CN107011220B - Thiamphenicol tetrafluoro propionic ester and its preparation method and application - Google Patents
Thiamphenicol tetrafluoro propionic ester and its preparation method and application Download PDFInfo
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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, preparation method is：By (4R, 5R) 2 dichloromethyl 4,5 dihydro, 5 (4 methylsulfonyl phenyl) 4 oxazole methanol and N, N diethyl 1,1,2,3,3,3 hexafluoro propylamine carry out reacting [(4R, 5R) 2 dichloromethyl, 4,5 dihydro 5 (4 methylsulfonyl phenyl) oxazoles, 4 base] methanol 2,3,3, after 3 tetrafluoro propionic esters, obtained through hydrolysis, the product of synthesis and separating obtained impurity mass spectrum having the same and1H H NMR spectroscopies.The Thiamphenicol tetrafluoro propionic ester synthesis technology that the present invention designs has many advantages, such as that raw material is easy to get, reaction condition is mild, reaction process is easy to control, 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 fields, 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, can be used for treating the gram-positive bacteria of animal, Gram-negative bacteria and
It is infected caused by Richettsia etc., and has the drug tolerant bacteria of Thiamphenicol, chloramphenicol compared with high inhibition effect, it is residual in vivo
It stays relatively low, has been 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 are fluorinated cyclocomplex (II) to obtain fluoride (III), and fluoride (III) hydrolyzes to obtain product fluorobenzene Buddhist nun
It examines.
According to《Republic of China Veterinary Pharmacopoeia》When (version in 2010) is using HPLC methods analysis Florfenicol related substance,
Chromatography records 2.5 times that the time is main peak retention time, and《Republic of China Veterinary Pharmacopoeia》(version in 2015) is then by chromatography
Time lengthening is recorded to 5 times of main peak retention time, keeps other conditions identical as version veterinary drug allusion quotation in 2010.Chromatography 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 has wide range of applications, and dosage is big, therefore its impurities is studied and is controlled in detail,
Drug safety will be greatly improved.When for opposite reservation emerging using version Chinese veterinary pharmacopoeia analysis Florfenicol in 2015
Between RRT3.1 unknown impurities, the relevant informations such as structure and preparation without the impurity such as various countries' veterinary drug allusion quotation and document, patent.
Invention content
In order to preferably control the quality of Florfenicol, the present invention is by having carried out point the unknown impuritie in Florfenicol
From, structural identification, a kind of Thiamphenicol tetrafluoro propionic ester and its preparation method and application is provided.
The present invention adopts the following technical scheme that：
Structural formula Thiamphenicol tetrafluoro propionic ester as shown in (IV)：
Structure above structure of Thiamphenicol tetrafluoro propionic ester 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 uniformly mixed with silica gel, with stone
Oily ether-ethyl acetate-ammonium hydroxide is eluent, crosses post separation with silica gel column chromatography, collects the eluent containing target unknown impuritie.
Above-mentioned eluent, appearance time and detection Florfenicol sample are detected with HPLC methods in 2015 editions Chinese veterinary pharmacopoeias
When unknown impuritie appearance time coincide, illustrate collect eluent contained substance be target impurity.
Column enrichment is crossed through multiple, merges the eluent containing target impurity, removal solvent is concentrated under reduced pressure, surplus material decompression is dry
It is dry, obtain off-white powder.
Obtained solid is dissolved with methanol, is analyzed by mass spectrometry using Esquire-LC type Electrospray ion trap mass spectrometry instrument.
It is typically detected in the positive-ion mode [M+H]+、[M+Na]+、[M+K]+Plasma peak, sample detect 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, other than solvent is not deuterated and 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 that 10 proton nearby has the group or atom of deshielding effect big (electronegativity is big).
13Observe that 13 groups of carbon signals (disregarding solvent carbon signal), wherein aromatic hydrocarbons region there are two groups of intensity in C-NMR collection of illustrative plates
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 2 ° of carbon that 135 ° of spectrums, which indicate two carbon not, so two groups of carbon signals are contributed by two fragrant methine carbons of equal value, therefore this is miscellaneous
Matter molecule is made of 15 carbon.
In conjunction with the preparation process of Florfenicol, according to the ESI of impurity+-MS、1H-NMR、13C-NMR, DEPT-135 ° of collection of illustrative plates,
Hydrocarbon correlation collection of illustrative plates (HMQC), hydrogen hydrogen correlation collection of illustrative plates (H-H Cosy), 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, point
Minor is C15H15Cl2F4NO5S, accurate molecular masses 482.99, structural formula is as follows：
The present invention also provides a kind of preparation methods of Thiamphenicol tetrafluoro propionic ester (IV), include 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, and compound [(4R, 5R) -2- dichloromethyls -4,5- dihydro-is obtained
5- (4- methylsulfonyl phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters, 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 obtains Thiamphenicol tetrafluoro propionic ester (IV).
Preferably, in step (1), the solvent for reacting 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, when reaction
Between be 3~24 hours.
Preferably, in step (1), the solvent for reacting used is dichloromethane, chloroform, tetrahydrofuran, methyl- tert
One kind in butyl ether, ether, toluene, reaction temperature are -5~40 DEG C, and the reaction time is 5~12 hours.
Preferably, in step (2), hydrolysis solvent is water, alcohol-water, methanol-water, isopropanol-water, n-butanol-
One kind in water, acetonitrile-water, tetrahydrofuran-water, reaction temperature are 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 comprises the 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
Amine, control material temperature is less than 10 DEG C during dropwise addition, is stirred to react 8 hours in 5~10 DEG C after adding；Reaction terminates, decompression
Dichloromethane is distilled off, 100ml cold water is then added into residue, stirs, original grease gradually cures in system,
Filtering, is used in combination cold water to wash；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 ethyl alcohol, 3 are stirred to react in 40 DEG C
Hour；It is cooled to 0 DEG C of crystallization, filters to obtain wet product；Gained wet product is recrystallized with 80ml alcohol-waters, and vacuum drying obtains Thiamphenicol
Tetrafluoro propionic ester.
The present invention detaches the unknown impuritie in Florfenicol with column chromatography, 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), hydrogen hydrogen correlation collection of illustrative plates (H-H Cosy), sentence
The fixed impurity is 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 present invention devises conjunction according to the structural information of the unknown impuritie in Florfenicol
At route, and Thiamphenicol tetrafluoro propionic ester (IV) is successfully made.Product is through high-efficient liquid phase chromatogram technique analysis, 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.
The present invention also provides a kind of application of Thiamphenicol tetrafluoro propionic ester in Florfenicol quality control.In drug
In the process of research and development and quality control, the discovery and preparation of unknown impuritie often have the quality research of the types of drugs
The important function that can not be ignored, the impurity quantification that can be applied in Florfenicol production technology and quantitative analysis, to
The quality standard of Florfenicol can be improved and be improved, its drug safety can be greatly improved, is that the safety of Florfenicol is used
Medicine provides great importance.
The beneficial effects of the present invention are：
The present invention detaches unknown impuritie in Florfenicol and passes through ESI+-MS、1H-NMR、13C-NMR、DEPT-
The information such as 135 ° of collection of illustrative plates, hydrocarbon related collection of illustrative plates (HMQC), hydrogen hydrogen correlation collection of illustrative plates (H-H COSY), confirm unknown in Florfenicol
Impurity is Thiamphenicol tetrafluoro propionic ester (IV), can the new impurity be applied to 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 technology it is raw materials used be easy to get, reaction condition is mild, reaction process is held
It is easy to control, product purity is high.
Description of the drawings
Fig. 1 is the MS-ESI that the embodiment of the present invention 2 detaches impurity+Collection of illustrative plates；
Fig. 2 is that the embodiment of the present invention 2 detaches impurity1H-NMR collection of illustrative plates；
Fig. 3 is that the embodiment of the present invention 2 detaches impurity13C-NMR collection of illustrative plates；
Fig. 4 is the DEPT-135 ° of collection of illustrative plates that the embodiment of the present invention 2 detaches impurity；
Fig. 5 is the HMQC collection of illustrative plates that the embodiment of the present invention 2 detaches impurity；
Fig. 6 is the H-H COSY collection of illustrative plates that the embodiment of the present invention 2 detaches impurity.
Specific implementation mode
The invention will be further described in the following with reference to the drawings and specific embodiments, but protection scope of the present invention and unlimited
In this.
Embodiment 1
It takes the Florfenicol sample 5g containing relative retention time RRT3.1 unknown impurities 0.83% to be dissolved in methanol, then adds
Enter 12g silica gel to be uniformly 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-ammonium hydroxide (90:60:0.1) be eluent into
Post separation of going collects the fraction containing relative retention time RRT3.1 impurity with TLC monitoring different fractions.
The fraction, principal goods matter appearance time and detection Florfenicol sample are detected with HPLC methods in 2015 editions Chinese veterinary pharmacopoeias
The appearance time of unknown impuritie coincide when product, illustrates that this fraction contained substance is target impurity.
Aforesaid operations are repeated, the obtained fraction containing relative retention time RRT3.1 impurity are merged, in 50 DEG C of water-baths
Middle reduced pressure removes solvent, and residue obtains off-white powder 48mg in 45 DEG C of vacuum drying.
Embodiment 2
Take 1 obtained solid of a small amount of embodiment to be dissolved with methanol, using Esquire-LC type Electrospray ion trap mass spectrometry instrument into
Row mass spectral analysis.The plasma peak of m/z=483.9,506.2,522.1 that sample detects in the positive-ion mode, 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, result is as shown in figs. 1 to 6.
1In H-NMR collection of illustrative plates, other than solvent DMSO is not deuterated and 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 indicate that 10 proton nearby exists and go 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 and the relationship for connecting carbon can be specified.Available information is as shown in table 1 from nuclear magnetic resoance spectrum：
Table 1
In conjunction with the preparation process of Florfenicol, according to the ESI of impurity+-MS、1H-NMR、13C-NMR, DEPT-135 collection of illustrative plates,
Hydrocarbon correlation collection of illustrative plates (HMQC), hydrogen hydrogen correlation collection of illustrative plates (H-H COSY), 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), molecular formula 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
Propylamine, control material temperature is less than 10 DEG C during dropwise addition, is stirred to react 8 hours in 5~10 DEG C after adding.Reaction terminates, and subtracts
Dichloromethane is distilled off in pressure, and 100ml cold water is then added into residue, stirs, and original grease is gradually solid in system
Change, filtering is used in combination cold water to wash.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 the above 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 ethyl alcohol, anti-in 40 DEG C of stirrings
It answers 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) it recrystallizes, vacuum is dry
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 comprises the 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
Propylamine, control material temperature is less than 15 DEG C during dropwise addition, is stirred to react 8 hours in 5~25 DEG C after adding.Reaction terminates, and subtracts
Dichloromethane is distilled off in pressure, and 100ml cold water is then added into residue, stirs, and original grease is gradually solid in system
Change, filtering is used in combination cold water to wash.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)
Be 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, adds 100g water and 35g isopropanols, is stirred to react in 45 DEG C 3 hours.Cooling
It is crystallized 2 hours to 5 DEG C, filters to obtain wet product.Gained wet product 80ml isopropanol-waters (4:1) it recrystallizes, it is white to obtain class for vacuum drying
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, it sets in 10ml measuring bottles, adds flowing phased soln and be diluted to scale, shake up, make
Test solution；Precision measurement test solution is appropriate, adds flowing phase dilution that the solution of the 20 μ g containing Florfenicol in every 1ml is made
Solution as a contrast；It is appropriate that precision weighs impurity Thiamphenicol tetrafluoro propionic ester, is made in every 1ml with flowing phased soln and diluting
The solution of 20 μ g of the propionic ester of tetrafluoro containing Thiamphenicol product solution as a contrast.According to《Republic of China Veterinary Pharmacopoeia》(2015
Year version) in, it is detected using HPLC methods.The separating degree of impurity Thiamphenicol tetrafluoro propionic ester and Florfenicol should meet regulation.Essence
10 μ l of close measurement reference substance solution inject liquid chromatograph, adjust detection sensitivity, and it is full scale to make the peak height of impurity peaks
10%~20%.It is accurate again to measure test solution, contrast solution and each 10 μ l of reference substance solution, inject liquid chromatograph, note
Record chromatogram.
Bound requirements：If any impurity peaks, wherein impurity Thiamphenicol tetrafluoro propionic ester in the chromatogram of test solution
(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 test 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 answer it is sensitive, exclusive, by suitable analytical technology by the impurity of different structure into
Row separation, detection, to reach effective control to impurity.It is an advantage of the invention that：Easy to operate, measurement result accurately may be used
It leans on, specificity is strong.
The Related substance of the equally applicable florfenicol formulations of this method.
Claims (8)
1. structural formula Thiamphenicol tetrafluoro propionic ester 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 include 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 compound [(4R, 5R) -2- dichloromethyl -4,5- dihydro -5- (4- methyl sulfone is obtained
Base phenyl) oxazole -4- bases] methanol -2,3,3,3- tetrafluoro propionic esters, 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 obtains 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
Answer solvent used be dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, tetrahydrofuran, methyl tertiary butyl ether(MTBE),
One kind in ether, toluene, benzene, reaction temperature are -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
It is one kind in dichloromethane, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ether, toluene, reaction to answer solvent used
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, is stirred to react 8 hours in 5~10 DEG C after adding；Reaction terminates, vacuum distillation
Dichloromethane is removed, 100ml cold water is then added into residue, is stirred, original grease gradually cures in system, mistake
Filter, is used in combination cold water to wash；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 add 100g water and 30g ethyl alcohol, are stirred to react in 40 DEG C 3 hours；
It is cooled to 0 DEG C of crystallization, filters to obtain wet product；Gained wet product is recrystallized with 80ml alcohol-waters, and vacuum drying obtains Thiamphenicol tetrafluoro
Propionic ester.
8. application of the Thiamphenicol tetrafluoro propionic ester in Florfenicol quality control described in claim 1.
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