CN107857739A - A kind of deuterated razaxaban key intermediate and preparation method thereof - Google Patents
A kind of deuterated razaxaban key intermediate and preparation method thereof Download PDFInfo
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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Abstract
The invention discloses a kind of deuterated deuterated ketone of 4 p-aminophenyl morpholine 3 of razaxaban key intermediate, has the structure as shown in (VI)：
Description
Technical field
The present invention relates to deuterated compound technical field, and it is deuterated to be more particularly to a kind of deuterated razaxaban key intermediate
4- p-aminophenyl morpholine -3- ketone and preparation method thereof.
Background technology
Razaxaban (Rivaroxaban), the entitled chloro- N- of 5- ({ (the 5S) -2- oxos -3- [4- (3- oxos -4- of chemistry
Quinoline base) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- thenoyl amines, molecular formula C19H18ClN3O5S, molecular weight are
435.88 structure is shown below.
Razaxaban is the antithrombotic reagent having good prospects, and is the oral direct Xa factor inhibitor in first, the whole world, can
The Xa factor and prothrombin activity that high selectivity, Reverse transcriptase dissociate and combined, are extended with dose-dependent fashion and activated
Partial thromboplastin time plate (PT) and prothrombin time (aPTT), so as to extend the clotting time, reduce fibrin ferment and formed.Its
The features such as high with bioavilability, treatment spectrum of disease is wide, dose-effect relationship stabilization, convenient oral, and bleeding risk is low.
Deuterium is hydrogen isotope existing for nature, that is to say, that the deuterated isotopic body in common drug all containing trace.
Deuterium is nontoxic, "dead", is safe to human body, and C-D keys are more stable (6-9 times) than c h bond, in other words replace with hydrogen
After deuterium, metabolism site may be closed, extend drug half-life, while do not influence pharmacological activity (H and D shape difference are small).And
Deuterated razaxaban is the compound after razaxaban isotopic, has isotope effect, prepares deuterated razaxaban
Key intermediate and preparation method thereof is not also reported at present.
The content of the invention
The technical problems to be solved by the invention are the provision of a kind of deuterated profit that can be used for preparing deuterated razaxaban
Cut down deuterated 4- p-aminophenyls morpholine -3- ketone of husky class's key intermediate and preparation method thereof.
The present invention is that solve above-mentioned technical problem by the following technical programs：
On the one hand, there is provided a kind of deuterated deuterated 4- p-aminophenyls morpholine -3- ketone of razaxaban key intermediate, have such as
(VI) structure shown in：
On the other hand, there is provided the system of the above-mentioned deuterated deuterated 4- p-aminophenyls morpholine -3- ketone of razaxaban key intermediate
Preparation Method, comprise the following steps：
(1) reaction will be substituted in the presence of cuprous iodide such as five deuterated bromobenzenes shown in formula (II) and monoethanolamine, extracted
Organic phase is concentrated after taking, then is purified through column chromatography, obtains the deuterated hydroxyethylaniline as shown in formula (III)；
(2) will be as anti-through cyclization such as the deuterated hydroxyethylaniline shown in formula (III) and sodium hydrate aqueous solution and chloracetyl chloride
Should, filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)；
(3) will be if deuterated 4- phenylmorpholines -3- ketone, the concentrated sulfuric acid and the nitric acid shown in formula (IV) are through nitration reaction, regulation pH
To 7, filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)；
(4) the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V) and hydrogen are anti-through reducing in the presence of palladium carbon
Should, palladium carbon is filtered to remove, concentrates filtrate to dry, obtains the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)；
Preferably, in the step (1),
Five deuterated bromobenzenes and the mass ratio of monoethanolamine and cuprous iodide as shown in formula (II) are 7~9:9~11:1；With/
Or
The process of the substitution reaction is cooled to 20~30 DEG C to be warming up to 90~110 DEG C of 6~10h of reaction；And/or
The process that organic phase is concentrated after the extraction is that addition volume ratio is 4~6:4 water and dichloromethane, divide after stirring
Layer, concentration organic phase remove dichloromethane.
Preferably, in the step (2),
The process of the ring-closure reaction is that the deuterated hydroxyethylaniline as shown in formula (III) is dissolved in ethanol water,
40~50 DEG C are warming up under stirring, it is 10~13 to control reaction solution pH, while 45% sodium hydrate aqueous solution and chloracetyl is added dropwise
Chlorine, 20~40min is reacted at 40~50 DEG C after being added dropwise, separate out solid, be cooled to 0 DEG C of 0.5~2h of stirring；And/or
The washing is to be washed 2 times with cold water；And/or
The temperature being dried under reduced pressure is 50~60 DEG C.
Preferably, the volume ratio of ethanol and water is 1~3 in the ethanol water:6；And/or
The deuterated hydroxyethylaniline addition sodium hydrate aqueous solutions of 4~8g 45% and 1~2mL chlorine shown in per 1g formulas (III)
Chloroacetic chloride.
Preferably, in the step (3),
The process of the nitration reaction for will as deuterated the 4- phenylmorpholines -3- ketone and the concentrated sulfuric acid shown in formula (IV) 20~
20~40min is stirred at 30 DEG C, is cooled to -5~10 DEG C, then 65% nitric acid is added dropwise, then at -5~10 DEG C stirring 0.5~
2h；And/or
The temperature being dried under reduced pressure is 50~60 DEG C.
Preferably, the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV) and the mass ratio of the concentrated sulfuric acid and nitric acid are 1~3:
6~9:1.
Preferably, in the step (4),
The process of the reduction reaction is that the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V) is dissolved in into methanol
In, 10% palladium carbon is added, hydrogenation to 3~5 atmospheric pressure, 40~50 DEG C of reaction 6h, is cooled to 20~30 DEG C.
Preferably, it is dissolved in per deuterated 4- p-nitrophenyl morpholine -3- ketone of the 1g as shown in formula (V) in 10~15mL methanol,
Deuterated 4- p-nitrophenyls morpholine -3- ketone per 1g as shown in formula (V) adds the palladium carbons of 0.05~0.1g 10%.
Another aspect, the deuterated 4- p-aminophenyls morpholine -3- ketone of above-mentioned deuterated razaxaban key intermediate is also provided and existed
Prepare the application in deuterated razaxaban.
The present invention has advantages below compared with prior art：Raw material is easy to get, and preparation process is easy to operate, reacts overall yield
Height, available for preparing deuterated razaxaban.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
All chemicals are commercial chemicals.
Embodiment 1
(1) preparation of the deuterated hydroxyethylaniline as shown in formula (III)
Synthesis flow is as follows：
Five deuterated bromobenzenes of 40g, 47g monoethanolamines and 4.8g cuprous iodides are added into reaction bulb, is warming up to 90~110 DEG C instead
8h is answered, is cooled to 20~30 DEG C, adds 100mL water and 80mL dichloromethane, liquid separation after stirring 10 minutes, organic phase concentration removes
Dichloromethane, residual liquid column chromatography purify to obtain deuterated hydroxyethylbenzene of the 30.3g pale yellow oils as shown in formula (III)
Amine, yield 84%.It is as a result as follows with mass spectrum and the above-mentioned faint yellow solid of magnetic resonance detection：1H NMR(CHC13,
400MHz):δ3.81(t,2H),3.37(bs,2H),3.29(t,2H)；MS(ESI):M/z=143 [M+H]+。
(2) preparation of the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)
Synthesis flow is as follows：
Add the deuterated hydroxyethylanilines of 100g into reaction bulb, 100mL ethanol and 300mL water, it is warming up to 40 under stirring~
50 DEG C, it is 10~13 to control reaction solution pH, while the sodium hydrate aqueous solutions of 580g 45% and 160mL chloracetyl chlorides is added dropwise, and is added dropwise
After reacted 30 minutes at 40~50 DEG C, separate out solid, be cooled to 0 DEG C of stirring 1h, filtering, filter cake washs 2 times with cold water, 50
It is dried under reduced pressure at DEG C, obtains deuterated 4- phenylmorpholine -3- ketone 92g of the white solid as shown in formula (IV), yield 72%.Use matter
Spectrum and the magnetic resonance detection white solid, it is as a result as follows：1H NMR(CHC13,400MHz):δ4.35(s,2H).4.05(t,
2H),3.77(t,2H)；MS(ESI):M/z=183 [M+H]+。
(3) preparation of the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)
Synthesis flow is as follows：
The deuterated 4- phenylmorpholines -3- ketone of 20g and the 82g concentrated sulfuric acids are added into reaction bulb, is stirred 30 minutes at 20~30 DEG C,
- 5~10 DEG C are cooled to, the nitric acid of 11.5g 65% is added dropwise, stirs 1h at -5~10 DEG C after being added dropwise, 100mL is slowly added dropwise
Water, then pH to 7 is adjusted with concentrated ammonia liquor, solid, filtering are separated out, filter cake is washed with water, and 60 DEG C are dried under reduced pressure to obtain 20.5g light browns
Deuterated 4- p-nitrophenyl morpholine -3- ketone of the solid as shown in formula (V), yield 83%.Should with mass spectrum and magnetic resonance detection
Light tan solid, it is as a result as follows：1H NMR(400MHz,CDCI3)δ4.37(s,2H),4.07(t,2H),3.85(t,2H)；MS
(ESI):M/z=227 [M+H]+。
(4) preparation of the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)
Synthesis flow is as follows：
The deuterated 4- p-nitrophenyls morpholine -3- ketone of 22.6g is added into hydriding reactor, 250mL methanol, adds 2g 10%
Palladium carbon, it is hydrogenated with to 4 atmospheric pressure, 40~50 DEG C of progress reduction reaction 6h, is cooled to 20~30 DEG C and is filtered to remove palladium carbon, filtrate subtracts
Pressure is concentrated to dryness, and obtains deuterated 4- p-aminophenyl morpholine -3- ketone 18.2g of the faint yellow solid as shown in formula (VI), and yield is
93%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(400MHz,CDCl3)δ4.32(s,2H),
4.00(t,2H),3.72(bs,2H),3.69(t,2H)；MS(ESI):M/z=197 [M+H]+。
Embodiment 2
(1) preparation of the deuterated hydroxyethylaniline as shown in formula (III)
Five deuterated bromobenzenes of 33.6g, 43.2g monoethanolamines and 4.8g cuprous iodides are added into reaction bulb, is warming up to 90~110
DEG C reaction 6h, is cooled to 20~30 DEG C, adds 80mL water and 80mL dichloromethane, liquid separation after stirring 10 minutes, organic phase concentration
Dichloromethane is removed, residual liquid column chromatography purifies to obtain deuterated ethoxy of the 25.3g pale yellow oils as shown in formula (III)
Aniline, yield 74%.It is as a result as follows with mass spectrum and the above-mentioned faint yellow solid of magnetic resonance detection：1H NMR(CHC13,
400MHz):δ3.81(t,2H),3.37(bs,2H),3.29(t,2H)；MS(ESI):M/z=143 [M+H]+。
(2) preparation of the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)
Add the deuterated hydroxyethylanilines of 100g into reaction bulb, 150mL ethanol and 300mL water, it is warming up to 40 under stirring~
50 DEG C, it is 10~13 to control reaction solution pH, while the sodium hydrate aqueous solutions of 400g 45% and 100mL chloracetyl chlorides is added dropwise, and is added dropwise
After reacted 20 minutes at 40~50 DEG C, separate out solid, be cooled to 0 DEG C of stirring 0.5h, filtering, filter cake washs 2 times with cold water,
It is dried under reduced pressure at 60 DEG C, obtains deuterated 4- phenylmorpholine -3- ketone 90g of the white solid as shown in formula (IV), yield 68%.With
Mass spectrum and the magnetic resonance detection white solid, it is as a result as follows：1H NMR(CHC13,400MHz):δ4.35(s,2H).4.05(t,
2H),3.77(t,2H)；MS(ESI):M/z=183 [M+H]+。
(3) preparation of the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)
The deuterated 4- phenylmorpholines -3- ketone of 11.5g and the 69g concentrated sulfuric acids are added into reaction bulb, 20 points are stirred at 20~30 DEG C
Clock, -5~10 DEG C are cooled to, the nitric acid of 11.5g 65% is added dropwise, stirs 0.5h at -5~10 DEG C after being added dropwise, is slowly added dropwise
100mL water, then pH to 7 is adjusted with concentrated ammonia liquor, solid, filtering are separated out, filter cake is washed with water, and 60 DEG C are dried under reduced pressure to obtain 18.5g
Deuterated 4- p-nitrophenyl morpholine -3- ketone of the light tan solid as shown in formula (V), yield 78%.With mass spectrum and nuclear magnetic resonance
The light tan solid is detected, it is as a result as follows：1H NMR(400MHz,CDCI3)δ4.37(s,2H),4.07(t,2H),3.85(t,
2H)；MS(ESI):M/z=227 [M+H]+。
(4) preparation of the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)
The deuterated 4- p-nitrophenyls morpholine -3- ketone of 22.6g is added into hydriding reactor, 226mL methanol, adds 1.15g
10% palladium carbon, it is hydrogenated with to 3 atmospheric pressure, 40~50 DEG C of progress reduction reaction 6h, is cooled to 20~30 DEG C and is filtered to remove palladium carbon, filter
Liquid is concentrated under reduced pressure into dry, obtains deuterated 4- p-aminophenyl morpholine -3- ketone 15.1g of the faint yellow solid as shown in formula (VI), receives
Rate is 82%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(400MHz,CDCl3)δ4.32(s,
2H),4.00(t,2H),3.72(bs,2H),3.69(t,2H)；MS(ESI):M/z=197 [M+H]+。
Embodiment 3
(1) preparation of the deuterated hydroxyethylaniline as shown in formula (III)
Five deuterated bromobenzenes of 43.2g, 52.8g monoethanolamines and 4.8g cuprous iodides are added into reaction bulb, is warming up to 90~110
DEG C reaction 10h, is cooled to 20~30 DEG C, adds 120mL water and 80mL dichloromethane, liquid separation after stirring 10 minutes, and organic phase is dense
Contracting removes dichloromethane, and residual liquid column chromatography purifies to obtain deuterated hydroxyl second of the 28.7g pale yellow oils as shown in formula (III)
Base aniline, yield 80%.It is as a result as follows with mass spectrum and the above-mentioned faint yellow solid of magnetic resonance detection：1H NMR(CHC13,
400MHz):δ3.81(t,2H),3.37(bs,2H),3.29(t,2H)；MS(ESI):M/z=143 [M+H]+。
(2) preparation of the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)
The deuterated hydroxyethylanilines of 100g, 50mL ethanol and 300mL water are added into reaction bulb, 40~50 are warming up under stirring
DEG C, it is 10~13 to control reaction solution pH, while the sodium hydrate aqueous solutions of 800g 45% and 200mL chloracetyl chlorides is added dropwise, and is dripped
Reacted 40 minutes at 40~50 DEG C after finishing, separate out solid, be cooled to 0 DEG C of stirring 1h, filtering, filter cake is washed 2 times, 60 DEG C with cold water
Under be dried under reduced pressure, obtain deuterated 4- phenylmorpholine -3- ketone 89g of the white solid as shown in formula (IV), yield 64%.Use mass spectrum
And the magnetic resonance detection white solid, it is as a result as follows：1H NMR(CHC13,400MHz):δ4.35(s,2H).4.05(t,2H),
3.77(t,2H)；MS(ESI):M/z=183 [M+H]+。
(3) preparation of the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)
The deuterated 4- phenylmorpholines -3- ketone of 34.5g and the 103.5g concentrated sulfuric acids are added into reaction bulb, 40 are stirred at 20~30 DEG C
Minute, -5~10 DEG C are cooled to, the nitric acid of 11.5g 65% is added dropwise, stirs 2h at -5~10 DEG C after being added dropwise, is slowly added dropwise
100mL water, then pH to 7 is adjusted with concentrated ammonia liquor, solid, filtering are separated out, filter cake is washed with water, and 50 DEG C are dried under reduced pressure to obtain 18.3g
Deuterated 4- p-nitrophenyl morpholine -3- ketone of the light tan solid as shown in formula (V), yield 70%.With mass spectrum and nuclear magnetic resonance
The light tan solid is detected, it is as a result as follows：1H NMR(400MHz,CDCI3)δ4.37(s,2H),4.07(t,2H),3.85(t,
2H)；MS(ESI):M/z=227 [M+H]+。
(4) preparation of the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)
The deuterated 4- p-nitrophenyls morpholine -3- ketone of 22.6g is added into hydriding reactor, 339mL methanol, adds 2.26g
10% palladium carbon, it is hydrogenated with to 5 atmospheric pressure, 40~50 DEG C of progress reduction reaction 6h, is cooled to 20~30 DEG C and is filtered to remove palladium carbon, filter
Liquid is concentrated under reduced pressure into dry, obtains deuterated 4- p-aminophenyl morpholine -3- ketone 17.9g of the faint yellow solid as shown in formula (VI), receives
Rate is 87%.It is as a result as follows with mass spectrum and the magnetic resonance detection white solid：1H NMR(400MHz,CDCl3)δ4.32(s,
2H),4.00(t,2H),3.72(bs,2H),3.69(t,2H)；MS(ESI):M/z=197 [M+H]+。
The above-mentioned deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI) can be used for preparing deuterated razaxaban.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
1. a kind of deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate, it is characterised in that have such as
(VI) structure shown in：
A kind of 2. system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate described in claim 1
Preparation Method, it is characterised in that comprise the following steps：
(1) reaction will be substituted in the presence of cuprous iodide such as five deuterated bromobenzenes shown in formula (II) and monoethanolamine, after extraction
Organic phase is concentrated, then is purified through column chromatography, obtains the deuterated hydroxyethylaniline as shown in formula (III)；
(2) will be if the deuterated hydroxyethylaniline shown in formula (III) and sodium hydrate aqueous solution and chloracetyl chloride are through ring-closure reaction, mistake
Filter cake is washed after filter, filter cake is dried under reduced pressure, obtains the deuterated 4- phenylmorpholines -3- ketone as shown in formula (IV)；
(3) pH to 7 will be adjusted if deuterated 4- phenylmorpholines -3- ketone, the concentrated sulfuric acid and the nitric acid shown in formula (IV) are through nitration reaction,
Filter cake is washed after filtering, filter cake is dried under reduced pressure, obtains the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V)；
(4) the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V) and hydrogen in the presence of palladium carbon through reduction reaction,
Palladium carbon is filtered to remove, concentrates filtrate to dry, obtains the deuterated 4- p-aminophenyls morpholine -3- ketone as shown in formula (VI)；
3. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 2
Preparation Method, it is characterised in that in the step (1),
Five deuterated bromobenzenes and the mass ratio of monoethanolamine and cuprous iodide as shown in formula (II) are 7~9:9~11:1；And/or
The process of the substitution reaction is cooled to 20~30 DEG C to be warming up to 90~110 DEG C of 6~10h of reaction；And/or
The process that organic phase is concentrated after the extraction is that addition volume ratio is 4~6:4 water and dichloromethane, is layered after stirring,
Concentrate organic phase and remove dichloromethane.
4. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 2
Preparation Method, it is characterised in that in the step (2),
The process of the ring-closure reaction stirs for the deuterated hydroxyethylaniline as shown in formula (III) is dissolved in ethanol water
Under be warming up to 40~50 DEG C, it is 10~13 to control reaction solution pH, while 45% sodium hydrate aqueous solution and chloracetyl chloride is added dropwise, drop
20~40min is reacted at 40~50 DEG C after adding, separates out solid, is cooled to 0 DEG C of 0.5~2h of stirring；And/or
The washing is to be washed 2 times with cold water；And/or
The temperature being dried under reduced pressure is 50~60 DEG C.
5. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 4
Preparation Method, it is characterised in that the volume ratio of ethanol and water is 1~3 in the ethanol water:6；And/or
The deuterated hydroxyethylaniline addition sodium hydrate aqueous solutions of 4~8g 45% and 1~2mL chloracetyls shown in per 1g formulas (III)
Chlorine.
6. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 2
Preparation Method, it is characterised in that in the step (3),
The process of the nitration reaction is will be if deuterated the 4- phenylmorpholines -3- ketone and the concentrated sulfuric acid shown in formula (IV) are at 20~30 DEG C
20~40min of lower stirring, is cooled to -5~10 DEG C, then 65% nitric acid is added dropwise, and 0.5~2h is then stirred at -5~10 DEG C；With/
Or
The temperature being dried under reduced pressure is 50~60 DEG C.
7. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 6
Preparation Method, it is characterised in that deuterated 4- phenylmorpholines -3- ketone and the mass ratio of the concentrated sulfuric acid and nitric acid as shown in formula (IV) are 1
~3:6~9:1.
8. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 2
Preparation Method, it is characterised in that in the step (4),
The process of the reduction reaction is that the deuterated 4- p-nitrophenyls morpholine -3- ketone as shown in formula (V) is dissolved in methanol, then
10% palladium carbon is added, hydrogenation to 3~5 atmospheric pressure, 40~50 DEG C of reaction 6h, is cooled to 20~30 DEG C.
9. the system of the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate according to claim 8
Preparation Method, it is characterised in that be dissolved in 10~15mL methanol per deuterated 4- p-nitrophenyl morpholine -3- ketone of the 1g as shown in formula (V)
In, the deuterated 4- p-nitrophenyls morpholine -3- ketone per 1g as shown in formula (V) adds the palladium carbons of 0.05~0.1g 10%.
10. the deuterated 4- p-aminophenyls morpholine -3- ketone of deuterated razaxaban key intermediate described in claim 1 is preparing deuterium
For the application in razaxaban.
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| CN111646903A (en) * | 2020-06-19 | 2020-09-11 | 北京理工大学 | Fully deuterated 2, 4-dinitroanisole and preparation method thereof |
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