CN106316898B - The synthetic method of Florfenicol - Google Patents
The synthetic method of Florfenicol Download PDFInfo
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- CN106316898B CN106316898B CN201610633162.8A CN201610633162A CN106316898B CN 106316898 B CN106316898 B CN 106316898B CN 201610633162 A CN201610633162 A CN 201610633162A CN 106316898 B CN106316898 B CN 106316898B
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Abstract
The invention discloses a kind of synthetic methods of Florfenicol, belong to medical synthesis technical field.By 1 R12 (R) [4 (methylsulfonyl) phenyl] formoxyl aziridine is dissolved in solvent, reacts to obtain single configuration chiral amino alcoholic compound 1 with big steric hindrance go back original reagent；Compound 1 with triethylamine hydrofluoride heats and (1R, 2S) 3 fluorine 1 [4 (methylsulfonyl) phenyl] 2 (R is obtained by the reaction in a solvent1Amino) 1 propyl alcohol；(1R, 2S) 3 fluorine 1 [4 (methylsulfonyl) phenyl] 2 (R1Amino) 1 propyl alcohol takes off blocking group and obtains (1R 2S) 2 amino 3 fluorine 1 [4 (methylsulfonyl) phenyl] 1 propyl alcohol in a solvent；Florfenicol is obtained by the reaction through dichloroacetyl in (1R, 2S) 2 amino 3 fluorine 1 [4 (methylsulfonyl) phenyl] 1 propyl alcohol.
Description
Technical field
The invention belongs to the synthetic methods of medical synthesis technical field, more particularly to Florfenicol.
Background technology
Florfenicol（Florfenicol）, it is that first refined (Schering- Plough) company is protected in spirit one by the U.S.
A kind of chloromycetin broad-spectrum antibiotic for animal specific that Nagab- hushan etc. are developed in late 1970s.Mirror
In on animal diseases control, the drug effect of Florfenicol has more wide application better than chloramphenicol and Thiamphenicol
Prospect, the synthesis of Florfenicol all receive very big attention always.
At present, there are mainly two types of the methods of domestic and international industrialized production Florfenicol：1st, D-pmethylsulfonyl phenyleneserine second
Ester successively makes standby oxazoline, Ishikawa reagents fluorination reaction, hydrolysis, two chloroethenes by reduction reaction, with benzonitrile reaction
Acylation reaction obtains Florfenicol；2nd, D-D-4-methylsulfonylphserine serine ethyl ester is successively by reduction reaction and dichloro acetonitrile reaction
Sheng oxazolines, Ishikawa reagents fluorination reaction, hydrolysis obtain Florfenicol.The latter is with respect to having lacked a step for the former
Dichloroacetylization is reacted, and effectively reduces production operation step and cost.
More than two synthetic routes be required for using D- D-4-methylsulfonylphserine serine ethyl esters, and industrially prepare at present this
The method of compound is still to pass through reduction reaction, methylation reaction, bromo oxygen along to p-methyl benzene sulfonic chloride for starting material
Change reaction, hydrolysis is obtained to methyl sulfone benzaldehyde, then prepares copper with to methyl sulfone benzaldehyde, glycine, copper sulphate reaction
It splits through esterification, tartaric acid to obtain D- D-4-methylsulfonylphserine serine ethyl esters after salt.Obtaining D- pmethylsulfonyl phenyleneserines
Substantial amounts of sulfuric acid copper waste water is generated in ethyl ester production process so that the processing cost of waste water is very high.
In recent years using the research of chiral catalyst progress asymmetric reduction synthesizing chiral compound than wide, fluorobenzene Buddhist nun
It examines product and is also doing relevant research.The applicant is directed to preparing fluorobenzene using chiral catalyst progress asymmetric reduction reaction
The research that Buddhist nun examines：The patent of publication number CN102827042A is disclosed using thioanisole as starting material, anti-by three steps chemistry
Compound [1- benzyl aziridine -2- bases] [4- (methyl mercapto) phenyl] ketone should be synthesized, product further utilizes chiral catalyst
Asymmetric hydrogenation reduction reaction obtains [1- benzyl aziridine -2- bases] [4- (methyl mercapto) phenyl] methanol then again by several steps
It learns reaction and prepares the scheme of Florfenicol, chiral catalyst used is trans-RuCl2 [(R)-xylbinap] in the program
[(S)-DPEN].In this scenario, chiral centre carbon is built using chiral catalyst asymmetric reduction reaction, avoids chirality and tear open
Point.But chiral catalyst has the shortcomings that preparing the difficult big, industrial production of deposit easily inactivates, and then cause application cost in itself
Height is unfavorable for industrialized production.
The applicant is directed to structure chiral amino ketone selective reduction and obtains chiral amino alcohol, recycles aziridine ternary
Ring synthesizes Florfenicol new process in the property of the easy open loop of sour environment：It is disclosed in the patent of Publication No. CN103936638A
Using Chiral Amine cyclization the aziridine ternary cycle compound nitrogen of diastereoisomer chiral amino ketone is obtained, by physical separation
Method it is isolated needed for R configurations amino ketones aziridine ternary cycle compound, be fluorinated using triethylamine hydrofluoride
Ring-opening reaction introduces fluorine atom, and Florfenicol finished product, i.e. synthetic route 1 is obtained by the reaction using several steps.
Synthetic route 1：
Wherein：Acetylation：Acylation reaction；Cyclization：Ring-closure reaction；Flrofenicol：Florfenicol.
R1：（S）- 1- phenethyls or（R）- 1- phenethyls；
R2：Phenyl or dichloromethyl or hydroxyl
One of 1 outstanding advantages of route are to obtain diastereoisomer aziridine three-membered ring using Chiral Amine cyclization to synthesize
Method by the separation method of physics purify repeatedly in high yield obtain the chiral amino ketone of single R configurations, using selectivity also
Original, configuration conversion idea finally obtain Florfenicol, and Atom economy is greatly improved, while is avoided in existing process
The contaminated wastewater brought greatly reduces the cost of processing waste water and the pollution to environment, reduces cost, simplify technique.
Advantage second is that on the basis of said synthesis route using triethylamine hydrofluoride as fluorination Ring Opening Reagent, liquid reaction compare gas
Precursor reactant security is improved, and in addition to the corrosivity very little of equipment, is conducive to technology production.But selectively also
The chiral alcohol and the configuration of the chiral alcohol of Florfenicol obtained when former by the configuration of hydroxyl just on the contrary, finally will convert ability
The chiral alcohol of configuration needed for obtaining.
In consideration of it, finding the chiral amino alcohol directly obtained during a kind of go back original reagent reduction amino ketones needed for Florfenicol is
It is very necessary.
The content of the invention
It is an object of the invention to provide a kind of new synthetic methods of Florfenicol.Florfenicol of the present invention
Synthetic method includes the following steps：
(1) by 1-R1 - 2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine is dissolved in solvent at room temperature, after cooling
Single configuration chiral amino alcoholic compound 1 is reacted to obtain with big steric hindrance go back original reagent：(R)-[4- (methylsulfonyl) phenyl] [(R) -1-
R1- aziridine -2- bases] methanol；
Compound 1
Wherein, R1It is（S）- 1- phenethyls or（R）- 1- phenethyls.
(2) compound 1 and triethylamine hydrofluoride（Et3N.xHF）(1R, 2S) -3- is obtained by the reaction in heating in a solvent
Fluoro- 1- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol.
(3) the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol takes off guarantor in a solvent
Protect group R1Obtain the fluoro- 1- of (1R 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol.
(4) the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol is reacted through dichloroacetyl
To Florfenicol, the process is identical with the acylation reaction process in (6) the step of patent CN103936638A.
Technical scheme and the invention of the applicant（CN103936638A）There is similar process route,
To obtain target product, from technological process, the two can share compound 1-R1 - 2- (R)-[4- (methylsulfonyl) phenyl] formyl
Base aziridine, thinking hereafter, which has, a little to be distinguished, when selective reduction this step structure chiral alcohol, hand that the two obtains
Property alcoholic compound configuration is just opposite.The chiral alcohol and the chiral alcohol of Florfenicol obtained in patent of invention CN103936638A
Configuration just on the contrary, finally to be converted by the configuration of hydroxyl（Hydroxyl sulfoacid esterification cyclization carries out configuration conversion reaction preparation
Compound 3, compound 3 obtain Florfenicol through hydrolyzing either acylated）The chiral alcohol of configuration needed for just obtaining；And in this patent
It is to utilize 1-R1 - 2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine after big steric hindrance go back original reagent selective reduction with obtaining
Configuration of compound it is just identical with the configuration of the chiral alcohol of Florfenicol, configuration conversion reaction need not be carried out, can so be contracted
Short processes route, reduces production cost.In addition in deprotection group R in the present invention1In, chlorinated hydrolysis side can also be used
Method, so can be to avoid precious metals pd be used, not only can be to avoid product heavy metals exceeding standard, and can be greatly reduced and be produced into
This.
For facing chiral alcohol problem and deprotection group R in Florfenicol building-up process1Two large problems, the present invention
Technological process rationally and effectively solve both of these problems：
First, using chiral amino ketone space steric effect, big steric hindrance go back original reagent is selected, selective reduction obtains institute
The chiral amino alcohol needed, in the big go back original reagent of selection steric hindrance, by changing reaction temperature, speed is added dropwise in go back original reagent equivalent
Spend to control the stereoselectivity of reactant, with some conventional big steric hindrance go back original reagents with regard to can solve chiral amino alcohol also
Former problem.
Secondly, using imines in acid condition unstable characteristic, in deprotection group R1When, first the hydrogen chloride on nitrogen,
The unstability of nitrogen chlorine key is recycled to carry out elimination reaction under alkalescence and obtains imines, then is taken off with sour water solution imines three-step reaction
Amino protecting group without using precious metal palladium, effectively reduces cost.
In general, one of outstanding advantages of the invention are to be imitated using the chiral amino ketone steric hindrance of single R configurations
Should, big steric hindrance go back original reagent is selected, selective reduction obtains required chiral amino alcohol, and direct single step reaction just solves fluorine
The problem of benzene Buddhist nun examines chiral alcohol, simplifies technique, reduces cost.Advantage second is that deprotection when can be with selective chlorination
The method of hydrolysis is avoided using precious metal palladium, and having to utilize reduces production cost.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, embodiment of the present invention is made below further
It is described in detail on ground.
The synthetic method of Florfenicol of the present invention can be described typically with following flow process：
Wherein：Reduction：Reduction reaction；Deprotecation：Deprotection reaction；Flrofenicol：Fluorobenzene Buddhist nun
It examines.
R1：（S）- 1- phenethyls or（R）- 1- phenethyls.
The specific embodiment of the synthetic method of Florfenicol of the present invention may not include have been recorded in above-mentioned flow
In part of the prior art, i.e. the first two steps, the synthetic method of Florfenicol of the present invention includes the following steps：
(1) by 1-R1 - 2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine is dissolved in organic solvent at room temperature, cooling
Single configuration chiral amino alcoholic compound 1 is reacted to obtain with big steric hindrance go back original reagent afterwards：(R)-[4- (methylsulfonyl) phenyl] [(R) -1-
R1- aziridine -2- bases] methanol；
Compound 1
Wherein, R1It is（S）- 1- phenethyls or（R）- 1- phenethyls.
(2) (R)-[4- (methylsulfonyl) phenyl] [(R) -1-R1- aziridine -2- bases] methanol and triethylamine hydrofluoride
（Et3N.xHF）The fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R are obtained by the reaction in heating in a solvent1- amino) -1-
Propyl alcohol.
(3) the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol takes off guarantor in a solvent
Protect group R1Obtain the fluoro- 1- of (1R 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol.
(4) the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol is obtained by the reaction through dichloroacetyl
Florfenicol.
In the specific embodiment of the present invention, reduction reaction is in step (1)：In a solvent, 1-R1 - 2- (R)-[4- (first
Sulfuryl) phenyl] molar ratio of formoxyl aziridine and big steric hindrance go back original reagent is 1:0.5-2.5, -78-0 DEG C of reaction temperature.
Wherein, big steric hindrance go back original reagent is slowly added into 1-R in step (1)1 - 2- (R)-[4- (methylsulfonyl) phenyl] first
For controlling the process of reaction in acyl group aziridine, specifically it is dissolved in solvent and is added to 1-R by the way of being added dropwise1 -2-
(R)-[4- (methylsulfonyl) phenyl] in formoxyl aziridine, when time for adding is 1-3 small.
Wherein, big steric hindrance go back original reagent is selected from LiAl (OCH3)3H、LiAl(Ot-Bu)3H、Red-Al、CBS-B2H6、
MeCBS-B2H6With NaB (OR2)n H4-nDeng.In NaB (OR2)n H4-nIn, wherein R2Group is selected from isopropyl, 2- butyl, tertiary fourth
One in the groups such as base, 3- amyls, cyclobutyl, cyclopenta, cyclohexyl, 1- phenethyls, benzhydryl, glucosyl group and fructosyl
The mixing of kind or two of which, n=1,2,3.
Wherein, organic solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, dioxane, different
Propyl alcohol and one kind in tert-butyl alcohol equal solvent or the mixing of two of which solvent.
In the specific embodiment of the present invention, fluorination ring-opening reaction is in step (2)：Compound 1 and triethylamine hydrogen fluorine
Hydrochlorate（Et3N.xHF salt）Molar ratio be 1:1.2-10 50-120 DEG C of reaction temperature；Wherein, x is in triethylamine hydrofluoride
3-10。
Wherein, solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, dioxane, chlorobenzene, first
Benzene, dimethylbenzene, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dichloroether, N-Methyl pyrrolidone（NMP）, N, N- dimethyl methyls
Amide（DMF）And dimethyl sulfoxide (DMSO)（DMSO）It is 3-15 Deng, solvent and 1 mass ratio of compound:1.
In the specific embodiment of the present invention, deprotection group R in step (3)1Method have following two methods.
Method 1, Pd/C catalytic hydrogenation methods：The wherein fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- ammonia
Base) -1- propyl alcohol is dissolved in solvent, add precious metals pd/C catalyst, hydrogenation reaction obtains the fluoro- 1- of (1R, 2S) -2- amino -3-
[4- (methylsulfonyl) phenyl] -1- propyl alcohol.
Method 2, chlorinolysis include the following steps：
(a) by the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol is dissolved in solvent, adds
Enter chlorination reagent, the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R are obtained by the reaction1- chloro amino) -1- propyl alcohol.
(b) by the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- chloro amino) -1- propyl alcohol is dissolved in solvent
In, generation elimination reaction obtains the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylene ammonia after adding in alkali
Base) -1- propyl alcohol.
(c) the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol is dissolved in molten
In agent, generation imines hydrolysis obtains the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- third after adding in acid
Alcohol.
In the specific embodiment of the present invention, in step (3) in Deprotection method 1, the fluoro- 1- [4- of (1R, 2S) -3-
(methylsulfonyl) phenyl] -2- (R1- amino) mass ratio of -1- propyl alcohol and Pd/C catalyst is 1:0.02-0.1, hydrogenation reaction pressure
Power 1-10atm, 20-50 DEG C of temperature.
Wherein, Pd/C catalyst is carbon-supported Pd catalyst, and wherein the mass percentage of Pd is 5%-10%.
Wherein, solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran and acetic acid etc..
In the specific embodiment 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) molar ratio of -1- propyl alcohol and chlorination reagent is 1:0.4-2, reaction time
When 0.5-3 is small, 10-50 DEG C of reaction temperature.
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 specific embodiment 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) molar ratio of -1- propyl alcohol and alkali is 1:1-3, reaction time 0.5-
3 it is small when, 20-50 DEG C of reaction temperature.
Wherein, solvent is selected from methanol, ethyl alcohol, isopropanol, dichloromethane, chloroform, 1,2- dichloroethanes, dioxane and four
Hydrogen furans etc..
Wherein, alkali is selected from potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus, triethylamine, diisopropylethylamine and pyridine
Deng.
In the specific embodiment of the present invention, in the Deprotection method 2 in step (3), (1R, 2S) in step (c)-
The molar ratio of the fluoro- 1- of 3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol and acid is 1:1-5, reaction time
When 3-12 is small, 20-50 DEG C of reaction temperature.
Wherein, solvent is selected from methanol, ethyl alcohol, isopropanol, dichloromethane, chloroform, 1,2- dichloroethanes, dioxane and four
Hydrogen furans etc..
Wherein, acid is selected from hydrochloric acid, sulfuric 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 are used to further illustrate the present invention the synthetic method of the Florfenicol, only understand
For the description of the invention and supplement, without any type of limitation should be generated to technical scheme.
Work as R1It is（S）The synthetic route of -1- phenethyls：
Embodiment 1：
Synthesize compound（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((S) -1- phenethyls) '-aziridino] methanol：
In 500ml there-necked flasks, N2Under gas shielded, 30g1-（S）Phenethyl -2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine is molten
In 200mlTHF（Tetrahydrofuran）In, -70 DEG C are cooled to, 182ml LiAl (Ot-Bu) are added dropwise3H（1Mol/L tetrahydrofurans are molten
Liquid）, dropping temperature is controlled below -60 DEG C, and when time for adding about 2 is small, it is anti-at -60 DEG C to drip rear reacting liquid temperature control
Answer 3 it is small when, then be warming up to room temperature reaction 1 it is small when, TLC point board monitorings, raw material reaction after, add in 100ml 5%NaOH aqueous solutions quench
It goes out reaction, stirs after half an hour substantial amounts of white solid again, it is organic laminated after dichloromethane extraction reaction solution 2 times after filtering
And after washing once, then with saturated common salt washing once, after anhydrous sodium sulfate drying, it is spin-dried for obtaining crude product, crude product 30ml second
After alcohol is heated to reflux dissolving, it is cooled to after adding in 90ml petroleum ether and stirrings after room temperature and 28.83g products is obtained by filtration.HPLC is detected
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：
Synthesize compound（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((S) -1- phenethyls) '-aziridino] methanol：
In 100ml there-necked flasks, N2Under gas shielded, 2.58gNaBH4It adds in 30ml tetrahydrofurans, is cooled to 0 DEG C or so, 5.84g is added dropwise
Propione, returned to after dripping off room temperature reaction 2 it is small when after, be cooled to -30 DEG C.By 15g 1-（S）Phenethyl -2- (R)-[4- (methyl sulfone
Base) phenyl] formoxyl aziridine is dissolved in 40mlTHF, is added drop-wise in above-mentioned sodium borohydride reaction solution, and when dropwise addition, is kept in reaction
Temperature control between -10 DEG C to 0 DEG C, when time for adding about 2 is small, after dripping off 0 DEG C reaction 2 it is small when.TCL detection reactions
After complete, water quenching is added dropwise and goes out reaction, for reaction solution with after dichloromethane extraction liquid separation twice, organic layer is evaporated to obtain crude product, crude product second
Alcohol recrystallizes to obtain 10.6g products.
Embodiment 3：
Synthesize compound（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- phenethyls）Amino] -1- third
Alcohol：In 100ml tetrafluoro single port bottles, 10.5g（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((S) -1- phenethyls) aziridine
Base] methanol is dissolved in 80g 1, and 2- dichloroethanes stirring and dissolving raw materials weigh 12g anhydrous triethylamines hydrofluoride and add in solution,
Be rapidly heated after closed to 85 DEG C of back flow reactions 16 it is small when, reaction solution is monitored with TLC or HPLC, and room temperature is down to after the reaction was complete,
The water stirring of 80ml is poured into, adds Na2CO3PH=8 or so are adjusted, are extracted with dichloromethane liquid separation, organic layer is tied again after being evaporated with ethyl alcohol
It is brilliant to obtain 9.8g products.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：
Synthesize compound (1R, 2S) -2- amino -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -1- propyl alcohol：In 250ml single port
In bottle, 15g is added in（1R,2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- phenethyls）Amino] -1- propyl alcohol is molten
In 120g methanol, 10% Pd/C of 2g are added in, 40 DEG C of hydrogenation reactions are stayed overnight, and Hydrogen Vapor Pressure 1.5atm is filtered out after having reacted
Pd/C, filtrate are spin-dried for obtaining crude product, and crude product filters to obtain product 9.6g, HPLC detection purity 97% after being beaten with isopropanol.
Embodiment 5：
Synthesize compound（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol：In 100ml there-necked flasks, 9.8g（1R,2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- benzene
Ethyl）Amino] -1- propyl alcohol is dissolved in the dichloromethane of 50 ml, at room temperature（25 DEG C or so）3.7g chloro ambers are added portionwise
Acid imide, the reaction was continued after adding half an hour.TLC points board raw material is after the reaction was complete, 30ml water quenchings is added to go out reaction, after liquid separation extraction
It is concentrated under reduced pressure to give 10.6g products（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol.
Embodiment 6：
Synthesize compound (1R, 2S) -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol：
In 100ml there-necked flasks, 10.6g（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（S）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol with 50ml methanol dissolve, at room temperature add in 4.2g triethylamines, 30 DEG C stirring 2 it is small when after, TLC points board raw material reaction
After complete, be concentrated under reduced pressure most of methanol, and dichloromethane and water are added in into residue, and stirring separates organic layer, and organic layer is again
It is washed with brine once, organic layer is concentrated to give 9.6g products.
Embodiment 7：
Synthesize compound (1R, 2S) -2- amino -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -1- propanol hydrochlorides：
In 100ml there-necked flasks, 9.6g (1R, 2S) -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylene ammonia is added at room temperature
Base) -1- propyl alcohol is dissolved in methanol, is added dropwise to the concentrated hydrochloric acid of 4.2ml, be stirred at room temperature 4 it is small when after, the reaction was complete for TLC points board raw material.
It is concentrated under reduced pressure after methanol, the ethyl alcohol of 10ml is added in into residue, a large amount of solids, after solid stirs evenly, ice are precipitated in stirring
Water cooling, filtration drying obtain 5.8g white solid products
Embodiment 8：
Synthesize compound Florfenicol：In 100ml there-necked flasks, 5.8g (1R, 2S) -2- amino -3- fluoro- 1- [4- (first
Sulfuryl) phenyl] -1- propanol hydrochlorides are dissolved in 30g methanol, 4.38g methyl dichloroacetates are added in, 2.58g sodium acid carbonates are heated to
When 50 DEG C of reactions 16 are small, TLC or HPLC monitoring reactions after having reacted, add in 50 DEG C of stirring half an hour of 0.5g activated carbons, while hot mistake
Filter, filtrate decompression are evaporated, and add in the stirring of 50ml water, and solid filtering drying is precipitated and obtains 6.2g products, crude product isopropyl alcohol and water weight
The product 5.6g for crystallizing qualified.
Work as R1It is（R）The synthetic route of -1- phenethyls：
Embodiment 9：
Synthesize compound（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((R) -1- phenethyls) '-aziridino] methanol：
In 500ml there-necked flasks, N2Under gas shielded, 30g1-（R）Phenethyl -2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine is molten
In 200mlTHF（Tetrahydrofuran）In, -70 DEG C are cooled to, 182ml LiAl (Ot-Bu) are added dropwise3H（1Mol/L tetrahydrofurans are molten
Liquid）, dropping temperature is controlled below -60 DEG C, and when time for adding about 2 is small, it is anti-at -60 DEG C to drip rear reacting liquid temperature control
Answer 3 it is small when, then be warming up to room temperature reaction 1 it is small when, TLC point board monitorings, raw material reaction after, add in 100ml 5wt%NaOH aqueous solutions
It is quenched reaction, stirs after half an hour substantial amounts of white solid again, after filtering, after dichloromethane extraction reaction solution 2 times, organic layer
After merging washing once, then with saturated common salt washing once, after anhydrous sodium sulfate drying, it is spin-dried for obtaining crude product, crude product 30ml
After ethyl alcohol is heated to reflux dissolving, it is cooled to after adding in 90ml petroleum ether and stirrings after room temperature and 27.5g products is obtained by filtration.Mass spectrum and core
Magnetic 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：
Synthesize compound（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((R) -1- phenethyls) '-aziridino] methanol：
In 100ml there-necked flasks, N2Under gas shielded, 2.58gNaBH4It adds in 30ml tetrahydrofurans, is cooled to 0 DEG C or so, 5.84g is added dropwise
Propione, returned to after dripping off room temperature reaction 2 it is small when after, be cooled to -30 DEG C.By 15g 1-（R）Phenethyl -2- (R)-[4- (methyl sulfone
Base) phenyl] formoxyl aziridine is dissolved in 40mlTHF, is added drop-wise in above-mentioned sodium borohydride reaction solution, and when dropwise addition, is kept in reaction
Temperature control between -10 DEG C to 0 DEG C, when time for adding about 2 is small, after dripping off 0 DEG C reaction 2 it is small when.TCL detection reactions
After complete, water quenching is added dropwise and goes out reaction, for reaction solution with after dichloromethane extraction liquid separation twice, organic layer is evaporated to obtain crude product, crude product second
Alcohol recrystallizes to obtain 10.2g products.
Embodiment 11：
Synthesize compound（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- phenethyls）Amino] -1- third
Alcohol：In 100ml tetrafluoro single port bottles, 10.5g（R）- [4- (methylsulfonyl) phenyl] [（R）- 1- ((R) -1- phenethyls) aziridine
Base] methanol is dissolved in 80g 1, and 2- dichloroethanes stirring and dissolving raw materials weigh 12g anhydrous triethylamines hydrofluoride and add in solution,
Be rapidly heated after closed to 85 DEG C of back flow reactions 16 it is small when, reaction solution is monitored with TLC or HPLC, and room temperature is down to after the reaction was complete,
The water stirring of 80ml is poured into, adds Na2CO3PH=8 or so are adjusted, are extracted with dichloromethane liquid separation, organic layer is tied again after being evaporated with ethyl alcohol
It is brilliant to obtain 9.6g products.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：
Synthesize compound (1R, 2S) -2- amino -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -1- propyl alcohol：In 250ml single port
In bottle, 15g is added in（1R,2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- phenethyls）Amino] -1- propyl alcohol is molten
In 120g methanol, 10% Pd/C of 2g are added in, 40 DEG C of hydrogenation reactions are stayed overnight, and Hydrogen Vapor Pressure 1.2atm is filtered out after having reacted
Pd/C, filtrate are spin-dried for obtaining crude product, and crude product filters to obtain product 9.4g, HPLC detection purity 97% after being beaten with isopropanol.
Embodiment 13：
Synthesize compound（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol：In 100ml there-necked flasks, 9.8g（1R,2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- benzene
Ethyl）Amino] -1- propyl alcohol is dissolved in the dichloromethane of 50 ml, at room temperature（25 DEG C or so）3.7g chloro ambers are added portionwise
Acid imide, the reaction was continued after adding half an hour.TLC points board raw material is after the reaction was complete, 30ml water quenchings is added to go out reaction, after liquid separation extraction
It is concentrated under reduced pressure to give 10.7g products（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol.
Embodiment 14：
Synthesize compound (1R, 2S) -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol：
In 100ml there-necked flasks, 10.7g（1R, 2S）Fluoro- 1- [the 4- of -3-（Methylsulfonyl）Phenyl] -2- [（（R）- 1- phenethyls）Chloro ammonia
Base] -1- propyl alcohol dissolves with 50 ml methanol, add in 4.2g anhydrous triethylamines at room temperature, when 30 DEG C of stirrings 2 are small after, TLC contact plates are former
After material has reacted, be concentrated under reduced pressure most of methanol, and dichloromethane and water are added in into residue, and stirring separates organic layer, has
Machine layer is washed with brine once again, and organic layer is concentrated to give 9.8g products.
Embodiment 15：
Synthesize compound (1R, 2S) -2- amino -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -1- propanol hydrochlorides：
In 100ml there-necked flasks, 9.8g (1R, 2S) -3- fluoro- 1- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylene ammonia is added at room temperature
Base) -1- propyl alcohol is dissolved in methanol, is added dropwise to the concentrated hydrochloric acid of 4.2ml, be stirred at room temperature 4 it is small when after, the reaction was complete for TLC points board raw material.
It is concentrated under reduced pressure after methanol, the ethyl alcohol of 10ml is added in into residue, a large amount of solids, after solid stirs evenly, ice are precipitated in stirring
Water cooling, filtration drying obtain 6.1g white solid products
Embodiment 16：
Synthesize compound Florfenicol：In 100ml there-necked flasks, 6.1g (1R, 2S) -2- amino -3- fluoro- 1- [4- (first
Sulfuryl) phenyl] -1- propanol hydrochlorides are dissolved in 30g methanol, 4.38g methyl dichloroacetates are added in, 2.58g sodium acid carbonates are heated to
When 50 DEG C of reactions 16 are small, TLC or HPLC monitoring reactions after having reacted, add in 50 DEG C of stirring half an hour of 0.5g activated carbons, while hot mistake
Filter, filtrate decompression are evaporated, and add in the stirring of 50ml water, and solid filtering drying is precipitated and obtains 6.2g products, crude product isopropyl alcohol and water weight
The product 5.7g for crystallizing qualified.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
Within principle, any modifications, equivalent replacements and improvements are made should all be included in the protection scope of the present invention.
Claims (8)
1. the synthetic method of Florfenicol, includes the following steps：
(1) by 1-R1 - 2- (R)-[4- (methylsulfonyl) phenyl] formoxyl aziridine is dissolved in solvent, anti-with big steric hindrance go back original reagent
Deserved compound 1：(R)-[4- (methylsulfonyl) phenyl] [(R) -1-R1- aziridine -2- bases] methanol；
Compound 1
Wherein, R1It is（S）- 1- phenethyls or（R）- 1- phenethyls；
The molar ratio of the compound 1 and big steric hindrance go back original reagent is 1:0.5-2.5, reaction temperature are -78-0 DEG C；
The solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, dioxane, isopropanol and tertiary fourth
One or both of alcoholic solvent;
The big steric hindrance go back original reagent is selected from LiAl (OCH3)3H、LiAl(Ot-Bu)3H、Red-Al、CBS-B2H6、MeCBS-B2H6
With NaB (OR2)n H4-n；Wherein, the R2Group be selected from isopropyl, 2- butyl, tertiary butyl, 3- amyls, cyclobutyl, cyclopenta,
One or both of cyclohexyl, 1- phenethyls, benzhydryl, glucosyl group and fructosyl, n=1,2,3；
(2) compound 1 with triethylamine hydrofluoride heats and the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) is obtained by the reaction in a solvent
Phenyl] -2- (R1- amino) -1- propyl alcohol；
(3) the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol takes off blocking group in a solvent
R1Obtain the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol；
(4) fluorobenzene is obtained by the reaction through dichloroacetyl in the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol
Buddhist nun examines.
2. the synthetic method of Florfenicol according to claim 1, which is characterized in that in step (2), the compound
1 with the molar ratio of triethylamine hydrofluoride is 1:1.2-10, reaction temperature are 50-120 DEG C；
The structural formula of the triethylamine hydrofluoride is Et3N.xHF, x 3-10；
The solvent is selected from dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, dioxane, chlorobenzene, toluene, two
Toluene, ether, methyl tertiary butyl ether(MTBE), isopropyl ether, dichloroether, N-Methyl pyrrolidone, N,N-dimethylformamide and diformazan
Base sulfoxide；
The solvent and the mass ratio of compound 1 are 3-15:1.
3. the synthetic method of Florfenicol according to claim 1, which is characterized in that the step (3) is urged using Pd/C
Change hydrogenation method, including：
The fluoro- 1- of (1R, the 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol is dissolved in solvent, add Pd/C
Catalyst, hydrogenation reaction obtain the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- propyl alcohol.
4. the synthetic method of Florfenicol according to claim 3, which is characterized in that the fluoro- 1- of (1R, the 2S) -3-
[4- (methylsulfonyl) phenyl] -2- (R1- amino) mass ratio of -1- propyl alcohol and Pd/C catalyst is 1:0.02-0.1, hydrogenation are anti-
The pressure answered is 1-10atm, and temperature is 20-50 DEG C；
The mass percentage of Pd is 5%-10% in the Pd/C catalyst；
The solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran and acetic acid.
5. the synthetic method of Florfenicol according to claim 1, which is characterized in that the step (3) uses chlorination water
Solution, including：
(a) by the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol is dissolved in solvent, add in chlorine
Change reagent, the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R are obtained by the reaction1- chloro amino) -1- propyl alcohol；
(b) by the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- chloro amino) -1- propyl alcohol is dissolved in solvent, adds
Generation elimination reaction obtains the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- after entering alkali
Propyl alcohol；
(c) the fluoro- 1- of (1R, 2S) -3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol is dissolved in solvent
In, generation imines hydrolysis obtains the fluoro- 1- of (1R, 2S) -2- amino -3- [4- (methylsulfonyl) phenyl] -1- third after adding in acid
Alcohol.
6. the synthetic method of Florfenicol according to claim 5, which is characterized in that in step (a),
The fluoro- 1- of (1R, the 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- amino) -1- propyl alcohol and chlorination reagent molar ratio
For 1:0.4-2, reaction temperature are 10-50 DEG C；
The solvent is selected from dichloromethane, chloroform and 1,2- dichloroethanes；
The chlorination reagent is selected from chlorosuccinimide, sym-closene and chlorine.
7. the synthetic method of Florfenicol according to claim 5, which is characterized in that in step (b),
The fluoro- 1- of (1R, the 2S) -3- [4- (methylsulfonyl) phenyl] -2- (R1- chloro amino) molar ratio of -1- propyl alcohol and alkali is
1:1-3, reaction temperature are 20-50 DEG C；
The solvent is selected from methanol, ethyl alcohol, isopropanol, dichloromethane, chloroform, 1,2- dichloroethanes, dioxane and tetrahydrochysene furan
It mutters；
The alkali is selected from potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus, triethylamine, diisopropylethylamine and pyridine.
8. the synthetic method of Florfenicol according to claim 5, which is characterized in that in step (c),
Mole of the fluoro- 1- of (1R, the 2S) -3- [4- (methylsulfonyl) phenyl] -2- (1- phenylethylenes amino) -1- propyl alcohol and acid
Than for 1:1-5, reaction temperature are 20-50 DEG C；
The solvent is selected from methanol, ethyl alcohol, isopropanol, dichloromethane, chloroform, 1,2- dichloroethanes, dioxane and tetrahydrochysene furan
It mutters；
It is described acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, monoxone, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid and
P-methyl benzenesulfonic acid.
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| CN111500652B (en) * | 2019-01-30 | 2024-03-26 | 苏州引航生物科技有限公司 | Method for preparing florfenicol |
| 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 |
| CN114163365B (en) * | 2021-11-17 | 2022-09-02 | 中国农业大学 | Florfenicol, florfenicol amine hapten and artificial antigen as well as preparation method and application thereof |
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| 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 |
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| 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 |
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