CN107011220A - Thiamphenicol tetrafluoro propionic ester and its preparation method and application - Google Patents
Thiamphenicol tetrafluoro propionic ester and its preparation method and application Download PDFInfo
- Publication number
- CN107011220A CN107011220A CN201710262304.9A CN201710262304A CN107011220A CN 107011220 A CN107011220 A CN 107011220A CN 201710262304 A CN201710262304 A CN 201710262304A CN 107011220 A CN107011220 A CN 107011220A
- Authority
- CN
- China
- Prior art keywords
- thiamphenicol
- propionic ester
- water
- tetrafluoro propionic
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Electrochemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of Thiamphenicol tetrafluoro propionic ester and its preparation method and application, specify that Thiamphenicol tetrafluoro propionic ester is unknown impuritie contained by Florfenicol, and its preparation method is：By (4R, 5R) 2 dichloromethyl 4, (4 methylsulfonyl phenyl) the 4 oxazole methanol of 5 dihydro 5 and N, N diethyl 1,1,2,3,3,3 hexafluoro propylamine carry out reacting [(4R, 5R) dihydro 5 of 2 dichloromethyl 4,5 (base of 4 methylsulfonyl phenyl) oxazoles 4] methanol 2,3,3, after 3 tetrafluoro propionic esters, obtained through hydrolysis, the product of synthesis and separating obtained impurity have identical mass spectrum and1H H NMR spectroscopies.The Thiamphenicol tetrafluoro propionic ester synthesis technique that the present invention is designed has the advantages that raw material is easy to get, reaction condition is gentle, course of reaction is easily controlled, and provides satisfactory reference substance for Florfenicol quality control, can greatly improve drug safety.
Description
Technical field
The invention belongs to medicine and Pharmaceutical Analysis technical field, concretely relate to unknown miscellaneous in a kind of Florfenicol
Matter Thiamphenicol tetrafluoro propionic ester and its preparation method and application.
Background technology
Florfenicol has broad spectrum antibiotic activity, available for the treatment gram-positive bacteria of animal, Gram-negative bacteria and
Infected caused by Richettsia etc., and have the drug tolerant bacteria of Thiamphenicol, chloramphenicol compared with high inhibition effect, it is residual in vivo
Stay relatively low, be widely used.Its main production flow is as follows：
I.e. thiamphenicol amine (I) and two chloroacetonitriles carry out cyclic condensation and obtain cyclocomplex (II), with N, N- diethyl -1,1, and 2,3,
3,3- hexafluoro propylamine to cyclocomplex (II) be fluorinated obtaining fluoride (III), and fluoride (III) hydrolyzes to obtain product fluorobenzene Buddhist nun
Examine.
According to《Republic of China Veterinary Pharmacopoeia》During (version in 2010) relevant using HPLC methods analysis Florfenicol material,
The chromatogram record time is 2.5 times of main peak retention time, and《Republic of China Veterinary Pharmacopoeia》(version in 2015) is then by chromatogram
Time lengthening is recorded to 5 times of main peak retention time, keeps other conditions identical with version veterinary drug allusion quotation in 2010.Chromatogram records the time
After extension, occur a larger unknown impuritie at relative retention time RRT3.1, then can not according to version veterinary drug allusion quotation detection in 2010
Detect the impurity.
Florfenicol is had wide range of applications, and consumption is big, therefore its impurities is studied and is controlled by detail,
Drug safety will be greatly improved.During for relative reservation emerging using version Chinese veterinary pharmacopoeia analysis Florfenicol in 2015
Between RRT3.1 unknown impurities, the relevant information such as the structure and preparation without the impurity such as various countries' veterinary drug allusion quotation and document, patent.
The content of the invention
In order to better control over the quality of Florfenicol, the present invention to the unknown impuritie in Florfenicol by having carried out point
From, there is provided a kind of Thiamphenicol tetrafluoro propionic ester and its preparation method and application for structural identification.
The present invention is adopted the following technical scheme that：
Thiamphenicol tetrafluoro propionic ester of the structural formula as shown in (IV)：
The structure of Thiamphenicol tetrafluoro propionic ester of the structure above as shown in (IV) judges to obtain by following methods：
The Florfenicol sample powder containing relative retention time RRT3.1 unknown impurities is taken to be well mixed with silica gel, with stone
Oily ether-ethyl acetate-ammoniacal liquor is eluent, and post separation is crossed with silica gel column chromatography, collects the eluent containing target unknown impuritie.
Above-mentioned eluent, its appearance time and detection Florfenicol sample are detected with HPLC methods in 2015 editions Chinese veterinary pharmacopoeias
When unknown impuritie appearance time coincide, illustrate the eluent contained substance collected for target impurity.
Post enrichment is crossed through multiple, merges the eluent containing target impurity, be concentrated under reduced pressure removal solvent, leftover materials decompression is dry
It is dry, obtain off-white powder.
Gained solid methanol is dissolved, mass spectral analysis is carried out using Esquire-LC type Electrospray ion trap mass spectrometries instrument.
It is typically detected in the positive-ion mode [M+H]+、[M+Na]+、[M+K]+Plasma peak, sample is detected in the positive-ion mode
To the plasma peak of m/z=483.9,506.2,522.1 meet the rule, illustrate the impurity molecular mass be 483.
Sample is dissolved in DMSO-d6, then carry out1H-NMR、13C-NMR, DEPT-135 °, hydrocarbon related (HMQC) and hydrogen
Hydrogen correlation (H-H Cosy) analysis.
1In H-NMR collection of illustrative plates, in addition to solvent is not deuterated with water proton, 10 group of 15 proton signal is observed altogether, wherein
5 chemical shift of proton refer in aromatic hydrocarbons or unsaturated proton region, the chemical displacement value of remaining 10 proton between 3~6.5ppm
Show there is the group or atom of deshielding effect big (electronegativity is big) near 10 proton.
1313 groups of carbon signals (disregarding solvent carbon signal) are observed in C-NMR collection of illustrative plates, wherein aromatic hydrocarbons region there are two groups of intensity
Big carbon signal.Hydrocarbon Correlated Spectroscopy shows that intensity big carbon signal in two groups of region of aromatic hydrocarbons is respectively related to two protons, while DEPT-
It is not 2 ° of carbon that 135 ° of spectrums, which indicate two carbon, so two groups of carbon signals are contributed by two fragrant methine carbons of equal value, therefore this is miscellaneous
Matter molecule is made up of 15 carbon.
With reference to the preparation technology of Florfenicol, according to the ESI of impurity+-MS、1H-NMR、13C-NMR, DEPT-135 ° of collection of illustrative plates,
Hydrocarbon related collection of illustrative plates (HMQC), the related collection of illustrative plates (H-H Cosy) of hydrogen hydrogen, thus it is speculated that the impurity is Thiamphenicol tetrafluoro propionic ester (IV),
I.e. 2,3,3,3- tetrafluoro propionic acid-[(2S, 3R) -2- dichloro acetamino -3- hydroxyls -3- (4- methylsulfonyls phenyl)]-propyl ester, its point
Minor is C15H15Cl2F4NO5S, accurate molecular masses are 482.99, and structural formula is as follows：
Present invention also offers a kind of preparation method of Thiamphenicol tetrafluoro propionic ester (IV), comprise the following steps：
(1) by (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazoles methanol (II) and N,
N- diethyl -1,1,2,3,3,3- hexafluoro propylamine are reacted, obtain compound [(4R, 5R) -2- dichloromethyls -4,5- dihydro -
5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters, its structural formula is such as shown in (V)：
(2) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,
3- tetrafluoros propionic ester (V) hydrolysis obtain Thiamphenicol tetrafluoro propionic ester (IV).
Preferably, in step (1), reaction solvent used is dichloromethane, chloroform, carbon tetrachloride, 1,2- bis-
One kind in chloroethanes, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, benzene, reaction temperature is -15~70 DEG C, during reaction
Between be 3~24 hours.
Preferably, in step (1), reaction solvent used is dichloromethane, chloroform, tetrahydrofuran, methyl- tert
One kind in butyl ether, ether, toluene, reaction temperature is -5~40 DEG C, and the reaction time is 5~12 hours.
Preferably, in step (2), hydrolysis solvent be water, alcohol-water, methanol-water, isopropanol-water, n-butanol-
One kind in water, acetonitrile-water, tetrahydrofuran-water, reaction temperature is 5~80 DEG C, and the reaction time is 1~8 hour.
Preferably, in step (2), hydrolysis solvent is water, alcohol-water, isopropanol-water, acetonitrile-water, tetrahydrochysene furan
Mutter-water in one kind, reaction temperature be 15~50 DEG C, the reaction time be 2~5 hours.
Preferably, the preparation method of Thiamphenicol tetrafluoro propionic ester, specifically includes following steps：
(1) 16.9g (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- Evil are put into reaction bulb
Azoles methanol and 200g dichloromethane, are cooled to -5 DEG C, and 15g N, N- diethyl -1,1,2,3,3,3- hexafluoros third are then slowly added dropwise
Control material temperature is less than 10 DEG C during amine, dropwise addition, adds after 5~10 DEG C of stirring reactions 8 hours；Reaction terminates, decompression
Dichloromethane is distilled off, grease original in 100ml cold water, stirring, system is then added into residue and is gradually solidified,
Filtering, and washed with cold water；Gained wet product 50g methanol dissolves, and is down to -5~0 DEG C of stirred crystallization, filtration drying, obtain [(4R,
5R) -2- dichloromethyls -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters；
(2) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl benzene obtained above is added in reaction bulb
Base) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic ester 15g add 100g water and 30g ethanol, in 40 DEG C of stirring reactions 3
Hour；0 DEG C of crystallization is cooled to, wet product is filtered to obtain；Gained wet product is recrystallized with 80ml alcohol-waters, vacuum drying, obtains Thiamphenicol
Tetrafluoro propionic ester.
The present invention is separated with column chromatography to the unknown impuritie in Florfenicol, according to the MS- of separated impurity
ESI+、1H-NMR、13C-NMR, DEPT-135 ° of collection of illustrative plates, hydrocarbon related collection of illustrative plates (HMQC), the related collection of illustrative plates (H-H Cosy) of hydrogen hydrogen, sentence
The fixed impurity be 2,3,3,3- tetrafluoros propionic acid-[(2S, 3R) -2- dichloro acetamino -3- hydroxyls -3- (4- methylsulfonyls phenyl)] -
Propyl ester, i.e. Thiamphenicol tetrafluoro propionic ester (IV).
In order to verify the accuracy of structure, the structural information of unknown impuritie of the present invention in Florfenicol devises conjunction
Into route, and Thiamphenicol tetrafluoro propionic ester (IV) is successfully made.Product is through high-efficient liquid phase chromatogram technique analysis, its appearance time
It is consistent with unknown impuritie retention time in Florfenicol sample, through ESI+-MS、1H-NMR is analyzed, and confirmation products therefrom is fluorobenzene Buddhist nun
The unknown impuritie Thiamphenicol tetrafluoro propionic ester (IV) passed the examination.
Present invention also offers a kind of application of Thiamphenicol tetrafluoro propionic ester in Florfenicol quality control.In medicine
Among the process of research and development and quality control, the discovery of unknown impuritie and the quality research prepared often for the types of drugs have
The important function that can not be ignored, the impurity quantification that can be applied in Florfenicol production technology and quantitative analysis, so that
The quality standard of Florfenicol can be improved and improved, its drug safety can be greatly improved, is the safety use of Florfenicol
Medicine provides great importance.
The beneficial effects of the present invention are：
The present invention is separated to unknown impuritie in Florfenicol and by ESI+-MS、1H-NMR、13C-NMR、DEPT-
The information such as 135 ° of collection of illustrative plates, hydrocarbon related collection of illustrative plates (HMQC), the related collection of illustrative plates (H-H COSY) of hydrogen hydrogen, confirm unknown in Florfenicol
Impurity is Thiamphenicol tetrafluoro propionic ester (IV), the new impurity can be applied into detection Florfenicol raw material medicine or its preparation sample
The quality of product, improves Florfenicol raw material medicine or the quality standard of its preparation, can greatly improve drug safety.In addition, this
Invent design Thiamphenicol tetrafluoro propionic ester (IV) synthesis technique it is raw materials used be easy to get, reaction condition is gentle, course of reaction is held
Easy to control, product purity is high.
Brief description of the drawings
Fig. 1 is the MS-ESI that the embodiment of the present invention 2 separates impurity+Collection of illustrative plates；
Fig. 2 is the separation impurity of the embodiment of the present invention 21H-NMR collection of illustrative plates；
Fig. 3 is the separation impurity of the embodiment of the present invention 213C-NMR collection of illustrative plates；
Fig. 4 is the DEPT-135 ° of collection of illustrative plates that the embodiment of the present invention 2 separates impurity；
Fig. 5 is the HMQC collection of illustrative plates that the embodiment of the present invention 2 separates impurity；
Fig. 6 is the H-H COSY collection of illustrative plates that the embodiment of the present invention 2 separates impurity.
Embodiment
The invention will be further described with specific embodiment below in conjunction with the accompanying drawings, but protection scope of the present invention is not limited
In this.
Embodiment 1
The Florfenicol sample 5g containing relative retention time RRT3.1 unknown impurities 0.83% is taken to be dissolved in methanol, Ran Houjia
Enter 12g silica gel to be well mixed, mixture steams methanol in decompression on Rotary Evaporators, obtains powdery solid.Florfenicol will be contained
The powdery solid of sample is uniformly laid on silicagel column upper end, with petroleum ether-ethyl acetate-ammoniacal liquor (90:60:0.1) enter for eluent
Go post separation, different fractions are monitored with TLC, and collect the cut containing relative retention time RRT3.1 impurity.
The cut is detected with HPLC methods in 2015 editions Chinese veterinary pharmacopoeias, its principal goods matter appearance time and detection Florfenicol sample
The appearance time of unknown impuritie coincide during product, and it is target impurity to illustrate this cut contained substance.
Aforesaid operations are repeated, the obtained cut containing relative retention time RRT3.1 impurity are merged, in 50 DEG C of water-baths
In be concentrated under reduced pressure removal solvent, residue obtains off-white powder 48mg in 45 DEG C of vacuum drying.
Embodiment 2
Take a small amount of gained solid methanol of embodiment 1 to dissolve, entered using Esquire-LC type Electrospray ion trap mass spectrometry instrument
Row mass spectral analysis.The plasma peak of m/z=483.9,506.2,522.1 that sample is detected in the positive-ion mode, is respectively [M+
H]+、[M+Na]+、[M+K]+, therefore the molecular mass of the impurity is 483.
Sample is dissolved in DMSO-d6, then carry out1H-NMR、13C-NMR, DEPT-135 °, hydrocarbon related (HMQC) and hydrogen
Hydrogen correlation (H-H COSY) analysis, its result is as shown in figs. 1 to 6.
1In H-NMR collection of illustrative plates, in addition to solvent DMSO is not deuterated with water proton, 10 group of 15 proton signal is observed altogether：1H-NMR(DMSO-d6, 500MHz) and δH：8.62 (d, J=7Hz, 1H), 7.86 (d, J=8Hz, 2H), 7.60 (dd, J=8.0,
3.5Hz, 2H), 6.41 (d, J=13Hz, 1H), 6.24 (q, J=4.5Hz, 1H), 6.09~6.19 (m, 1H), 5.0 (s, 1H),
4.35~4.55 (m, 2H), 4.31~4.33 (m, 1H), 3.16 (s, 3H).Above-mentioned proton have 5 chemical shift of proton in aromatic hydrocarbons or
Unsaturated proton region, the chemical displacement value of remaining 10 proton is indicated to exist near 10 proton and gone between 3~6.5ppm
The group or atom of screen effect big (electronegativity is big).
1313 groups of carbon signals (disregarding solvent carbon signal) are observed in C-NMR collection of illustrative plates,13C-NMR(DMSO-d6, 125MHz)
δC：44.1,53.7 (d, J=8.9Hz), 66.1 (d, J=35Hz), 66.7,70.2 (d, J=13Hz), 84.1 (m, J=Hz),
121.1 (m, J=Hz), 127.0 (strong), 127.6 (strong), 140.1,148.2 (d, J=4.8Hz), 162.3 (d, J=
22.8Hz), the carbon signal at 164.2 (d, J=3.3Hz), wherein 127.0ppm and 127.6ppm is slightly big.Hydrocarbon Correlated Spectroscopy
(HMQC) intensity big carbon signal in display aromatic hydrocarbons two groups of region is respectively related to two protons, at the same DEPT-135 ° of collection of illustrative plates indicate this two
Carbon is not 2 ° of carbon, so two groups of carbon signals are contributed by two fragrant methine carbons of equal value, therefore the impurity molecule is by 15 carbon
Composition.
In DEPT-135 ° of collection of illustrative plates, quaternary carbon in molecular structure not appearance, and secondary carbon then shows as negative peak, according to sample
DEPT-135 ° of profile information, the attribute of each carbon atom in impurity molecule can be specified.At hydrogen hydrogen Correlated Spectroscopy (H-H COSY)
In, it may be determined that fitting relations, the order of connection between chemical shift of proton and proton.In hydrocarbon Correlated Spectroscopy (HMQC) collection of illustrative plates
In, each proton can be specified with being connected the relation of carbon.Available information is as shown in table 1 from nuclear magnetic resoance spectrum：
Table 1
With reference to the preparation technology of Florfenicol, according to the ESI of impurity+-MS、1H-NMR、13C-NMR, DEPT-135 collection of illustrative plates,
Hydrocarbon related collection of illustrative plates (HMQC), the related collection of illustrative plates (H-H COSY) of hydrogen hydrogen, especially13δ in C-NMRC121.1ppm、δCAt 84.1pp
Carbon splits a point information, thus it is speculated that the impurity is 2,3,3,3- tetrafluoro propionic acid-[(2S, 3R) -2- dichloro acetamino -3- hydroxyls -3-
(4- methylsulfonyls phenyl)]-propyl ester, i.e. Thiamphenicol tetrafluoro propionic ester (IV), its molecular formula is C15H15Cl2F4NO5S, accurate point
Son amount is 482.99, and structural formula is：
According to related profile information, the ownership of each proton and carbon signal is as shown in table 2：
Table 2
Embodiment 3
Preparing Thiamphenicol tetrafluoro propionic ester (IV) process route is：
(1) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,
The preparation of 3- tetrafluoros propionic ester (V)
16.9g (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazoles are put into reaction bulb
Methanol (II) and 200g dichloromethane, are cooled to -5 DEG C, and 15g N, N- diethyl -1,1,2,3,3,3- hexafluoros are then slowly added dropwise
Control material temperature is less than 10 DEG C during propylamine, dropwise addition, adds after 5~10 DEG C of stirring reactions 8 hours.Reaction terminates, and subtracts
Dichloromethane is distilled off in pressure, grease original in 100ml cold water, stirring, system is then added into residue gradually solid
Change, filtering, and washed with cold water.Gained wet product 50g methanol dissolves, and is down to -5~0 DEG C of stirred crystallization, filtration drying obtains light
Yellow solid 18.5g, i.e., [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -
2,3,3,3- tetrafluoros propionic ester (V).1H-NMR(DMSO-d6, 400MHz) and δH：8.9 (d, J=6.4Hz, 2H), 7.64, (d, J=
7.2Hz, 2H), 7.28 (s, 1H), 6.13~6.23 (m, 1H), 5.78~5.84 (m, 1H) 4,45~4,57 (m, 3H) 3.23 (s,
3H)。13C-NMR(DMSO-d6, 100MHz) and δC：43.9,67.1 (d, J=7Hz), 73.0,82.5,83.9 (dt, J=193Hz,
34Hz), 121.1 (dd, J=280Hz, 26Hz), 126.8 (strong), 128.1 (strong), 141.5,145.4,162.2 (d, J=
25Hz), 162.6.MS(ESI+)：m/z 465.9[M+H]+。
(2) preparation of Thiamphenicol tetrafluoro propionic ester (IV)
[(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl benzene made from said process is added in reaction bulb
Base) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic ester (V) 15g add 100g water and 30g ethanol, anti-in 40 DEG C of stirrings
Answer 3 hours.It is cooled to 0 DEG C to crystallize 2 hours, filters to obtain wet product.Gained wet product 80ml alcohol-waters (4:1) recrystallize, vacuum is done
It is dry, obtain off-white powder 10.5g, i.e. Thiamphenicol tetrafluoro propionic ester (IV).1H-NMR(DMSO-d6, 400MHz) and δH：8.61(d,
J=7Hz, 1H), 7.85 (d, J=8.4Hz, 2H), 7.59 (dd, J=8.0,3.5Hz, 2H), 6.40 (d, J=13Hz, 1H),
6.23 (q, J=4.5Hz, 1H), 6.08~6.19 (m, 1H), 4.98 (s, 1H), 4.34~4.54 (m, 2H), 4.29~4.33
(m, 1H), 3.15 (s, 3H).MS(ESI+)：m/z 483.9[M+H]+。
Embodiment 4
A kind of preparation method of Thiamphenicol tetrafluoro propionic ester, specifically includes following steps：
(1) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,
The preparation of 3- tetrafluoros propionic ester (V)
16.9g (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazoles are put into reaction bulb
Methanol (II) and 200g dichloromethane, are cooled to -5 DEG C, and 20g N, N- diethyl -1,1,2,3,3,3- hexafluoros are then slowly added dropwise
Control material temperature is less than 15 DEG C during propylamine, dropwise addition, adds after 5~25 DEG C of stirring reactions 8 hours.Reaction terminates, and subtracts
Dichloromethane is distilled off in pressure, grease original in 100ml cold water, stirring, system is then added into residue gradually solid
Change, filtering, and washed with cold water.Gained wet product 50g methanol dissolves, and is down to -5~0 DEG C of stirred crystallization, filtration drying obtains light
Yellow solid 19.1g, [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,
3,3,3- tetrafluoros propionic ester (V).
(2) preparation of Thiamphenicol tetrafluoro propionic ester (IV)
Added in reaction bulb [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] first
Alcohol -2,3,3,3- tetrafluoro propionic ester (V) 15g, added 100g water and 35g isopropanols, in 45 DEG C of stirring reactions 3 hours.Cooling
Crystallized 2 hours to 5 DEG C, filter to obtain wet product.Gained wet product 80ml isopropanol-waters (4:1) recrystallize, vacuum drying obtains class white
Color solid 9.8g, i.e. Thiamphenicol tetrafluoro propionic ester (IV).
Embodiment 5
Application of the Thiamphenicol tetrafluoro propionic ester in Florfenicol quality control
Florfenicol 20mg is taken, it is accurately weighed, put in 10ml measuring bottles, plus flow phased soln and be diluted to scale, shake up, make
Need testing solution；Precision measures need testing solution in right amount, plus the solution of the μ g containing Florfenicol 20 in every 1ml is made in flowing phase dilution
It is used as contrast solution；Precision weighs impurity Thiamphenicol tetrafluoro propionic ester in right amount, is made with flowing phased soln and dilution in every 1ml
The μ g of the propionic ester of tetrafluoro containing Thiamphenicol 20 solution is used as reference substance solution.According to《Republic of China Veterinary Pharmacopoeia》(2015
Year version) in, detected using HPLC methods.The separating degree of impurity Thiamphenicol tetrafluoro propionic ester and Florfenicol should meet regulation.Essence
It is close to measure the μ l of reference substance solution 10 injection liquid chromatographs, detection sensitivity is adjusted, it is full scale to make the peak height of impurity peaks
10%~20%.Precision measures need testing solution, contrast solution and each 10 μ l of reference substance solution again, injects liquid chromatograph, note
Record chromatogram.
Bound requirements：If any impurity peaks in the chromatogram of need testing solution, wherein impurity Thiamphenicol tetrafluoro propionic ester
(IV) amount, with calculated by peak area, must not exceed 0.15% by external standard method；Remaining single impurity peaks (disregarding at gradient solvent peak)
Area must not exceed 0.3 times (0.3%) of contrast solution main peak area, and total impurities must not cross 1.0% and (be less than in need testing solution
The chromatographic peak that 0.05 times of contrast solution main peak area can be ignored).
Impurity of the drug Inspection and analysis method should be sensitive, exclusive, is entered the impurity of different structure by suitable analytical technology
Row separation, detection, so as to reach effective control to impurity.It is an advantage of the invention that：Easy to operate, measurement result accurately may be used
Lean on, specificity is strong.
The Related substance of the equally applicable florfenicol formulations of this method.
Claims (8)
1. Thiamphenicol tetrafluoro propionic ester of the structural formula as shown in (IV)：
2. the preparation method of Thiamphenicol tetrafluoro propionic ester described in a kind of claim 1, it is characterised in that comprise the following steps：
(1) by (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazoles methanol and N, N- diethyl -
1,1,2,3,3,3- hexafluoro propylamine is reacted, and obtains compound [(4R, 5R) -2- dichloromethyl -4,5- dihydro -5- (4- MSMs
Base phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters, its structural formula is such as shown in (V)：
(2) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,3- four
Fluorine propionic ester hydrolysis obtain Thiamphenicol tetrafluoro propionic ester.
3. the preparation method of Thiamphenicol tetrafluoro propionic ester according to claim 2, it is characterised in that：In step (1), instead
Solvent that should be used is dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, tetrahydrofuran, methyl tertiary butyl ether(MTBE),
One kind in ether, toluene, benzene, reaction temperature is -15~70 DEG C, and the reaction time is 3~24 hours.
4. the preparation method of Thiamphenicol tetrafluoro propionic ester according to claim 3, it is characterised in that：In step (1), instead
Solvent that should be used is one kind in dichloromethane, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, reaction
Temperature is -5~40 DEG C, and the reaction time is 5~12 hours.
5. the preparation method of Thiamphenicol tetrafluoro propionic ester according to claim 2, it is characterised in that：In step (2), water
Solution reaction dissolvent is one in water, alcohol-water, methanol-water, isopropanol-water, n-butanol-water, acetonitrile-water, tetrahydrofuran-water
Kind, reaction temperature is 5~80 DEG C, and the reaction time is 1~8 hour.
6. the preparation method of Thiamphenicol tetrafluoro propionic ester according to claim 5, it is characterised in that：In step (2), water
Solution reaction dissolvent is one kind in water, alcohol-water, isopropanol-water, acetonitrile-water, tetrahydrofuran-water, and reaction temperature is 15~50
DEG C, the reaction time is 2~5 hours.
7. the preparation method of Thiamphenicol tetrafluoro propionic ester according to claim 2, it is characterised in that specifically include as follows
Step：
(1) 16.9g (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first is put into reaction bulb
Alcohol and 200g dichloromethane, are cooled to -5 DEG C, are then slowly added dropwise 15g N, N- diethyl -1,1,2,3,3,3- hexafluoro propylamine,
Control material temperature is less than 10 DEG C during dropwise addition, adds after 5~10 DEG C of stirring reactions 8 hours；Reaction terminates, vacuum distillation
Dichloromethane is removed, grease original in 100ml cold water, stirring, system is then added into residue and is gradually solidified, mistake
Filter, and washed with cold water；Gained wet product 50g methanol dissolves, and is down to -5~0 DEG C of stirred crystallization, filtration drying, obtain [(4R,
5R) -2- dichloromethyls -4,5- dihydros -5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters；
(2) [(4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyl phenyl) Evil obtained above are added in reaction bulb
Azoles -4- bases] methanol -2,3,3,3- tetrafluoro propionic ester 15g added 100g water and 30g ethanol, in 40 DEG C of stirring reactions 3 hours；
0 DEG C of crystallization is cooled to, wet product is filtered to obtain；Gained wet product is recrystallized with 80ml alcohol-waters, vacuum drying, obtains Thiamphenicol tetrafluoro
Propionic ester.
8. application of the Thiamphenicol tetrafluoro propionic ester in Florfenicol quality control described in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710262304.9A CN107011220B (en) | 2017-04-20 | 2017-04-20 | Thiamphenicol tetrafluoro propionic ester and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710262304.9A CN107011220B (en) | 2017-04-20 | 2017-04-20 | Thiamphenicol tetrafluoro propionic ester and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107011220A true CN107011220A (en) | 2017-08-04 |
| CN107011220B CN107011220B (en) | 2018-08-14 |
Family
ID=59447765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710262304.9A Active CN107011220B (en) | 2017-04-20 | 2017-04-20 | Thiamphenicol tetrafluoro propionic ester and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107011220B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO126606A0 (en) * | 2010-08-31 | 2011-08-30 | Maria Neagu | Analytical () method for identifying, dosing fluorfenicol and the chemically related impurities in the pharmaceutical products fluorfenidem 10%-oral solution, fluorfenidem 50 and fluorfenicol asactive pharmaceutical ingredient |
| CN103304505A (en) * | 2013-06-06 | 2013-09-18 | 江苏恒盛药业有限公司 | Preparation method for florfenicol intermediate |
-
2017
- 2017-04-20 CN CN201710262304.9A patent/CN107011220B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO126606A0 (en) * | 2010-08-31 | 2011-08-30 | Maria Neagu | Analytical () method for identifying, dosing fluorfenicol and the chemically related impurities in the pharmaceutical products fluorfenidem 10%-oral solution, fluorfenidem 50 and fluorfenicol asactive pharmaceutical ingredient |
| CN103304505A (en) * | 2013-06-06 | 2013-09-18 | 江苏恒盛药业有限公司 | Preparation method for florfenicol intermediate |
Non-Patent Citations (3)
| Title |
|---|
| 秦峰 等: "RP一HPLC 法测定甲讽霉素及其胶囊剂的含量和有关物质", 《药物分析杂志》 * |
| 钱坤: "氟苯尼考纯度及其相关理化性能测定", 《中国动物保健》 * |
| 陈英 等: "HPLC 法测定氟苯尼考原料甲砜胺的相关物质", 《山东化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107011220B (en) | 2018-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10280173B2 (en) | Ibrutinib solid forms and production process therefor | |
| CN107037153B (en) | The method that high performance liquid chromatography detects genotoxicity impurity in AL58805 bulk pharmaceutical chemicals or pharmaceutical preparation | |
| Li et al. | A strategy to improve the oral availability of baicalein: The baicalein-theophylline cocrystal | |
| CN103030605A (en) | Preparation method and detection method of febuxostat raw material | |
| WO2016206534A1 (en) | New crystal form of apremilast and preparation method therefor | |
| JP6379286B2 (en) | Raw material chlorogenic acid or drug substance chlorogenic acid, its preparation method and mass detection method | |
| CN103804357B (en) | A kind of Rupatadine fumarate compound, its synthetic method and pharmaceutical composition thereof | |
| BRPI0611116A2 (en) | an anastrozole intermediate impurity and its uses | |
| CA2995133C (en) | Crystalline form of 3-(6-(1-(2,2-difluorobenzo [d] [1,3] dioxole-5-yl) cyclopropanecarboxamido)-3-methylpyridine-2-yl) benzoic acid and process of preparation thereof | |
| CN107011220B (en) | Thiamphenicol tetrafluoro propionic ester and its preparation method and application | |
| CN102114008B (en) | Clathrate of paeonol and preparation method and quality detection method thereof | |
| CN111995616A (en) | Tedizolid phosphate impurity and preparation method and application thereof | |
| US9776959B2 (en) | Crystal forms of azetidinone compounds and preparing methods thereof | |
| CN109293682A (en) | A kind of support method is for cloth impurity and preparation method thereof | |
| CN104945300B (en) | Purification method for I-type atorvastatin calcium | |
| WO2020254584A1 (en) | Recrystallisation of 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) in methyl tert.-butyl ether (mtbe) and less than 5 wt% of an aliphatic anti-solvent | |
| CN106661040A (en) | 6-aryl amino pyridone formamide compound crystal and preparation method therefor | |
| CN105891342B (en) | The preparation method of Allylestrenol impurity and its application in Allylestrenol quality analysis | |
| CN108373465B (en) | Dabigatran etexilate impurity and preparation and detection methods thereof | |
| EP3002286A1 (en) | Preparation method for polymorphic 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine and use thereof | |
| Petruševski et al. | Pholcodine monohydrate: Crystal structure and polymorphism | |
| CN116751185A (en) | Impurity in triazole compound preparation, preparation method, detection method and application of impurity | |
| Wang et al. | A Simple and Rapid High-Performance Liquid Chromatography Method for Preparation and Content Detection of the Mainly Numbing Taste Substances of Zanthoxylum bungeanum Maxim | |
| Ravikumar et al. | Enantiomeric separation of docetaxel starting material by chiral LC using amylose based stationary phase | |
| CN116626188A (en) | Method for detecting impurity morpholine in pebiprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |