CN115974700A - Preparation method of florfenicol fluoriding agent tetrafluoromethylethylamine - Google Patents
Preparation method of florfenicol fluoriding agent tetrafluoromethylethylamine Download PDFInfo
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- CN115974700A CN115974700A CN202310141569.9A CN202310141569A CN115974700A CN 115974700 A CN115974700 A CN 115974700A CN 202310141569 A CN202310141569 A CN 202310141569A CN 115974700 A CN115974700 A CN 115974700A
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- florfenicol
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- tetrafluoromethylethylamine
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 26
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000012025 fluorinating agent Substances 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 7
- 238000004334 fluoridation Methods 0.000 claims 1
- 238000003682 fluorination reaction Methods 0.000 abstract description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 abstract description 8
- 208000012839 conversion disease Diseases 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000001030 gas--liquid chromatography Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 238000004821 distillation Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- OBDFQUSHNJZDSN-UHFFFAOYSA-N n-ethylethanamine;1,1,2,3,3,3-hexafluoroprop-1-ene Chemical compound CCNCC.FC(F)=C(F)C(F)(F)F OBDFQUSHNJZDSN-UHFFFAOYSA-N 0.000 description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BNTFCVMJHBNJAR-UHFFFAOYSA-N n,n-diethyl-1,1,2,3,3,3-hexafluoropropan-1-amine Chemical compound CCN(CC)C(F)(F)C(F)C(F)(F)F BNTFCVMJHBNJAR-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- STZZWJCGRKXEFF-UHFFFAOYSA-N Dichloroacetonitrile Chemical compound ClC(Cl)C#N STZZWJCGRKXEFF-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- PBWZKZYHONABLN-UHFFFAOYSA-M difluoroacetate Chemical compound [O-]C(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-M 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ADABDSJWQOSQMO-NSHDSACASA-N ethyl (2s)-3-hydroxy-2-(4-methylsulfonylanilino)propanoate Chemical compound CCOC(=O)[C@H](CO)NC1=CC=C(S(C)(=O)=O)C=C1 ADABDSJWQOSQMO-NSHDSACASA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- CSSYKHYGURSRAZ-UHFFFAOYSA-N methyl 2,2-difluoroacetate Chemical compound COC(=O)C(F)F CSSYKHYGURSRAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- -1 tetrafluoroethylene diethylamine Chemical compound 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and discloses a preparation method of florfenicol fluoridizing agent tetrafluoroethylamine, which comprises the steps of introducing tetrafluoroethylene into the same mole number ethylamine or the same mole number ethylamine containing 0.7-2.08 times of mole number of organic solvent under the conditions of-10 ℃ and 100-400 r/min of rotating speed, and keeping the temperature for 3-5 hours after the introduction is finished; the resulting product was then distilled at 70 ℃ to yield the fraction of tetrafluoroethylamine product. The preparation method is simple, mild in reaction condition, high in yield, high in product purity, high in fluorination reaction conversion rate and good in application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a florfenicol fluoriding agent, namely tetrafluoromethylethylamine.
Background
Florfenicol is also called florfenicol, cloransularfine, and the like, is a new generation of broad-spectrum antibacterial drug special for animals, and has been approved and allowed to be sold and used in more than 20 countries in the world. At present, two main methods for industrially producing florfenicol at home and abroad are available: 1. d, carrying out reduction reaction on the p-methylsulfonylphenylserine ethyl ester, reacting with benzonitrile to prepare oxazoline, carrying out Ishikawa reagent fluorination reaction, carrying out hydrolysis reaction, and carrying out dichloro acetylation reaction to obtain florfenicol; 2. d-p-methylsulfonylphenylserine ethyl ester is subjected to reduction reaction, then reacts with dichloroacetonitrile to generate oxazoline, and then is subjected to Ishikawa reagent fluorination reaction and hydrolysis reaction to obtain the florfenicol. Regardless of the route employed, it is desirable to carry out the fluorination reaction using a fluorinating agent.
At present, the fluorinating agent adopted in the florfenicol production is mainly fluoroacetate or hexafluoropropylene diethylamine, wherein the fluoroacetate comprises difluoroacetate or methyl difluoroacetate, but the fluorination reaction by using the fluorinating agent has the defects of high cost, low yield, complex three-waste treatment and the like. Therefore, a new fluorinating agent which overcomes the defects is needed to be searched and applied to the florfenicol production.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the florfenicol fluorinating agent tetrafluoromethylethylamine overcomes the defects in the prior art, and has the advantages of simple preparation method, mild reaction conditions, high yield, high product purity, high fluorination reaction conversion rate and good application prospect.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a preparation method of florfenicol fluoriding agent tetrafluoromethylethylamine comprises the following steps:
a. in a high-pressure kettle, introducing tetrafluoroethylene (gas) into methylethylamine with the mole number equal to that of the tetrafluoroethylene or the methylethylamine with the mole number equal to that of the tetrafluoroethylene containing organic solvent of 0.7-2.08 times of the tetrafluoroethylene (gas) at the temperature of-10 ℃ (the pressure is generated in the reaction process and is 0.5-1 MPa), stirring at the rotating speed of 100-400 rpm, and keeping the temperature for 3-5 hours after the introduction is finished;
b. distilling the product obtained in the step a at 70 ℃ to obtain a fraction which is a tetrafluoroethylamine product;
wherein, the organic solvent in the step a is dichloromethane, diethyl ether or toluene.
Preferably, the organic solvent in step a is dichloromethane.
Preferably, the reaction condition in the step a is 0 ℃, the addition amount of the organic solvent is 1.4 times of the mol number of the tetrafluoroethylene, the introduction speed of the tetrafluoroethylene gas is 1g/min, and the heat preservation is continued for 4 hours after the dropwise addition.
Preferably, the stirring speed in step a is 150rpm.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the invention adopts the reaction of the methylethylamine and the tetrafluoroethylene to obtain the tetrafluoroethylamine, but not adopts the reaction of the dimethylamine and the diethylamine with the tetrafluoroethylene to obtain the corresponding fluorinating agent, because the dimethylamine and the tetrafluoroethylene have high selectivity in the synthesis process but can not carry out high-selectivity fluorination on higher alcohol, although the diethylamine can carry out high-selectivity fluorination on the higher alcohol, the diethylamine has low selectivity in the process of reacting with the tetrafluoroethylene to generate the tetrafluoroethylene diethylamine (fluorinating agent of florfenicol); and the methylethylamine has the advantages of dimethylamine and diethylamine, so that a novel florfenicol fluorinating agent can be synthesized with high yield, and high-selectivity fluorination can be carried out on higher alcohol.
In a word, the preparation method is simple, the reaction condition is mild, the yield is high, the product purity is high, the fluorination reaction conversion rate is high, and the method has a good application prospect.
Drawings
FIG. 1 is a gas liquid chromatogram of the product of example 1 of the present invention;
FIG. 2 is a gas liquid chromatogram of the product of example 2 of the present invention;
FIG. 3 is a gas liquid chromatogram of the product of example 3 of the present invention;
FIG. 4 is a gas liquid chromatogram of the product of example 4 of the present invention;
FIG. 5 is a gas liquid chromatogram of the product of example 5 of the present invention;
FIG. 6 is a gas liquid chromatogram of the product of example 6 of the present invention;
FIG. 7 is a gas liquid chromatogram of the product of example 7 of the present invention;
FIG. 8 is a gas liquid chromatogram of the product of example 8 of the present invention;
FIG. 9 is a gas-liquid chromatogram of a product produced by using a fluorinating agent of the present invention in an application example of the present invention;
FIG. 10 is a gas liquid chromatogram of a product produced with a prior art fluorinating agent in an application example of the present invention.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
Adding 59g of methylethylamine (1.0 mol) into an autoclave, cooling to-10 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine at the speed of 1g/min, controlling the introduction temperature to be at-10 ℃, simultaneously stirring at the speed of 100rpm, and after the introduction is finished, continuously keeping at-10 ℃ for 4 hours; after 4 hours, the product is transferred to a kettle for distillation, and the distillation is carried out at 70 ℃, so that the fraction is the final tetrafluoroethylmethylamine product, the yield is 127.2g, the yield is 80%, and the GLC (gas liquid chromatography) analysis purity is 87.34% (see figure 1); it contained 12.66% amide. The reaction has an insufficient conversion rate and a relatively slow reaction rate.
Example 2
Adding 59g of methylethylamine (1.0 mol) into an autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine at the speed of 1g/min, controlling the introduction temperature to be 0 ℃, simultaneously stirring at the speed of 400rpm, and after the introduction is finished, continuously keeping at 0 ℃ for 4 hours; after 4 hours, the product was transferred to a still for distillation at 70 ℃ to give the final tetrafluoroethylamine product as a distillate with a yield of 143.1g, 90% yield and GLC purity of 94.63% (see fig. 2); it contains 3.57% amide.
Example 3
Adding 59g of methylethylamine (1.0 mol) into an autoclave, cooling to 10 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine at the speed of 1g/min, controlling the introduction temperature to be 10 ℃, simultaneously stirring at the speed of 150rpm, and after the introduction is finished, continuously keeping at 10 ℃ for 4 hours; after 4 hours, the product was transferred to a still for distillation at 70 ℃ to give a final tetrafluoroethylamine product as a distillate with a yield of 135.81g, 85% yield and GLC purity of 98.71% (see fig. 3); the impurities are mainly high molecular polymers.
Example 4
Adding 59g of methylethylamine (1.0 mol) into an autoclave, weighing 118g of dichloromethane as a solvent, adding into the autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine and the dichloromethane at the speed of 1g/min, controlling the introduction temperature to be 0 ℃, simultaneously stirring at the speed of 150rpm, and after the introduction is finished, continuously keeping at 0 ℃ for 4 hours; after 4 hours the product was transferred to a still for distillation at 70 ℃ to give the final tetrafluoroethylmethylamine product as a distillate in 151.05g yield 95% with GLC analytical purity of 99.20% (see figure 4).
Example 5
Adding 59g of methylethylamine (1.0 mol) into an autoclave, weighing 118g of diethyl ether as a solvent, adding into the autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine and the diethyl ether at a speed of 1g/min, controlling the introduction temperature to be 0 ℃, simultaneously stirring at a speed of 150rpm, and after the introduction is finished, continuously keeping at 0 ℃ for 3 hours; the product was transferred to a still for distillation at 70 ℃ for 3 hours to give the final tetrafluoroethylamine product as a distillate in 143.1g yield of 90% with GLC analytical purity of 98.51% (see figure 5).
Example 6
Adding 59g of methylethylamine (1.0 mol) into an autoclave, weighing 118g of toluene as a solvent, adding the solvent into the autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine and the toluene at the speed of 1g/min, controlling the introduction temperature to be 0 ℃, simultaneously stirring at the speed of 150rpm, and after the introduction is finished, continuously keeping at 0 ℃ for 4 hours; after 4 hours the product was transferred to a still for distillation at 70 ℃ to give the final tetrafluoroethylmethylamine product as a distillate in 135.15g yield of 85% with GLC analytical purity of 97.21% (see figure 6).
Example 7
Adding 59g of methylethylamine (1.0 mol) into an autoclave, weighing 59g of dichloromethane as a solvent, adding into the autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the methylethylamine and the dichloromethane at the speed of 1g/min, controlling the introduction temperature to be 0 ℃, simultaneously stirring at the speed of 150rpm, and after the introduction is finished, continuously keeping at 0 ℃ for 5 hours; after 5 hours, the product was transferred to a still for distillation, and distilled at 70 ℃ to give a final tetrafluoroethylamine product as a distillate with a yield of 146.28g, 85% yield, and 90.58% purity by GLC analysis (see fig. 7); it contained 1.90% amide.
Example 8
Adding 59g of ethylamine (1.0 mol) into an autoclave, weighing 177g of dichloromethane as a solvent, adding into the autoclave, cooling to 0 ℃ for later use, introducing 100 g (1.0 mol) of tetrafluoroethylene into the autoclave filled with the ethylamine and the dichloromethane at a speed of 1g/min, controlling the introduction temperature at 0 ℃, simultaneously stirring at a speed of 150rpm, and after the introduction is finished, continuing to keep at 0 ℃ for 4 hours; after 4 hours, the product was transferred to a still for distillation at 70 ℃ to give a final tetrafluoroethylamine product as a distillate with a yield of 144.69g, a yield of 91% and GLC purity of 96.71% (see fig. 8); the reaction was not completed.
Application example
The product obtained in example 4 (tetrafluoroethylamine) and the existing fluorinating agent hexafluoropropylene diethylamine are used as the control under the same conditions in florfenicol production, and the specific production conditions are as follows:
1.0 mole of cyclic compound (D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [4- (methylsulfonyl) -phenyl ] -4-oxazole methanol) and 1.2 moles of fluorinating agent are subjected to high-temperature high-pressure reaction in an autoclave, the reaction temperature is 90 ℃, the reaction pressure is 0.7MPa, the reaction time is 3 hours, after the reaction is finished, the product is hydrolyzed, the hydrolysis is layered, the water layer is cooled and crystallized, the hydrolyzed florfenicol is refined, and the yield of the refined product is detected.
The results obtained were as follows:
the invention comprises the following steps: florfenicol is produced by adopting the product of tetrafluoromethylethylamine obtained in example 4 as a fluorinating agent, the yield of the obtained florfenicol is 91%, and the purity of GLC analysis is 99.64% (see figure 9); it contains 0.36% of impurities.
The prior art is as follows: the hexafluoropropylene diethylamine is used as a fluorinating agent to produce the florfenicol, the yield of the florfenicol is 92%, and the GLC analysis purity is 99.14% (see figure 10).
And (4) analyzing results: as can be seen from the above experimental data, in example 4, the optimal reaction conditions are set, the yield is preferably 95%, and the purity is at most 99.20%, and the practical application in the production of florfenicol shows that the fluorinating agent of the invention has the yield equivalent to that of the existing fluorinating agent, but the purity is better, and the fluorinating agent of the invention has the effects of low production cost and stable yield.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Claims (4)
1. A preparation method of florfenicol fluoridation agent tetrafluoromethylethylamine is characterized by comprising the following steps:
a. in a high-pressure autoclave, introducing tetrafluoroethylene into methylethylamine with the same mole number or the methylethylamine with the same mole number and containing 0.7-2.08 times of the organic solvent at the temperature of-10 ℃, stirring at the rotating speed of 100-400 rpm, and continuously preserving the heat for 3-5 hours after the introduction is finished;
b. distilling the product obtained in the step a at 70 ℃ to obtain a fraction which is a tetrafluoroethylamine product;
wherein, the organic solvent in the step a is dichloromethane, diethyl ether or toluene.
2. The process for the preparation of tetrafluoromethylethylamine, a florfenicol fluorinating agent, as claimed in claim 1, wherein: the organic solvent in the step a is dichloromethane.
3. The process for the preparation of tetrafluoromethylethylamine, a florfenicol fluorinating agent, as claimed in claim 1, wherein: in the step a, the reaction condition is 0 ℃, the addition amount of the organic solvent is 1.4 times of the mol number of the tetrafluoroethylene, the introduction speed of the tetrafluoroethylene gas is 1g/min, and the temperature is kept for 4 hours after the addition.
4. The process for the preparation of tetrafluoromethylethylamine, a florfenicol fluorinating agent, as claimed in claim 1, wherein: the stirring speed in step a is 150rpm.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310141569.9A CN115974700A (en) | 2023-02-21 | 2023-02-21 | Preparation method of florfenicol fluoriding agent tetrafluoromethylethylamine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310141569.9A CN115974700A (en) | 2023-02-21 | 2023-02-21 | Preparation method of florfenicol fluoriding agent tetrafluoromethylethylamine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050075506A1 (en) * | 2003-10-06 | 2005-04-07 | Handa Vijay Kumar | Process for preparing florfenicol |
| CN103254103A (en) * | 2013-06-05 | 2013-08-21 | 南通金利油脂工业有限公司 | Application of fluorinating agent in florfenicol preparation technology |
| CN111423391A (en) * | 2020-03-18 | 2020-07-17 | 浙江康牧药业有限公司 | Preparation method of florfenicol intermediate |
| CN113045477A (en) * | 2019-12-26 | 2021-06-29 | 中蓝晨光化工研究设计院有限公司 | Preparation method of fluorine-containing primary amine intermediate |
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- 2023-02-21 CN CN202310141569.9A patent/CN115974700A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050075506A1 (en) * | 2003-10-06 | 2005-04-07 | Handa Vijay Kumar | Process for preparing florfenicol |
| CN103254103A (en) * | 2013-06-05 | 2013-08-21 | 南通金利油脂工业有限公司 | Application of fluorinating agent in florfenicol preparation technology |
| CN113045477A (en) * | 2019-12-26 | 2021-06-29 | 中蓝晨光化工研究设计院有限公司 | Preparation method of fluorine-containing primary amine intermediate |
| CN111423391A (en) * | 2020-03-18 | 2020-07-17 | 浙江康牧药业有限公司 | Preparation method of florfenicol intermediate |
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