CN114409676A - Preparation method of 7-ACF - Google Patents
Preparation method of 7-ACF Download PDFInfo
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- CN114409676A CN114409676A CN202111602302.2A CN202111602302A CN114409676A CN 114409676 A CN114409676 A CN 114409676A CN 202111602302 A CN202111602302 A CN 202111602302A CN 114409676 A CN114409676 A CN 114409676A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a 7-ACF (anisotropic conductive film), belonging to the technical field of preparation of 7-ACF, and comprising the following steps of: step one, preparing the 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, adding dichloromethane for acid adjustment and extraction after the reaction is finished, and recovering dichloromethane to obtain the thiofuroic acid; step two, preparing an ACF hydrochloride wet product, namely 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; and step three, refining the 7-ACF, dissolving the wet ACF hydrochloride product obtained in the step two in water, adding activated carbon, filtering, adding an organic solvent into filtrate, adjusting pH to be = 2.0-3.0 by using alkaline liquor, crystallizing, filtering and drying to obtain a white product, namely the 7-ACF. The method has the advantages of recoverable solvent, less waste water and waste gas, high purity of the 7-ACF product of more than 99.0 percent, high reaction yield of more than 90 percent, simple process, short production period, economy and environmental protection.
Description
Technical Field
The invention relates to the technical field of preparation of 7-ACF, in particular to a preparation method of 7-ACF.
Background
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, is developed successfully by the company Famaxiya-Puqiang, and is marketed as a suspension of sodium salt freeze-dried powder and hydrochloride thereof. Because of strong antibacterial activity, excellent pharmacokinetic characteristics, small toxic and side effects and low residue, the compound is widely applied to the treatment of bacterial diseases of cattle, sheep, pigs, dogs, chickens and the like all over the world.
The method disclosed in patent CN102234289A is characterized in that 7-ACA reacts with thiofuroic acid under the catalysis of boron trifluoride ethyl acetate complex, an intermediate is obtained through acid-base purification treatment, the intermediate is washed with tap water three times after being synthesized, and then washed with acetone three times, so that the production cycle is long, the consumption of acetone is high, and acetone cannot be recovered and used, the production cost is high, and the method is not suitable for industrial production.
In the method disclosed in patent CN1639169A, 7-ACA reacts with thiofuroic acid under the catalytic action of boron trifluoride etherate, which has high yield, but boron trifluoride etherate and catalytic gas catalysis of boron trifluoride have high operational difficulty and high risk in process production.
In the method disclosed in patent CN108912146A, 7-ACA reacts with thiofuroic acid under the catalytic action of a solid base catalyst γ -Al2O2-O22-Na + with zeolite and water, and the method has high product purity and yield, but the solid base catalyst is not easily available, which is not beneficial to industrial production.
Therefore, it is desirable to provide a method for preparing 7-ACF, which solves the above existing problems.
Disclosure of Invention
In view of the above, the invention provides a preparation method of 7-ACF, which has the advantages of simple process, mild reaction conditions, short production period, high product purity and high yield, and simultaneously the method has the advantages of economical and easily obtained raw materials, safety and stability, good economic value and suitability for industrial production.
In order to solve the technical problem, the invention provides a preparation method of a 7-ACF, which comprises 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.
Furthermore, the molar ratio of the sodium hydrosulfide to the furoyl chloride is 1.05-1.5.
Furthermore, the molar ratio of the furoyl chloride to the 7-ACA is 1.1-1.5.
Further, the alkali liquor comprises one or more of sodium bicarbonate, sodium carbonate, potassium carbonate and potassium bicarbonate aqueous solution.
Further, the boron trifluoride complex comprises boron trifluoride dimethyl carbonate and/or boron trifluoride acetonitrile.
Further, in the second step, after the condensation reaction is finished, the acid is hydrochloric acid.
Further, the mass ratio of the water used in the third step to the 7-ACA used in the second step is 2-4.
Furthermore, in the third step, the volume ratio of the organic solvent to the water is 2-6.
Further, the organic solvent used in step three comprises one or more of acetone, acetonitrile and tetrahydrofuran.
The technical scheme of the invention at least comprises the following beneficial effects:
1. the 7-ACF preparation method reduces the using amount of sodium hydrosulfide and the generation of hydrogen sulfide gas;
2. the thiofuroic acid is extracted by dichloromethane, one-time extraction is completed, the solvent is easy to recover, and the influence of dehydration operation and hydrogen sulfide gas on the product quality is avoided;
3. the product is separated out by hydrochloric acid, which is beneficial to the recovery of the solvent;
4. the organic solvent is used for crystallization, the product purity and yield are high, and the organic solvent can be recycled.
Detailed Description
The following examples illustrate the invention in detail, but are not intended to limit the invention thereto. The described embodiments are only some, but not all embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
A preparation method of a 7-ACF comprises 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.
Furthermore, the molar ratio of the sodium hydrosulfide to the furoyl chloride is 1.05-1.5.
Furthermore, the molar ratio of the furoyl chloride to the 7-ACA is 1.1-1.5.
Further, the alkali liquor comprises one or more of sodium bicarbonate, sodium carbonate, potassium carbonate and potassium bicarbonate aqueous solution.
Further, the boron trifluoride complex comprises boron trifluoride dimethyl carbonate and/or boron trifluoride acetonitrile.
Further, in the second step, after the condensation reaction is finished, the acid is hydrochloric acid.
Further, the mass ratio of the water used in the third step to the 7-ACA used in the second step is 2-4.
Furthermore, in the third step, the volume ratio of the organic solvent to the water is 2-6.
Further, the organic solvent used in step three comprises one or more of acetone, acetonitrile and tetrahydrofuran.
Example 1
Step one, preparing the furothioate: adding 70g of water and 9.8g of sodium hydrosulfide into a reaction bottle, stirring for dissolving, controlling the temperature to be 25 ℃, dropwise adding 12.9g of furoyl chloride and a sodium carbonate solution, controlling the pH to be =7.2, reacting for 2 hours after dropwise adding, adding 70ml of dichloromethane, dropwise adding hydrochloric acid, adjusting the pH to be =1.0, stirring for 5 minutes, standing for layering, keeping an organic phase, and distilling to obtain the thiofuroic acid;
step two, preparing an ACF hydrochloride wet product: adding the sulfo-furoic acid prepared in the step one, 20g of 7-ACA and 90ml of ethyl acetate into a reaction bottle, adding 70g of boron trifluoride dimethyl carbonate, stirring, heating to 35-40 ℃, stirring, reacting for 1.5h, cooling to 15-20 ℃, dropwise adding 30ml of hydrochloric acid, cooling to 5-10 ℃, growing crystals for 30min, and performing suction filtration to obtain an ACF hydrochloride wet product;
step three, refining the 7-ACF: and (3) adding the wet ACF hydrochloride prepared in the step two and 50ml of water into a reaction bottle, stirring for dissolving, adding 2g of activated carbon after dissolving, stirring for decoloring for 30min, filtering, adding 150ml of acetonitrile into filtrate, continuously dropwise adding a saturated sodium carbonate aqueous solution until the pH is =2.1, cooling to 5-10 ℃ for crystal growth for 30min, carrying out suction filtration, leaching filter cake with water, pumping, drying, and obtaining 22.8g of white crystal powder with the content of 99.2%.
The production table for this example is as follows:
example 2
Step one, preparing the furothioate: adding 70g of water and 9g of sodium hydrosulfide into a reaction bottle, stirring and dissolving, controlling the temperature to be 25 ℃, dropwise adding 12.0g of furoyl chloride and a sodium carbonate solution, controlling the ph to be =7.2, reacting for 2 hours after dropwise adding, adding 70ml of dichloromethane, dropwise adding hydrochloric acid, adjusting the ph to be =1.0, stirring for 5 minutes, standing and layering, keeping an organic phase, and distilling to obtain the furothioate;
step two, preparing an ACF hydrochloride wet product: adding the sulfo-furoic acid prepared in the step one, 20g of 7-ACA and 90ml of ethyl acetate into a reaction bottle, adding 60g of boron trifluoride dimethyl carbonate acetonitrile, stirring, heating to 35-40 ℃, stirring, reacting for 2 hours, cooling to 15-20 ℃, dropwise adding 40ml of hydrochloric acid, cooling to 5-10 ℃, growing crystals for 30min, and performing suction filtration to obtain an ACF hydrochloride wet product;
step three, refining the 7-ACF: and (3) adding the wet ACF hydrochloride prepared in the step two and 40ml of water into a reaction bottle, stirring for dissolving, adding 2g of activated carbon after dissolving, stirring for decoloring for 30min, filtering, adding 200ml of acetone into the filtrate, continuously dropwise adding a saturated sodium carbonate aqueous solution until the pH is =2.5, cooling to 5-10 ℃ for crystal growth for 30min, carrying out suction filtration, leaching the filter cake with water, drying, and drying to obtain 23.1g of white crystal powder with the content of 99.4%.
The production table for this example is as follows:
example 3
Step one, preparing the furothioate: adding 70g of water and 10.2g of sodium hydrosulfide into a reaction bottle, stirring for dissolving, controlling the temperature to be 25 ℃, dropwise adding 13.5g of furoyl chloride and a sodium carbonate solution, controlling the pH to be =7.2, reacting for 2 hours after dropwise adding, adding 70ml of dichloromethane, dropwise adding hydrochloric acid, adjusting the pH to be =1.0, stirring for 5 minutes, standing for layering, keeping an organic phase, and distilling to obtain the thiofuroic acid;
step two, preparing an ACF hydrochloride wet product: adding the sulfo-furoic acid prepared in the step one, 20g of 7-ACA and 90ml of ethyl acetate into a reaction bottle, adding 70g of boron trifluoride acetonitrile carbonate, stirring and heating to 35-40 ℃, stirring and reacting for 1.5h, cooling to 15-20 ℃, dropwise adding 45ml of hydrochloric acid, cooling to 5-10 ℃, growing crystals for 30min, and performing suction filtration to obtain an ACF hydrochloride wet product;
step three, refining the 7-ACF: and (3) adding the wet ACF hydrochloride prepared in the step two and 30ml of water into a reaction bottle, stirring for dissolving, adding 2g of activated carbon after dissolving, stirring for decoloring for 30min, filtering, adding 120ml of tetrahydrofuran into the filtrate, continuously dropwise adding a saturated sodium carbonate aqueous solution until the pH is =2.8, cooling to 5-10 ℃ for crystal growth for 30min, carrying out suction filtration, leaching the filter cake with water, pumping, and drying to obtain 22.9g of white crystal powder with the content of 99.1%.
The production table for this example is as follows:
the foregoing is a preferred embodiment of the present invention, and it should be noted that it would be apparent to those skilled in the art that various modifications and enhancements can be made without departing from the principles of the invention, and such modifications and enhancements are also considered to be within the scope 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.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| WO2003055893A1 (en) * | 2002-01-04 | 2003-07-10 | Orchid Chemicals And Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| CN103804394A (en) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur intermediate |
| CN104356146A (en) * | 2014-11-14 | 2015-02-18 | 浙江浙邦制药有限公司 | Method for preparing cefotiam hydrochloride |
| CN104530085A (en) * | 2014-12-07 | 2015-04-22 | 河南领先科技药业有限公司 | New preparation method of ceftiofur sodium |
| CN109422766A (en) * | 2017-08-24 | 2019-03-05 | 王小桥 | A kind of preparation method of Ceftiofur intermediate |
-
2021
- 2021-12-24 CN CN202111602302.2A patent/CN114409676A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| WO2003055893A1 (en) * | 2002-01-04 | 2003-07-10 | Orchid Chemicals And Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| CN1639169A (en) * | 2002-01-04 | 2005-07-13 | 奥齐德化学和制药有限公司 | An improved synthesis of ceftiofur intermediate |
| CN103804394A (en) * | 2014-01-24 | 2014-05-21 | 瑞普（天津）生物药业有限公司 | Preparation method of ceftiofur intermediate |
| CN104356146A (en) * | 2014-11-14 | 2015-02-18 | 浙江浙邦制药有限公司 | Method for preparing cefotiam hydrochloride |
| CN104530085A (en) * | 2014-12-07 | 2015-04-22 | 河南领先科技药业有限公司 | New preparation method of ceftiofur sodium |
| CN109422766A (en) * | 2017-08-24 | 2019-03-05 | 王小桥 | A kind of preparation method of Ceftiofur intermediate |
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