CN103204819A - Deuterated diazepam and preparation method thereof - Google Patents
Deuterated diazepam and preparation method thereof Download PDFInfo
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- CN103204819A CN103204819A CN2013101276387A CN201310127638A CN103204819A CN 103204819 A CN103204819 A CN 103204819A CN 2013101276387 A CN2013101276387 A CN 2013101276387A CN 201310127638 A CN201310127638 A CN 201310127638A CN 103204819 A CN103204819 A CN 103204819A
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Abstract
The invention discloses deuterated diazepam and a preparation method thereof. The preparation method of deuterated diazepam comprises the following steps of: (1) mixing 7-chlorine-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone and N,N-dimethyl formamide, and stirring; (2) adding potassium carbonate and deuterated chloroform, heating the mixture to more than 40 DEG C and stirring; and (3) carrying out separation to obtain the deuterated diazepam. The preparation method provided by the invention is short, simple and convenient to operate, low in cost and easy to purify. The commercially available non-deuterated diazepam uses a small amount of deuterated reagents as deuterium sources in a non-deuterated solvent atmosphere, so that deuterated diazepam is obtained in a relatively short period of time, and through simple column chromatography purification, a purified product is purified. The deuterated diazepam standard product prepared according to the invention is high in purity and stable in chemical property; and the preparation of the standard product for analysis is convenient. The preparation method provided by the invention can be used for producing deuterated internal standard substance used for analyzing and detecting diazepam.
Description
Technical field
The present invention relates to the chemical analysis detection range, be specifically related to a kind of deuterium for diazepam standard substance and preparation method thereof.
Background technology
Diazepam is the benzodiazepines central nervous depressant, can cause the inhibition of central nervous system different sites, and along with the increasing of consumption, clinical manifestation can be from slight calmness to hypnosis even stupor.In recent years, the criminal cases such as poisoning, commit suiside, wrongly take that causes because of such medicine happens occasionally.This just requires police and judicial evaluation department that the sample sample that relates to such medicine is detected.And guarantee that means are to add internal standard substance when detecting to detection method accurately, reliably, deuterium then is best internal standard substance for thing, because its purposes is non-civilian, has singularity, for this reason, relative less with production for the research of these type of standard substance in China, and these class standard product are essential and indispensable in analyzing and testing, and for a long time, the used deuterium of China all is dependence on import for internal standard substance, because its price is extremely expensive, seriously limited being extensive use of at home of such standard substance.
The bibliographical information method selects for use the rotten deuterium of easy suction to prepare deuterium for thing for sodium hydroxide and expensive deuterated methanol as deuterium source and reaction medium, even the extremely strong organic bases of selection potassium tert.-butoxide, this method has the condition harshness, and cost is more expensive, shortcomings such as complex operation.
Summary of the invention
The object of the invention provides a kind of deuterium that is used as internal standard substance for diazepam standard substance and preparation method thereof, and a kind of internal standard substance standard substance that supply analyzing and testing to use are provided on the one hand; Developed a kind of easy deuterium cheaply on the other hand for the diazepam preparation method.
The technical solution adopted in the present invention is: deuterium is for diazepam, suc as formula compound shown in (I):
Deuterium comprises the steps: for the preparation method of diazepam
(1) with 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone and N, dinethylformamide mixes, and stirs; Utilize N, dinethylformamide as the advantage of reaction solvent is: this solvent boiling point height, can arrive 120 degrees centigrade, help the reaction among the present invention comparatively fast to carry out under the high temperature, N in addition, dinethylformamide is in dissolved organic matter preferably, and also solubilized mineral alkali (salt of wormwood) carries out the target chemical reaction among the present invention smoothly.
(2) add salt of wormwood and deuterochloroform, be heated to more than 40 degrees centigrade, stir;
(3) separate the deuterium that is shown below for diazepam:
Above-mentioned deuterium is for the preparation method of diazepam, in step (1): 7-chloro-1-methyl-5-phenyl-1 of every adding 142mg, and when 3-dihydro-1,4-benzodiazepine-2-ketone, N, the add-on of dinethylformamide is 5mL-20mL; Can dissolve 7-chloro-1-methyl-5-phenyl-1 of 142mg fully, 3-dihydro-1, under the situation of 4-benzodiazepine-2-ketone, the N that adds 10mL, dinethylformamide is optimal addn, and too much solvent at first causes waste unnecessary, secondly causes more waste liquid to aftertreatment, last too much solvent makes reactant concn descend the delayed response time.
Above-mentioned deuterium is for the preparation method of diazepam, the add-on of salt of wormwood and deuterochloroform all is with 7-chloro-1-methyl-5-phenyl-1 in step (2), 3-dihydro-1, the amount of substance of 4-benzodiazepine-2-ketone is reference, 7-chloro-1-methyl-5-phenyl-1 of every adding 142mg, 3-dihydro-1,4-benzodiazepine-2-ketone, the add-on of salt of wormwood are 69mg-276mg, the target product yield the best that obtains during wherein with adding 138mg salt of wormwood, because salt of wormwood is as the alkali of reaction needed, according to 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone add-on, theory demands salt of wormwood is 1mmol, and the way it goes for actual verification; 7-chloro-1-methyl-5-phenyl-1 of every adding 142mg, 3-dihydro-1,4-benzodiazepine-2-ketone, the add-on of deuterochloroform is 0.5mL-3mL, wherein reaction effect the best when adding the deuterochloroform of 1mL.The optimal addn of above-mentioned substance all is that too much adding no longer increases yield, can cause unnecessary waste on the contrary in the minimum usage quantity that guarantees to reach under maximum yield and the experiment demand condition.
Above-mentioned deuterium is heated to 60-120 degree centigrade for the preparation method of diazepam in step (2), wherein the shortest with 120 degrees centigrade of required reaction times, effect is best.
Above-mentioned deuterium is for the preparation method of diazepam, in step (3): at first the mixture that obtains in the step (2) is extracted, extraction agent is that toluene, benzene, ether, methylene dichloride, chloroform or ethyl acetate are (from the contrast of extraction agent chemistry rerum natura, the toxicity of benzene, toluene, methylene dichloride, chloroform is all greater than ethyl acetate, and shortcoming such as that ether exists is volatile, point of ignition is low, and the extraction efficiency of toluene, benzene, ether, methylene dichloride and chloroform all is lower than ethyl acetate; Therefore, ethyl acetate is best extraction agent in the present invention, extraction fully, extraction efficiency reaches 99.9%, namely 99.9% target product in the mixed solution can be transferred in the ethyl acetate, removes extraction agent then, last column chromatography purification.
Above-mentioned deuterium is for the preparation method of diazepam, the stationary phase of column chromatography is 200-300 purpose silica gel, moving phase is methylene dichloride and methanol mixture, the ratio of methylene dichloride and the ratio of the volume of methyl alcohol is more than or equal to 1, that is: V (methylene dichloride): V (methyl alcohol) 〉=1, the separate targets product is removed impurity preferably; When V (methylene dichloride): V (methyl alcohol)=100: 10, the separation purity liquid phase analysis shows and reaches 99.5%, can directly use as standard substance.
Above-mentioned deuterium comprises the steps: for the preparation method of diazepam
(1) in the 100mL there-necked flask of taking back the stream prolong, put into stirrer, adopt magnetic agitation, the 7-chloro-1-methyl-5-phenyl-1 that adds 710mg then in the there-necked flask, 3-dihydro-1,4-benzodiazepine-2-ketone adds 50mLN again, dinethylformamide, stirring at room fully dissolved it in 30 minutes;
(2) add 5 milliliters of powder salt of wormwood 690mg and deuterochloroforms again in the there-necked flask, (also can replace there-necked flask with argon gas with nitrogen this moment, but the argon gas price is higher than nitrogen) replace three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, is warmed up to 120 degrees centigrade, and (wherein reaction finishes 2 hours the time for stirring reaction 2 hours 0.5-4 hour, time expand, do not increase yield to reaction), close oil bath;
(3) reaction flask is positioned under the room temperature cools off, to be cooledly add water 100 milliliters in the there-necked flask after the room temperature (consumption of water is N, 1 times of dinethylformamide more than the amount, be used for diluting preferably N, dinethylformamide, be conducive to the extraction agent extraction), transfer to mixed solution in the there-necked flask in the 500mL separating funnel this moment, and add ethyl acetate 100mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 100mL ethyl acetate, extracts so repeatedly 3 times, the ethyl acetate solution that obtains for three times is merged, with anhydrous sodium sulfate drying (can also use anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, 4A molecular sieve or Vanadium Pentoxide in FLAKES carry out drying, but Magnesium Chloride Anhydrous and Calcium Chloride Powder Anhydrous cause side reaction easily, so do not adopt; Vanadium Pentoxide in FLAKES has strongly-acid, so also do not adopt; 4A molecular sieve drying effect is slower; By contrast, anhydrous sodium sulphate is better), dry 3 hours after-filtration are removed the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, room temperature was placed after 2 hours becomes Powdered faint yellow solid, and this Powdered faint yellow solid column chromatography is further purified, and separating silica gel is the 200-300 order, moving phase is methylene dichloride: methyl alcohol=100: 10 obtains white powder solid 682mg.
The invention has the beneficial effects as follows: the present invention selects more cheap deuterochloroform and non-deuterium for diazepam (7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone) be commercially available stable, can directly buy from the market and obtain) be raw material, be reaction medium with common non-deuterated reagent, do alkali with common salt of wormwood, have more simple and easy, easy to operate, the advantages such as yield is high, easy purification of reaction conditions.
Preparation method of the present invention is brief, and is easy and simple to handle, with low cost, easily purifying.With commercially available non-deuterium for diazepam in non-deuterated solvent atmosphere, do the deuterium source with a small amount of deuterated reagent, obtain deuterium in the short period for diazepam, by obtaining pure product behind the simple column chromatography purification.For diazepam standard substance purity height, chemical property is stable according to the deuterium of the present invention preparation; Can conveniently be used for analyzing the preparation with standard substance.The deuterium that preparation method of the present invention uses when can be used for production analyzing and testing diazepam is for internal standard substance.
Embodiment
The reaction scheme of following examples:
Diazepam: Chinese another name: diazepam, stable; Chemical name: 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone
Embodiment 1
Take back in the 100mL there-necked flask that flows prolong at one, put into stirrer, adopt magnetic agitation, in there-necked flask, add 142mg then, 0.5mmol7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone, add 10mLN again, dinethylformamide, stirring at room fully dissolved it in 30 minutes, add 1 milliliter of powder salt of wormwood 138mg and deuterochloroform again in the there-necked flask, this moment is with there-necked flask nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, be warmed up to 120 degrees centigrade, stirring reaction 2 hours, close oil bath, reaction flask is positioned under the room temperature cools off, to be cooledly after room temperature, in there-necked flask, add water 20 milliliters, transfer to mixed solution in the there-necked flask in the 100mL separating funnel this moment, and add ethyl acetate 20mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 20mL ethyl acetate, (liquid phase analysis shows that extraction efficiency is 99.9% to extract 3 times so repeatedly, be target product deuterium in the mixed solution have for diazepam 99.9% transfer in the ethyl acetate), the ethyl acetate solution that obtains for three times is merged, with 3 hours after-filtration of anhydrous sodium sulfate drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, room temperature was placed after 2 hours becomes Powdered faint yellow solid, this Powdered faint yellow solid column chromatography is further purified, separating silica gel is the 200-300 order, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 10, (liquid phase analysis shows: deuterium is 99.5% for the purity of diazepam for diazepam 120mg to obtain white powder solid deuterium this moment, can directly use as standard substance), yield 84% (is supposed 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone complete reaction calculates).
1H?NMR(300MHz，CDCl3)：δ7.59-7.62(d，2H)，7.50-7.52(dd，1H)，9.47-7.49(m，1H)，7.40-7.43(t，2H)，7.26-7.30(m，2H)，3.39(s，3H).
ESI-MS：m/z(％)calcd?for[C16H11D2ClN2O+H]+286.75，found286.8；
HPLC：100％(λ＝214nm)，100％(λ＝254nm)
Embodiment 2 (comparative example): take back in the 100mL there-necked flask that flows prolong at one, put into stirrer, adopt magnetic agitation, in there-necked flask, add 7-chloro-1-methyl-5-phenyl-1 then, 3-dihydro-1,4-benzodiazepine-2-ketone (142mg, 0.5mmol), add 10mL N again, dinethylformamide, stirring at room fully dissolved it in 30 minutes, add 1 milliliter of powder salt of wormwood 138mg and deuterochloroform again in the there-necked flask, this moment is with there-necked flask nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is after stirring 24 hours under the room temperature, in there-necked flask, add water 20 milliliters, transfer to mixed solution in the there-necked flask in the 100mL separating funnel this moment, and add ethyl acetate 20mL to this separating funnel, after fully concussion shakes up, standing demix, tell ethyl acetate layer after, water layer continues to shake up concussion with the 20mL ethyl acetate and extracts, extract so repeatedly 3 times, the ethyl acetate solution that obtains for three times is merged, with 3 hours after-filtration of anhydrous sodium sulfate drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, this material column chromatography is further purified, and separating silica gel is the 200-300 order, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 10, obtain white powder solid 135mg, nuclear-magnetism is accredited as raw material 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone does not have the target product deuterium to generate for diazepam substantially.
Embodiment 3
Take back in the 100mL there-necked flask that flows prolong at one, put into stirrer, adopt magnetic agitation, in there-necked flask, add 7-chloro-1-methyl-5-phenyl-1 then, 3-dihydro-1,4-benzodiazepine-2-ketone (142mg, 0.5mmol), add 10mL N again, dinethylformamide, stirring at room fully dissolved it in 30 minutes, add 0.5 milliliter of powder salt of wormwood 138mg and deuterochloroform again in the there-necked flask, this moment is with there-necked flask nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, be warmed up to 120 degrees centigrade, stirring reaction 6 hours, close oil bath, in there-necked flask, add water 20 milliliters, transfer to mixed solution in the there-necked flask in the 100mL separating funnel this moment, and add ethyl acetate 20mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 20mL ethyl acetate, (liquid phase analysis shows that extraction efficiency is 99.9% to extract 3 times so repeatedly, be target product deuterium in the mixed solution have for diazepam 99.9% transfer in the ethyl acetate), the ethyl acetate solution that obtains for three times is merged, with 3 hours after-filtration of anhydrous sodium sulfate drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, room temperature was placed after 2 hours becomes Powdered faint yellow solid, this Powdered faint yellow solid column chromatography is further purified, separating silica gel is the 200-300 order, and moving phase is V (methylene dichloride): V (methyl alcohol)=100: 10, and (liquid phase analysis shows: deuterium is 99.5% for the purity of diazepam for diazepam 100.8mg to obtain white powder solid product deuterium, can directly use as standard substance), yield 71% (suppose 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone complete reaction calculates).
1H?NMR(300MHz，CDCl3)：δ7.59-7.62(d，2H)，7.50-7.52(dd，1H)，9.47-7.49(m，1H)，7.40-7.43(t，2H)，7.26-7.30(m，2H)，3.39(s，3H).
ESI-MS：m/z(％)calcd?for[C16H11D2ClN2O+H]+286.75，found286.8；
HPLC：10096(λ＝214nm)，100％(λ＝254nm)
Embodiment 4
Take back in the 100mL there-necked flask that flows prolong at one, put into stirrer, adopt magnetic agitation, in there-necked flask, add 7-chloro-1-methyl-5-phenyl-1 then, 3-dihydro-1,4-benzodiazepine-2-ketone (142mg, 0.5mmol), add 10mL N again, dinethylformamide, stirring at room fully dissolved it in 30 minutes, add 1 milliliter of powder salt of wormwood 69mg and deuterochloroform again in the there-necked flask, this moment is with there-necked flask nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, be warmed up to 120 degrees centigrade, stirring reaction 8 hours, close oil bath, reaction flask is positioned under the room temperature cools off, to be cooledly after room temperature, in there-necked flask, add water 20 milliliters, transfer to mixed solution in the there-necked flask in the 100mL separating funnel this moment, and add ethyl acetate 20mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 20mL ethyl acetate, (liquid phase analysis shows that extraction efficiency is 99.9% to extract 3 times so repeatedly, be target product deuterium in the mixed solution have for diazepam 99.9% transfer in the ethyl acetate), the ethyl acetate solution that obtains for three times is merged, with 3 hours after-filtration of anhydrous sodium sulfate drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, room temperature was placed after 2 hours becomes Powdered faint yellow solid, this Powdered faint yellow solid column chromatography is further purified, separating silica gel is the 200-300 order, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 10, (liquid phase analysis shows: deuterium is 99.5% for the purity of diazepam for diazepam 97mg to obtain white powder solid deuterium this moment, can directly use as standard substance), yield 68% (is supposed 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone complete reaction calculates).
1H?NMR(300MHz，CDCl3)：δ7.59-7.62(d，2H)，7.50-7.52(dd，1H)，9.47-7.49(m，1H)，7.40-7.43(t，2H)，7.26-7.30(m，2H)，3.39(s，3H).
ESI-MS：m/z(％)calcd?for[C16H11D2ClN2O+H]+286.75，found286.8；
HPLC：100％(λ＝214nm)，100％(λ＝254nm)
Embodiment 5
Take back in the 100mL there-necked flask that flows prolong at one, put into stirrer, adopt magnetic agitation, in there-necked flask, add 7-chloro-1-methyl-5-phenyl-1 then, 3-dihydro-1,4-benzodiazepine-2-ketone (710mg, 2.5mmo1), add 50mLN again, dinethylformamide, stirring at room fully dissolved it in 30 minutes, add 5 milliliters of powder salt of wormwood 690mg and deuterochloroforms again in the there-necked flask, this moment is with there-necked flask nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, be warmed up to 120 degrees centigrade, stirring reaction 2 hours, close oil bath, reaction flask is positioned under the room temperature cools off, to be cooledly after room temperature, in there-necked flask, add water 100 milliliters, transfer to mixed solution in the there-necked flask in the 500mL separating funnel this moment, and add ethyl acetate 100mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 100mL ethyl acetate, (liquid phase analysis shows that extraction efficiency is 99.9% to extract 3 times so repeatedly, be target product deuterium in the mixed solution have for diazepam 99.9% transfer in the ethyl acetate), the ethyl acetate solution that obtains for three times is merged, with 3 hours after-filtration of anhydrous sodium sulfate drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators, obtain thick faint yellow solid, room temperature was placed after 2 hours becomes Powdered faint yellow solid, this Powdered faint yellow solid column chromatography is further purified, separating silica gel is the 200-300 order, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 10, (liquid phase analysis shows: deuterium is 99.5% for the purity of diazepam for diazepam 682mg to obtain white powder solid deuterium this moment, can directly use as standard substance), yield 96% (is supposed 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone complete reaction calculates).
1H?NMR(300MHz，CDCl3)：δ7.59-7.62(d，2H)，7.50-7.52(dd，1H)，9.47-7.49(m，1H)，7.40-7.43(t，2H)，7.26-7.30(m，2H)，3.39(s，3H).
ESI-MS：m/z(％)calcd?for[C16H11D2ClN2O+H]+286.75，found286.8；
HPLC：100％(λ＝214nm)，100％(λ＝254nm)
Embodiment 6: the difference of present embodiment and embodiment 5 is: during column chromatography, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 100, and carry out liquid phase analysis and show obtaining solid product behind the column chromatography: deuterium is 80% for the purity of diazepam.
Embodiment 7: the difference of present embodiment and embodiment 5 is: during column chromatography, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 50, and carry out liquid phase analysis and show obtaining solid product behind the column chromatography: deuterium is 82% for the purity of diazepam.
Embodiment 8: the difference of present embodiment and embodiment 5 is: during column chromatography, moving phase is V (methylene dichloride): V (methyl alcohol)=100: 30, and carry out liquid phase analysis and show obtaining solid product behind the column chromatography: deuterium is 85% for the purity of diazepam.
Claims (8)
1. deuterium is characterized in that for diazepam, suc as formula compound shown in (I):
2. deuterium is characterized in that for the preparation method of diazepam, comprises the steps:
(1) with 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-ketone and N, dinethylformamide mixes, and stirs;
(2) add salt of wormwood and deuterochloroform, be heated to more than 40 degrees centigrade, stir;
(3) separate the deuterium that is shown below for diazepam:
3. deuterium according to claim 2 is characterized in that for the preparation method of diazepam, in step (1): 7-chloro-1-methyl-5-phenyl-1 of every adding 142mg, 3-dihydro-1, during 4-benzodiazepine-2-ketone, N, the add-on of dinethylformamide is 5mL-20mL.
4. deuterium according to claim 2 is for the preparation method of diazepam, it is characterized in that, in step (2): 7-chloro-1-methyl-5-phenyl-1 of every adding 142mg, 3-dihydro-1, during 4-benzodiazepine-2-ketone, the add-on of salt of wormwood is 69mg-276mg, and the add-on of deuterochloroform is 0.5mL-3mL.
5. deuterium according to claim 2 is characterized in that for the preparation method of diazepam, is heated to 60-120 degree centigrade in step (2).
6. deuterium according to claim 2 is for the preparation method of diazepam, it is characterized in that, in step (3): at first the mixture that obtains in the step (2) is extracted, extraction agent is toluene, benzene, ether, methylene dichloride, chloroform or ethyl acetate, remove extraction agent then, last column chromatography purification.
7. deuterium according to claim 6 is for the preparation method of diazepam, it is characterized in that, the stationary phase of column chromatography is 200-300 purpose silica gel, and moving phase is methylene dichloride and methanol mixture, and the two the ratio of ratio of volume of methylene dichloride and methyl alcohol is more than or equal to 1.
8. according to the preparation method of the arbitrary described deuterium of claim 2-7 for diazepam, it is characterized in that, comprise the steps:
(1) in the 100mL there-necked flask of taking back the stream prolong, put into stirrer, adopt magnetic agitation, the 7-chloro-1-methyl-5-phenyl-1 that adds 710mg then in the there-necked flask, 3-dihydro-1,4-benzodiazepine-2-ketone adds 50mLN again, dinethylformamide, stirring at room fully dissolved it in 30 minutes;
(2) add 5 milliliters of powder salt of wormwood 690mg and deuterochloroforms again in the there-necked flask, this moment with there-necked flask with nitrogen replacement three times, to remove air and moisture in the there-necked flask, after this there-necked flask is positioned in the oil bath, be warmed up to 120 degrees centigrade, stirring reaction 2 hours is closed oil bath;
(3) reaction flask is positioned under the room temperature cools off, to be cooledly after room temperature, in there-necked flask, add water 100 milliliters, transfer to mixed solution in the there-necked flask in the 500mL separating funnel this moment, and add ethyl acetate 100mL to this separating funnel, after fully concussion shakes up, standing demix, after telling ethyl acetate layer, water layer continues to shake up the concussion extraction with the 100mL ethyl acetate, extract so repeatedly 3 times, the ethyl acetate solution that obtains for three times is merged, use anhydrous sodium sulfate drying, 3 hours after-filtration of drying, remove the sodium sulfate solid, ethyl acetate filtrate solvent removed by evaporation at reduced pressure on Rotary Evaporators obtains thick faint yellow solid, and room temperature was placed after 2 hours becomes Powdered faint yellow solid, this Powdered faint yellow solid column chromatography is further purified, separating silica gel is the 200-300 order, and moving phase is methylene dichloride: methyl alcohol=100: 10 obtains white powder solid 682mg.
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| CN103864798A (en) * | 2014-03-14 | 2014-06-18 | 公安部物证鉴定中心 | Deuterated estazolam and preparation method thereof |
| CN107365276A (en) * | 2017-08-08 | 2017-11-21 | 公安部物证鉴定中心 | A kind of diazepam D5 preparation method |
| CN107501196A (en) * | 2017-08-08 | 2017-12-22 | 公安部物证鉴定中心 | Intermediate for preparing diazepam D5 and diazepam D8 and preparation method thereof |
| CN107522667A (en) * | 2017-08-08 | 2017-12-29 | 公安部物证鉴定中心 | Diazepam D8 and preparation method thereof |
| CN107365276B (en) * | 2017-08-08 | 2019-09-24 | 公安部物证鉴定中心 | A kind of preparation method of diazepam-D5 |
| CN107501196B (en) * | 2017-08-08 | 2020-02-11 | 公安部物证鉴定中心 | Intermediates for the preparation of diazepam-D5 and diazepam-D8 and processes for their preparation |
| CN107522667B (en) * | 2017-08-08 | 2020-05-19 | 公安部物证鉴定中心 | diazepam-D8 and preparation method thereof |
| CN113773266A (en) * | 2021-09-28 | 2021-12-10 | 公安部物证鉴定中心 | clonazepam-D2 and preparation method thereof |
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