate; the pH is adjusted to 0.1 to 3 with hydrochloric acid; and the reaction time is 4 to 10 hours.

4. The method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt according to claim 1, characterized in that: In the oximation reaction of step S3, compound (III) furanone acid is first dissolved in an organic solvent, and the amount of the organic solvent used is 15 to 35 molar equivalents relative to furanone acid; the amount of methoxyamine hydrochloride used is 1.0 to 2.0 molar equivalents relative to furanone acid; the reaction time is 5-12 hours.

5. The method for synthesizing (Z)-2-methoxyimino-2-furanyl acetic acid ammonium salt according to claim 1, characterized in that: In the salt-forming reaction of step S4, compound IV furanone acid is dissolved in an organic solvent, and the amount of the organic solvent dichloromethane used is 15 to 35 molar equivalents relative to furanone acid; the reaction temperature is -20 to 10° C.; and the reaction time is 0.1 to 1.0 h.

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