CN109851534B - Synthetic method of florfenicol intermediate - Google Patents
Synthetic method of florfenicol intermediate Download PDFInfo
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- CN109851534B CN109851534B CN201711237554.3A CN201711237554A CN109851534B CN 109851534 B CN109851534 B CN 109851534B CN 201711237554 A CN201711237554 A CN 201711237554A CN 109851534 B CN109851534 B CN 109851534B
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Abstract
The invention relates to a synthesis method of a florfenicol Intermediate (IV), which specifically comprises the following steps: dissolving a compound (II) in an organic solvent, and carrying out mesylation under an alkaline condition to obtain a compound (III); the compound (III) is subjected to ring closing under the action of alkali to obtain a compound (IV); and (3) carrying out fluorination ring opening on the compound (IV) to obtain the florfenicol intermediate (I). The method has the advantages of novel design, mild conditions and simple and convenient operation, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical raw material medicine synthesis, and particularly relates to a synthetic method of a florfenicol intermediate.
Background
Florfenicol (Florfenicol) is a special broad-spectrum antibiotic of chloramphenicol for animals, which is developed on the basis of thiamphenicol by Nagab-hushan and the like of Schering-Plough company in 1979. In view of the fact that the drug effect of florfenicol is superior to that of chloramphenicol and thiamphenicol in the prevention and treatment of animal diseases, the florfenicol has a wider application prospect, and the synthesis of the florfenicol is always paid great attention.
At present, the method for industrially producing florfenicol at home and abroad comprises the following steps: 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 florfenicol, namely a synthetic route 1.
Scheme 1:
in the synthesis of florfenicol, a key step is fluorination reaction, hydroxyl is replaced by fluorine atoms, and a common fluorinating reagent is DAST or Deoxo-Fluor, but the fluorinating reagent is unstable and is easy to decompose at a higher temperature to generate explosive substances, and the fluorinating reagent also generates strong corrosive hydrofluoric acid in use, so that the requirement on a container is high, and the operation is not changed.
In Schering-Plough, the introduction of fluorine atoms uses Ishikawa reagent, which is expensive and requires high temperature and pressure conditions in the reaction to carry out the fluorination reaction. The Ishikawa reagent is decomposed into tetrafluoropropionamide as a byproduct after the fluorination reaction is finished, and an effective method for recovering and regenerating the tetrafluorofenicol in the process of synthesizing the florfenicol in industrial production is not available at present, so that the Ishikawa reagent is still one of important problems to be solved in the industrial fluorination process.
The main problem in the prior florfenicol intermediate fluorination step is that a byproduct tetrafluoro-propionamide generated by a fluorination reagent can not be recovered, so that the reaction production cost and the environmental protection cost in the step are higher, and meanwhile, the fluorination reagent has lower finished product yield; high requirements on the container and reaction conditions and inconvenience for operation.
Therefore, the method for synthesizing the florfenicol intermediate introduced with the fluorine atom, which is environment-friendly, convenient to operate and easy for industrial production, is urgently needed to be designed in the field.
Disclosure of Invention
The invention provides a synthetic method which is environment-friendly, convenient to operate and easy for industrial production of florfenicol intermediates.
In a first aspect of the present invention, there is provided a method for synthesizing a florfenicol intermediate (i), comprising the steps (1) to (3):
wherein R is1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is methylmercapto or methylsulfonyl;
(1) in an inert solvent, in the presence of alkali, esterifying the compound (II) and a sulfonylation reagent to obtain a compound (III);
(2) in an inert solvent, in the presence of alkali, carrying out a ring closing reaction on the compound (III) to obtain a compound (IV);
(3) reacting compound (iv) with a fluorinating agent in an inert solvent to obtain compound (i), said fluorinating agent being selected from the group consisting of: triethylamine hydrofluoride, N-dimethylpropylurea hydrogen fluoride complex, hydrogen fluoride pyridine complex, hydrogen fluoride, preferably triethylamine hydrofluoride.
In another preferred embodiment, in the step (1), the sulfonylation reagent is selected from the group consisting of: methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, preferably methanesulfonyl chloride.
In another preferred embodiment, the inert solvent is an organic solvent.
In another preferred embodiment, in the step (1), the molar ratio of the compound (ii) to methanesulfonyl chloride is 1:1 to 5, preferably 2 to 4.
In another preferred embodiment, in the step (1), the molar ratio of the compound (ii) to the base is 1: 1-5, preferably 1: 2-4.
In another preferred example, in the step (1), the reaction temperature is-20 to 0 ℃, preferably-10 to-5 ℃.
In another preferred example, in the step (1), the reaction time is 0.5-6 h.
In another preferred embodiment, in the step (1), the base used is an inorganic base or an organic base, wherein the inorganic base is selected from the following group: potassium or sodium hydroxide (e.g., potassium hydroxide or potassium hydroxide), potassium or sodium bicarbonate or potassium or sodium carbonate (sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate), or a combination thereof; preferably potassium carbonate; the organic base is selected from the following group: c1-C4A tri-substituted amine (such as triethylamine or diisopropylethylamine), pyridine, or a combination thereof; triethylamine is preferred.
In another preferred embodiment, in the step (1), the organic solvent used is selected from the group consisting of: c1-C4A halogenated hydrocarbon of (dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride), tetrahydrofuran, methyl tert-butyl ether, or toluene, or a combination thereof; tetrahydrofuran, dichloromethane, or combinations thereof are preferred.
In another preferred embodiment, in the step (2), the molar ratio of the compound (iii) to the base is 1: 2.0-10.0, preferably 1: 4-6.
In another preferred embodiment, in the step (2), the reaction temperature is 50-110 ℃, preferably 50-60 ℃.
In another preferred embodiment, in the step (2), the reaction time is 2 to 10 hours, preferably 2 to 3 hours.
In another preferred embodiment, in the step (2), the base used is an inorganic base or an organic base, wherein the inorganic base is selected from the following group: a potassium or sodium hydroxide (preferably potassium hydroxide or potassium hydroxide), a potassium or sodium bicarbonate, or a potassium or sodium carbonate (preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate), or a combination thereof; the organic base is selected from the following group: c1-C4Tri-substituted amines (preferably triethylamine or diisopropylethylamine) or pyridine, or combinations thereof(ii) a Preferably, the base is potassium carbonate.
In another preferred embodiment, in the step (2), the solvent used is C1-C4Halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), C1-C4An alcohol (such as methanol, ethanol, isopropanol or n-butanol), ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, or a combination thereof, preferably acetonitrile.
In another preferred embodiment, in the step (3), the molar ratio of the compound (IV) to triethylamine hydrofluoride salt is 1: 1.2-10, preferably 1: 8-10.
In another preferred embodiment, in the step (3), the reaction temperature is 40-110 ℃, preferably 70-80 ℃.
In another preferred embodiment, in the step (3), the reaction time is 6-24h, preferably 8-10 h.
In another preferred embodiment, in the step (3), the solvent is selected from the group consisting of: dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, chlorobenzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloroethyl ether, NMP, DMF, DMSO, or combinations thereof; 1, 2-dichloroethane is preferred.
In another preferred embodiment, in the step (3), the mass ratio of the solvent to the compound (iv) is 3-15: 1.
in a second aspect of the present invention, there is provided a compound represented by the following formula (iv):
wherein R is1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is methylmercapto or methylsulfonyl.
In another preferred embodiment, the compound of formula (IV) has the structure shown below:
in another preferred embodiment, the method comprises the following steps:
wherein R is1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is methylmercapto or methylsulfonyl;
in an inert solvent and in the presence of alkali, carrying out a ring closing reaction on the compound (III) to obtain a compound (IV).
In a third aspect of the present invention, there is provided a process for the preparation of formula (III) as described in the second aspect of the present invention, the process further comprising the steps of:
(1) the compound (II) is esterified with a sulfonylating agent in an inert solvent in the presence of a base to obtain a compound (III).
In another preferred embodiment, the preparation method of the compound (ii) comprises the steps of:
(a) reacting the compound (VI) with an acylating reagent in an inert solvent to obtain a compound (VII);
(b) reacting the compound (VII) with a negative hydrogen reagent in an inert solvent to obtain a compound (II);
in another preferred embodiment, said step (a) is carried out in the presence of a base; preferably, the selected base is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine, or a combination thereof; sodium bicarbonate is preferred.
In another preferred embodiment, in the step (a), the molar ratio of the compound (vi) to the acylating agent is 1: 1.0-3.0, preferably 1: 1.1-1.5.
In another preferred embodiment, in the step (a), the molar ratio of the compound (vi) to the base is 1: 1.2-4.0.
In another preferred embodiment, in said step (a), the reaction temperature is 0-30 ℃, preferably 15-25 ℃.
In another preferred embodiment, in the step (a), the reaction time is 2-10h, preferably 6-8 h.
In another preferred embodiment, in the step (a), the inert solvent is selected from methanol, tetrahydrofuran, dichloromethane, chloroform and 1, 2-dichloroethane, or a combination thereof; preferably selected from tetrahydrofuran, dichloromethane, or combinations thereof.
In another preferred embodiment, in the step (a), the acylating agent is selected from the group consisting of: (Boc)2O, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, preferably (Boc)2O。
In another preferred embodiment, in the step (b), the reaction molar ratio of the compound (vii) to the hydrogen-negative reagent is 1: 1-5, preferably 1: 2-3.
In another preferred embodiment, in the step (b), the reaction temperature is 0-40 ℃, and the reaction temperature is preferably 15-25 ℃.
In another preferred embodiment, in the step (b), the reaction time is 0.5 to 10 hours, preferably 6 to 8 hours.
In another preferred embodiment, in the step (b), the negative hydrogen reagent is selected from potassium borohydride, sodium borohydride, lithium borohydride or calcium borohydride, preferably potassium borohydride or sodium borohydride.
In another preferred embodiment, in the step (b), the organic reagent is selected from the group consisting of: methanol, ethanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran, dioxane, or a combination thereof; methanol is preferred.
In a fourth aspect of the present invention, there is provided a method for synthesizing a florfenicol intermediate (i), comprising the steps of:
and (3) reacting the compound (IV) with triethylamine hydrofluoride in an inert solvent to obtain a compound (I).
In a fifth aspect of the present invention, there is provided a process for preparing florfenicol intermediate (v), comprising the steps of:
(i) preparing compound (i) by a process according to the fourth aspect of the invention;
(ii) taking the compound (I) as a substrate to prepare an intermediate (V), namely (1R,2S) -2-amino-3-fluoro-1- [4- (methylsulfonyl) phenyl ] -1-propanol;
wherein R is1Is C1-C4 alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is a methylsulfonyl group.
In a sixth aspect of the present invention, there is provided a method for preparing florfenicol, comprising the steps of:
(i) the preparation of compound (I) by the process according to the fourth aspect of the invention, wherein R1Is C1-C4 alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl, R2Is a methylsulfonyl group;
(ii) taking the compound (I) as a substrate to prepare an intermediate (V), namely (1R,2S) -2-amino-3-fluoro-1- [4- (methylsulfonyl) phenyl ] -1-propanol;
(iii) dichloroacetylation with intermediate (v) to form florfenicol:
it is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has long and intensive research and unexpectedly found that the florfenicol is prepared from the intermediate shown as the formula (IV), the obtained by-products are less, and the preparation cost of the florfenicol can be effectively reduced. Based on the above findings, the inventors have completed the present invention.
Preparation of florfenicol intermediate (I)
The invention provides a synthesis method of a florfenicol intermediate (I), which comprises the following steps of (1) to (3):
wherein R is1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is methylmercapto or methylsulfonyl;
(1) in an inert solvent, in the presence of alkali, carrying out esterification reaction on the compound (II) and a sulfonylation reagent to obtain a compound (III);
(2) in an inert solvent, in the presence of alkali, carrying out ring closing reaction on the compound (III) to obtain a compound (IV);
(3) and (3) reacting the compound (IV) with triethylamine hydrofluoride in an inert solvent to obtain a compound (I).
In the step (1), the sulfonylation reagent is selected from the group consisting of: methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride or a combination thereof, preferably methanesulfonyl chloride; the inert solvent is an organic solvent, and the organic solvent is selected from the following group: c1-C4A halogenated hydrocarbon of (dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride), tetrahydrofuran, methyl tert-butyl ether, or toluene, or a combination thereof; tetrahydrofuran, dichloromethane, or combinations thereof are preferred. The molar ratio of the compound (II) to methanesulfonyl chloride is 1: 1-1.5, preferably 1: 1-1.2; the molar ratio of compound (ii) to base is 1: 1-3, preferably 1: 1.5-2; the reaction temperature is-20 to 0 ℃, and the preferable temperature is-10 to-5 ℃; the reaction time is 0.5-6 h(ii) a The used base is inorganic base or organic base, wherein the inorganic base is selected from the following group: potassium or sodium hydroxide (e.g., potassium hydroxide or potassium hydroxide), potassium or sodium bicarbonate or potassium or sodium carbonate (sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate), or a combination thereof; preferably potassium carbonate; the organic base is selected from the following group: c1-C4Tri-substituted amines (such as triethylamine or diisopropylethylamine), pyridine, or combinations thereof, preferably triethylamine;
in the step (2), the molar ratio of the compound (iii) to the base is 1: 2.0-10.0, preferably 1: 4-6; the reaction temperature is 50-110 ℃, preferably 50-60 ℃; the reaction time is 2 to 10 hours, preferably 2 to 3 hours; the used base is inorganic base or organic base, wherein the inorganic base is selected from the following group: a potassium or sodium hydroxide (preferably potassium hydroxide or potassium hydroxide), a potassium or sodium bicarbonate, or a potassium or sodium carbonate (preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate), or a combination thereof, preferably potassium carbonate; the organic base is selected from the following group: c1-C4A tri-substituted amine (preferably triethylamine or diisopropylethylamine) or pyridine, or a combination thereof; the solvent used is C1-C4Halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), C1-C4An alcohol (such as methanol, ethanol, isopropanol or n-butanol), ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, or a combination thereof, preferably acetonitrile.
In the step (3), the molar ratio of the compound (IV) to triethylamine hydrofluoride is 1: 1.2-10, preferably 1: 8-10; the reaction temperature is 40-110 ℃, preferably 70-80 ℃; the reaction time is 6-24h, preferably 8-10 h; the solvent is selected from the following group: dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, chlorobenzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloroethyl ether, NMP, DMF, DMSO, or combinations thereof; preferably 1, 2-dichloroethane; the mass ratio of the solvent to the compound (IV) is 3-15: 1.
preparation of florfenicol intermediate (V)
In a second aspect, the present invention provides a process for the preparation of florfenicol intermediate (v), comprising the steps of:
(1) the process according to the first aspect of the invention is used for preparing a compound (I), wherein R1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl; r2Is methylmercapto or methylsulfonyl;
(2) deprotection of compound (i) in an inert solvent provides intermediate (v).
In the step (2) above, in the deprotection of the compound (i) to produce the compound (v), the molar ratio of the compound (i) to the acid is 1: 1-10, preferably 1: 2-3. The reaction temperature is from 0 to 35 ℃ and preferably from 10 to 25 ℃. The reaction time is 0.5 to 4 hours, preferably 1 to 2 hours. The acid used is trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, or a combination thereof, preferably trifluoroacetic acid, hydrochloric acid, or a combination thereof. The solvent is water or C1-C4Halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride), C1-C4An alcohol (methanol, ethanol, isopropanol or n-butanol), ethyl acetate, acetonitrile, tetrahydrofuran or dioxane, or a combination thereof, preferably water or dichloromethane. The molar ratio of compound (I) to acid is 1: 2-3. The reaction temperature is 10-25 ℃. The reaction time is 1-2 h.
Preparation of florfenicol
The third aspect of the invention provides a preparation method of florfenicol, which comprises the following steps:
(a) the process according to the first aspect of the invention is used for the preparation of compound (I), wherein R1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl; r2Is methylmercapto or methylsulfonyl;
(b) compound (V) is prepared by a process according to the second aspect of the invention, wherein R1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl; r2Is methylmercapto or methylsulfonyl;
(c) under the alkaline condition in an inert solvent, the intermediate (V) is acetylated to form florfenicol by dichloro, and the reaction formula is as follows:
in step (c) above, the molar ratio of compound (v) to acylating agent is 1:1 to 1.5, preferably 1: 1.1.1 to 1.2; the molar ratio of compound (v) to basic agent is 1:1 to 3; the reaction temperature is 20-70 ℃, preferably 50-60 ℃; the reaction time is 1-10h, preferably 8-10 h; the solvent is selected from methanol, tetrahydrofuran, dichloromethane, trichloromethane and 1, 2-dichloroethane or a combination thereof, preferably tetrahydrofuran or dichloromethane; the base is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and pyridine or a combination thereof, preferably triethylamine; the acylating agent is selected from dichloroacetyl chloride and methyl dichloroacetate or combinations thereof.
The above-described process for preparing florfenicol intermediate (i) according to the present invention may also be integrated with the prior art for the preparation of compound (vi), comprising the steps of:
in the formula, R1Is C1～C4Alkyl (preferably methyl, ethyl, isopropyl or tert-butyl) or benzyl;
R2is methylmercapto or methylsulfonyl;
(1) in an inert solvent, under the alkaline condition, using a compound (VI) to perform acylation reaction to obtain a (compound (VII);
(2) reacting the compound (VII) with a negative hydrogen reagent in an inert solvent to obtain a compound (II);
in the step (1), the molar ratio of the compound (VI) to the acylating agent is 1: 1.0-3.0, preferably 1: 1.1-1.5; molar ratio of compound (vi) to base 1: 1.2-4.0; the reaction temperature is 0-30 ℃, preferably 15-25 ℃; the reaction time is 2-10h, preferably 6-8 h; the above-mentionedThe solvent is selected from methanol, tetrahydrofuran, dichloromethane, trichloromethane and 1, 2-dichloroethane or a combination thereof, preferably tetrahydrofuran, dichloromethane or a combination thereof; the selected base is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine or a combination thereof, preferably sodium bicarbonate; said acylating reagent is selected from (Boc)2O, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, or a combination thereof, preferably (Boc)2O；
In the step (2), the reaction molar ratio of the compound (VII) to the hydrogen-bearing reagent is 1: 1-5, preferably 1: 2-3; the reaction temperature is 0-40 ℃, preferably 15-25 ℃, and the reaction time is 0.5-10 hours, preferably 6-8 hours. The negative hydrogen reagent is selected from potassium borohydride, sodium borohydride, lithium borohydride or calcium borohydride, and preferably the sodium borohydride or the potassium borohydride. The organic agent is selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran, dioxane solvent or combination thereof, preferably methanol.
Compared with the prior art, the invention has the following advantages:
(1) the invention has the outstanding advantages that the compound (IV) is prepared by adopting a new synthetic route, fluorine atoms are introduced by the compound (IV) through the ring opening of a triethylamine hydrogen fluoride reagent, and the triethylamine hydrogen fluoride reagent has lower price than a Ishikawa reagent used in the existing production process, has small corrosion to equipment and is safer to operate. Thereby greatly reducing the pollution to the environment, reducing the cost and simplifying the process.
(2) In the present invention, the difference in activity between the primary and secondary alcohols of compound (II) is used, and a suitable sulfonylating agent is selected so that the primary alcohol is selectively activated, and methanesulfonyl chloride is preferred.
(3) The method overcomes the defects of the prior art, has mild reaction conditions, simple and convenient operation and high yield, and has certain industrial production prospect.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Synthesis of (1R,2R) -3-methanesulfonyl-2- (tert-butyloxycarboxamide) -1- (4-methylsulfonylphenyl) -1-propanol (III)
In a 250mL three-necked flask, 7g of (1R,2R) -2- (tert-butyloxycarboxamido) -1- (4-methylsulfonylphenyl) -1, 3-propanediol (II) was dissolved in 150mL of dry methylene chloride, 7.2g of triethylamine was added, the mixture was cooled to-5 ℃ and 7g of methanesulfonyl chloride was slowly added dropwise. After dropping, the reaction was carried out at-5 ℃ for 1 hour. After the reaction, triethylamine hydrochloride was removed by filtration, the filtrate was quenched with saturated brine (200mL), the aqueous phase was extracted with dichloromethane (60 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 8.1g of crude product, which was put to the next step without purification, and the HPLC purity was checked for 84.3%.
Example 2
Synthesis of (R) - [4- (methylsulfonyl) phenyl ] [ (R) -1- (tert-butyloxycarboryl amido) aziridinyl ] methanol (IV)
In a 250mL three-necked flask, 8g of (1R,2R) -3-methanesulfonyl-2- (tert-butyloxycarboxamido) -1- (4-methylsulfonylphenyl) -1-propanol (III) is dissolved in 80mL of dry acetonitrile, 8g of potassium carbonate is added, the temperature is raised to 50 ℃ for reflux reaction for 5h, the reaction is monitored by TLC or HPLC, after the reaction of the raw materials is completed, the temperature is reduced to room temperature, the acetonitrile is removed by spinning off, 50mL of water is added, dichloromethane (30mL × 3) is added for extraction, the organic phases are combined, washed with saturated brine (10mL), dried with anhydrous sodium sulfate, filtered, the solvent is removed under reduced pressure, and the residue is subjected to column chromatography (petroleum ether/ethyl acetate ═ 2: 1, v/v) to obtain 4.3g of colorless oily substance, and the purity is detected by HPLC to be 98..
1H NMR(600MHz，CDCl3,D2O)：δ＝7.86(d,J＝8.34Hz,2H),7.61(d,J＝8.28Hz,2H),4.49(d,J＝5.64Hz,1H),3.00(s,3H),2.64(m,1H),2.32(d,J＝6.06Hz,1H),2.22(d,J＝3.66Hz,1H),1.38(s,9H)
13C NMR(600MHz，CDCl3)：δ＝161.86,147.22,139.74,127.35,127.33,81.86,72.46,44.33,42.23,29.06,27.72
HR-MS calcd for C15H21NNaO5S[M+Na]+m/z 350.1033，found m/z 350.1032。
Example 3
Synthesis of (1R,2S) -3-fluoro-1- (4-methylsulfonylphenyl) -2- (tert-butyloxycarboryl amido) -1-propanol (I)
In a 100mL three-necked bottle, 3g of (R) - [4- (methylsulfonyl) phenyl ] [ (R) -1- (tert-butyloxycarboxamido) aziridinyl ] methanol (IV) is dissolved in 30mL of 1, 2-dichloroethane solvent, 12g of triethylamine hydrofluoride is added, the temperature is raised to 70 ℃ for reflux reaction for 8h, TLC or HPLC is used for monitoring the reaction, the temperature is reduced to room temperature after the raw materials are reacted, 80mL of saturated sodium bicarbonate solution is added for quenching reaction, the mixture is stirred for 30min, standing and liquid separation are carried out, an organic layer is washed twice by clear water, the organic layer is dried and spun, and the residue is subjected to column chromatography (petroleum ether/ethyl acetate is 2: 1, v/v) to obtain 3.1g of white solid, and the HPLC purity is 99.2%.
1H NMR(600MHz，CDCl3)：δ＝7.85(d,J＝8.22Hz,2H),7.57(d,J＝8.22Hz,2H),6.62(d,J＝9.24Hz,1H),5.73(d,J＝5.16Hz,1H),4.87(t,J＝4.02Hz,1H),4.50-4.61(m,1H),4.24-4.35(m,1H),3.94(m,1H),3.15(s,3H),1.23(s,9H)
13C NMR(600MHz，DMSO-d6)：δ＝155.62,148.98,139.77,127.70,126.87,83.51,82.39,78.38,70.63,70.59,56.02,55.89,44.08,28.48
HR-MS calcd for C15H22FNNaO5S[M+Na]+m/z 370.1095，found m/z 370.1096。
Example 4
Synthesis of (1R,2S) -2-amino-3-fluoro-1- [4- (methylsulfonyl) phenyl ] -1-propanol (V)
In a 150mL three-necked flask, 3g of (1R,2S) -3-fluoro-1- (4-methylsulfonylphenyl) -2- (tert-butyloxycarboxamide) -1-propanol (I) was dissolved in 10mL of ethyl acetate, cooled to 0 ℃ and 10mL of a hydrogen chloride-ethyl acetate solution (2mol/L) was added dropwise. After the dripping is finished, the temperature is raised to the room temperature for reaction for 2 hours, and white solid is separated out. After the reaction, 2.1g of crude hydrochloride is obtained by filtration, the crude hydrochloride is directly put into the next step without purification, and the HPLC purity is detected to be 98.4%.
1H NMR(600MHz，DMSO-d6)：δ＝8.54(s,3H),7.94(d,J＝8.46Hz,2H),7.67(d,J＝8.34Hz,2H),6.66(d,J＝4.5Hz,1H),4.89(q,J＝4.26Hz,1H),4.58(dddd,J＝3.06Hz,3Hz,3.06Hz,3,06Hz,1H),4.25(dddd,J＝4.62Hz,4.56Hz,4.62Hz,4,56Hz,1H),3.57-3,64(m,1H),3,22(s,3H)
13C NMR(600MHz，DMSO-d6)：δ＝146.64,141.00,128.42,127.65,81.87,80.75,69.63,69.59,56.21,56.09,43,97
HR-MS calcd for C10H15FNO3S[M+H]+m/z 248.0751，found m/z 248.0752。
Example 5
Synthesis of florfenicol
In a 100mL three-necked flask, 5g of (1R,2S) -2-amino-3-fluoro-1- [4- (methylsulfonyl) phenyl ] -1-propanol (V) was dissolved in 25mL of methanol, 6.1g of triethylamine was added, 7.2g of methyl dichloroacetate was added, the mixture was heated to 50 ℃ for reaction for 10 hours, after completion of TLC monitoring reaction, methanol was removed by decantation, 30mL of water was added, dichloromethane (30mL × 3) was added for extraction, the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate ═ 2: 1, V/V) to give 7.1g of a white solid, and HPLC purity was 99.6%.
1H NMR(600MHz，DMSO-d6)：δ＝8.61(d,J＝9.06Hz,1H,NHCO),7.85(d,J＝8.4Hz,2H,Ar-H),7.61(d,J＝8.28Hz,2H,Ar-H),6.46(s,1H,COHCl2),6.15(d,J＝4.4Hz,1H),4.99(t,J＝3,6Hz,1H),4.33-4.76(m,2H,CH2F),4.25-4.31(m,1H,CHNHCO),3.16(s,3H,CH3)
13C NMR(600MHz，DMSO-d6)：δ＝164.19,148.39,140.02,127.62,126.97,83.39,82.26,69.82,69.78,66.72,55.16,55.03,44.04
HR-MS calcd for C12H14Cl2FNNaO4S[M+Na]+m/z 379.9897，found m/z 379.9900。
Example 6
Synthesis of ethyl (2S,3R) -3-hydroxy-2- (tert-butyloxycarboxamide) -3- (4-methylsulfonylphenyl) propionate (VII)
In a 250mL three-necked flask, 10g of (2S,3R) -2-amino-3-hydroxy-3- (4-methylsulfonylphenyl) propionate (VI) was added to 150mL of methylene chloride, 10g of sodium bicarbonate was added, and 9.1g of (Boc) was weighed2Dissolving O in 10mL of dichloromethane, dropwise adding the Boc anhydride solution, reacting at room temperature for 8h after dropwise adding, monitoring by TLC, standing for liquid separation after reaction, extracting a water layer twice with dichloromethane, combining organic layers, drying, and spin-drying the solvent to obtain 13.5g of a crude product, directly putting the crude product into the next step without purification, and detecting the HPLC purity by 93.4%.
1H NMR(600MHz，CDCl3)：δ＝7.79(d,J＝7.8Hz,2H),7.54(d,J＝8.16Hz,2H),5.36(d,J＝9.12Hz,1H),5.34(s,1H),4.49(d,J＝8.52Hz,1H),4,21(q,2H),3.60(s,1H),2.98(s,3H),1.27(s,9H),1.22(t,7.17Hz,3H)
13C NMR(600MHz，CDCl3)：δ＝170.28,155.61,146.75,139.53,127.22,127.18,80.19,73.20,62.02,59.22,44.48,28.10,14.15
HR-MS calcd for C17H25NNaO7S[M+Na]+m/z 410.1244，found m/z 410.1245。
Example 7
Synthesis of (1R,2R) -2- (tert-butyloxycarboxamido) -1- (4-methylsulfonylphenyl) -1, 3-propanediol (II)
In a 250mL three-necked flask, 13.5g of (2S,3R) -3-hydroxy-2- (tert-butyloxycarboxamido) -3- (4-methylsulfonylphenyl) propionic acid ethyl ester (VII) are dissolved in 100mL of methanol, the temperature is reduced to 0 ℃ by stirring, and after stirring for half an hour, 4g of NaBH is added in portions4After the addition, the reaction is carried out for 8h at 0 ℃, the reaction solution is monitored by TLC, after the reaction of the raw materials is finished, the temperature is raised to room temperature, water is added for quenching, the reaction is quenched by adding water, dichloromethane is added for separating liquid for extraction, an organic layer is dried in a spinning mode to obtain 12.1g of crude product, the crude product is directly put into the next step without purification, and the HPLC purity is detected to be 96.1%.
1H NMR(600MHz，DMSO-d6)：δ＝7.84(d,J＝8.16Hz,2H),7.54(d,J＝8.16Hz,2H),6.11(d,J＝9.3Hz,1H),5.51(d,J＝5.52Hz,1H),4.91(m,1H),4.75(t,J＝5.46Hz,1H),3.50-3.68(m,2H),3.28(m,1H),3.15(s,3H),1.23(s,9H)
13C NMR(600MHz，DMSO-d6)：δ＝155.62,150.27,139.44,127.52,126.82,78.12,70.42,61.14,58.02,44.11,28.51
HR-MS calcd for C15H23NNaO6S[M+Na]+m/z 368.1138，found m/z 368.1138。
Comparative example
Synthesis of (R) - [4- (methylsulfonyl) phenyl ] [ (R) -1- (tert-butyloxycarboryl amido) aziridinyl ] methanol
In a 250mL three-necked flask, 1g of (1R,2R) -2- (tert-butyloxycarboxamido) -1- (4-methylsulfonylphenyl) -1, 3-propanediol is dissolved in dry 20mL of diethyl ether, 0.66g of p-toluenesulfonyl chloride and 0.65g of powdered potassium hydroxide are added, the reaction is heated under reflux at 35 ℃ for 2h, and the reaction is monitored by TLC,
after the reaction of the starting materials was completed, the reaction mixture was poured into ice water, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. This step produces a trace of product, and the crude product obtained has a purity of < 5% as monitored in the liquid phase.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (17)
1. A synthetic method of a florfenicol intermediate (I) is characterized by comprising the following steps (1) to (3):
wherein R is1Is C1～C4Alkyl or benzyl;
R2is methylmercapto or methylsulfonyl;
(1) in an inert solvent, in the presence of alkali, esterifying a compound (II) and a sulfonylation reagent to obtain a compound (III), wherein the sulfonylation reagent is methanesulfonyl chloride;
(2) reacting the compound (III) in an inert solvent in the presence of a base to obtain a compound (IV);
(3) reacting compound (iv) with a fluorinating agent in an inert solvent to obtain compound (i), said fluorinating agent being selected from the group consisting of: triethylamine hydrofluoride, N-dimethyl propyl urea hydrogen fluoride complex, hydrogen fluoride pyridine complex and hydrogen fluoride.
2. The method of claim 1, wherein R is1Is methyl, ethyl, isopropyl, tert-butyl, or benzyl.
3. The method of claim 1, wherein the fluorination agent is triethylamine hydrofluoride.
4. The process of claim 1, wherein in step (1), the molar ratio of compound (ii) to methanesulfonyl chloride is 1: 1-5.
5. The method of claim 1, wherein in step (2), the molar ratio of compound (iii) to base is 1: 2.0-10.0.
6. The method of claim 1, wherein in step (2), the molar ratio of compound (iii) to base is 1:4 to 6.
7. The method according to claim 1, wherein in the step (3), the fluorination reagent is triethylamine hydrofluoride, and the molar ratio of the compound (IV) to the triethylamine hydrofluoride is 1: 1.2-10.
8. The method of claim 7, wherein in step (3), the fluorination reagent is triethylamine hydrofluoride, and the molar ratio of the compound (IV) to the triethylamine hydrofluoride is 1: 8-10.
9. A compound represented by the following formula (IV):
wherein R is1Is C1～C4Alkyl or benzyl;
R2is methylmercapto or methylsulfonyl.
10. The compound of formula (iv) of claim 9, wherein R is1Is methyl, ethyl, isopropyl, tert-butyl, or benzyl.
11. A process for the preparation of a compound of formula (IV) according to claim 9, comprising the steps of:
wherein R is1Is C1～C4Alkyl or benzyl;
R2is methylmercapto or methylsulfonyl;
the compound (IV) is obtained by reacting the compound (III) in an inert solvent in the presence of a base.
12. A process for the preparation of a compound of formula (IV) as claimed in claim 11, R1Is methyl, ethyl, isopropyl, tert-butyl or benzyl.
13. A process for the preparation of a compound of formula (IV) according to claim 11, characterized in that it comprises the steps of:
in an inert solvent, in the presence of alkali, esterifying the compound (II) and a sulfonylation reagent to obtain a compound (III), wherein the sulfonylation reagent is methanesulfonyl chloride.
14. A synthetic method of a florfenicol intermediate (I) is characterized by comprising the following steps:
the compound (I) is obtained by reacting the compound (IV) with triethylamine hydrofluoride in an inert solvent.
15. A process for the preparation of florfenicol intermediate (v), comprising the steps of:
(i) preparing compound (i) by the process of claim 14;
(ii) preparing an intermediate (V) by using the compound (I) as a substrate;
wherein R is1Is C1-C4 alkyl or benzyl;
R2is a methylsulfonyl group.
16. The method of claim 15, wherein R is1Is methyl, ethyl, isopropyl, tert-butyl or benzyl.
17. A preparation method of florfenicol is characterized by comprising the following steps:
(i) the process of claim 14 for preparing compound (i) wherein R is1Is C1-C4 alkyl or benzyl, R2Is a methylsulfonyl group;
(ii) preparing an intermediate (V) by using the compound (I) as a substrate;
(iii) dichloroacetylation with intermediate (v) to form florfenicol:
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| CN106316898A (en) * | 2016-08-04 | 2017-01-11 | 湖北美天生物科技股份有限公司 | Method for synthesis of florfenicol |
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| CN1649829A (en) * | 2002-03-08 | 2005-08-03 | 先灵-普劳有限公司 | Novel florfenicol-type antibiotics |
| CN106316898A (en) * | 2016-08-04 | 2017-01-11 | 湖北美天生物科技股份有限公司 | Method for synthesis of florfenicol |
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| A convenient one-pot coversion of N-Boc-β-Aminoalcohols into N-Boc-Aziridines;Pablo Wessing et al.;《SYNLETT》;19970831;第893页右栏Scheme1 * |
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