CN106316898A - Method for synthesis of florfenicol - Google Patents
Method for synthesis of florfenicol Download PDFInfo
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- CN106316898A CN106316898A CN201610633162.8A CN201610633162A CN106316898A CN 106316898 A CN106316898 A CN 106316898A CN 201610633162 A CN201610633162 A CN 201610633162A CN 106316898 A CN106316898 A CN 106316898A
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- phenyl
- methylsulfonyl
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- propanol
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/10—Radicals substituted by singly bound oxygen atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses a method for synthesis of florfenicol and belongs to the technical field of medicine synthesis. 1-R1-2-(R)-4- methylsulfino phenyl formyl aziridine is dissolved in solvent to react with sterically hindered reductant to form chiral alkamine compound 1 with a single configuration; compound 1 is heated and reacts with triethylamine hydrofluoride in the solvent to form (1R, 2S)-3-fluoride-1-4-(methylsulfino phenyl)-2-(R1-amido)-1-propyl alcohol; (1R, 2S)-3-fluoride-1-4-(methylsulfino phenyl)-2-(R1-amido)-1-propyl alcohol has the blocking group taken away in the solvent to form (1R 2S)-2-amido-3-fluoride-1-4-methylsulfino phenyl-1-propyl alcohol; florfenicol can then be obtained through dichloro-acetylation reaction of (1R, 2S)-2-amido-3-fluoride-1-4-methylsulfino phenyl-1-propyl alcohol.
Description
Technical field
The invention belongs to medicine synthesis technical field, particularly to the synthetic method of florfenicol.
Background technology
Florfenicol (Florfenicol), is to be protected refined (Schering-Plough) company by the U.S.'s first spirit one
The chloromycetin broad ectrum antibiotic of a kind of animal specific that Nagab-hushan etc. developed in late 1970s.Mirror
In on animal diseases control, the drug effect of florfenicol is better than chloromycetin and thiamphenicol, therefore has the most wide application
Prospect, the synthesis of florfenicol the most all receives the biggest attention.
At present, the method for domestic and international industrialized production florfenicol mainly has two kinds: 1, D pmethylsulfonyl phenyleneserine second
Ester successively reacts preparation oxazoline, Ishikawa reagent fluorination reaction, hydrolysis, two chloroethenes through reduction reaction and benzonitrile
Acylation reaction obtains florfenicol；2, D D-4-methylsulfonylphserine serine ethyl ester is successively through reduction reaction and dichloro acetonitrile reaction
Generation oxazoline, Ishikawa reagent fluorination reaction, hydrolysis obtain florfenicol.The latter is relative to having lacked a step for the former
Dichloroacetylization is reacted, and effectively reduces production operation step and cost.
Above two synthetic routes are required for using D-D-4-methylsulfonylphserine serine ethyl ester, and current industrial prepare this
It is that initiation material is through reduction reaction, methylation reaction, bromo oxygen in order to p-methyl benzene sulfonic chloride that the method for compound is still edge
Changing reaction, hydrolysis obtains methylsulfonyl benzaldehyde, then prepares copper with to methylsulfonyl benzaldehyde, glycine, copper sulfate reaction
Split obtain D-D-4-methylsulfonylphserine serine ethyl ester through esterification, tartaric acid after salt.Obtaining D-pmethylsulfonyl phenyleneserine
Ethyl ester production process produces substantial amounts of copper sulfate waste water so that the processing cost of waste water is the highest.
Chiral catalyst is utilized to carry out the research ratio of asymmetric reduction synthesizing chiral compound in recent years wide, fluorobenzene Buddhist nun
Examine product and also do relevant research.The applicant is devoted to utilize chiral catalyst to carry out asymmetric reduction reaction and prepares fluorobenzene
The research that Buddhist nun examines: the patent of publication number CN102827042A discloses with thioanisole as initiation material, anti-through three step chemistry
Should synthesize compound [1-benzyl aziridine-2-base] [4-(methyl mercapto) phenyl] ketone, product is further with chiral catalyst
Asymmetric hydrogenation reduction reaction obtains [1-benzyl aziridine-2-base] [4-(methyl mercapto) phenyl] methanol the most again by several steps
Learning reaction and prepare the scheme of florfenicol, chiral catalyst used in the program is trans-RuCl2 [(R)-xylbinap]
[(S)-DPEN].In this scenario, chiral catalyst asymmetric reduction reaction is utilized to build chiral centre carbon, it is to avoid chirality is torn open
Point.But chiral catalyst itself has the shortcomings such as preparation difficult big, the commercial production easily inactivation of deposit, and then causes application cost
High, be unfavorable for industrialized production.
The applicant is devoted to build chiral amino ketone selective reduction and obtains chiral amino alcohol, recycles aziridine ternary
Ring synthesizes florfenicol new technology in the character of the easy open loop of sour environment: open in the patent of Publication No. CN103936638A
The Chiral Amine cyclization is utilized to obtain the aziridine three-membered ring compound nitrogen of diastereomer chiral amino ketone, through physical separation
Method isolated needed for the aziridine three-membered ring compound of amino ketones of R configuration, then be fluorinated through triethylamine hydrofluoride
Ring-opening reaction introduces fluorine atom, then obtains florfenicol finished product, i.e. synthetic route 1 through the reaction of several steps.
Synthetic route 1:
Wherein: Acetylation: acylation reaction；Cyclization: ring-closure reaction；Flrofenicol: florfenicol.
R1: (S)-1-phenethyl or (R)-1-phenethyl；
R2: phenyl or dichloromethyl or hydroxyl
One of route 1 outstanding advantages is i.e. the method utilizing Chiral Amine cyclization to obtain the synthesis of diastereomer aziridine three-membered ring
By the chiral amino ketone obtaining single R configuration of the separation method of physics purification height yield repeatedly, utilize selective reduction, structure
Type conversion idea finally obtains florfenicol, and Atom economy is greatly improved, and avoids in existing technique simultaneously and brings
Contaminated wastewater, greatly reduce cost and the pollution to environment processing waste water, reduce cost, simplify technique.Advantage
Two be on the basis of said synthesis route with triethylamine hydrofluoride for fluorination Ring Opening Reagent, it is anti-that liquid reaction compares gas
Answering safety to be improved, additionally the least to the corrosivity of equipment, beneficially technology produces.But when selective reduction
The chiral alcohol obtained is the most contrary with the configuration of the chiral alcohol of florfenicol, and the configuration conversion of hydroxyl to be passed through just can obtain
The chiral alcohol of required configuration.
In consideration of it, find a kind of go back original reagent reduction amino ketones time directly obtain florfenicol needed for chiral amino alcohol be
The most necessary.
Summary of the invention
It is an object of the invention to provide the new synthetic method of a kind of florfenicol.Florfenicol of the present invention
Synthetic method comprises the steps:
(1) by 1-R1 -2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine is at room temperature dissolved in solvent, after cooling with
Big steric hindrance reduction reagent reacting obtains single configuration chiral amino alcoholic compound 1:(R)-[4-(methylsulfonyl) phenyl] [(R)-1-R1-
Aziridine-2-base] methanol；
Compound 1
Wherein, R1It is (S)-1-phenethyl or (R)-1-phenethyl.
(2) compound 1 and triethylamine hydrofluoride (Et3N.xHF) reacting by heating obtains (1R, 2S)-3-in a solvent
Fluoro-1-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol.
(3) the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol takes off guarantor in a solvent
Protect group R1Obtain (1R 2S) fluoro-1-of-2-amino-3-[4-(methylsulfonyl) phenyl]-1-propanol.
(4) (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol reacts through dichloroacetyl
To florfenicol, this process is identical with the acylation reaction process in the step of patent CN103936638A (6).
Technical scheme has similar process route to the invention of the applicant (CN103936638A),
To obtain target product, from technological process, the two can share compound 1-R1 -2-(R)-[4-(methylsulfonyl) phenyl] formyl
Base aziridine, thinking hereafter has some difference, this step of selective reduction builds chiral alcohol when, the hands that both obtain
Property alcoholic compound configuration is the most contrary.The chiral alcohol obtained in patent of invention CN103936638A and the chiral alcohol of florfenicol
Configuration just contrary, (hydroxyl sulfoacid is esterified cyclization to carry out configuration conversion reaction and prepares for the configuration conversion of hydroxyl pass through
Compound 3, compound 3 obtains florfenicol through hydrolyzing either acylated) just can obtain the chiral alcohol of required configuration；And in this patent
It is to utilize 1-R1 -2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine obtains after the reduction reagent selectivity reduction of big steric hindrance
Configuration of compound just identical with the configuration of the chiral alcohol of florfenicol, it is not necessary to carry out configuration conversion reaction, so can contract
Short processes route, reduces production cost.In addition at deprotection group R in the present invention1In, it is also possible to use chlorinated hydrolysis side
Method, so can avoid using precious metals pd, be possible not only to avoid product heavy metals exceeding standard, can greatly reduce again and produce into
This.
For institute in florfenicol building-up process in the face of chiral alcohol problem and deprotection group R1Two large problems, the present invention
Technological process solve the two problem rationally and effectively:
First, utilizing chiral amino ketone space steric effect, select big steric hindrance also original reagent, selective reduction obtains required
Chiral amino alcohol, select steric hindrance big go back in original reagent, by change reaction temperature, go back original reagent equivalent, rate of addition come
Controlling the stereo selectivity of reactant, the reduction that just can solve chiral amino alcohol with some conventional big steric hindrance also original reagents is asked
Topic.
Secondly, utilize imines in acid condition unstable characteristic, at deprotection group R1Time, first the hydrogen chloride on nitrogen,
The unstability of recycling nitrogen chlorine key carries out eliminating reaction under alkalescence and obtains imines, then takes off with acid hydrolysis imines three-step reaction
Amino protecting group, does not use precious metal palladium, effectively reduces cost.
In general, one of outstanding advantages of the present invention is i.e. the sterically hindered effect of chiral amino ketone utilizing single R configuration
Should, selecting big steric hindrance also original reagent, selective reduction obtains required chiral amino alcohol, and direct single step reaction just solves fluorine
Benzene Buddhist nun examines the problem of chiral alcohol, simplifies technique, reduces cost.The two of advantage are can be with selective chlorination deprotection when
The method of hydrolysis is avoided using precious metal palladium, has utilization to reduce production cost.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearer, below embodiment of the present invention is made further
Ground describes in detail.
The synthetic method of florfenicol of the present invention can describe with following flow process typically:
Wherein: Reduction: reduction reaction；Deprotecation: deprotection reaction；Flrofenicol: florfenicol.
R1: (S)-1-phenethyl or (R)-1-phenethyl.
The detailed description of the invention of the synthetic method of florfenicol of the present invention may not include in above-mentioned flow process and records
In part of the prior art, i.e. the first two steps, the synthetic method of florfenicol of the present invention comprises the steps:
(1) by 1-R1 -2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine is dissolved in organic solvent, after cooling at room temperature
Single configuration chiral amino alcoholic compound 1:(R is obtained with big steric hindrance reduction reagent reacting)-[4-(methylsulfonyl) phenyl] [(R)-1-
R1-aziridine-2-base] methanol；
Compound 1
Wherein, R1It is (S)-1-phenethyl or (R)-1-phenethyl.
(2) (R)-[4-(methylsulfonyl) phenyl] [(R)-1-R1-aziridine-2-base] methanol and triethylamine hydrofluoride
(Et3N.xHF) reacting by heating obtains the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R in a solvent1-amino)-1-
Propanol.
(3) the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol takes off guarantor in a solvent
Protect group R1Obtain (1R 2S) fluoro-1-of-2-amino-3-[4-(methylsulfonyl) phenyl]-1-propanol.
(4) (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol obtains through dichloroacetylization reaction
Florfenicol.
In the detailed description of the invention of the present invention, in step (1), reduction reaction is: in a solvent, 1-R1 -2-(R)-[4-(first
Sulfuryl) phenyl] mol ratio of formoxyl aziridine and big steric hindrance also original reagent is 1:0.5-2.5, reaction temperature-78-0 DEG C.
Wherein, in step (1), big steric hindrance also original reagent is slowly added into 1-R1 -2-(R)-[4-(methylsulfonyl) phenyl] first
For controlling the process of reaction in acyl group aziridine, it is specifically dissolved in solvent and uses the mode of dropping to join 1-R1 -2-
(R) ,-[4-(methylsulfonyl) phenyl] in formoxyl aziridine, time for adding is 1-3 hour.
Wherein, big steric hindrance also original reagent is selected from LiAl (OCH3)3H、LiAl(Ot-Bu)3H、Red-Al、CBS-B2H6、
MeCBS-B2H6With NaB (OR2)n H4-nDeng.At NaB (OR2)n H4-nIn, wherein R2Group is selected from isopropyl, 2-butyl, tertiary fourth
In the groups such as base, 3-amyl group, cyclobutyl, cyclopenta, cyclohexyl, 1-phenethyl, benzhydryl, glucosyl group and fructosyl one
Plant or the mixing of two of which, n=1,2,3.
Wherein, organic solvent selected from dichloromethane, chloroform, 1,2-dichloroethanes, oxolane, dioxane, different
A kind of or the mixing of two of which solvent in propanol and tert-butyl alcohol equal solvent.
In the detailed description of the invention of the present invention, in step (2), fluorination ring-opening reaction is: compound 1 and triethylamine hydrogen fluorine
Hydrochlorate (Et3N.xHF salt) mol ratio be 1:1.2-10, reaction temperature 50-120 DEG C；Wherein, in triethylamine hydrofluoride, x is
3-10。
Wherein, solvent selected from dichloromethane, chloroform, 1,2-dichloroethanes, oxolane, dioxane, chlorobenzene, first
Benzene, dimethylbenzene, ether, methyl tertiary butyl ether(MTBE), diisopropyl ether, dichloroether, N-Methyl pyrrolidone (NMP), N, N-dimethyl methyl
Amide (DMF) and dimethyl sulfoxide (DMSO) etc., solvent and compound 1 mass ratio are 3-15:1.
In the detailed description of the invention of the present invention, deprotection group R in step (3)1Method have following two method.
Method 1, Pd/C catalytic hydrogenation method: the wherein fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-ammonia
Base)-1-propanol is dissolved in solvent, adds precious metals pd/C catalyst, and hydrogenation reaction obtains (1R, 2S)-2-fluoro-1-of amino-3-
[4-(methylsulfonyl) phenyl]-1-propanol.
Method 2, chlorinolysis comprise the steps:
A () is by the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol is dissolved in solvent, adds chlorine
Changing reagent, reaction obtains the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino)-1-propanol.
B () is by the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino)-1-propanol is dissolved in solvent
In, occur to eliminate reaction after adding alkali and obtain the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene ammonia
Base)-1-propanol.
C the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol is dissolved in molten by ()
In agent, imines hydrolysis after adding acid, is occurred to obtain (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-third
Alcohol.
In the detailed description of the invention of the present invention, in step (3) in Deprotection method 1, (1R, 2S)-3-fluoro-1-[4-
(methylsulfonyl) phenyl]-2-(R1-amino) mass ratio of-1-propanol and Pd/C catalyst is 1:0.02-0.1, hydrogenation reaction pressure
Power 1-10atm, temperature 20-50 DEG C.
Wherein, Pd/C catalyst is carbon-supported Pd catalyst, and wherein the weight/mass percentage composition of Pd is 5%-10%.
Wherein, solvent selected from methanol, ethanol, isopropanol, oxolane and acetic acid etc..
In the detailed description of the invention of the present invention, in step (3) in Deprotection method 2, (1R, 2S)-3-in step (a)
Fluoro-1-[4-(methylsulfonyl) phenyl]-2-(R1-amino) mol ratio of-1-propanol and chlorination reagent is 1:0.4-2, the response time
0.5-3 hour, reaction temperature 10-50 DEG C.
Wherein, solvent is selected from dichloromethane, chloroform and 1,2-dichloroethanes etc..
Wherein, chlorination reagent is selected from chlorosuccinimide, sym-closene and chlorine etc..
In the detailed description of the invention of the present invention, in step (3) in Deprotection method 2, (1R, 2S)-3-in step (b)
Fluoro-1-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino) mol ratio of-1-propanol and alkali is 1:1-3, response time 0.5-
3 hours, reaction temperature 20-50 DEG C.
Wherein, solvent selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethanes, dioxane and four
Hydrogen furan etc..
Wherein, alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and pyridine
Deng.
In the detailed description of the invention of the present invention, in the Deprotection method 2 in step (3), (1R, 2S) in step (c)-
The fluoro-1-of 3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol is 1:1-5 with the mol ratio of acid, the response time
3-12 hour, reaction temperature 20-50 DEG C.
Wherein, solvent selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethanes, dioxane and four
Hydrogen furan etc..
Wherein, acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, monoxone, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, first sulphur
Acid and p-methyl benzenesulfonic acid etc..
Following non-limiting embodiments, for further illustrating the synthetic method of florfenicol of the present invention, only understands
For the description of the invention and supplement, and should to technical scheme produce any type of restriction.
Work as R1It is the synthetic route of (S)-1-phenethyl:
Embodiment 1:
Synthesis compound (R)-[4-(methylsulfonyl) phenyl] [(R)-1-((S)-1-phenethyl) '-aziridino] methanol: at 500ml
In there-necked flask, N2Under gas shielded, 30g1-(S) phenethyl-2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine is dissolved in
200mlTHF(oxolane) in, it is cooled to-70 DEG C, dropping 182ml LiAl (Ot-Bu)3H(1Mol/L oxolane is molten
Liquid), dropping temperature controls below-60 DEG C, time for adding about 2 hours, drips rear reacting liquid temperature and controls at-60 DEG C anti-
Answer 3 hours, then be warming up to room temperature reaction 1 hour, TLC point board monitoring, after raw material reaction, add 100ml 5%NaOH aqueous solution and quench
Go out reaction, the most substantial amounts of white solid after stirring half an hour, after filtration, after dichloromethane extractive reaction liquid 2 times, organic lamination
And after washing once, then wash once with saturated common salt, anhydrous sodium sulfate is dried, is spin-dried for obtaining crude product, crude product 30ml second
After alcohol is heated to reflux dissolving, after adding 90ml petroleum ether and stirring after being cooled to room temperature, it is filtrated to get 28.83g product.HPLC detects
Purity 98.6%.Mass spectrum and magnetic resonance detection data are as follows:
LCMS:[M+1] 332, [M+Na] 354
HNMR (400MHz,CDCl3) δ7.67(m,2H),7.17-7.26(m,7H),4.43(m,1H), 2.98(s,3H),
2.85(d,J=5.6Hz,1H), 2.48-2.52(m,1H), 2.08(d,J=3.4,1H), 1.74-1.77(m,1H), 1.60
(d,J=6.4Hz,1H),1.45(d,J=6.6Hz,3H)。
Embodiment 2:
Synthesis compound (R)-[4-(methylsulfonyl) phenyl] [(R)-1-((S)-1-phenethyl) '-aziridino] methanol: at 100ml
In there-necked flask, N2Under gas shielded, 2.58gNaBH4Add in 30ml oxolane, be cooled to about 0 DEG C, drip 5.84g 3-penta
Ketone, after returning to room temperature reaction 2 hours, is cooled to-30 DEG C after dripping off.By 15g 1-(S) phenethyl-2-(R)-[4-(methylsulfonyl)
Phenyl] formoxyl aziridine is dissolved in 40mlTHF, is added drop-wise in above-mentioned sodium borohydride reactant liquor, in keeping reaction during dropping
Temperature controls between-10 DEG C to 0 DEG C, time for adding about 2 hours, reacts 2 hours at 0 DEG C after dripping off.TCL detection has been reacted
After, dropping shrend is gone out reaction, and after reactant liquor extracts separatory twice with dichloromethane, organic layer is evaporated to obtain crude product, crude product ethanol
Recrystallization obtains 10.6g product.
Embodiment 3:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) amino]-1-propanol:
In 100ml tetrafluoro single port bottle, 10.5g(R)-[4-(methylsulfonyl) phenyl] [(R)-1-((S)-1-phenethyl) '-aziridino] first
Alcohol is dissolved in 80g 1,2-dichloroethanes stirring and dissolving raw material, weighs 12g anhydrous triethylamine hydrofluoride and adds in solution, airtight after
Being rapidly heated to 85 DEG C of back flow reaction 16 hours, reactant liquor TLC or HPLC monitors, and is down to room temperature, pours into after reaction completely
The water stirring of 80ml, adds Na2CO3Adjusting about pH=8, extract with dichloromethane separatory, organic layer obtains with ethyl alcohol recrystallization after being evaporated
9.8g product.Mass spectrum and magnetic resonance detection data are as follows:
LCMS:[M+1] 352, [M+Na] 374
HNMR (400MHz,MeOD) δ7.93-7.96 (m,2H), 7.56-7.59 (m,2H), 7.44 (m,5H), 5.01
(d,J=8Hz,1H), 4.67-4.82 (m,2H), 4.35-4.50 (m,1H), 3.34-3.45(m,1H), 3.14(s,
3H),1.73(d,J=6.8Hz,3H)。
Embodiment 4:
Synthesis compound (1R, the 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol: in 250ml single port bottle,
Add the fluoro-1-of 15g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) amino]-1-propanol and be dissolved in 120g
In methanol, adding 2g 10% Pd/C, overnight, Hydrogen Vapor Pressure is 1.5atm to 40 DEG C of hydrogenation reactions, filters out Pd/C after having reacted,
Filtrate is spin-dried for obtaining crude product, filters to obtain product 9.6g, HPLC and detect purity 97% after the making beating of crude product isopropanol.
Embodiment 5:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) chloro amino]-1-
Propanol: in 100ml there-necked flask, and the fluoro-1-of 9.8g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) ammonia
Base]-1-propanol is dissolved in the dichloromethane of 50 ml, and at room temperature (about 25 DEG C) are dividedly in some parts 3.7g chlorosuccinimide,
Continue after adding to react half an hour.After the reaction completely of TLC point board raw material, adding 30ml shrend and go out reaction, separatory reduces pressure dense after extracting
Contracting obtains the fluoro-1-of 10.6g product (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) chloro amino]-1-
Propanol.
Embodiment 6:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol:
In 100ml there-necked flask, 10.6g(1R, 2S) the fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-[((S)-1-phenethyl) chloro ammonia
Base] the 50ml methanol dissolving of-1-propanol, add 4.2g triethylamine under room temperature, after 30 DEG C are stirred 2 hours, TLC point board raw material reacts
After complete, concentrating under reduced pressure falls major part methanol, adds dichloromethane and water in residue, and stirring separates organic layer, and organic layer is again
Washed once with saline, organic layer is concentrated to give 9.6g product.
Embodiment 7:
Synthesis compound (1R, the 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol hydrochloride: at 100ml tri-
In mouth bottle, under room temperature, add the fluoro-1-of 9.6g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-third
Alcohol is dissolved in methanol, is added dropwise to the concentrated hydrochloric acid of 4.2ml, and after being stirred at room temperature 4 hours, the reaction of TLC point board raw material is completely.Concentrating under reduced pressure
After falling methanol, adding the ethanol of 10ml in residue, stirring separates out a large amount of solids, and after solid stirs, frozen water cools down, mistake
It is filtered dry dry 5.8g white solid product.
Embodiment 8:
Synthesis compound florfenicol: in 100ml there-necked flask, 5.8g (1R, 2S)-2-amino-3-fluoro-1-[4-(MSM
Base) phenyl]-1-propanol hydrochloride is dissolved in 30g methanol, and add 4.38g methyl dichloroacetate, 2.58g sodium bicarbonate, be heated to 50
DEG C reaction 16 hours, TLC or HPLC monitor reaction, after having reacted, addition 0.5g activated carbon 50 DEG C stir half an hour, while hot mistake
Filter, filtrate decompression is evaporated, and adds the stirring of 50ml water, separates out solid filtering drying and obtains 6.2g product, crude product isopropyl alcohol and water weight
The product 5.6g crystallizing qualified.
Work as R1It is the synthetic route of (R)-1-phenethyl:
Embodiment 9:
Synthesis compound (R)-[4-(methylsulfonyl) phenyl] [(R)-1-((R)-1-phenethyl) '-aziridino] methanol: at 500ml
In there-necked flask, N2Under gas shielded, 30g1-(R) phenethyl-2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine is dissolved in
200mlTHF(oxolane) in, it is cooled to-70 DEG C, dropping 182ml LiAl (Ot-Bu)3H(1Mol/L tetrahydrofuran solution),
Dropping temperature controls below-60 DEG C, time for adding about 2 hours, drips rear reacting liquid temperature and controls to react 3 at-60 DEG C
Hour, then it is warming up to room temperature reaction 1 hour, and TLC point board monitoring, after raw material reaction, add 100ml 5wt%NaOH aqueous solution and quench
Go out reaction, the most substantial amounts of white solid after stirring half an hour, after filtration, after dichloromethane extractive reaction liquid 2 times, organic lamination
And after washing once, then wash once with saturated common salt, anhydrous sodium sulfate is dried, is spin-dried for obtaining crude product, crude product 30ml second
After alcohol is heated to reflux dissolving, after adding 90ml petroleum ether and stirring after being cooled to room temperature, it is filtrated to get 27.5g product.Mass spectrum and nuclear-magnetism
Resonance detection data are as follows:
LCMS:[M+1] 332, [M+Na] 354
HNMR (400MHz,CDCl3) δ7.65(m,2H),7.18-7.23(m,7H),4.51(m,1H), 2.92(s,3H),
2.75(d,J=5.6Hz,1H), 2.58-2.64(m,1H), 2.08(d,J=3.8,1H), 1.74-1.77(m,1H), 1.60
(d,J=5.6Hz,1H),1.62(d,J=6.4Hz,3H)。
Embodiment 10:
Synthesis compound (R)-[4-(methylsulfonyl) phenyl] [(R)-1-((R)-1-phenethyl) '-aziridino] methanol: at 100ml
In there-necked flask, N2Under gas shielded, 2.58gNaBH4Add in 30ml oxolane, be cooled to about 0 DEG C, drip 5.84g 3-penta
Ketone, after returning to room temperature reaction 2 hours, is cooled to-30 DEG C after dripping off.By 15g 1-(R) phenethyl-2-(R)-[4-(methylsulfonyl)
Phenyl] formoxyl aziridine is dissolved in 40mlTHF, is added drop-wise in above-mentioned sodium borohydride reactant liquor, in keeping reaction during dropping
Temperature controls between-10 DEG C to 0 DEG C, time for adding about 2 hours, reacts 2 hours at 0 DEG C after dripping off.TCL detection has been reacted
After, dropping shrend is gone out reaction, and after reactant liquor extracts separatory twice with dichloromethane, organic layer is evaporated to obtain crude product, crude product ethanol
Recrystallization obtains 10.2g product.
Embodiment 11:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) amino]-1-propanol:
In 100ml tetrafluoro single port bottle, 10.5g(R)-[4-(methylsulfonyl) phenyl] [(R)-1-((R)-1-phenethyl) '-aziridino]
Methanol is dissolved in 80g 1,2-dichloroethanes stirring and dissolving raw material, weighs 12g anhydrous triethylamine hydrofluoride and adds in solution, airtight
After be rapidly heated to 85 DEG C of back flow reaction 16 hours, reactant liquor TLC or HPLC monitors, and is down to room temperature, pours into after reaction completely
The water stirring of 80ml, adds Na2CO3Adjusting about pH=8, extract with dichloromethane separatory, organic layer obtains with ethyl alcohol recrystallization after being evaporated
9.6g product.Mass spectrum and magnetic resonance detection data are as follows:
LCMS:[M+1] 352, [M+Na] 374
HNMR (400MHz,MeOD) δ7.91-7.94 (m,2H), 7.52-7.56 (m,2H), 7.44 (m,5H), 5.10
(d,J=7.6Hz,1H), 4.62-4.82 (m,2H), 4.35-4.50 (m,1H), 3.41-3.48(m,1H), 3.14(s,
3H),1.81(d,J=6.6Hz,3H)。
Embodiment 12:
Synthesis compound (1R, the 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol: in 250ml single port bottle,
Add the fluoro-1-of 15g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) amino]-1-propanol and be dissolved in 120g
In methanol, adding 2g 10% Pd/C, overnight, Hydrogen Vapor Pressure is 1.2atm to 40 DEG C of hydrogenation reactions, filters out Pd/C after having reacted,
Filtrate is spin-dried for obtaining crude product, filters to obtain product 9.4g, HPLC and detect purity 97% after the making beating of crude product isopropanol.
Embodiment 13:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) chloro amino]-1-
Propanol: in 100ml there-necked flask, and the fluoro-1-of 9.8g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) ammonia
Base]-1-propanol is dissolved in the dichloromethane of 50 ml, and at room temperature (about 25 DEG C) are dividedly in some parts 3.7g chlorosuccinimide,
Continue after adding to react half an hour.After the reaction completely of TLC point board raw material, adding 30ml shrend and go out reaction, separatory reduces pressure dense after extracting
Contracting obtains the fluoro-1-of 10.7g product (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) chloro amino]-1-
Propanol.
Embodiment 14:
The synthesis fluoro-1-of compound (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol:
In 100ml there-necked flask, 10.7g(1R, 2S) the fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-[((R)-1-phenethyl) chloro ammonia
Base]-1-propanol dissolves with 50 ml methanol, adds 4.2g anhydrous triethylamine under room temperature, and after 30 DEG C of stirrings 2 hours, TLC point plate is former
After material has reacted, concentrating under reduced pressure falls major part methanol, adds dichloromethane and water in residue, and stirring separates organic layer, has
Machine layer washed once with saline again, and organic layer is concentrated to give 9.8g product.
Embodiment 15:
Synthesis compound (1R, the 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol hydrochloride: at 100ml tri-
In mouth bottle, under room temperature, add the fluoro-1-of 9.8g (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-third
Alcohol is dissolved in methanol, is added dropwise to the concentrated hydrochloric acid of 4.2ml, and after being stirred at room temperature 4 hours, the reaction of TLC point board raw material is completely.Concentrating under reduced pressure
After falling methanol, adding the ethanol of 10ml in residue, stirring separates out a large amount of solids, and after solid stirs, frozen water cools down, mistake
It is filtered dry dry 6.1g white solid product.
Embodiment 16:
Synthesis compound florfenicol: in 100ml there-necked flask, 6.1g (1R, 2S)-2-amino-3-fluoro-1-[4-(MSM
Base) phenyl]-1-propanol hydrochloride is dissolved in 30g methanol, and add 4.38g methyl dichloroacetate, 2.58g sodium bicarbonate, be heated to 50
DEG C reaction 16 hours, TLC or HPLC monitor reaction, after having reacted, addition 0.5g activated carbon 50 DEG C stir half an hour, while hot mistake
Filter, filtrate decompression is evaporated, and adds the stirring of 50ml water, separates out solid filtering drying and obtains 6.2g product, crude product isopropyl alcohol and water weight
The product 5.7g crystallizing qualified.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all in the spirit and principles in the present invention
Within, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (10)
1. the synthetic method of florfenicol, comprises the steps:
(1) by 1-R1-2-(R)-[4-(methylsulfonyl) phenyl] formoxyl aziridine is dissolved in solvent, anti-with big steric hindrance also original reagent
Deserved compound 1:(R)-[4-(methylsulfonyl) phenyl] [(R)-1-R1-aziridine-2-base] methanol；
Wherein, R1It is (S)-1-phenethyl or (R)-1-phenethyl；
(2) compound 1 and triethylamine hydrofluoride reacting by heating in a solvent obtain (1R, 2S)-3-fluoro-1-[4-(methylsulfonyl)
Phenyl]-2-(R1-amino)-1-propanol；
(3) the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol takes off blocking group in a solvent
R1Obtain (1R 2S) fluoro-1-of-2-amino-3-[4-(methylsulfonyl) phenyl]-1-propanol；
(4) (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol obtains fluorobenzene through dichloroacetylization reaction
Buddhist nun examines.
The synthetic method of florfenicol the most according to claim 1, it is characterised in that in step (1), described compound
1 is 1:0.5-2.5 with the mol ratio of big steric hindrance also original reagent, and reaction temperature is-78-0 DEG C；
Described solvent is selected from dichloromethane, chloroform, 1,2-dichloroethanes, oxolane, dioxane, isopropanol and tertiary fourth
One or both in alcoholic solvent.
The synthetic method of florfenicol the most according to claim 1, it is characterised in that described big steric hindrance also original reagent is selected from
LiAl(OCH3)3H、LiAl(Ot-Bu)3H、Red-Al、CBS-B2H6、MeCBS-B2H6With NaB (OR2)nH4-n；
Wherein, described R2Group is selected from isopropyl, 2-butyl, the tert-butyl group, 3-amyl group, cyclobutyl, cyclopenta, cyclohexyl, 1-benzene second
One or both in base, benzhydryl, glucosyl group and fructosyl, n=1,2,3.
The synthetic method of florfenicol the most according to claim 1, it is characterised in that in step (2), described compound
1 is 1:1.2-10 with the mol ratio of triethylamine hydrofluoride, and reaction temperature is 50-120 DEG C；
The structural formula of described triethylamine hydrofluoride is Et3N.xHF, x are 3-10；
Described solvent selected from dichloromethane, chloroform, 1,2-dichloroethanes, oxolane, dioxane, chlorobenzene, toluene, two
Toluene, ether, methyl tertiary butyl ether(MTBE), diisopropyl ether, dichloroether, N-Methyl pyrrolidone, N,N-dimethylformamide and diformazan
Base sulfoxide；
Described solvent is 3-15:1 with the mass ratio of compound 1.
The synthetic method of florfenicol the most according to claim 1, it is characterised in that described step (3) uses Pd/C to urge
Change hydrogenation method, including:
Described (1R, 2S) fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol is dissolved in solvent, adds Pd/C and urge
Agent, hydrogenation reaction obtains (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol.
The synthetic method of florfenicol the most according to claim 5, it is characterised in that described (1R, 2S)-3-fluoro-1-[4-
(methylsulfonyl) phenyl]-2-(R1-amino) mass ratio of-1-propanol and Pd/C catalyst is 1:0.02-0.1, hydrogenation reaction
Pressure is 1-10atm, and temperature is 20-50 DEG C；
In described Pd/C catalyst, the weight/mass percentage composition of Pd is 5%-10%；
Described solvent selected from methanol, ethanol, isopropanol, oxolane and acetic acid.
The synthetic method of florfenicol the most according to claim 1, it is characterised in that described step (3) uses chlorination water
Solution, including:
A () is by the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol is dissolved in solvent, adds chlorination
Reagent, reaction obtains the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino)-1-propanol；
B () is by the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino)-1-propanol is dissolved in solvent, adds
Occur to eliminate reaction after alkali and obtain the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-third
Alcohol；
C the fluoro-1-of (1R, 2S)-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol is dissolved in solvent by (),
Imines hydrolysis is occurred to obtain (1R, 2S)-2-fluoro-1-of amino-3-[4-(methylsulfonyl) phenyl]-1-propanol after adding acid.
The synthetic method of florfenicol the most according to claim 7, it is characterised in that in step (a),
Described (1R, 2S) fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-(R1-amino)-1-propanol with the mol ratio of chlorination reagent is
1:0.4-2, reaction temperature is 10-50 DEG C；
Described solvent is selected from dichloromethane, chloroform and 1,2-dichloroethanes；
Described chlorination reagent is selected from chlorosuccinimide, sym-closene and chlorine.
The synthetic method of florfenicol the most according to claim 7, it is characterised in that in step (b),
Described (1R, 2S) fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-(R1-chloro amino) mol ratio of-1-propanol and alkali is 1:
1-3, reaction temperature is 20-50 DEG C；
Described solvent selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethanes, dioxane and tetrahydrochysene furan
Mutter；
Described alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine and pyridine.
The synthetic method of florfenicol the most according to claim 7, it is characterised in that in step (c),
Described (1R, 2S) fluoro-1-of-3-[4-(methylsulfonyl) phenyl]-2-(1-phenylethylene amino)-1-propanol and sour mol ratio
For 1:1-5, reaction temperature is 20-50 DEG C；
Described solvent selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethanes, dioxane and tetrahydrochysene furan
Mutter；
Described acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, monoxone, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid and
P-methyl benzenesulfonic acid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109851534A (en) * | 2017-11-30 | 2019-06-07 | 上海医药工业研究院 | A kind of synthetic method of florfenicol midbody |
| CN111333553A (en) * | 2020-03-09 | 2020-06-26 | 浙江普洛家园药业有限公司 | Synthetic method of florfenicol dimer impurity |
| CN111500652A (en) * | 2019-01-30 | 2020-08-07 | 苏州引航生物科技有限公司 | Method for preparing florfenicol |
| CN114163365A (en) * | 2021-11-17 | 2022-03-11 | 中国农业大学 | Florfenicol, florfenicol amine hapten and artificial antigen as well as preparation method and application thereof |
| CN117185972A (en) * | 2023-11-06 | 2023-12-08 | 苏州开元民生科技股份有限公司 | Preparation method of florfenicol intermediate |
| CN118084747A (en) * | 2024-04-28 | 2024-05-28 | 山东国邦药业有限公司 | Preparation method of florfenicol |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265220A (en) * | 2008-04-30 | 2008-09-17 | 上海立科药物化学有限公司 | Method for synthesizing florfenicol |
| CN102827042A (en) * | 2012-09-17 | 2012-12-19 | 湖北美天生物科技有限公司 | Chiral synthesis method of florfenicol |
| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
| CN103980168A (en) * | 2014-05-29 | 2014-08-13 | 京山瑞生制药有限公司 | Novel synthetic method of high-purity florfenicol |
-
2016
- 2016-08-04 CN CN201610633162.8A patent/CN106316898B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265220A (en) * | 2008-04-30 | 2008-09-17 | 上海立科药物化学有限公司 | Method for synthesizing florfenicol |
| CN102827042A (en) * | 2012-09-17 | 2012-12-19 | 湖北美天生物科技有限公司 | Chiral synthesis method of florfenicol |
| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
| CN103980168A (en) * | 2014-05-29 | 2014-08-13 | 京山瑞生制药有限公司 | Novel synthetic method of high-purity florfenicol |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109851534A (en) * | 2017-11-30 | 2019-06-07 | 上海医药工业研究院 | A kind of synthetic method of florfenicol midbody |
| CN109851534B (en) * | 2017-11-30 | 2021-04-27 | 上海医药工业研究院 | Synthetic method of florfenicol intermediate |
| CN111500652A (en) * | 2019-01-30 | 2020-08-07 | 苏州引航生物科技有限公司 | Method for preparing florfenicol |
| CN111500652B (en) * | 2019-01-30 | 2024-03-26 | 苏州引航生物科技有限公司 | Method for preparing florfenicol |
| CN111333553A (en) * | 2020-03-09 | 2020-06-26 | 浙江普洛家园药业有限公司 | Synthetic method of florfenicol dimer impurity |
| CN111333553B (en) * | 2020-03-09 | 2021-10-08 | 浙江普洛家园药业有限公司 | Synthetic method of florfenicol dimer impurity |
| CN114163365A (en) * | 2021-11-17 | 2022-03-11 | 中国农业大学 | Florfenicol, florfenicol amine hapten and artificial antigen as well as preparation method and application thereof |
| CN117185972A (en) * | 2023-11-06 | 2023-12-08 | 苏州开元民生科技股份有限公司 | Preparation method of florfenicol intermediate |
| CN117185972B (en) * | 2023-11-06 | 2024-02-13 | 苏州开元民生科技股份有限公司 | Preparation method of florfenicol intermediate |
| CN118084747A (en) * | 2024-04-28 | 2024-05-28 | 山东国邦药业有限公司 | Preparation method of florfenicol |
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