CN117603153A - Asymmetric synthesis method of florfenicol intermediate - Google Patents

Asymmetric synthesis method of florfenicol intermediate Download PDF

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Publication number
CN117603153A
CN117603153A CN202311644696.7A CN202311644696A CN117603153A CN 117603153 A CN117603153 A CN 117603153A CN 202311644696 A CN202311644696 A CN 202311644696A CN 117603153 A CN117603153 A CN 117603153A
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substrate
reaction
florfenicol
florfenicol intermediate
synthesizing
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吴璇
胡振宇
杨多
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Jiangsu Hansyn Pharmaceutical Co ltd
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Jiangsu Hansyn Pharmaceutical Co ltd
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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
    • C07D263/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • 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
    • C07D263/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses an asymmetric synthesis method of a florfenicol intermediate, which comprises the steps of adding an organic solvent and a substrate I, a catalyst III into a dried reaction bottle, then adding a substrate II, controlling a heat preservation reaction at a certain temperature, and performing post-treatment to obtain a product IV. The invention obtains the target product through a proper chiral catalyst, the method has mild condition, high chiral selectivity, molar yield of more than 80 percent, chiral purity of more than 99 percent ee and cis-trans selectivity of more than 90 percent dr.

Description

Asymmetric synthesis method of florfenicol intermediate
Technical Field
The invention relates to an asymmetric synthesis method of a florfenicol intermediate, in particular to a method for synthesizing the florfenicol intermediate by asymmetric catalysis of a chiral catalyst.
Background
Florfenicol (Florfenicol) is an artificially synthesized third generation chloramphenicol antibiotic, developed by Schering-Plough, U.S. in 1979. In contrast to thiamphenicol, florfenicol uses an F atom in place of the hydroxyl group of thiamphenicol according to the isostere rule. The change of the groups brings about further improvement of the antibacterial activity of the florfenicol, and compared with thiamphenicol and chloramphenicol, the safety and the effectiveness are greatly improved, and the toxic and side effects such as aplastic anemia, teratogenicity and the like are not generated. As a broad-spectrum antibiotic, florfenicol has a strong inhibitory effect on a number of harmful bacteria, and has been successfully used in the livestock industry for the prevention and treatment of various bacterial diseases in livestock such as fish, poultry and cattle and sheep.
The key to the synthesis of florfenicol is the construction of two chiral centers. The method for constructing the chiral center mainly comprises the following steps:
1. splitting by a chemical method:
chemical resolution generally uses the form of an enantiomer salt for resolution purposes. Such a process makes use of the fact that diastereoisomeric salts having different physicochemical properties can be formed, which are then separated by crystallization or filtration etc. using physicochemical properties to give pure enantiomer salts. Finally, the salt is decomposed by treatment to obtain pure enantiomer.
Since 1952, the U.S. Cutler group synthesized racemic thiamphenicol for the first time, D-tartaric acid was used to resolve the appropriate chiral intermediate during the preparation.
The method is simple and convenient to operate under proper conditions, but the yield after resolution is not more than half at maximum due to the existence of isomers, so that certain atom waste is caused.
2. Splitting by an enzymatic method:
enzymatic resolution has evolved over the last decades into methods that utilize either enzymatic or cellular direct catalytic resolution. The method generally comprises the steps of carrying out certain biochemical reactions to carry out resolution, and degrading one of two isomers of the raceme medicines by using certain microorganisms such as yeast cells, moulds, bacteria and the like through self enzymatic reactions, wherein the other isomer is not degraded and assimilated and remains in a reaction solution to obtain a pure enantiomer.
In 1990, the Clark group of Schering-Plough, U.S. developed a method for the enzymatic hydrolysis of racemic phenylserine ethyl esters. In 1998, the Dutch DSM Kaptein group reported a method for enzymatic resolution of racemic phenylserine amide. Other groups have also made corresponding results in the following.
3. Asymmetric synthesis:
methods of asymmetric synthesis have been studied more recently. The method is mainly divided into two aspects: firstly, chiral auxiliary induces asymmetric synthesis. In 1994, davis et al reported asymmetric synthesis based on substrate-induced aza-Darzens reactions. In 2006, the Hajra group of the indian institute of technology reported an asymmetric synthesis method using chiral auxiliary to induce asymmetric bromo-hydroxylation.
In 2014 Myers et al developed the use of Pseudoephenamine to mediate cis-selective aldol reactions. In the following China, many groups develop and research on the florfenicol derivative as a chiral auxiliary to promote self asymmetric synthesis.
The other is asymmetric synthesis catalyzed by chiral catalysts. In 1994, wu doctor of American Schering-Plough reported a synthesis of florfenicol based on Sharpless asymmetric epoxidation. Other groups have evolved on this basis. In 2006, china Lin Guojiang developed an asymmetric synthetic route for the methyls and florfenicol based on asymmetric hydrocyanation.
In 2016, dixon et al published a chiral catalytic process. The method is that p-nitrobenzaldehyde and isocyanoacetate are catalyzed by silver ions and cinchona amine derivatives to obtain chiral intermediates of chloramphenicol. The reaction equation is as follows
Wherein when R is benzhydryl, the chiral selectivity of the two carbons of the chiral intermediate is high (ee value 89%, dr selectivity is also above 90).
Thereafter, the university of double denier Chen Fener teaches that the subject group reacts 4-substituted benzaldehyde with diethyl isocyanate to give an intermediate, which is further reacted to give a chiral intermediate, using the novel cinchona amine derivative as a catalyst.
The method has the advantages that silver ions are not needed to be used for the catalyst, the chiral selectivity of the reaction is better, but the subsequent reaction steps are more, and the method is somewhat complicated.
Disclosure of Invention
The invention aims to solve the problems of severe process conditions, low chiral reagent selectivity and high production cost of the existing florfenicol intermediate asymmetric synthesis process, and provides a method for synthesizing the florfenicol intermediate by asymmetric catalysis of a chiral catalyst. The molar yield of the method is more than 80%, the chiral purity can reach more than 99% ee at the highest, and the cis-trans selectivity is also more than 90% dr. In addition, the reaction method has mild reaction conditions and reaction temperature of between 40 ℃ below zero and 40 ℃ and is very favorable for realizing industrial production.
The technical scheme of the invention is as follows:
an asymmetric synthesis method for preparing florfenicol intermediate comprises the following steps:
1) Adding an organic solvent, a substrate I and a catalyst III into a dried reaction bottle, and controlling the reaction system at a certain temperature (-40 ℃ to 40 ℃);
2) Adding a substrate II into the reaction bottle under the protection of nitrogen, and stirring for 20-60 hours under the heat preservation;
3) And after the reaction is finished, distilling the solvent under reduced pressure, and carrying out column chromatography on distillation residues to obtain a product IV.
The substrate II in the step 2) is isocyanatoacetate;
the reaction temperature is preferably controlled in step 2) at-20℃to 20℃and more preferably at-10℃to 10 ℃.
The structure of the catalyst III in the step 1) is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 ；
The molar ratio of catalyst III to substrate I in step 1) is between 0.01:1 and 0.10:1;
the organic solvent in the step 1) is selected from one or a mixture of more than one of the following: dichloromethane, chloroform and toluene;
the molar ratio of substrate II to substrate I is between 1:1 and 2:1.
The chemical reaction equation of the invention is shown as follows:
wherein R is a C2-C8 branched or straight chain alkyl group; 3-8 membered alicyclic hydrocarbon group; an aryl group; heteroaryl; ar (CH) 2 ) n -a group Ar represents an aryl or heteroaryl group, n=1-6;
the structure of the catalyst III is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 。
The general preparation method of the catalyst comprises the following steps:
adding 3, 4-dimethoxy cyclobutyl-3-alkene-1, 2-dione and methanol into a reaction flask, stirring to dissolve, controlling 25deg.C, adding aromatic amine (R) 1 -NH 2 ). Reaction mixingStirring at 25deg.C for 48 hr to obtain precipitate, filtering to obtain intermediate, and drying under reduced pressure; adding the dried intermediate into a reaction bottle, adding dichloromethane, stirring for dissolution, controlling the temperature to 25 ℃, adding quinine amine, and stirring the reaction mixture at room temperature for 48 hours. At the end of the reaction, the purified water was washed twice. The organic phase is dried by spinning, added with methanol and pulped for 0.5 hour, filtered and dried under reduced pressure to obtain the catalyst.
The principle of catalysis and chiral selectivity of the catalyst is as follows: the catalyst is combined with isocyanato, the combination process not only improves the reactivity of carbon-nitrogen double bonds, but also fixes the position of isocyanato acetate, and when the methanesulfonyl benzaldehyde is in reaction, NH on the catalyst is determined as a space structure of the combined catalyst, so that a substrate II can only react with a substrate I in one direction, and a chiral substitution product needed by people is obtained.
The florfenicol intermediate is a product VI oxazolidinone ester, and the structural formula is as follows:
wherein R is a C2-C8 branched or straight chain alkyl group; 3-8 membered alicyclic hydrocarbon group; an aryl group; heteroaryl; ar (CH) 2 ) n -a group Ar represents an aryl or heteroaryl group, n=1-6;
the synthetic route for preparing florfenicol from florfenicol intermediate comprises the following steps:
the beneficial effects are that:
the invention selects an effective catalyst, the catalyst consumption is small, and the cost is greatly reduced. The molar yield of the method is more than 80%, the chiral purity can reach more than 90% ee at the highest, and the cis-trans selectivity is also more than 90% dr. In addition, the reaction method has mild reaction conditions and reaction temperature of between 40 ℃ below zero and 40 ℃ and is very favorable for realizing industrial production.
Detailed Description
For a better understanding of the present invention, reference will be made in detail to the following examples, which are not intended to limit the scope of the invention, but are capable of numerous modifications and variations within the scope of the invention as will be apparent to those skilled in the art from the description herein.
General preparation method of catalyst:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4
3, 4-Dimethoxycyclobutyl-3-ene-1, 2-dione 8 (1.42 g,10.0 mmol), methanol (20 ml) was added to a reaction flask, and the mixture was dissolved in methanol (20 ml) under stirring at 25℃under stirring, and arylamine (R) 1 -NH 2 ). The reaction mixture was stirred at 25 ℃ for 48 hours to precipitate, filtered to give an intermediate, and dried under reduced pressure.
The dried intermediate was weighed (1.0 mmol) and added to the reaction flask, 10ml of dichloromethane was added and dissolved with stirring, quinine amine was added at 25℃and the reaction mixture was stirred at room temperature for 48 hours. At the end of the reaction, 10ml of purified water was washed twice. The organic phase is dried by spinning, 5ml of methanol is added for pulping for 0.5 hour, and the catalyst is obtained by filtering and drying under reduced pressure.
Example 1
The reaction flask was ready for drying in advance and kept dry. Chloroform (50 mL), p-methanesulfonyl benzaldehyde (1.84 g,10.0 mmol) and catalyst (0.63 g,1.0 mmol) were added separately to the reaction flask, and the temperature was lowered to-10 ℃. After the temperature reached, a solution of substrate II (2.29 g,12.0 mmol) in chloroform (50 mL) was added dropwise to the flask. Stirring at controlled temperature for 56 hours, and the reaction was complete. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (3.15 g. Yield 84%,99% ee,97:3 dr).
1 H-NMR(400MHz,DMSO-d 6 ):δ8.20(s,1H),8.01(d,J＝8.0Hz,2H),7.64-7.38(m,7H),5.72(d,J＝4.4Hz,1H),5.07(s,2H),4.52(d,J＝4.4Hz,1H),,3.07(s,3H)。
Example 2
The reaction flask was ready for drying in advance and kept dry. Chloroform (50 mL), p-methanesulfonyl benzaldehyde (1.84 g,10.0 mmol) and catalyst (0.63 g,1.0 mmol) were added separately to the reaction flask, and the temperature was lowered to-10 ℃. After the temperature reached, a solution of substrate II (1.55 g,12.0 mmol) in chloroform (50 mL) was added dropwise to the flask. Stirring at controlled temperature for 56 hours, and the reaction was complete. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and spin-dried to give product IV (2.91 g. Yield 93%,91% ee,89:11 dr).
1 H-NMR(400MHz,DMSO-d 6 ):δ8.20(s,1H),8.01(d,J＝8.0Hz,2H),7.64(d,J＝8.0Hz,2H),5.72(d,J＝4.4Hz,1H),4.52(d,J＝4.4Hz,1H),4.38-4.25(m,2H),3.07(s,3H),1.30(t,J＝4.4Hz,3H)。
Example 3
The reaction flask was ready for drying in advance and kept dry. Chloroform (50 mL), p-methanesulfonyl benzaldehyde (1.84 g,10.0 mmol) and catalyst (0.56 g,1.0 mmol) were added separately to the reaction flask, and the temperature was lowered to-10 ℃. After the temperature reached, a solution of substrate II (2.29 g,12.0 mmol) in chloroform (50 mL) was added dropwise to the flask. Stirring at controlled temperature for 56 hours, and the reaction was complete. The solvent was removed under reduced pressure and the crude product was isolated by column chromatography and dried by spin-drying to give product IV (3.34 g. Yield 89%,92% ee,90:10 dr).
The product IV was taken as an example for the preparation of florfenicol using oxazolidinone ethyl ester. The method comprises the following steps:
example 4
The reaction flask was ready for drying in advance and kept dry. 50ml of methanol, oxazolidinone ethyl IV (8.00 g,25.5 mmol) are added to the reaction flask. Stirring for dissolution, controlling the temperature to 20 ℃, adding potassium borohydride (1.95 g,36.2 mmol) in batches, heating to 50 ℃ and preserving the temperature for 1 hour. At the end of the incubation, the temperature was lowered to 35℃and acetic acid (1.20 g,19.8 mmol) was added dropwise for incubation for 1 hour. Distilling under reduced pressure until no solvent is distilled off. To the reaction flask was added 20ml of 30% aqueous isopropanol, stirred for 0.5 hour, cooled to 10 ℃, filtered with suction, and dried to give intermediate V (6.37 g, yield 92%).
Example 5
The autoclave is prepared for drying in advance and kept dry. 10ml of methylene chloride, oxazolidinone alcohol V (6.00 g,22.1 mmol) and 21.0ml (25.9 mmol) of a prepared solution of the Ishikawa reagent in methylene chloride were added to the autoclave. Sealing and heating to 100 ℃, preserving heat and stirring for 1 hour. After cooling to room temperature, the reaction mixture was transferred to a reaction flask, sodium acetate (1.14 g,13.9 mmol) was added, 10ml of water was added, and the mixture was distilled under reduced pressure after normal pressure until no solvent was distilled off. To the reaction flask was added 60ml of 25% aqueous isopropanol, and the mixture was warmed to 80℃and kept at that temperature for 1 hour, cooled to 10℃and suction-filtered, followed by drying to give intermediate VII (5.19 g, yield 95%).
Example 6
The reaction flask was ready for drying in advance and kept dry. Tetrahydrofuran (50 ml), intermediate VII (5.00 g,20.2 mmol), sodium acetate (2.48 g,30.3 mmol) were added to the flask, and dichloroacetyl chloride (3.13 g,21.2 mmol) was added dropwise at 20℃and the temperature was raised to 30℃at the end of the addition and maintained for 1 hour. Vacuum distilling to remove solvent, adding 35% isopropanol 30ml, active carbon 0.20g, heating to 80deg.C, hot filtering, cooling filtrate to 10deg.C, vacuum filtering, and drying to obtain florfenicol (6.66 g, yield 92%).

Claims (7)

1. The asymmetric synthesis method of the florfenicol intermediate is characterized in that a substrate I and a substrate II react under the catalysis of a catalyst III to obtain a product, and the chemical reaction equation is as follows:
wherein R is a C2-C8 branched or straight chain alkyl group; 3-8 membered alicyclic hydrocarbon group; an aryl group; heteroaryl; ar (CH) 2 ) n -a group Ar represents an aryl or heteroaryl group, n=1-6;
the structure of the catalyst III is as follows:
wherein r1=3, 5- (CF) 3 ) 2 C 6 H 3 ；4-CF 3 C 6 H 4 ；4-FC 6 H 4 。
2. The method for synthesizing the florfenicol intermediate according to claim 1, comprising the following steps:
1) Adding an organic solvent, a substrate I and a catalyst III into a dried reaction bottle, and controlling the temperature of a reaction system to be between 40 ℃ below zero and 40 ℃;
2) Adding a substrate II into the reaction bottle under the protection of nitrogen, and stirring for 20-60 hours under the heat preservation;
3) And after the reaction is finished, distilling the solvent under reduced pressure, and carrying out column chromatography on distillation residues to obtain a product IV.
3. A synthetic process for preparing florfenicol intermediate according to claim 1, characterized in that the molar ratio of catalyst III to substrate I is between 0.01:1 and 0.10:1.
4. A method of synthesizing a florfenicol intermediate according to claim 1, wherein the substrate II is isocyanatoacetate.
5. The method for synthesizing florfenicol intermediate according to claim 2, wherein the organic solvent is selected from one or a mixture of several of the following: dichloromethane, chloroform, toluene.
6. The method for synthesizing florfenicol intermediate according to claim 2, wherein the reaction temperature is controlled at-20 ℃ to 20 ℃ in step 1).
7. A method of synthesizing a florfenicol intermediate according to claim 2, characterized in that the molar ratio of substrate II to substrate I is between 1:1 and 2:1.
CN202311644696.7A 2023-12-04 2023-12-04 Asymmetric synthesis method of florfenicol intermediate Pending CN117603153A (en)

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