CN107827791B - A kind of synthetic method of stable isotope labeling Thiamphenicol - Google Patents
A kind of synthetic method of stable isotope labeling Thiamphenicol Download PDFInfo
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Abstract
The present invention relates to a kind of synthetic methods of isotope labelling Thiamphenicol, belong to organic synthesis field.A kind of synthetic method of entitled stable isotope labeling Thiamphenicol, using p-bromobenzaldehyde and the dimethyl sulfoxide of isotope labelling as raw material, synthesis obtain isotope labelling to methyl mercapto benzaldehyde, further aoxidize isotope labelling to methyl sulfone benzaldehyde, imines is condensed into benzhydrylamine in next step, then in (R) -2, 2 '-diphenyl -3, 3 '-(4- joins phenanthrol), triphenyl borate effect is lower and ethyl diazoacetate constructs azacyclopropane structure fragment, finally by azacyclopropane open loop under the conditions of dichloroacetic acid, ester group reduction synthesis isotope labelling Thiamphenicol, raw material needed for synthesizing, intermediate is simple and easy to get, target product isotope labelling Thiamphenicol chemical purity and isotope abundance are higher, it can be used for the internal standard compound of field of food safety detection of veterinary drugs in food and the research of Thiamphenicol metabolic mechanism , there is important practical application value.
Description
Technical field
The present invention relates to a kind of synthetic methods of stable isotope labeling Thiamphenicol, belong to organic synthesis field.
Background technique
The derivative of Thiamphenicol system chloramphenicol belongs to the amphenicols broad-spectrum antibiotic of synthesis, is clinically widely used in
Prevent and treat animal infectious disease.But it is residual in animal food since there is toxic side effect to hematological system etc.
Staying may be detrimental to health.So many countries and international organization define Thiamphenicol in animal food in the world
Maximum residue limit.But it is to cause occur medicament residue in food that unreasonable application and abuse phenomenon, which still has its consequence,
Domestic traditional detection method is all made of external standard method to be measured, since there is to be measured during wild animal resources at present
Material concentration is low, sample substrate is complicated, interfering substance is more, metabolite is various or it is indefinite the features such as, testing result is not achieved
The regulation of residue criterion.It is specified in No. 2483 bulletin -8 using stabilization so the Ministry of Agriculture issued on December 23rd, 2016
Isotope labelling Thiamphenicol detects the residual of Thiamphenicol, and reality from the standard and on April 1st, 2017 as internal standard
It applies.Therefore, synthetic isotope label Thiamphenicol is of great significance to the detection work of the relevant food safety Regulation in China.
Currently without the study on the synthesis document of the Thiamphenicol of stable isotope labeling, the Thiamphenicol of natural abundance can be with
By being obtained to methyl sulfone benzaldehyde through condensation, cyclisation, reduction, open loop, catalytic hydrogenation, substitution series reaction through natural abundance
(Tetrahedron,2011,67,9199-9203).But this method route is partially long, and the intermediate of stable isotope labeling from
There is not document report, and total recovery is relatively low, stable isotope labeling intermediate utilization rate is not high.
Summary of the invention
The object of the present invention is to provide a kind of stable isotope labeling Thiamphenicol and its mark intermediate synthetic method,
The synthetic method can reduction obtains final products after direct open loop after cyclisation, and total recovery can double.And the compound
Document report is had no with various stable isotope labeling intermediates, and raw material is easy to get, and product yield is high, and isotope abundance is not dilute
It releases, effectively reduces production cost.
The purpose of the present invention can be achieved through the following technical solutions:
The synthetic method of a kind of stable isotope labeling Thiamphenicol and its intermediate, the Thiamphenicol of the isotope labelling
Chemical structure such as formula (I) shown in:
Wherein, R is H or D in (I), and * is12C or13C, synthesis step general line are as follows:
Wherein, R is H or D, and * is12C or13C
(1) in the presence of a catalyst, be added p-bromobenzaldehyde, be then added it is deuterium-labeled or13The diformazan of C flag is sub-
Sulfone under the conditions of 120 DEG C~160 DEG C, reacts 12~48 hours under nitrogen protection.Raw material is extracted after having reacted with organic solvent
The mixture is taken, organic phase, filtering are merged, filtrate is successively washed with saturated sodium bicarbonate solution, water washing, and saturated sodium-chloride is molten
Liquid washing, is added desiccant dryness.Vacuum distillation removes solvent, residue through column chromatograph to obtain it is deuterium-labeled or13C flag to first
Base sulfenyl benzaldehyde.
(2) in a solvent, in the presence of an oxidizer, under the conditions of -50 DEG C~100 DEG C, the deuterium mark that step (1) obtains is added
Note or13C flag to methylsulfany benzaldehyde, after reaction 1~10 hour, reaction solution is extracted with organic solvent, merge organic phase,
It is successively washed with saturated sodium bicarbonate solution, desiccant dryness is added in saturated sodium chloride solution washing.Vacuum distillation removes molten
Agent, residue through column chromatograph to obtain it is deuterium-labeled or13C flag to methyl sulfone benzaldehyde.
(3) in organic solvent, be added step (2) obtain deuterium-labeled or13C flag to methyl sulfone benzaldehyde, be added
Benzhydrylamine is cooled to room temperature after reacting 1~10 hour under the conditions of 20 DEG C~80 DEG C, there is light yellow crystal analysis in reaction solution
Out, be obtained by filtration it is deuterium-labeled or13N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine of C flag.
(4) in organic solvent, be added step (3) obtain deuterium-labeled or13N- hexichol methylamino -1- (the 4- first of C flag
Sulfuryl phenyl) methylene imine, organic ligand, triphenyl borate and ethyl diazoacetate is added, it is anti-under the conditions of -10 DEG C~10 DEG C
It is warming up to after room temperature that the reaction was continued 1~6 hour after answering 0.5~5 hour.Reaction solution is extracted with organic solvent, merges organic phase, according to
Secondary to be washed with saturated sodium bicarbonate solution, desiccant dryness is added in saturated sodium chloride solution washing.Vacuum distillation removes solvent,
Residue through column chromatograph to obtain it is deuterium-labeled or13(2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) azacyclo- third of C flag
Alkane -2- carboxylic acid, ethyl ester.
(5) in organic solvent, be added step (4) obtain deuterium-labeled or13(2S, the 3S) -1- benzhydryl-of C flag
Dichloroacetic acid is added in 3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester, reacts 0.5~5 hour under reflux conditions
After be warming up to after room temperature that the reaction was continued 1~6 hour.It is extracted with organic solvent, merges organic phase, successively use saturated sodium carbonate solution
Washing, saturated sodium chloride solution washing, is added desiccant dryness.Vacuum distillation removes solvent, and residue chromatographs to obtain deuterium through column
Label or13(2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate of C flag.
(6) in organic solvent, be added step (5) obtain deuterium-labeled or13(2S, 3R) -2- (2,2- dichloro of C flag
Acetylamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate, reducing agent is added, is reacted under the conditions of -10 DEG C~60 DEG C
0.5~12 hour, reaction mixture, which is poured into water, to be quenched, and was extracted with organic solvent, and organic phase is merged, and successively used unsaturated carbonate hydrogen
Sodium solution washing, saturated sodium chloride solution washing, is added desiccant dryness.Vacuum distillation removes solvent, and residue is chromatographed through column
Obtain it is deuterium-labeled or13The Thiamphenicol of C flag.
In the step (1), catalyst is one of copper bromide, cupric iodide, zinc fluoride, zinc acetate, zinc chloride or several
Kind；It is deuterium-labeled or13The dimethyl sulfoxide of C flag and the Molar ratio of p-bromobenzaldehyde are 1mL:0.1mmoL~1mL:
0.5mmoL, it is deuterium-labeled or13The dimethyl sulfoxide of C flag and the Molar ratio of catalyst are 1mL:0.1mmoL~1mL:
0.5mmoL.Preferred catalyst is one or more of cupric iodide, zinc fluoride, zinc acetate；It is deuterium-labeled or13The diformazan of C flag
The Molar of sulfoxide and p-bromobenzaldehyde ratio be 1mL:0.2mmoL~1mL:0.3mmoL, it is deuterium-labeled or13The diformazan of C flag is sub-
The Molar of sulfone and catalyst ratio is 1mL:0.2mmoL~1mL:0.3mmoL.
In the step (2), solvent is water, acetonitrile, tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE), 1-4 carbon original
One or more of the fatty alcohol of son；Oxidant is metachloroperbenzoic acid, in hydrogen peroxide, sodium hypochlorite, postassium hypochlorite
One or more；It is deuterium-labeled or13The molar ratio to Nitrobromobenzene and oxidant of C flag is 1:1.5~1:5.It is preferred molten
Agent is one or more of water, acetonitrile, tetrahydrofuran；Oxidant is one of metachloroperbenzoic acid, hydrogen peroxide
Or it is several；It is deuterium-labeled or13The molar ratio to Nitrobromobenzene and oxidant of C flag is 1:2~1:3.
In the step (3), organic solvent is one or more of ethyl alcohol, methylene chloride, toluene；It is deuterium-labeled or13C mark
The molar ratio to methyl sulfone benzaldehyde and benzhydrylamine of note is 1:1~1:1.5.Preferred organic solvent is ethyl alcohol or dichloromethane
Alkane；It is deuterium-labeled or13The molar ratio to methyl sulfone benzaldehyde and benzhydrylamine of C flag is 1:1~1:1.2.
In the step (4), organic solvent is one or more of benzene, toluene, methylene chloride, 1,2- dichloroethanes；
Organic ligand is 1,1 '-binaphthol, 1,1 '-Lian Fei -, 10,10 '-glycol, 3,3 '-diphenyl-[2,2 '-binaphthalene] -1,
1 '-glycol, 2,2 '-diphenyl -3, one of 3 '-(4- joins phenanthrol)；It is deuterium-labeled or13The N- hexichol methylamino -1- of C flag
The molar ratio of (4- methylsulfonyl phenyl) methylene imine and organic ligand is 1:0.05~1:0.2；It is deuterium-labeled or13The N- bis- of C flag
The molar ratio of aminotoluene base -1- (4- methylsulfonyl phenyl) methylene imine and triphenyl borate is 1:0.2~1:0.5；It is deuterium-labeled or13N- hexichol methylamino -1- (the 4- methylsulfonyl phenyl) methylene imine of C flag and the molar ratio of ethyl diazoacetate are 1:1~1:
2.Preferred organic solvent is toluene or methylene chloride；Organic ligand is 1,1 '-binaphthol, 1,1 '-Lian Fei -10,10 '-two
Alcohol, 3,3 '-diphenyl-[2,2 '-binaphthalene] -1, one or more of 1 '-glycol；It is deuterium-labeled or13The N- hexichol first of C flag
The molar ratio of amino -1- (4- methylsulfonyl phenyl) methylene imine and organic ligand is 1:0.1~1:0.15；It is deuterium-labeled or13C flag
N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine and triphenyl borate molar ratio be 1:0.3~1:0.4；Deuterium
Label or13N- hexichol methylamino -1- (the 4- methylsulfonyl phenyl) methylene imine of C flag and the molar ratio of ethyl diazoacetate are 1:
1.1~1:1.5.
In the step (5), organic solvent is one or more of methylene chloride, 1,2- dichloroethanes；It is deuterium-labeled or13(2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester of C flag and dichloroacetic acid
Molar ratio is 1:5~1:15.Preferred organic solvent is 1,2- dichloroethanes, it is deuterium-labeled or13(2S, 3S) -1- hexichol of C flag
The molar ratio of methyl -3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester and dichloroacetic acid is 1:8~1:12.
In the step (6), organic solvent is methanol, in ethyl alcohol, tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE)
It is one or more of；Reducing agent is potassium borohydride, sodium borohydride, sodium cyanoborohydride, one in sodium borohydride-boron trifluoride ether
Kind is several；It is deuterium-labeled or13(2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- mesyl benzene of C flag
Base) molar ratio of ethyl propionate and reducing agent is 1:1~1:10.Preferred organic solvent is methanol or tetrahydrofuran；Reducing agent
For potassium borohydride or sodium borohydride；It is deuterium-labeled or13(2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- of C flag
The molar ratio of (4- methanesulfonylphenYl) ethyl propionate and reducing agent is 1:2~1:6.
Compared with prior art, the beneficial effects of the present invention are the Thiamphenicols of stable isotope labeling of the invention
And its synthesis of intermediate, the synthesis step of method is simple, high income and isotope labeling reagent utilization rate height, isotope abundance
It does not dilute substantially, product and isotope labelling intermediate do not have CAS number, and synthetic route and method do not have document report.It closes
At stable isotope labeling Thiamphenicol purity be greater than 99%, mark point abundance be greater than 98%.And the road of this synthetic method
Line shortens 2 steps compared with original method, and total recovery improves a lot, the stable isotope labeling reagent that raw material can be sold using market,
Effectively reduce production cost.The stable isotope labeling Thiamphenicol that this synthetic method obtains can be used for field of food safety
The research of detection of veterinary drugs in food and Thiamphenicol metabolic mechanism.
Specific embodiment:
Below with reference to embodiment and it is further discussed below the present invention.
Embodiment 1: the synthetic method of deuterium-labeled 4- (methyl mercapto) benzaldehyde
In 25mL glass tube sealing, be added p-bromobenzaldehyde (368mg, 2mmoL), cuprous iodide (76mg, 0.4mmoL),
Zinc acetate (364mg, 4mmoL) and dry deuterated dimethyl sulfoxide (6.5mL).It is filled with nitrogen, reacts 12- at 150 DEG C
36h.After reaction, it is cooled to room temperature, Filtration of catalyst.Filtrate is extracted with ethyl acetate (3 × 50mL), merges organic
Phase is washed (3 × 50mL), and saturated sodium chloride solution washs (3 × 50mL), and anhydrous sodium sulfate is dry.Solvent is removed after filtering to obtain
Crude product, then 4- (methyl mercapto) benzaldehyde (263mg, 85%) for chromatographing deuterium-labeled by column.1H NMR(CDCl3,600M)δ
ppm 9.92(s,1H),7.77(d,2H),7.32(d,2H)；MS ESI+156[M+1].
Embodiment 2: the synthetic method of deuterium-labeled 4- methyl sulfone benzaldehyde
In 50mL there-necked flask, the mixed solution (10mL, volume ratio 1:1) of water and n-butanol is added, 30% peroxide is added
Change hydrogen (2mL), stir evenly, 4- (methyl mercapto) benzaldehyde-methyl D is added3(155mg, 1mmoL) is stirred at 0~5 DEG C
2 hours.Filtering, filtrate are extracted with ethyl acetate (3 × 20mL), merge organic phase, successively wash (3 with saturated sodium bicarbonate solution
× 20mL), it washes (3 × 20mL), saturated sodium chloride solution is washed (3 × 20mL), and it is dry that anhydrous sodium sulfate is added.It is filtered to remove dry
Drying prescription, vacuum distillation remove solvent, and residue chromatographs to obtain deuterium-labeled 4- methyl sulfone benzaldehyde (172mg, 92%) through column.1H
NMR(CDCl3,600M)δppm 9.88(s,1H),7.81(d,2H),7.36(d,2H)；MS ESI+188[M+1].
Embodiment 3: the synthetic method of deuterium-labeled N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine
In 100mL there-necked flask, dehydrated alcohol (50mL), deuterated 4- methyl sulfone benzaldehyde (935mg, 5mmoL), two is added
Benzene methanamine (920mg, 5mmoL) reacts 2 hours at 80 DEG C, is cooled to room temperature, the crystal of precipitation is collected by filtration, with a small amount of cold
Ethanol washing, with 45 DEG C vacuum drying obtain deuterium-labeled N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine (1.67g,
95%).1H NMR(CDCl3, 600M) δ ppm:8.49 (s, 1H), 8.02 (m, 4H), 7.24~7.41 (m, 10H), 5.67 (s,
1H)；MS ESI+353[M+1].
Embodiment 4: deuterium-labeled (2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid second
The synthetic method of ester
It in 10mL single-necked flask, sequentially adds (R) -2,2 '-diphenyl -3,3 '-(4- joins phenanthrol) (54mg,
0.1mmoL), triphenyl borate (87mg, 0.3mmoL) and methylene chloride 2mL return stirring 2 hours, are spin-dried for solvent, cooling
The toluene solution of addition ethyl diazoacetate (0.11m, 1.1mmoL) and deuterium-labeled N- hexichol methylamino -1- (4- first to 0 DEG C
Sulfuryl phenyl) methylene imine (352mg, 1mmoL) toluene solution, at such a temperature react 5 hours, by reaction mixture second
Acetoacetic ester extracts (3 × 10mL), merges organic phase, is successively washed with water (3 × 10mL), and saturated sodium chloride solution washes (3 × 10mL),
Anhydrous sodium sulfate dries, filters removing desiccant, and vacuum distillation removes solvent, residue through column chromatograph to obtain it is deuterium-labeled (2S,
3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester (368mg, 84%)1H NMR(CDCl3,
600M) δ ppm 7.80 (d, 2H), 7.62 (d, 2H), 7.20~7.58 (m, 10H), 3.98 (s, 1H), 3.95 (q, 2H), 3.25
(d, 1H), 2.70 (d, 1H), 1.00 (t, 3H)；MS ESI+439[M+1].
Embodiment 5: deuterium-labeled (2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl)
The synthetic method of ethyl propionate
In 25mL three-necked flask, deuterium-labeled (2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) is sequentially added
Aziridine -2- carboxylic acid, ethyl ester (438mg, 1mmoL) and 1,2- dichloroethanes (5mL), add dichloroacetic acid (0.83mL,
10mmoL), return stirring 2 hours, vacuum distillation remove extra dichloroacetic acid, residue be extracted with dichloromethane (3 ×
20mL), merge organic phase, successively washed (3 × 20mL) with saturated sodium carbonate solution, washed (3 × 20mL), saturated sodium chloride solution
It washes (3 × 20mL), anhydrous sodium sulfate dries, filters removing desiccant, and vacuum distillation removes solvent, and residue chromatographs to obtain through column
Deuterium-labeled (2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate (298mg,
74.5%).1H NMR(CDCl3, 600M) and δ ppm 8.21 (d, 2H), 7.62 (d, 2H), 7.25 (d, 1H), 6.47 (s, 1H),
5.81 (s, 1H), 5.55 (d, 1H), 4.85 (dd, 1H), 4.31 (dq, 2H), 1.33 (t, 3H)；MS ESI+401[M+1].
Embodiment 6: the synthetic method of deuterium-labeled Thiamphenicol
In 10mL single-necked flask, deuterium-labeled (2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- is added
MethanesulfonylphenYl) ethyl propionate (120mg, 0.3mmoL) and methanol (0.5mL), it is added sodium borohydride (53mg, 1.4mmoL),
It is reacted 1 hour at 0 DEG C, pours into ice water (10mL) and be quenched, be extracted with ethyl acetate (3 × 10mL), merge organic phase, successively
It is washed with water (3 × 10mL), saturated sodium chloride solution is washed (3 × 10mL), and anhydrous sodium sulfate dries, filters removing desiccant, decompression
Solvent is distilled off, residue chromatographs to obtain deuterium-labeled Thiamphenicol (89mg, 82%) through column.1H NMR(DMSO-d6,
600M) δ ppm 8.28 (d, 1H), 8.17 (d, 2H), 7.61 (d, 2H), 6.48 (d, 1H), 6.07 (d, 1H), 5.07 (brs,
1H), 5.01 (t, 3H), 3.95 (m, 1H), 3.61 (m, 1H), 3.39 (m, 1H)；MS ESI+359[M+1].
13C flag and13CD3Synthesis of the Thiamphenicol synthesis step of double labelling with Thiamphenicol deuterated in above-described embodiment
Route.
The above is presently preferred embodiments of the present invention, but the present invention should not be limited to disclosed in the embodiment
Content.So all do not depart from the lower equivalent or modification completed of spirit disclosed in this invention, the model that the present invention protects is both fallen within
It encloses.
Claims (13)
1. a kind of synthetic method of stable isotope labeling Thiamphenicol, it is characterised in that the Thiamphenicol of the isotope labelling
Shown in chemical structure such as formula (I):
Wherein, R is H or D in (I), and * is12C or13C, synthesis step are as follows:
(1) in the presence of a catalyst, be added p-bromobenzaldehyde, be then added it is deuterium-labeled or13The dimethyl sulfoxide of C flag,
Under nitrogen protection, under the conditions of 120 DEG C~160 DEG C, react 12~48 hours；Raw material extracts this with organic solvent after having reacted and mixes
Object is closed, organic phase, filtering are merged, filtrate is successively washed with saturated sodium bicarbonate solution, and water washing, saturated sodium chloride solution is washed
It washs, desiccant dryness is added；Vacuum distillation removes solvent, residue through column chromatograph to obtain it is deuterium-labeled or13C flag to methyl sulphur
Benzaldehyde；
(2) in a solvent, in the presence of an oxidizer, under the conditions of -50 DEG C~100 DEG C, addition step (1) obtains deuterium-labeled
Or13C flag to methylsulfany benzaldehyde, after reaction 1~10 hour, reaction solution is extracted with organic solvent, merge organic phase, according to
Secondary to be washed with saturated sodium bicarbonate solution, desiccant dryness is added in saturated sodium chloride solution washing；Vacuum distillation removes solvent,
Residue through column chromatograph to obtain it is deuterium-labeled or13C flag to methyl sulfone benzaldehyde；
(3) in organic solvent, be added step (2) obtain deuterium-labeled or13C flag to methyl sulfone benzaldehyde, hexichol is added
Methylamine is cooled to room temperature after reacting 1~10 hour under the conditions of 20 DEG C~80 DEG C, there is light yellow crystal precipitation, mistake in reaction solution
Filter obtain it is deuterium-labeled or13N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine of C flag；
(4) in organic solvent, be added step (3) obtain deuterium-labeled or13N- hexichol methylamino -1- (the 4- methylsulfonyl of C flag
Phenyl) methylene imine, organic ligand, triphenyl borate and ethyl diazoacetate is added, is reacted under the conditions of -10 DEG C~10 DEG C
It is warming up to after room temperature that the reaction was continued 1~6 hour after 0.5~5 hour；Reaction solution is extracted with organic solvent, merges organic phase, successively
It is washed with saturated sodium bicarbonate solution, desiccant dryness is added in saturated sodium chloride solution washing；Vacuum distillation removes solvent, residual
Stay object through column chromatograph to obtain it is deuterium-labeled or13(2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl phenyl) azacyclo- third of C flag
Alkane -2- carboxylic acid, ethyl ester；
(5) in organic solvent, be added step (4) obtain deuterium-labeled or13(2S, 3S) -1- benzhydryl -3- (4- of C flag
Methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester, dichloroacetic acid is added, is risen after reacting 0.5~5 hour under reflux conditions
The reaction was continued 1~6 hour after warming to room temperature；It is extracted with organic solvent, merges organic phase, successively washed with saturated sodium carbonate solution
It washs, desiccant dryness is added in saturated sodium chloride solution washing；Vacuum distillation removes solvent, and residue chromatographs to obtain deuterium mark through column
Note or13(2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate of C flag；
(6) in organic solvent, be added step (5) obtain deuterium-labeled or13(2S, 3R) -2- (2,2- dichloroacetyl of C flag
Amino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate, reducing agent is added, reaction 0.5 under the conditions of -10 DEG C~60 DEG C~
12 hours, reaction mixture, which is poured into water, to be quenched, and was extracted with organic solvent, and organic phase is merged, successively molten with saturated sodium bicarbonate
Liquid washing, saturated sodium chloride solution washing, is added desiccant dryness；Vacuum distillation removes solvent, and residue chromatographs to obtain through column
It is deuterium-labeled or13The Thiamphenicol of C flag.
2. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
(1) in, catalyst is one or more of copper bromide, cupric iodide, zinc fluoride, zinc acetate, zinc chloride；It is deuterium-labeled or13C flag
Dimethyl sulfoxide and p-bromobenzaldehyde Molar ratio be 1mL:0.1mmoL~1mL:0.5mmoL, it is deuterium-labeled or13C flag
The Molar of dimethyl sulfoxide and catalyst ratio is 1mL:0.1mmoL~1mL:0.5mmoL.
3. the synthetic method of stable isotope labeling Thiamphenicol according to claim 2, which is characterized in that the step
(1) in, catalyst is one or more of cupric iodide, zinc fluoride, zinc acetate；It is deuterium-labeled or13The dimethyl sulfoxide of C flag and right
The Molar ratio of bromobenzaldehyde be 1mL:0.2mmoL~1mL:0.3mmoL, it is deuterium-labeled or13The dimethyl sulfoxide of C flag and catalysis
The Molar ratio of agent is 1mL:0.2mmoL~1mL:0.3mmoL.
4. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
(2) in, solvent is one in the fatty alcohol of water, acetonitrile, tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE), 1-4 carbon atom
Kind is several；Oxidant is one or more of metachloroperbenzoic acid, hydrogen peroxide, sodium hypochlorite, postassium hypochlorite；Deuterium mark
Note or13The molar ratio to Nitrobromobenzene and oxidant of C flag is 1:1.5~1:5.
5. the synthetic method of stable isotope labeling Thiamphenicol according to claim 4, which is characterized in that the step
(2) in, solvent is one or more of water, acetonitrile, tetrahydrofuran；Oxidant is metachloroperbenzoic acid, in hydrogen peroxide
One or more；It is deuterium-labeled or13The molar ratio to Nitrobromobenzene and oxidant of C flag is 1:2~1:3.
6. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
(3) in, organic solvent is one or more of ethyl alcohol, methylene chloride, toluene；It is deuterium-labeled or13C flag to methylsulfonyl benzene first
The molar ratio of aldehyde and benzhydrylamine is 1:1~1:1.5.
7. the synthetic method of stable isotope labeling Thiamphenicol according to claim 6, which is characterized in that the step
(3) in, organic solvent is ethyl alcohol or methylene chloride；It is deuterium-labeled or13Mole to methyl sulfone benzaldehyde and benzhydrylamine of C flag
Than for 1:1~1:1.2.
8. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
(4) in, organic solvent is one or more of benzene, toluene, methylene chloride, 1,2- dichloroethanes；Organic ligand is 1,1 '-
Binaphthol, 1,1 '-Lian Fei -, 10,10 '-glycol, 3,3 '-diphenyl-[2,2 '-binaphthalene] -1,1 '-glycol, 2,2 '-hexichol
One of base -3,3 '-(4- joins phenanthrol)；It is deuterium-labeled or13N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methyl of C flag
The molar ratio of imines and organic ligand is 1:0.05~1:0.2；It is deuterium-labeled or13N- hexichol methylamino -1- (the 4- methyl sulfone of C flag
Base phenyl) molar ratio of methylene imine and triphenyl borate is 1:0.2~1:0.5；It is deuterium-labeled or13Bis- aminotoluene of N- of C flag
The molar ratio of base -1- (4- methylsulfonyl phenyl) methylene imine and ethyl diazoacetate is 1:1~1:2.
9. the synthetic method of stable isotope labeling Thiamphenicol according to claim 8, which is characterized in that the step
(4) in, organic solvent is toluene or methylene chloride；Organic ligand is 1,1 '-binaphthol, 1,1 '-Lian Fei-, 10,10 '-glycol,
3,3 '-diphenyl-[2,2 '-binaphthalene] -1, one or more of 1 '-glycol；It is deuterium-labeled or13Bis- aminotoluene of N- of C flag
The molar ratio of base -1- (4- methylsulfonyl phenyl) methylene imine and organic ligand is 1:0.1~1:0.15；It is deuterium-labeled or13C flag
The molar ratio of N- hexichol methylamino -1- (4- methylsulfonyl phenyl) methylene imine and triphenyl borate is 1:0.3~1:0.4；Deuterium mark
Note or13N- hexichol methylamino -1- (the 4- methylsulfonyl phenyl) methylene imine of C flag and the molar ratio of ethyl diazoacetate are 1:
1.1~1:1.5.
10. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
Suddenly in (5), organic solvent is one or more of methylene chloride, 1,2- dichloroethanes；It is deuterium-labeled or13C flag (2S,
3S) molar ratio of -1- benzhydryl -3- (4- methylsulfonyl phenyl) aziridine -2- carboxylic acid, ethyl ester and dichloroacetic acid be 1:5~
1:15。
11. the synthetic method of stable isotope labeling Thiamphenicol according to claim 10, which is characterized in that the step
Suddenly in (5), organic solvent 1,2- dichloroethanes, it is deuterium-labeled or13(2S, 3S) -1- benzhydryl -3- (4- methylsulfonyl of C flag
Phenyl) molar ratio of aziridine -2- carboxylic acid, ethyl ester and dichloroacetic acid is 1:8~1:12.
12. the synthetic method of stable isotope labeling Thiamphenicol according to claim 1, which is characterized in that the step
Suddenly in (6), organic solvent is one or more of methanol, ethyl alcohol, tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE)；Reduction
Agent is one or more of potassium borohydride, sodium borohydride, sodium cyanoborohydride, sodium borohydride-boron trifluoride ether；It is deuterium-labeled
Or13(2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate of C flag and also
The molar ratio of former agent is 1:1~1:10.
13. the synthetic method of stable isotope labeling Thiamphenicol according to claim 12, which is characterized in that the step
Suddenly in (6), organic solvent is methanol or tetrahydrofuran；Reducing agent is potassium borohydride or sodium borohydride；It is deuterium-labeled or13C flag
Mole of (2S, 3R) -2- (2,2- dichloro acetamino) -3- hydroxyl -3- (4- methanesulfonylphenYl) ethyl propionate and reducing agent
Than for 1:2~1:6.
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