A preparation method of (Z)-α-(methoxyimino)furan-2-acetic acid

Abstract

The present invention provides a preparation method of (Z)-α-(methoxyimino)furan-2-acetic acid, which belongs to the field of pharmaceutical intermediates. Furfural and methoxyamine hydrochloride are condensed under an acid binding agent to obtain 2-furaldehyde O-methyloxime, followed by addition with a cyanating agent in DMSO to obtain 2-(furan-2-yl)-2-(methoxyamino)acetonitrile, which is then oxidized with ferric chloride to obtain (Z)-N-methoxyfuran-2-imido cyanide, and finally hydrolyzed with sulfuric acid solution to obtain (Z)-α-(methoxyimino)furan-2-acetic acid. The preparation method of the present invention has the advantages of continuous operation between steps, high yield, purity of more than 99%, and avoids the problems of purification difficulty and color caused by configuration.

Description

Technical Field

[0001] The invention relates to a preparation method of (Z)-α-(methoxyimino)furan-2-acetic acid, belonging to the technical field of pharmaceutical intermediates. Background Art

[0002] (Z)-α-(Methoxyimino)furan-2-acetic acid is primarily used as an important intermediate in the synthesis of cephalosporins, cefuroxime, and cefuroxime sodium (for injection) or cefuroxime axetil (for oral use), namely, the side chain of cefuroxime. Cefuroxime belongs to the second generation of cephalosporin antibiotics and is primarily used to treat infections of the lower respiratory tract, urinary tract, skin and soft tissue, bones and joints, and female genitalia caused by sensitive Gram-negative bacteria. It is characterized by a broad antimicrobial spectrum, low renal toxicity, and strong permeability. Due to the methoxyimino group attached to the 7-position side chain of the cephalosporin ring, it has high stability and tolerance to β-lactamase.

[0003] (Z)-α-(Methoxyimino)furan-2-acetic acid and (Z)-2-methoxyimino-2-(furan-2-yl)ammonium acetate have the same properties in the production process of cefuroxime. (Z)-2-Methoxyimino-2-(furan-2-yl)ammonium acetate is the ammonium salt of (Z)-α-(methoxyimino)furan-2-acetic acid, which is also impurity I of cefuroxime sodium.

[0004] In the prior art, (Z)-α-(methoxyimino)furan-2-acetic acid is mainly prepared by the oximation reaction of α-oxo-2-furanacetic acid with methoxyamine, and the reaction equation is as follows:

[0005]

[0006] The (Z)-α-(methoxyimino)furan-2-acetic acid prepared according to the above procedure is prone to moisture absorption and agglomeration during production, storage, and use, making purification difficult and dark in color. It often requires salting with ammonia to prepare (Z)-2-methoxyimino-2-(furan-2-yl)ammonium acetate. In comparison, (Z)-2-methoxyimino-2-(furan-2-yl)ammonium acetate has a better crystalline form and is easier to store. While this solves the problem of purifying the cis- and trans-configuration of (Z)-α-(methoxyimino)furan-2-acetic acid, it does require additional steps, and the cefuroxime condensation process requires the dissociation of the ammonium salt, resulting in a waste of manpower and material resources.

[0007] To address the shortcomings of existing cefuroxime synthesis methods, it is necessary to improve the preparation of (Z)-α-(methoxyimino)furan-2-acetic acid and develop a synthetic route with higher yield, lower cost, and greater suitability for industrial production. This is particularly important to avoid the issues of isomer purification and low yield, thereby meeting the growing market demand. Summary of the Invention

[0008] In order to better solve the above problems and address the color, crystal form, and cis-trans isomerization issues of (Z)-α-(methoxyimino)furan-2-acetic acid, the present invention provides a method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid, comprising condensing furfural and methoxyamine hydrochloride in the presence of an acid binder to obtain 2-furaldehyde O-methyloxime, followed by addition of a cyanating agent in DMSO to obtain 2-(furan-2-yl)-2-(methoxyamino)acetonitrile, followed by oxidation with ferric chloride to obtain (Z)-N-methoxyfuran-2-imido cyanide, and finally hydrolysis with sulfuric acid solution to obtain (Z)-α-(methoxyimino)furan-2-acetic acid. The preparation method of the present invention has the advantages of consistent operation between steps, high yield, and purity of over 99%; it avoids purification difficulties and color problems caused by configuration.

[0009] To achieve the above object, a process for chemically preparing (Z)-α-(methoxyimino)furan-2-acetic acid comprises the following steps:

[0010] Step 1): Furfural and methoxyamine hydrochloride are mixed in toluene, an acid binding agent is slowly added at room temperature, and then the temperature is raised to react to obtain 2-furfural O-methyloxime;

[0011] Step 2): 2-furaldehyde O-methyloxime reacts with a cyanation reagent in DMSO at elevated temperature to obtain 2-(furan-2-yl)-2-(methoxyamino)acetonitrile;

[0012] Step 3): Ferric chloride and methanol are mixed, and a mixed solution of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile and methanol is slowly added to oxidize to obtain (Z)-N-methoxyfuran-2-imido cyanide;

[0013] Step 4): (Z)-N-methoxyfuran-2-imido cyanide is mixed with sulfuric acid and subjected to a hydrolysis reaction at elevated temperature to obtain (Z)-α-(methoxyimino)furan-2-acetic acid.

[0014] The reaction equation is shown as follows:

[0015]

[0016] Furthermore, the acid binding agent in step 1) is selected from pyridine or triethylamine.

[0017] Furthermore, in step 1), the molar ratio of furfural, methoxyamine hydrochloride and acid binding agent is 1:1.15-1.20:1.20-1.22.

[0018] Furthermore, the cyanation reagent in step 2) is selected from sodium cyanide, potassium cyanide or cyanotrimethylsilane.

[0019] Furthermore, in step 2), the molar ratio of 2-furaldehyde O-methyloxime to the cyanation reagent is 1:1.4-1.8.

[0020] Furthermore, in step 3), the molar ratio of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile to ferric chloride is 1:2.5-3.0.

[0021] Furthermore, the sulfuric acid in step 4) is selected from a 60-65% sulfuric acid aqueous solution.

[0022] Furthermore, in step 4), the molar ratio of (Z)-N-methoxyfuran-2-imido cyanide to sulfuric acid is 1:2.2-2.5.

[0023] Advantageous Effects of the Invention

[0024] The preparation method of (Z)-α-(methoxyimino)furan-2-acetic acid provided by the present invention solves the purification difficulty caused by the configuration, is simple to operate, and ultimately obtains the target product in high yield with a purity greater than 99.0%. DETAILED DESCRIPTION

[0025] In order to make those skilled in the art clearly understand the preparation method of the cefuroxime intermediate (Z)-α-(methoxyimino)furan-2-acetic acid provided by the present invention, it is further illustrated below with reference to the following examples, but these examples should not be construed as limiting the scope of protection of the present invention.

[0026] Example 1

[0027]

[0028] 96.1 g (1.0 mol) of furfural, 96.1 g (1.15 mol) of methoxyamine hydrochloride and 1000 mL of toluene were added to the reactor, the temperature was controlled at 45-55 ° C, 121.4 g (1.20 mol) of triethylamine was slowly added dropwise with stirring, and then the reaction was carried out at 60 ° C for 3 hours. TLC showed no residual raw material. The toluene was concentrated under reduced pressure, 600 mL of toluene was added, the mixture was filtered, the filter cake was washed with toluene, the filtrate was washed with citric acid aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, the filter cake was washed with toluene, and the filtrate was concentrated under reduced pressure to dryness to obtain 121.6 g of 2-furaldehyde O-methyl oxime, with a yield of 97.2% and an HPLC index of 97.7%. 1H-NMR (400MHz, CDCl3): 8.89 (s, 1H), 7.84-7.80 (m, 1H), 6.94-6.90 (m, 1H), 6.64-6.60 (m, 1H), 3.93 (s, 3H).

[0029] Example 2

[0030]

[0031] 96.1 g (1.0 mol) of furfural, 96.1 g (1.15 mol) of methoxyamine hydrochloride and 1000 mL of toluene were added to the reactor, the temperature was controlled at 45-55 ° C, 96.5 g (1.22 mol) of pyridine was slowly added dropwise with stirring, and then the reaction was carried out at 60 ° C for 3 hours. TLC showed no residual raw material. The toluene was concentrated under reduced pressure, 600 mL of toluene was added, the mixture was filtered, the filter cake was washed with toluene, the filtrate was washed with citric acid aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, the filter cake was washed with toluene, and the filtrate was concentrated under reduced pressure to dryness to give 120 g of 2-furaldehyde O-methyl oxime, with a yield of 95.9% and an HPLC index of 98.3%.

[0032] Example 3

[0033]

[0034] 118.9g (0.95mol) of 2-furaldehyde O-methyloxime, 83.3g (1.7mol) of sodium cyanide, 68g of water and 840mL of DMSO were added to the reactor connected to the tail gas absorption, and the reaction was heated to 80-85°C for 3 hours. No raw material remained after TLC detection. 1000mL of water was added under stirring to quench the mixture and 1100mL of methyl tert-butyl ether was added. The reaction solution was allowed to stand for stratification, and the organic phase methyl tert-butyl ether layer was separated and washed with water (the aqueous phase was treated with sodium hypochlorite solution), washed with saturated brine, and the methyl tert-butyl ether was concentrated under reduced pressure, recrystallized by adding 85% methanol solution, filtered at-10°C, and dried to give 128.1g of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile in a yield of 88.6% and an HPLC index of 98.7%. 1 H-NMR(400MHz, CDCl3):7.36-7.32(m,1H),6.29-6.12(m,2H),5.14(t,1H),3.57(s,3H),2.18(s,1H).

[0035] Example 4

[0036]

[0037] To a reactor connected to a tail gas absorption reactor, 118.9 g (0.95 mol) of 2-furaldehyde O-methyloxime, 138.9 g (1.4 mol) of cyanotrimethylsilane, 0.5 g of cesium fluoride, 68 g of water, and 840 mL of DMSO were added, and the reaction was heated to 80-85 ° C for 4 hours. TLC detected that no raw material remained, and 1000 mL of water was added under stirring to quench the reaction, and 1100 mL of methyl tert-butyl ether was added. The reaction solution was allowed to stand and decomposed, and the organic phase was separated. The methyl tert-butyl ether layer was washed with water (the aqueous phase was treated with sodium hypochlorite solution), washed with saturated brine, and the methyl tert-butyl ether was concentrated under reduced pressure, recrystallized by adding 85% methanol solution, filtered at -10 ° C, and dried to give 115.3 g of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile in a yield of 79.8% and an HPLC index of 98.5%.

[0038] Example 5

[0039]

[0040] 900 mL of methanol was added to the reactor, the temperature was lowered to -5°C, 304.1 g (1.875 mol) of ferric chloride was added, the temperature was slowly raised to 10°C, and a mixed solution of 114.1 g (0.75 mol) of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile and 200 mL of methanol was slowly added dropwise. The reaction was carried out at room temperature for 8 hours, filtered, the filter cake was rinsed with methanol, the filtrate was concentrated under reduced pressure to obtain methanol, 700 mL of methyl tert-butyl ether and 800 mL of water were added under stirring, the mixture was allowed to stand for stratification, the organic phase methyl tert-butyl ether layer was washed with aqueous sodium thiosulfate solution and aqueous sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain methyl tert-butyl ether, heptane was added to precipitate crystals, filtered, and dried to obtain 102.1 g of (Z)-N-methoxyfuran-2-imido cyanide, with a yield of 90.7% and an HPLC index of 95.9%. 1 H-NMR(400MHz, CDCl3):7.84-7.80(m,1H),6.55-6.49(m,2H),3.95(s,3H).

[0041] Example 6

[0042]

[0043] 165.8 g (1.1 mol) of 65% sulfuric acid was added to the reactor and the temperature was raised to 55°C. 75.1 g (0.5 mol) of (Z)-N-methoxyfuran-2-imido cyanide was added in batches and the temperature was raised to 85-90°C. The reaction was stirred for 6 hours. HPLC detected that the remaining raw material was 0.05%. 300 mL of toluene and 350 mL of water were added, the temperature was lowered to 50°C, 20% sodium hydroxide was added to adjust the pH to 12.5, and the mixture was allowed to stand at this temperature for separation. The lower aqueous phase was cooled to 0°C and 5% sulfuric acid was slowly added dropwise to adjust the pH to 2. .0, 200mL*3 ethyl acetate was added to extract the aqueous phase, the organic phase was concentrated under reduced pressure to ethyl acetate, 850mL of toluene was added to concentrate and replace it once, then 850mL of toluene was added and the temperature was raised to 90-100°C, 1.5g of activated carbon, 8.5g of 100-200 mesh silica gel, and 5g of anhydrous magnesium sulfate were added, stirred for 1 hour, hot filtered, the filter cake was rinsed with hot toluene, the filtrate was slowly cooled to precipitate a white solid, filtered, and dried to obtain 74.7g of (Z)-α-(methoxyimino)furan-2-acetic acid, with a yield of 88.3%, and an HPLC index of 99.2%. 1 H-NMR (400MHz, DMSO-d6): 10.05(s,1H),7.87-7.83(m,1H),6.79-6.75(m,1H),6.67-6.63(m,1H),3.92(s,3H).

[0044] The above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these shall fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be based on the appended claims.

Claims

1. A method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid, characterized in that: The steps include: Step 1): Furfural and methoxyamine hydrochloride are mixed in toluene, an acid binding agent is slowly added at room temperature, and then the temperature is raised to react to obtain 2-furfural O-methyloxime; Step 2): 2-furaldehyde O-methyloxime reacts with a cyanation reagent in DMSO at elevated temperature to obtain 2-(furan-2-yl)-2-(methoxyamino)acetonitrile; Step 3): Ferric chloride and methanol are mixed, and a mixed solution of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile and methanol is slowly added to oxidize to obtain (Z)-N-methoxyfuran-2-imido cyanide; Step 4): (Z)-N-methoxyfuran-2-imido cyanide is mixed with sulfuric acid and subjected to a hydrolysis reaction at elevated temperature to obtain (Z)-α-(methoxyimino)furan-2-acetic acid.

2. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 1), the acid binding agent is selected from pyridine or triethylamine.

3. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 1), the molar ratio of furfural, methoxyamine hydrochloride and acid binding agent is 1:1.15-1.20:1.20-1.

22.

4. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 2), the cyanation reagent is selected from sodium cyanide, potassium cyanide or cyanotrimethylsilane.

5. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 2), the molar ratio of the 2-furaldehyde O-methyloxime to the cyanation reagent is 1:1.4-1.

8.

6. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 3), the molar ratio of 2-(furan-2-yl)-2-(methoxyamino)acetonitrile to ferric chloride is 1:2.5-3.

0.

7. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 4), the sulfuric acid is selected from a 60-65% sulfuric acid aqueous solution.

8. The method for preparing (Z)-α-(methoxyimino)furan-2-acetic acid according to claim 1, wherein: In step 4), the molar ratio of the (Z)-N-methoxyfuran-2-imido cyanide to sulfuric acid is 1:2.2-2.5.

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