CN114409676A - A kind of preparation method of 7-ACF - Google Patents

Abstract

The invention provides a preparation method of 7-ACF, belonging to the technical field of preparation of 7-ACF, comprising the following steps: step 1, preparation of thiofuroic acid, dissolving sodium hydrosulfide in water, adding furoyl chloride dropwise, and simultaneously adding dropwise The lye is controlled to pH=7～8, after the reaction is finished, add dichloromethane for acid extraction, recycle dichloromethane to obtain thiofuroic acid; Step 2, preparation of ACF hydrochloride wet product, using 7-ACA as a raw material, Under the catalysis of boron trifluoride complex, the thiofuroic acid obtained in step 1 is added, and after the condensation reaction is completed, acid is added to separate out, and filtered to obtain ACF hydrochloride wet product; step 3, purifying 7-ACF, Dissolve the ACF hydrochloride wet product obtained in step 2 in water, add activated carbon for filtration, add an organic solvent to the filtrate, adjust pH=2.0~3.0 with lye, crystallize, filter, and dry to obtain a white product, which is 7-ACF . The solvent of the invention can be recovered, the waste water and waste gas are few, the purity of the product 7-ACF is over 99.0%, the reaction yield is over 90%, the process is simple, the production cycle is short, and the product is economical and environmentally friendly.

Description

A kind of preparation method of 7-ACF

technical field

The invention relates to the technical field of preparation of 7-ACF, in particular to a preparation method of 7-ACF.

Background technique

7-ACF, also known as 3-thiofuroyl-7-aminocephalosporanic acid, is an important intermediate of ceftiofur. Ceftiofur is the first third-generation cephalosporin antibiotic specially used for animals. It was successfully developed by Pharmacia-Upjohn Company and marketed in its sodium salt lyophilized powder and hydrochloride suspension. Due to its strong antibacterial activity, excellent pharmacokinetic characteristics, small toxic and side effects, and low residues, it is widely used in the treatment of bacterial diseases such as cattle, sheep, pigs, dogs, and chickens around the world.

The method disclosed in patent CN102234289A uses 7-ACA to react with thiofuroic acid under the catalysis of boron trifluoride ethyl acetate complex, and the intermediate is obtained through acid-base purification. After the intermediate synthesis is completed, it is washed three times with tap water, Washing with acetone three times, the production cycle is long, the consumption of acetone is large, and the acetone cannot be recycled, the production cost is high, and it is not suitable for industrial production.

In the method disclosed in patent CN1639169A, 7-ACA reacts with thiofuroic acid under the catalysis of boron trifluoride etherate, the yield of this method is high, but boron trifluoride etherate and boron trifluoride catalytic gas catalyze It is difficult to operate and has a relatively high risk in process production.

In the method disclosed in patent CN108912146A, 7-ACA reacts with thiofuroic acid under the catalytic action of solid alkali catalyst γ-Al2O2-O22-Na+, zeolite and water, the product purity and yield of this method are higher, but the solid alkali The catalyst is not easy to obtain, which is not conducive to industrial production.

Therefore, a preparation method of 7-ACF needs to be provided to solve the above-mentioned existing problems.

SUMMARY OF THE INVENTION

In view of this, the present invention provides a preparation method of 7-ACF, which has the advantages of simple process, mild reaction conditions, short production cycle, high product purity and high yield, and at the same time, the method has economical and easy-to-obtain raw materials, is safe and stable, and has good economical efficiency. value, suitable for industrial production.

In order to solve the above-mentioned technical problems, the present invention provides a kind of preparation method of 7-ACF, comprising the steps:

Step 1. Preparation of thiofuroic acid

Dissolve sodium hydrosulfide in water, add furoyl chloride dropwise, and add lye solution dropwise to control pH=7~8, after the reaction is finished, add dichloromethane for acid extraction, recover dichloromethane, and obtain thiofuroic acid;

Step 2. Preparation of ACF hydrochloride wet product

Using 7-ACA as a raw material, under the catalysis of boron trifluoride complex, add the thiofuroic acid obtained in step 1, after the condensation reaction is completed, add acid to separate out, and filter to obtain ACF hydrochloride wet product;

Step 3. Refining 7-ACF

Dissolve the ACF hydrochloride wet product obtained in step 2 in water, add activated carbon for filtration, add an organic solvent to the filtrate, adjust pH=2.0~3.0 with lye, crystallize, filter and dry to obtain a white product, namely 7-ACF .

Further, the molar ratio of sodium hydrosulfide to furoyl chloride is 1.05-1.5.

Further, the molar ratio of furoyl chloride to 7-ACA is 1.1-1.5.

Further, the lye solution includes one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, and an aqueous solution of potassium bicarbonate.

Further, the boron trifluoride complex includes boron trifluoride dimethyl carbonate and/or boron trifluoride acetonitrile.

Further, in step 2, after the condensation reaction is completed, the acid used is hydrochloric acid.

Further, the mass ratio of the water used in step 3 to the 7-ACA used in step 2 is 2 to 4.

Further, in step 3, the volume ratio of organic solvent and water is 2～6.

Further, the organic solvent used in step 3 includes one or more of acetone, acetonitrile, and tetrahydrofuran.

The above-mentioned technical solutions of the present invention at least include the following beneficial effects:

1, 7-ACF preparation method of the present invention reduces sodium hydrosulfide consumption, reduces hydrogen sulfide gas generation;

2. The thiofuroic acid is extracted with dichloromethane, and the extraction is completed in one time, the solvent is easy to recover, and the dehydration operation and the influence of hydrogen sulfide gas on the product quality are avoided;

3. Use hydrochloric acid to separate out the product, which is beneficial to solvent recovery;

4. Using organic solvent water crystallization, the product purity and yield are high, and the organic solvent can be recycled.

Detailed ways

The following examples illustrate the present invention in detail, but do not limit the present invention. The described embodiments are some, but not all, embodiments of the invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art fall within the protection scope of the present invention.

A preparation method of 7-ACF, comprising the steps:

Step 1. Preparation of thiofuroic acid

Dissolve sodium hydrosulfide in water, add furoyl chloride dropwise, and add lye solution dropwise to control pH=7~8, after the reaction is finished, add dichloromethane for acid extraction, recover dichloromethane, and obtain thiofuroic acid;

Step 2. Preparation of ACF hydrochloride wet product

Using 7-ACA as a raw material, under the catalysis of boron trifluoride complex, add the thiofuroic acid obtained in step 1, after the condensation reaction is completed, add acid to separate out, and filter to obtain ACF hydrochloride wet product;

Step 3. Refining 7-ACF

Dissolve the ACF hydrochloride wet product obtained in step 2 in water, add activated carbon for filtration, add an organic solvent to the filtrate, adjust pH=2.0~3.0 with lye, crystallize, filter and dry to obtain a white product, namely 7-ACF .

Further, the molar ratio of sodium hydrosulfide to furoyl chloride is 1.05-1.5.

Further, the molar ratio of furoyl chloride to 7-ACA is 1.1-1.5.

Further, the lye solution includes one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, and an aqueous solution of potassium bicarbonate.

Further, the boron trifluoride complex includes boron trifluoride dimethyl carbonate and/or boron trifluoride acetonitrile.

Further, in step 2, after the condensation reaction is completed, the acid used is hydrochloric acid.

Further, the mass ratio of the water used in step 3 to the 7-ACA used in step 2 is 2 to 4.

Further, in step 3, the volume ratio of organic solvent and water is 2～6.

Further, the organic solvent used in step 3 includes one or more of acetone, acetonitrile, and tetrahydrofuran.

Example 1

Step 1. Preparation of thiofuroic acid: add 70g of water and 9.8g of sodium hydrosulfide to the reaction flask, stir to dissolve, control the temperature to 25°C, add 12.9g of furoyl chloride and sodium carbonate solution dropwise, control pH=7.2, and complete the reaction for 2h, Add 70ml of dichloromethane, drop hydrochloric acid, adjust pH=1.0, stir for 5 minutes, stand for stratification, retain the organic phase, and distill to obtain thiofuroic acid;

Step 2. Preparation of ACF hydrochloride wet product: add the thiofuroic acid, 20g 7-ACA, and 90ml ethyl acetate obtained in step 1 into the reaction flask, then add 70g boron trifluoride dimethyl carbonate, stir and heat up 35-40°C, stirring and reacting for 1.5h, cooling to 15-20°C, dropwise adding 30ml hydrochloric acid, cooling to 5-10°C for culturing for 30min, suction filtration to obtain ACF hydrochloride wet product;

Step 3. Refining 7-ACF: add the ACF hydrochloride wet product obtained in step 2 and 50ml of water into the reaction flask, stir to dissolve, add 2g of activated carbon after dissolution, stir and decolorize for 30min, filter, add 150ml of acetonitrile to the filtrate, Continue to add saturated sodium carbonate aqueous solution dropwise to pH=2.1, cool down to 5-10°C for crystal growth for 30min, suction filter, rinse the filter cake with water, drain and dry to obtain 22.8g of white crystalline powder with a content of 99.2% .

The production table of this embodiment is as follows:

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Example 2

Step 1. Preparation of thiofuroic acid: add 70g of water and 9g of sodium hydrosulfide to the reaction flask, stir to dissolve, control the temperature to 25°C, add 12.0g of furoyl chloride and sodium carbonate solution dropwise, control pH=7.2, complete the reaction for 2h, add 70ml of dichloromethane, drop hydrochloric acid, adjust pH=1.0, stir for 5 minutes, stand for stratification, retain the organic phase, and distill to obtain thiofuroic acid;

Step 2. Preparation of ACF hydrochloride wet product: add thiofuroic acid, 20g 7-ACA, and 90ml ethyl acetate obtained in step 1 into the reaction flask, then add 60g boron trifluoride dimethyl carbonate acetonitrile, stir The temperature was raised to 35-40°C, stirred for 2 hours, cooled to 15-20°C, 40ml of hydrochloric acid was added dropwise, cooled to 5-10°C for 30min, and the wet product of ACF hydrochloride was obtained by suction filtration;

Step 3. Refining 7-ACF: add the ACF hydrochloride wet product obtained in step 2 and 40ml of water into the reaction flask, stir to dissolve, add 2g of activated carbon after dissolution, stir and decolorize for 30min, filter, add 200ml of acetone to the filtrate, Continue to dropwise add saturated sodium carbonate aqueous solution, drop to pH=2.5, cool to 5-10°C for crystal growth for 30min, suction filtration, filter cake water rinse, suction dry, and dry to obtain 23.1g of white crystalline powder with a content of 99.4% .

The production table of this embodiment is as follows:

Example 3

Step 1. Preparation of thiofuroic acid: add 70g of water and 10.2g of sodium hydrosulfide to the reaction flask, stir to dissolve, control the temperature to 25°C, add 13.5g of furoyl chloride and sodium carbonate solution dropwise, control pH=7.2, and complete the reaction for 2h, Add 70ml of dichloromethane, drop hydrochloric acid, adjust pH=1.0, stir for 5 minutes, stand for stratification, retain the organic phase, and distill to obtain thiofuroic acid;

Step 2. Preparation of ACF hydrochloride wet product: add the thiofuroic acid, 20g 7-ACA, and 90ml ethyl acetate obtained in step 1 into the reaction flask, then add 70g boron trifluoride carbonic acid acetonitrile, stir and heat up for 35- 40°C, stirring and reacting for 1.5h, cooling to 15-20°C, dropwise adding 45ml of hydrochloric acid, cooling to 5-10°C for crystal growth for 30min, suction filtration to obtain ACF hydrochloride wet product;

Step 3. Refining 7-ACF: add the ACF hydrochloride wet product obtained in step 2 and 30ml of water into the reaction flask, stir to dissolve, add 2g of activated carbon after dissolution, stir and decolorize for 30min, filter, add 120ml of tetrahydrofuran to the filtrate, Continue to add saturated sodium carbonate aqueous solution dropwise to pH=2.8, cool down to 5-10°C for crystal growth for 30min, suction filtration, filter cake water rinsing, suction dry, and dry to obtain 22.9g of white crystalline powder with a content of 99.1% .

The production table of this embodiment is as follows:

The above are the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can also be made, and these improvements and modifications should also be regarded as the present invention. the scope of protection of the invention.

Claims (9)

1. A preparation method of a 7-ACF is characterized by comprising the following steps:

step one, preparation of thiofuroic acid

Dissolving sodium hydrosulfide in water, dropwise adding furoyl chloride, dropwise adding alkali liquor at the same time to control the ph to be 7-8, after the reaction is finished, adding dichloromethane for acid adjustment and extraction, and recovering dichloromethane to obtain thiofuroic acid;

step two, ACF hydrochloride wet product preparation

Adding the thiofuroic acid obtained in the step one into 7-ACA serving as a raw material under the catalysis of a boron trifluoride complex, adding acid to separate out after the condensation reaction is finished, and filtering to obtain an ACF hydrochloride wet product;

step three, refining the 7-ACF

And D, dissolving the wet ACF hydrochloride obtained in the step two in water, adding activated carbon, filtering, adding an organic solvent into filtrate, adjusting the pH to be 2.0-3.0 by using alkaline liquor, crystallizing, filtering and drying to obtain a white product, namely the 7-ACF.

2. The method of preparing 7-ACF according to claim 1, wherein the molar ratio of sodium hydrosulfide to furoyl chloride is 1.05 to 1.5.

3. The method of preparing 7-ACF according to claim 1, wherein the molar ratio of furoyl chloride to 7-ACA is 1.1-1.5.

4. The method of claim 1, wherein the alkali solution comprises one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate.

5. The method of preparing 7-ACF of claim 1 wherein the boron trifluoride complex comprises boron trifluoride dimethyl carbonate and/or boron trifluoride acetonitrile.

6. The method of claim 1, wherein in the second step, the acid used is hydrochloric acid after the condensation reaction.

7. The method for preparing 7-ACF according to claim 1, wherein the mass ratio of the water used in the third step to the 7-ACA used in the second step is 2-4.

8. The method for preparing 7-ACF according to claim 1, wherein the volume ratio of the organic solvent to the water in the third step is 2 to 6.

9. The method for preparing 7-ACF according to claim 1, wherein the organic solvent used in step three comprises one or more of acetone, acetonitrile, tetrahydrofuran.