CN110218199B - Preparation method of florfenicol cyclic compound intermediate - Google Patents
Preparation method of florfenicol cyclic compound intermediate Download PDFInfo
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- CN110218199B CN110218199B CN201910612322.4A CN201910612322A CN110218199B CN 110218199 B CN110218199 B CN 110218199B CN 201910612322 A CN201910612322 A CN 201910612322A CN 110218199 B CN110218199 B CN 110218199B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
Abstract
The invention discloses a preparation method of a florfenicol key intermediate, which takes D-threo-p-methylsulfonylphenylserine ethyl ester as an initial raw material, firstly directly performs cyclization reaction with dichloroacetonitrile, directly performs reduction reaction without separating the obtained cyclization product, and prepares a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol.
Description
Technical Field
The invention belongs to the technical field of veterinary drug synthesis, and particularly relates to a preparation method of a florfenicol cyclic compound intermediate.
Background
Florfenicol (Florfenicol) chinese name: flurbiprofen; florfenicol; fluorothiamphenicol is a novel broad-spectrum antibacterial of special chloramphenicol for veterinarians successfully developed in the late eighties. Florfenicol is a commonly used veterinary antibiotic at present, has wide antibacterial spectrum, strong antibacterial action, low Minimum Inhibitory Concentration (MIC) and 15-20 times of the antibacterial effect of chloramphenicol and thiamphenicol. Currently, China is the main production and export country of Florfenicol (Florfenicol), an antibacterial drug for veterinary use. According to statistics, in 2015, the export of florfenicol in China reaches 2199 tons, and with the regulation of food safety in the years, the consumption of the international mobile security market is continuously expanded.
D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol is a key intermediate for synthesizing florfenicol, and the synthesis of D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol at present in China is performed by adopting the following basic synthetic route:
the raw material D-threo-p-methylsulfonylphenylserine ethyl ester is firstly subjected to reduction reaction, and then subjected to cyclization reaction with dichloroacetonitrile to obtain the product. In particular, the glycerol is used as a solvent in the process of preparing the D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol from the D-threo-2-amino-1- [ (p-methylsulfonyl) phenyl ] -1, 3-propylene glycol, and the process has the defects of difficult recovery of the glycerol, large amount of water for washing, large discharge capacity, high cost and long reaction time of more than 20 hours. And obviously, the cyclization reaction has competitive cyclization reaction in two directions, so that more side reactions are caused, and the product yield is low.
In conclusion, the prior art has more defects.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a florfenicol cyclic compound intermediate. Therefore, the invention adopts the following technical scheme:
the invention discloses a preparation method of a florfenicol cyclic compound intermediate, which takes D-threo-p-methylsulfonylphenylserine ethyl ester as an initial raw material, firstly directly performs a cyclization reaction with dichloroacetonitrile, directly performs a reduction reaction without separating an obtained cyclization product, and prepares a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol, wherein the chemical reaction formula is as follows:
the preparation method comprises the following specific steps:
1) and cyclization reaction: d-threo-p-methylsulfonylphenylserine ethyl ester is prepared by adding dichloroacetonitrile into methanol or ethanol as a solvent at 40-80 ℃ for 2-5 hours to obtain a cyclization product intermediate;
2) and reduction reaction: the cyclization product obtained in the step 1) does not need to be separated, a reducing reagent is added after the temperature is reduced, the reaction is carried out for 2 to 4 hours at 20 to 60 ℃, water is added after the reaction is finished, the temperature is reduced, the product is separated out, and the florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol is obtained after the filtration.
As a further improvement, in the step 1) of the method, the molar ratio of dichloroacetonitrile to D-threo-p-methylsulfonylphenylserine ethyl ester is 1.2-2.0: 1.
As a further improvement, in step 2) of the present invention, the reducing agent is one of sodium borohydride, potassium borohydride and lithium aluminum hydride.
As a further improvement, the molar ratio of the reducing agent to the D-threo-p-methylsulfonylphenylserine ethyl ester is 1.0-2.0: 1.
as a further improvement, the solvents used in the steps 1) and 2) are the same, and the preparation method adopts a one-pot method to directly prepare the product.
The invention has the beneficial effects that:
(1) d-threo-p-methylsulfonylphenylserine ethyl ester is directly subjected to cyclization reaction with dichloroacetonitrile, only one amino group and one hydroxyl group exist in a molecular structure at the moment, and no competitive side reaction exists in the cyclization reaction, so that the reaction rate is high and the selectivity is high. Because the occurrence of competitive cyclization side reaction is avoided, the glycerin solvent used in the traditional process can be avoided, and the configuration conversion can be obtained without long-time reaction time. The glycerol solvent is viscous and difficult to recover, the product yield is reduced due to the dissolution of the product, the process avoids side reaction and the use of the glycerol solvent, and the economy is greatly improved.
(2) After the cyclization reaction is finished, the reaction system is directly in a weakly alkaline environment, the cyclization product is not required to be separated at the moment, reducing reagents of sodium borohydride, potassium borohydride and lithium aluminum hydride are directly added, the reduction activity of the reaction system is strong in the state, the generated intermediate is easy to decompose, the reduced product can be quickly obtained, the subsequent treatment steps are simplified, and the product yield is further improved.
In conclusion, the process has the advantages of high economical efficiency, simple process, short time, few steps and high benefit.
Detailed Description
The invention discloses a preparation method of a florfenicol key intermediate, which takes D-threo-p-methylsulfonylphenylserine ethyl ester as an initial raw material, firstly directly performs cyclization reaction with dichloroacetonitrile, directly performs reduction reaction without separating the obtained cyclization product, and prepares a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol, wherein the chemical reaction formula is as follows:
the preparation method comprises the following specific steps:
1) and cyclization reaction: d-threo-p-methylsulfonylphenylserine ethyl ester is prepared by adding dichloroacetonitrile into methanol or ethanol as a solvent at 40-80 ℃ for 2-5 hours to obtain a cyclization product intermediate;
2) and reduction reaction: the cyclization product obtained in the step 1) does not need to be separated, a reducing reagent is added after the temperature is reduced, the reaction is carried out for 2 to 4 hours at 20 to 60 ℃, water is added after the reaction is finished, the temperature is reduced, the product is separated out, and the florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol is obtained after the filtration.
In the step 1), the molar ratio of dichloroacetonitrile to D-threo-p-methylsulfonylphenylserine ethyl ester is 1.2-2.0: 1.
In the step 2), the reducing reagent is one of sodium borohydride, potassium borohydride and lithium aluminum hydride.
The mol ratio of the reducing agent to the D-threo-p-methylsulfonylphenylserine ethyl ester is 1.0-2.0: 1, the solvents used in the steps 1) and 2) are the same, and the preparation method adopts a one-pot method to directly prepare the compound.
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
Example 1
(1) And (3) cyclization reaction: 287.3g of D-threo-p-methylsulfonylphenylserine ethyl ester is added into 2000ml of ethanol, 132g of dichloroacetonitrile is added, and the reaction time is 2 hours at the reaction temperature of 80 ℃ to obtain a cyclization product intermediate;
(2) reduction reaction: and (2) the cyclization product obtained in the step (1) does not need to be separated, and after the temperature is reduced, 37.9g of reducing agent sodium borohydride is added to react for 4 hours at 20 ℃. After the reaction is finished, adding water, cooling to separate out a product, and filtering to obtain a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol.
The dried product has the mass of 320g, the yield of 94.6 percent and the content of more than 99 percent.
Example 2
(1) And (3) cyclization reaction: 287.3g of D-threo-p-methylsulfonylphenylserine ethyl ester is added into 2000ml of methanol, 220g of dichloroacetonitrile is added, and the reaction time is 5 hours at the reaction temperature of 40 ℃ to obtain a cyclization product intermediate;
(2) reduction reaction: and (2) the cyclization product obtained in the step (1) does not need to be separated, and after the temperature is reduced, 107.9g of reduction reagent potassium borohydride is added to react for 2 hours at 60 ℃. After the reaction is finished, adding water, cooling to separate out a product, and filtering to obtain a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol.
The dried product has the mass of 330g, the yield is 97.6 percent, and the content is more than 99 percent.
Example 3
(1) And (3) cyclization reaction: 287.3g of D-threo-p-methylsulfonylphenylserine ethyl ester is added into 2000ml of methanol, 165g of dichloroacetonitrile is added, and the reaction time is 4 hours at the reaction temperature of 60 ℃ to obtain a cyclization product intermediate;
(2) reduction reaction: and (2) the cyclization product obtained in the step (1) does not need to be separated, and after the temperature is reduced, 45g of reducing reagent lithium aluminum hydride is added to react for 3 hours at 40 ℃. After the reaction is finished, adding water, cooling to separate out a product, and filtering to obtain a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol.
The dried product has the mass of 333g, the yield of 98.5 percent and the content of more than 99 percent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and additions can be made without departing from the principle of the present invention, and these should also be considered as the protection scope of the present invention.
Claims (4)
1. A preparation method of a florfenicol cyclic compound intermediate is characterized in that D-threo-p-methylsulfonylphenylserine ethyl ester is used as an initial raw material, firstly, the initial raw material is directly subjected to a cyclization reaction with dichloroacetonitrile, an obtained cyclization product is directly subjected to a reduction reaction without separation, and a florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol is prepared, wherein the chemical reaction formula is as follows:
the preparation method comprises the following specific steps:
1) and cyclization reaction: d-threo-p-methylsulfonylphenylserine ethyl ester is prepared by adding dichloroacetonitrile into methanol or ethanol as a solvent at 40-80 ℃ for 2-5 hours to obtain a cyclization product intermediate;
2) and reduction reaction: the cyclization product obtained in the step 1) does not need to be separated, a reducing reagent is added after the temperature is reduced, the reaction is carried out for 2 to 4 hours at 20 to 60 ℃, water is added after the reaction is finished, the temperature is reduced, the product is separated out, and the florfenicol key intermediate compound D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazole methanol is obtained after the filtration;
after the reaction in the step 1) is finished, the reaction in the step 2) is directly carried out without post-treatment or solvent replacement.
2. The preparation method according to claim 1, wherein in the step 1), the molar ratio of dichloroacetonitrile to D-threo-p-methylsulfonylphenylserine ethyl ester is 1.2-2.0: 1.
3. The method according to claim 1, wherein in step 2), the reducing agent is one of sodium borohydride, potassium borohydride and lithium aluminum hydride.
4. The method according to claim 1, 2 or 3, wherein the molar ratio of the reducing agent to the D-threo-p-methylsulfonylphenylserine ethyl ester is 1.0-2.0: 1.
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