CN102491953A - Method for synthesizing florfenicol midbody RT0131 - Google Patents
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Abstract
The invention provides a method for synthesizing a florfenicol midbody RT0131, which comprises the following steps of: dissolving RT0130 into an aprotic polar solvent and leading RT0130 to generate fluorination reaction under XtalFluor-E and base catalysis so as to generate the florfenicol midbody RT0131. On the other hand, the invention provides a method for generating thiamphenicol into the florfenicol midbody RT0131 through hydrolysis, condensation and fluorination reaction. The method has the advantages of convenience in operation, less by-products, easiness for purification of products and good environmentally-friendly effect.
Description
Technical field
The present invention relates to the synthetic field of a kind of compound, the concrete method that relates to a kind of synthetic florfenicol midbody.
Background technology
Since nineteen fifty-seven, the research of fluorine-containing medicine constantly makes progress, and at present, 150 kinds of fluorine-containing medicines listings has been arranged in the world, accounts for 20% of medicine sum, and fluoro-containing pesticide even up to 30%.The researchist has more and more profoundly recognized the introducing in organic molecule of fluorine atom or fluoro-containing group; Possibly bring the delicate variation on the biological activity to organic molecule; China has carried out the research and development of organic fluorine midbody fine chemicals, over nearly 20 years in succession from the seventies in 20th century; China has stepped into flourish period having obtained significant achievement aspect the development of fluoro-containing intermediate especially.
Florfenicol (Florfenicol) claim Florfenicol again; Chlorine sulfone Buddhist nun can; Be that Ling-Bao Ya (Schering-Plough) company of U.S. elder generation is to seek the medicine that better chloromycetin verivate is developed in the seventies; Successively in many 20 country's listings such as Japan, Korea S, Norway, France, the demand of mainly supplying animal health market has had mass production in China at present.Florfenicol had passed through the U.S. FDA registration in 1996, become replace paraxin and thiamphenicol of new generation feeding microbiotic.Florfenicol is a kind of broad-spectrum antibiotics; Have the characteristics such as wide, safe and efficient that distribute in the has a broad antifungal spectrum, good absorption, body; It is the choice drug of the bacillary Animal diseases that cause such as treatment Corynebacterium diphtheriae, paratyphosum Bacterium, Salmonellas; Anti-microbial activity is superior to paraxin and thiamphenicol (low 10 times approximately of minimum inhibition concentration MIC), and the big enterobacteria of anti-paraxin and thiamphenicol, streptococcus aureus, Cray primary formula bacterium etc. are also had positive effect.
In florfenicol synthetic, a committed step is a fluoridation, uses the fluorine atom substituted hydroxy; General fluorination reagent commonly used is DAST or Deoxo-Fluor, but such fluorination reagent is unstable, under not really high temperature, just decomposes easily; Produce volatile material; And these fluorination reagents in use also generate the hydrofluoric acid of severe corrosive, container are required high, make troubles to operation.In the florfenicol synthesis technique that spirit formerly-Schering-Plough announces; They have adopted the Ishikawa fluorination reagent; Nineteen ninety-five, Clark has applied for the patent of synthetic florfenicol, has adopted two chloromethyl cyanides to promote the configuration conversion of florfenicol midbody in its building-up process; Use Ishikawa reagent to make it to fluoridize, make it acetylize and obtain florfenicol with potassium acetate at last.Yet, use Ishikawa reagent also to have deficiency, mainly be that reagent costs an arm and a leg, in reaction, need high-temperature and high-pressure conditions just can carry out fluoridation.
At present synthetic florfenicol midbody, the subject matter of existence are that the by product of synthetic florfenicol midbody is more, and not easily separated, and the finished product pick-up rate is lower; Perhaps container and reaction conditions are required height, make troubles to operation.
Therefore, it is few that this area presses for the design by product, can reduce three waste discharge, easy to operate, the method for the synthetic florfenicol midbody of easy purification of products.
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of synthetic florfenicol midbody newly, thus three waste discharge reduced, reduce by product, be easy to purifying.
First aspect present invention provides the method for a kind of synthetic florfenicol midbody RT0131, it is characterized in that, may further comprise the steps:
With RT0130; Its chemical molecular formula is dissolved in the aprotic polar solvent for
(formula I); Under XtalFluor-E and base catalysis; Fluoridation takes place in RT0130; Generate florfenicol midbody RT0131, its chemical molecular formula is
(formula II).
Above-mentioned alkali is organic bases or mineral alkali.
Above-mentioned organic bases is pyridine, quinoline, tertiary amine or ring amidine compound; Above-mentioned mineral alkali is yellow soda ash, salt of wormwood, Pottasium Hydroxide, sodium ethylate or potassium tert.-butoxide.
The temperature of reaction of above-mentioned fluoridation is-100 a ℃-room temperature, and the reaction times is 8-48 hour.
Above-mentioned XtalFluor-E and alkali add under protection of inert gas, and said rare gas element is helium, argon gas, nitrogen, other non-reactive gas or its combination.
Above-mentioned aprotic polar solvent is methyl-sulphoxide, N, dinethylformamide, acetone, DMSO 99.8MIN., HMPA, methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether.Preferably, said aprotic polar solvent is a methylene dichloride.
The reaction times of above-mentioned fluoridation is 12-36 hour.
Above-mentioned alkali is DBU.
In the above-mentioned steps, the mol ratio of RT0130: DBU: XtalFluor-E=1: 1-3: 1-3.Preferably, the mol ratio of above-mentioned RT0130: DBU: XtalFluor-E=1: 1.5: 1.5.
The mol ratio of above-mentioned RT0130: alkali: XtalFluor-E=1: 1-3: 1-3.Preferably, said RT0130: the mol ratio of alkali: XtalFluor-E=1: 1.5-2.95: 1.5-2.95.
Second aspect of the present invention provides the method for a kind of synthetic florfenicol midbody RT0131, it is characterized in that, may further comprise the steps:
(a) with the thiamphenicol hydrolysis; Obtain compound R T0130-SM, its chemical formula is
(formula III);
(b) compound R T0130-SM is dissolved in the protonic solvent, in the presence of highly basic, adds RCN, wherein, R is aryl and substituted aryl, C
1-C
6Alkyl and substituted alkyl, benzyl or substituted benzyl; Condensation reaction takes place in RT0130-SM, generates RT0130;
(c) RT0130 is dissolved in the aprotic polar solvent, under XtalFluor-E and base catalysis, fluoridation takes place in RT0130, generates florfenicol midbody RT0131.
In the above-mentioned steps (a), thiamphenicol is in strong alkali aqueous solution, and solubility promoter ethanol exists down, is heated to 85-130 ℃, and the thiamphenicol hydrolysis obtains RT0130-SM through extraction.
In the above-mentioned steps (a), highly basic is sodium hydroxide, Pottasium Hydroxide, potassium tert.-butoxide, sodium ethylate, potassium ethylate, potassium tert.-butoxide or its combination.
In the above-mentioned steps (b), said protonic solvent is USP Kosher, methyl alcohol, ethanol or Virahol; Said RT0130-SM: RCN: alkaline mol ratio=1: 1-3: 1-2.
R is a phenyl in the above-mentioned steps (b).
Highly basic is salt of wormwood, Pottasium Hydroxide or DBU in the above-mentioned steps (b).
In the above-mentioned steps (c), the mol ratio of RT0130: alkali: XtalFluor-E=1: 1-3: 1-3.
Aprotic polar solvent is methyl-sulphoxide, N in the above-mentioned steps (c), dinethylformamide, acetone, DMSO 99.8MIN., HMPA, methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether.Preferably, said aprotic polar solvent is a methylene dichloride.
Alkali is organic bases or mineral alkali in the above-mentioned steps (c); Said organic bases is pyridine, quinoline, tertiary amine or ring amidine compound; Said mineral alkali is yellow soda ash, salt of wormwood, Pottasium Hydroxide, sodium ethylate or potassium tert.-butoxide.
The temperature of reaction of above-mentioned fluoridation is-100 a ℃-room temperature, and the reaction times is 8-48 hour.
Above-mentioned XtalFluor-E and alkali add under protection of inert gas, and said rare gas element is helium, argon gas, nitrogen, other non-reactive gas or its combination.
Above-mentioned aprotic polar solvent is methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether.
The reaction times of above-mentioned fluoridation is 12-36 hour.
In the above-mentioned steps (c), alkali is DBU.
In the above-mentioned steps (c), the mol ratio of RT0130: alkali: XtalFluor-E=1: 1-3: 1-3.Preferably, the mol ratio of RT0130: alkali: XtalFluor-E is 1: 1.5-2.95: 1.5-2.95.
In the above-mentioned steps (c), the mol ratio of RT0130: DBU: XtalFluor-E=1: 1-3: 1-3.Preferably, the mol ratio of RT0130: DBU: XtalFluor-E=1: 1.5: 1.5.
Non-reactive gas is meant that performance is more stable, is difficult for the gas with other chemical substance generation chemical reactions.
The chemistry of DBU is called 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene, and molecular formula is shown in the lower left, and the lower right is the molecular formula of fluorination reagent XtalFluor-E:
Canada Ou Mige chemistry (Omegachem) company has developed one type of novel fluorination reagent, and name is called XtalFluor-E and XtalFluor-M.This type fluorination reagent is the crystal type solid, and is very stable, only just decomposes being higher than under 200 ℃ the temperature, and the heat that discharges during decomposition is less than other fluorination reagents of mentioning.Simultaneously, the fluoridation of XtalFluor does not produce the hydrofluoric acid of severe corrosive, and the condition of reaction is a normal temperature and pressure, and therefore, XtalFluor class reagent is the fluorination reagent of safety and environmental protection, and can reduce production costs greatly.The contriver proves that through a large amount of experiments XtalFluor-E is the fluorination reagent that is suitable for synthetic RT0131.
Aprotic polar solvent of the present invention is meant that said solvent has polarity but the solvent of proton can not be provided; For example methyl-sulphoxide, N, dinethylformamide, acetone, DMSO 99.8MIN. (DMSO), HMPA (HMPA), methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether etc.Preferred methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether.Most preferred, said aprotic polar solvent is a methylene dichloride.
To achieve these goals, the present invention adopts wide material sources, and cheap antibacterials thiamphenicol RT0130-A (formula III) is a raw material, successively through hydrolysis, condensation, reactions step such as fluoridize and prepare florfenicol midbody RT0131.In specific embodiment, at first, make RT0130-A and sodium hydroxide hydrolytic reactions under 60 ℃ of conditions, the amido linkage on the RT0130-A molecule is broken off, produce RT0130-SM; Secondly; Make RT0130-SM and Anhydrous potassium carbonate and cyanobenzene that condensation reaction take place under 115 ℃ of conditions and generate florfenicol midbody 1-RT0130, form benzene oxazolin ring, protection 2; Amino and hydroxyl on 3 carbon atoms, and the molecular configuration of stable florfenicol midbody; At last, use new fluorinating agent XtalFluor-E and RT0130 to carry out fluoridation, promote that the primary hydroxyl group in the RT0130 molecular structure is replaced by the F atom, generate florfenicol midbody 2-RT0131.
In above-mentioned reaction, for the charging capacity and the ingredient proportion of reactant, the present invention has carried out comprehensive research and improvement.Wherein, the first step reaction, preferred 1.00: 4.0 o'clock of the feed ratio (mol ratio) of RT0130-A and NaOH solution, basic hydrolysis is comparatively thorough; In second step, preferred 1.00: 1.85: 1.50 of the mol ratio of RT0130-SM and cyanobenzene and salt of wormwood when temperature of reaction is 115 ℃, can be accomplished condensation reaction well, makes amino and hydroxyl cyclisation on the 2nd and 3 carbon atom to receive benzyl protection; The 3rd step; Excellent 1.00: 1.50: 1.50 of the mol ratio of RT0130 and DBU (diazabicylo) and fluorination reagent XtalFluor-E; According to this mol ratio, the terminal free hydroxyl of RT0130 molecule can more fully be replaced by fluorine atom, thereby obtains the RT0131 of higher degree.
Synthesis technique effect of the present invention very significantly at first, has adopted the raw material thiamphenicol RT0130-A that obtains easily on the market to produce the florfenicol midbody, has greatly reduced production cost; Secondly, in the preparation process of florfenicol midbody, adopt the separating and purifying technology of optimizing, by product is less; Aftertreatment is simple; Transformation efficiency is high, and the recovery of synthetic product RT0131 reaches 95% (table one), for further synthetic florfenicol provides the fine midbody.
Description of drawings
The result that the purity of each midbody in the synthetic florfenicol midbody RT0131 process is identified respectively through mass spectrum (MS) and nucleus magnetic resonance (NMR) technology is shown in the following figure.
The mass spectrum of Fig. 1, RT0130 (MS spectrogram)
The theoretical molecular of RT0130 is 331.39, after protonated, is with [a H
+] the molecular weight of RT0130 be 332.39, matter/lotus is 332 than m/z, and is very high by the relative concentration of visible this spectral line molion of MS spectrogram.
m/z：332.0(M+1)
+，354.0(M+23)
+
Fig. 2., the hydrogen nuclear magnetic resonance spectrogram of RT0130 (
1H NMR spectrogram)
1H?NMR(300MHz，CDCl
3)：δ3.06(s，
3H，Me)，3.85-3.90(dd，
1H)，4.02-4.08(m，
1H)?4.22-4.33(m，
2H)，5.63-5.65(d，
1H)，7.43-7.59(m，
5H)，7.95-8.04(m，
4H).
Fig. 3., the hydrogen nuclear magnetic resonance spectrogram (1H NMR spectrogram) of RT0131
1H?NMR(300MHz，CDCl
3)：δ3.06(s，
3H，Me)，4.36-4.87(m，
3H)，5.66-5.69(d，
1H)，7.44-7.59(m，
5H)，7.66-8.06(dd，
4H).
Embodiment
Below in conjunction with embodiment the present invention is further explained.
The present invention provides the method for a kind of synthetic florfenicol midbody RT0131, and said method is for to be dissolved in RT0130 in the aprotic solvent, and under XtalFluor-E and base catalysis, fluoridation takes place RT0130, generates florfenicol midbody RT0131.
Reaction formula C is as follows:
Ingredient proportion (mol ratio)
RT0130: alkali: XtalFluor-E reagent=1: 1-3: 1-3
Solvent: aprotic polar solvent
Said aprotic polar solvent is methyl-sulphoxide, N, dinethylformamide, acetone, DMSO 99.8MIN., HMPA, methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether etc.Preferred methylene dichloride.
Said alkali is organic bases or mineral alkali.Said organic bases is pyridine, quinoline, tertiary amine or ring amidine compound etc.; Said mineral alkali is yellow soda ash, salt of wormwood, Pottasium Hydroxide, sodium ethylate or potassium tert.-butoxide etc.Preferably, said alkali DBU.
In specific embodiment, said RT0130: alkali: the mol ratio of XtalFluor-E reagent is 1: 1.5-2.95: 1.5-2.95.Preferably, RT0130: DBU: the mol ratio of XtalFluor-E reagent=1: 1.5: 1.5.
Second aspect of the present invention provides a kind of method from the synthetic florfenicol midbody RT0131 of RT0130-A, may further comprise the steps:
(a), obtain compound R T-0130-SM with thiamphenicol (RT0130-A) hydrolysis;
(b) compound R T0130-SM is dissolved in the protonic solvent, in the presence of highly basic, adds nitrile compounds RCN, wherein, R is aryl and substituted aryl, C
1-C
6Alkyl and substituted alkyl, benzyl or substituted benzyl; Condensation reaction takes place in RT0130-SM, generates RT0130;
(c) RT0130 is dissolved in the organic solvent, under XtalFluor-E and base catalysis, fluoridation takes place in RT0130, generates florfenicol midbody RT0131.
In step (a), thiamphenicol (RT0130-A) is in strong alkali aqueous solution, and solubility promoter ethanol exists down, is heated to 85-130 ℃, and the thiamphenicol hydrolysis obtains RT0130-SM through extraction.
A is following for step (a) reaction formula:
Ingredient proportion (mol ratio):
RT0130-A: highly basic=1: 3-6
Solubility promoter: ethanol
Said highly basic is NaOH, KOH, sodium ethylate, potassium ethylate, potassium tert.-butoxide or its combination.
Preferably, RT0130-A: highly basic=1: 4; The preferred NaOH of highly basic.
B is following for step (b) reaction formula:
Ingredient proportion (mol ratio):
RT0130-SM: RCN: highly basic=1: 1-3: 1-2
Solvent: protonic solvent.
Said protonic solvent is USP Kosher, methyl alcohol, ethanol or Virahol etc.Preferred USP Kosher.
Said alkali is salt of wormwood, Pottasium Hydroxide or DBU etc.
Preferably, said R is a phenyl, and promptly RCN is a cyanobenzene.
Preferably, RT0130-SM: RCN: alkaline mol ratio=1: 1.5-2: 1-2
Preferred, RT0130-SM: RCN: alkaline mol ratio=1: 1.85: 1.50
Step (c) shown in previous reaction formula C, concrete steps, reagent is not done here and is given unnecessary details with the above yet.
Embodiment 1:RT0130-A goes amidation to generate RT0130-SM through basic hydrolysis
50.0 gram (0.14 mole) solid RT0130-A are added 373 milliliters of sodium hydroxide solution (1.5 mol; 0.56 mole), 60 ℃ were stirred 2.5 hours fast, are cooled to room temperature; Add 500 milliliters of extractions of MTBE; Tell organic phase, concentrate, vacuum-drying obtains the RT0130-SM of white solid.
Ingredient proportion (mol ratio):
RT0130-A∶NaOH＝1∶4
Solvent: ethanol
Reaction formula is following:
Embodiment 2:RT0130-SM and benzyl cyanide reaction condensation generate RT0130
24.5 gram (0.10 mole) RT0130-SM, 20.7 gram (0.15 mole) Anhydrous potassium carbonates are dissolved in 46 milliliters of USP Kosher, stir and be heated to 115 ℃, 19.0 gram cyanobenzenes (PhCN) are splashed into above-mentioned white suspension solution in half a hour; Insulation was also stirred 18 hours fast; TCL detects to reaction and accomplishes, and is cooled to room temperature, and 400 milliliters of dilutions of adding frozen water also stir; Insulation is 1 hour under 4～10 ℃ of conditions; Filter, frozen water washing, vacuum-drying obtain 31.5 gram (0.095 mole) RT0130 white solids.
Ingredient proportion (mol ratio)
RT0130-SM: cyanobenzene: salt of wormwood=1.00: 1.85: 1.50
Protonic solvent: USP Kosher
Reaction formula is following:
Embodiment 3:RT0130 is fluoridized generation RT0131 by XtalFluor-E
31.5 gram (0.095 mole) solid RT0130 are dissolved in 315 milliliters of exsiccant dioxs.Under nitrogen protection, slowly add salt of wormwood (0.28 mole) and solid XtalFluor-E (0.28 mole) reagent; After stirring; Slowly be raised to stirring at room reaction 24 hours, TLC (Thin Layer Chromatography, thin plate chromatography chromatogram) detects to the reaction completion.Reaction liquid is slowly poured in the ice-cold potassium bicarbonate aqueous solution (0.1 mol), organic phase is separated, 5% decolorizing with activated carbon, drying, concentrate 28.5 gram (0.090 mole) RT0131 light tan solids.
Ingredient proportion (mol ratio)
RT0130: K
2CO
3: XtalFluor-E reagent=1.00: 2.95: 2.95
Solvent: diox
Embodiment 4:RT0130 is fluoridized generation RT-0131 by XtalFluor-E
31.5 gram (0.095 mole) solid RT0130 are dissolved in 315 milliliters of exsiccant methylene dichloride.The liquid D BU (0.142 mole) and solid XtalFluor-E (0.142 mole) reagent that under nitrogen protection, slowly add 21.2 milliliters after stirring, slowly are raised to stirring at room reaction 24 hours, and TLC detects extremely reaction and accomplishes.Reaction liquid is slowly poured in the ice-cold sodium bicarbonate aqueous solution (0.1 mol), organic phase is separated, 5% decolorizing with activated carbon, drying, concentrate 30.0 gram (0.095 mole) RT0131 light tan solids.
Ingredient proportion (mol ratio)
RT0130: DBU: XtalFluor-E reagent=1.00: 1.50: 1.50
Solvent: methylene dichloride
Reaction formula is following:
Conclusion
Visible by table one, in the building-up process of florfenicol midbody RT0131, each step reaction all has the high recovery (95～99%), and experimental procedure is easy to operate, and by product is few, and product is easy to purifying, and is environmentally friendly.
| Compound | Product appearance | Solvent | Fusing point (℃) | The recovery (%) |
| RT0130-A | / | Ethanol and water | ND | / |
| RT0130-SM | White solid | USP Kosher | ND | 99 |
| RT0130 | White solid | Methylene dichloride | 206-209 | 95 |
| RT0131 (embodiment 3) | The light tan solid | / | 117-119 | 95 |
| RT0131 (embodiment 4) | The light tan solid | / | 117-119 | 95 |
[0116]Table one. the physicochemical property of each midbody that is obtained in the florfenicol midbody RT0131 building-up process
ND: undetermined
According to embodiments of the invention describing the present invention property and nonrestrictive description, but should be understood that and do not breaking away under the situation of the relevant protection domain that limits claim that those skilled in the art can make various changes and/or modification.
Claims (21)
1. the method for a synthetic florfenicol midbody RT0131 is characterized in that, may further comprise the steps:
With RT0130; Its chemical molecular formula is dissolved in the aprotic polar solvent for
(formula I); Under XtalFluor-E and base catalysis; Fluoridation takes place in RT0130; Generate florfenicol midbody RT0131, its chemical molecular formula is
(formula II).
2. synthesize the method for florfenicol midbody RT0131 according to claim 1, it is characterized in that said alkali is organic bases or mineral alkali.
3. like the method for the said synthetic florfenicol midbody RT0131 of claim 2, it is characterized in that said organic bases is pyridine, quinoline, tertiary amine or ring amidine compound; Said mineral alkali is yellow soda ash, salt of wormwood, Pottasium Hydroxide, sodium ethylate or potassium tert.-butoxide.
4. synthesize the method for florfenicol midbody RT0131 according to claim 1, it is characterized in that the temperature of reaction of said fluoridation is-100 a ℃-room temperature, the reaction times is 8-48 hour.
5. synthesize the method for florfenicol midbody RT0131 according to claim 1, it is characterized in that said XtalFluor-E and alkali add under protection of inert gas, said rare gas element is helium, argon gas, nitrogen, other non-reactive gas or its combination.
6. like the method for the said synthetic florfenicol midbody RT0131 of the arbitrary claim of claim 1-5; It is characterized in that; Said aprotic polar solvent is methyl-sulphoxide, N, dinethylformamide, acetone, DMSO 99.8MIN., HMPA, methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether.
7. like the method for the said synthetic florfenicol midbody RT0131 of claim 6, it is characterized in that the reaction times of said fluoridation is 12-36 hour.
8. like the method for the said synthetic florfenicol midbody RT0131 of claim 6, it is characterized in that said aprotic polar solvent is a methylene dichloride.
9. like the method for claim 1-5, the said synthetic florfenicol midbody RT0131 of 7 or 8 arbitrary claims, it is characterized in that said alkali is DBU.
10. like the method for the said synthetic florfenicol midbody RT0131 of claim 9, it is characterized in that the mol ratio of said RT0130: DBU: XtalFluor-E=1: 1.5: 1.5.
11. the method like claim 1-5, the said synthetic florfenicol midbody RT0131 of 7 or 8 arbitrary claims is characterized in that the mol ratio of said RT0130: alkali: XtalFluor-E=1: 1-3: 1-3.
12. the method like the said synthetic florfenicol midbody RT0131 of claim 11 is characterized in that, the mol ratio of said RT0130: alkali: XtalFluor-E=1: 1.5-2.95: 1.5-2.95.
13. the method for a synthetic florfenicol midbody RT0131 is characterized in that, may further comprise the steps:
(a) with the thiamphenicol hydrolysis; Obtain compound R T0130-SM, its chemical formula is
(formula III);
(b) compound R T0130-SM is dissolved in the protonic solvent, in the presence of highly basic, adds RCN, condensation reaction takes place in RT0130-SM, generation RT0130, and wherein, R is aryl and substituted aryl, C
1-C
6Alkyl and substituted alkyl, benzyl or substituted benzyl;
(c) RT0130 is dissolved in the aprotic polar solvent, under XtalFluor-E and base catalysis, fluoridation takes place in RT0130, generates florfenicol midbody RT0131.
14. the method like the said synthetic florfenicol midbody RT0131 of claim 13 is characterized in that, in the said step (a); Thiamphenicol is in strong alkali aqueous solution, and solubility promoter ethanol exists down, is heated to 85-130 ℃; The thiamphenicol hydrolysis obtains RT0130-SM through extraction.
15. the method like the said synthetic florfenicol midbody RT0131 of claim 14 is characterized in that, said highly basic is sodium hydroxide, Pottasium Hydroxide, potassium tert.-butoxide, sodium ethylate, potassium ethylate, potassium tert.-butoxide or its combination.
16. the method like the said synthetic florfenicol midbody RT0131 of the arbitrary claim of claim 13-15 is characterized in that, in the said step (b), said protonic solvent is USP Kosher, methyl alcohol, ethanol or Virahol; Said RT0130-SM: RCN: alkaline mol ratio=1: 1-3: 1-2.
17. the method like the said synthetic florfenicol midbody RT0131 of claim 16 is characterized in that, R is a phenyl in the said step (b).
18. the method like claim 13-15 or the said synthetic florfenicol midbody RT0131 of 17 arbitrary claims is characterized in that, highly basic is salt of wormwood, Pottasium Hydroxide or DBU in the said step (b).
19. the method like the said synthetic florfenicol midbody RT0131 of the arbitrary claim of claim 13-15 is characterized in that, in the said step (c), and the mol ratio of RT0130: alkali: XtalFluor-E=1: 1-3: 1-3.
20. the method like the said synthetic florfenicol midbody RT0131 of claim 19 is characterized in that, aprotic polar solvent is methylene dichloride, THF, ether 、 diox, chloroform or diethylene glycol dimethyl ether in the said step (c).
21. the method like the said synthetic florfenicol midbody RT0131 of claim 19 is characterized in that, alkali is organic bases or mineral alkali in the said step (c); Said organic bases is pyridine, quinoline, tertiary amine or ring amidine compound; Said mineral alkali is yellow soda ash, salt of wormwood, Pottasium Hydroxide, sodium ethylate or potassium tert.-butoxide.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
| CN106631872A (en) * | 2016-12-13 | 2017-05-10 | 浙江普洛家园药业有限公司 | Synthesis method of florfenicol analogue intermediate |
| CN110229087A (en) * | 2019-07-02 | 2019-09-13 | 绍兴民生医药股份有限公司 | The purification process of (1R, 2R) -1- [(4- mesyl) phenyl] -2- amino -1,3- propylene glycol |
| CN110330463A (en) * | 2019-08-02 | 2019-10-15 | 山东国邦药业股份有限公司 | A kind of preparation method of florfenicol midbody |
| CN116574040A (en) * | 2023-05-16 | 2023-08-11 | 浙江知行药业有限公司 | Preparation method for efficiently recycling thiamphenicol amine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936638A (en) * | 2014-04-16 | 2014-07-23 | 湖北美天生物科技有限公司 | Synthetic method of florfenicol |
| CN103936638B (en) * | 2014-04-16 | 2015-12-02 | 湖北美天生物科技有限公司 | The synthetic method of florfenicol |
| CN106631872A (en) * | 2016-12-13 | 2017-05-10 | 浙江普洛家园药业有限公司 | Synthesis method of florfenicol analogue intermediate |
| CN110229087A (en) * | 2019-07-02 | 2019-09-13 | 绍兴民生医药股份有限公司 | The purification process of (1R, 2R) -1- [(4- mesyl) phenyl] -2- amino -1,3- propylene glycol |
| CN110229087B (en) * | 2019-07-02 | 2020-11-24 | 绍兴民生医药股份有限公司 | Purification method of (1R,2R) -1- [ (4-methylsulfonyl) phenyl ] -2-amino-1, 3-propanediol |
| CN110330463A (en) * | 2019-08-02 | 2019-10-15 | 山东国邦药业股份有限公司 | A kind of preparation method of florfenicol midbody |
| CN110330463B (en) * | 2019-08-02 | 2021-05-14 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN116574040A (en) * | 2023-05-16 | 2023-08-11 | 浙江知行药业有限公司 | Preparation method for efficiently recycling thiamphenicol amine |
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