CN103880847B - Deuterated triazolam and preparation method thereof - Google Patents
Deuterated triazolam and preparation method thereof Download PDFInfo
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Abstract
The present invention discloses deuterated triazolam and preparation method thereof, the preparation method of deuterated triazolam, comprise the steps: that (1) is by chloro-for 8-6-(2-chloro-phenyl-)-1-methyl-4H-[1,2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine join dimethyl sulfoxide (DMSO) or N, mix in dinethylformamide, stir; (2) add cesium carbonate or salt of wormwood as catalyzer, and add deuterochloroform, be heated to more than 40 degrees Celsius, stir; (3) deuterated triazolam is separated to obtain.Preparation method of the present invention is brief, easy and simple to handle, with low cost, easy purifying.By commercially available non-deuterated triazolam in non-deuterated solvent atmosphere, doing deuterium source with a small amount of deuterated reagent, obtaining deuterated triazolam in the short period, by obtaining sterling after simple column chromatography purification.The deuterated triazolam standard substance purity prepared according to the present invention is high, stable chemical nature; Can conveniently for the preparation of analysis standard substance.The deuterated internal standard substance that preparation method of the present invention uses when can be used for production analyzing and testing triazolam.
Description
Technical field
The present invention relates to chemical analysis detection field, be specifically related to a kind of deuterated triazolam standard substance and preparation method thereof.
Background technology
Triazolam is benzodiazepines central nervous depressant, can cause the suppression of central nervous system different sites, and along with the increasing of consumption, clinical manifestation even can be gone into a coma to hypnosis from slight calmness.In recent years, that causes because of such medicine poisons, commits suiside, the criminal case such as to wrongly take and happen occasionally.This just requires that judicial identification of public security organs department is detected the sample sample relating to such medicine.And guarantee that accurate, the reliable means of detection method add internal standard substance, deuterated thing is then best internal standard substance, because its purposes is non-civilian, band has specific characteristics, for this reason, relative less with production for the research of these type of standard substance in China, and this kind of standard substance are required and indispensable in analyzing and testing, for a long time, China's deuterated internal standard substance used is all dependence on import, because its price is extremely expensive, seriously limit the widely using at home of such standard substance.
Literature procedure selects deuterated sodium hydroxide that easily water suction is rotten and expensive deuterated methanol as deuterium source and reaction medium to prepare deuterated thing, even select the organic bases that potassium tert.-butoxide is extremely strong, the method has condition harshness, the shortcomings such as cost is more expensive, complex operation.
Summary of the invention
The object of the invention is to provide a kind of deuterated triazolam standard substance as internal standard substance and preparation method thereof, provides a kind of internal standard substance standard substance for analyzing and testing on the one hand; Develop a kind of deuterated triazolam preparation method of easy low cost on the other hand.
The technical solution adopted in the present invention is: deuterated triazolam, compound as shown in formula I:
formula I.
The preparation method of deuterated triazolam, comprises the steps:
(1) by chloro-for 8-6-(2-chloro-phenyl-)-1-methyl-4H-[1,2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine join in dimethyl sulfoxide (DMSO) or DMF and mix, stir.Utilize dimethyl sulfoxide (DMSO) as the advantage of reaction solvent to be: dimethyl sulfoxide (DMSO) boiling point is high, at 160 degrees Celsius and can to react above, the reaction contributed in the present invention is comparatively fast carried out, Reaction time shorten; In addition, dimethyl sulfoxide (DMSO) can dissolve the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2 preferably, 4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine, and cesium carbonate can be dissolved well, the target chemical in the present invention is reacted and carries out smoothly.
(2) add cesium carbonate or salt of wormwood as catalyzer, and add deuterochloroform, be heated to more than 40 degrees Celsius, stir; Cesium carbonate can be dissolved in dimethyl sulfoxide (DMSO) well, and also comparatively salt of wormwood is better for catalyzed reaction efficiency.
(3) the deuterated triazolam that is shown below is separated to obtain:
The preparation method of above-mentioned deuterated triazolam, in step (1): the chloro-6-of 8-(2-the chloro-phenyl-)-1-methyl-4H-[1 often adding 171mg, 2,4] triazole also [4,3-a] [1,4], during benzodiazepine, the add-on of dimethyl sulfoxide (DMSO) or DMF is 5mL-20mL; The chloro-6-of 8-(2-the chloro-phenyl-)-1-methyl-4H-[1 of 171mg can dissolved completely, 2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine when, add the dimethyl sulfoxide (DMSO) of 8mL or the N of 10mL, dinethylformamide is optimal addn, and first too much solvent is cause waste unnecessary, secondly causes more waste liquid to aftertreatment, finally too much solvent makes reactant concn decline, the delayed response time.
The preparation method of above-mentioned deuterated triazolam, in step (2), the add-on of cesium carbonate or salt of wormwood and deuterochloroform is all with the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] amount of substance of benzodiazepine is reference, often add the chloro-6-of 8-(2-the chloro-phenyl-)-1-methyl-4H-[1 of 171mg, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine, the add-on of cesium carbonate or salt of wormwood is 69mg-652mg, the target product yield obtained time wherein to add 138mg salt of wormwood or 326mg cesium carbonate is best, because salt of wormwood or cesium carbonate are as the alkali of reaction needed, according to the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine add-on, theory demands salt of wormwood or cesium carbonate are 1mmol, the way it goes for actual verification, the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2, the 4] triazole often adding 171mg also [4,3-a] [1,4] benzodiazepine, the add-on of deuterochloroform is 0.5mL-3mL, and time wherein to add the deuterochloroform of 1mL, reaction effect is best.The optimal addn of above-mentioned substance is all ensureing to reach maximum yield and the minimum usage quantity under experiment demand condition, and too much adding no longer increases yield, can cause unnecessary waste on the contrary.
The preparation method of above-mentioned deuterated triazolam, is heated to 60-160 degree Celsius in step (2); Temperature raises, and is conducive to fast reaction speed, Reaction time shorten, improves reaction yield; Wherein the shortest with the reaction times needed for 160 degrees Celsius, effect is best.
The preparation method of above-mentioned deuterated triazolam, in step (3): first the mixture obtained in step (2) is extracted, extraction agent is toluene, benzene, ether, methylene dichloride, chloroform, ethyl acetate, propyl carbinol, the mixture of t-butyl methyl ether or propyl carbinol and t-butyl methyl ether is (from the contrast of extraction agent chemistry physical property, benzene, toluene, methylene dichloride, chloroform, the toxicity of ethyl acetate is all greater than propyl carbinol, and ether exists volatile, the shortcomings such as point of ignition is low, and toluene, benzene, ether, the extraction efficiency of methylene dichloride and chloroform is all lower than propyl carbinol, the mixture of t-butyl methyl ether or propyl carbinol and t-butyl methyl ether, therefore, the mixture of propyl carbinol, t-butyl methyl ether or propyl carbinol and t-butyl methyl ether is best extraction agent in the present invention, extraction completely, extraction efficiency is up to 99.9%, namely can by mixed solution 99.9% target product transfer in the mixture of propyl carbinol, t-butyl methyl ether or propyl carbinol and t-butyl methyl ether), then extraction agent is removed, last column chromatography purification.Remove than being easier to as after solvent extraction by t-butyl methyl ether, and this solvent has safer operability (its burning-point is higher than ether) compared with other solvents; Propyl carbinol can better extract the large chemical substance of polarity, and does not dissolve each other with water, can be separated with water preferably, not volatile, operational safety.
The preparation method of above-mentioned deuterated triazolam, the stationary phase of column chromatography is 200-300 object silica gel or 300-400 object neutral alumina, and moving phase is the mixture of trichloromethane and methyl alcohol or the mixture of methylene dichloride and methyl alcohol.300-400 object neutral alumina is as stationary phase, less to Adsorption of Organic, can reduce the loss of product column chromatography, and neutral alumina stable chemical nature, does not have the acidity of acidic alumina, thus can not destroy and degraded product simultaneously.Moving phase is trichloromethane and methyl alcohol, and this combination has better wash-out separating effect, is conducive to the purity improving product.Methylene dichloride is more than or equal to 10 with the ratio of the ratio of the volume of methyl alcohol, that is: V(methylene dichloride): V(methyl alcohol) >=10, energy is separate targets product preferably, removing impurity.Trichloromethane is more than or equal to 6, when V(trichloromethane with the ratio of the ratio of the volume of both methyl alcohol): V(methyl alcohol) when being more than or equal to 6 and being less than or equal to 8.5, the display of separation purity liquid phase analysis reaches more than 99.7%, can directly use as standard substance.
The preparation method of above-mentioned deuterated triazolam, comprises the steps:
(1) in the 100mL there-necked flask of band reflux condensing tube, put into stirrer, adopt magnetic agitation, then the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2, the 4] triazole adding 858mg in there-necked flask also [4,3-a] [1,4] benzodiazepine, then add 40mL dimethyl sulfoxide (DMSO), stirring at room temperature makes it fully dissolve in 17 minutes;
(2) in there-necked flask, powder cesium carbonate 1630mg and deuterochloroform 5 milliliters is added again, now there-necked flask nitrogen (also can be replaced with argon gas, but argon gas price is higher than nitrogen) replace three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, is warmed up to 160 degrees Celsius, and within stirring reaction 0.5-1 hour, (wherein 1 little reaction constantly is terminated, time expand, does not increase yield to reaction again), close oil bath;
(3) cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 100 milliliters, water (consumption of water is more than 2 times of dimethyl sulfoxide (DMSO), for diluting dimethyl sulfoxide (DMSO) preferably, be conducive to extraction agent extraction), now mixed solution in there-necked flask is transferred in 500mL separating funnel, and add the mixture 100mL of propyl carbinol or t-butyl methyl ether or propyl carbinol and t-butyl methyl ether as extraction agent to this separating funnel, after abundant concussion shakes up, stratification, after separating organic layer, water layer continuation 100mL extraction agent shakes up concussion extraction, so repeatedly extract 3 times, the organic phase obtained three times merges, (anhydrous magnesium sulfate can also be used with anhydrous sodium sulfate drying, Calcium Chloride Powder Anhydrous, 4A molecular sieve or Vanadium Pentoxide in FLAKES carry out drying, but Magnesium Chloride Anhydrous and Calcium Chloride Powder Anhydrous easily cause side reaction, therefore do not adopt, Vanadium Pentoxide in FLAKES has strongly-acid, therefore does not also adopt, 4A molecular sieve drying effect is slower, by contrast, anhydrous sodium sulphate is better), filter after dry 2 hours, removing solid sodium sulfate, filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, and this Powdered faint yellow solid column chromatography is further purified, and Separation of Neutral aluminum oxide is 300-400 order, moving phase is the mixture of trichloromethane and methyl alcohol, and the ratio of the ratio of trichloromethane and the volume both methyl alcohol is 6 ~ 8.5.
The invention has the beneficial effects as follows: the present invention selects more cheap deuterochloroform and non-deuterated triazolam (the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2,4] triazole also [4,3-a] [1,4] benzodiazepine) namely commercially available stable, can directly commercially obtain) be raw material, with common non-deuterated reagent for reaction medium, do alkali with cesium carbonate or salt of wormwood, there is the advantages such as reaction conditions is more simple and easy, easy to operate, yield is high, easy purification.
Preparation method of the present invention is brief, easy and simple to handle, with low cost, easy purifying.By commercially available non-deuterated triazolam in non-deuterated solvent atmosphere, doing deuterium source with a small amount of deuterated reagent, obtaining deuterated triazolam in the short period, by obtaining sterling after simple column chromatography purification.The deuterated triazolam standard substance purity prepared according to the present invention is high, stable chemical nature; Can conveniently for the preparation of analysis standard substance.The deuterated internal standard substance that preparation method of the present invention uses when can be used for production analyzing and testing triazolam.
Embodiment
The reaction scheme of following examples:
Triazolam: Chinese another name: U-33030, surazepam; The chloro-6-of chemical name: 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine.
Embodiment 1
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, 171mg is added, the chloro-6-of 0.5mmol8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine, add 8mL dimethyl sulfoxide (DMSO) again, stirring at room temperature makes it fully dissolve in 17 minutes, powder cesium carbonate 326mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 160 degrees Celsius, stirring reaction 1 hour, close oil bath, cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 20 milliliters, water, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add propyl carbinol 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating n-butanol layer, water layer continuation 20mL propyl carbinol shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 97.3% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 97.3% to transfer in propyl carbinol), the butanol solution obtained three times merges, filter after 2 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, propyl carbinol filtrate solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is V(trichloromethane): V(methyl alcohol)=6:1, now obtain the display of white powder solid deuterated triazolam 148.5mg(liquid phase analysis: the purity of deuterated triazolam is 98.1%), yield 86%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Embodiment 2
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 8mL dimethyl sulfoxide (DMSO) again, stirring at room temperature makes it fully dissolve in 17 minutes, powder cesium carbonate 326mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is in stirred at ambient temperature after 24 hours, 20 milliliters, water is added in there-necked flask, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add propyl carbinol 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating n-butanol layer, water layer continuation 20mL propyl carbinol shakes up concussion extraction, so repeatedly extract 3 times, the butanol solution obtained three times merges, filter after 3 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, propyl carbinol filtrate solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, this material column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is V(trichloromethane): V(methyl alcohol)=6:1, obtain white powder solid 160mg, nuclear-magnetism is accredited as the chloro-6-of raw material 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine, substantially the deuterated triazolam of target product is not had to generate.
Embodiment 3
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 10mL dimethyl sulfoxide (DMSO) again, stirring at room temperature makes it fully dissolve in 30 minutes, powder cesium carbonate 326mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 160 degrees Celsius, stirring reaction 1 hour, close oil bath, 20 milliliters, water is added in there-necked flask, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add t-butyl methyl ether 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating tertbutyl methyl ether layer, water layer continuation 20mL t-butyl methyl ether shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 97.8% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 97.8% to transfer in t-butyl methyl ether), the t-butyl methyl ether solution obtained three times merges, filter after 2 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, t-butyl methyl ether filtrate solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is V(trichloromethane): V(methyl alcohol)=6:1, obtain the display of white powder solid product deuterated triazolam 127.7mg(liquid phase analysis: the purity of deuterated triazolam is 98.5%), yield 74%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Embodiment 4
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 8mL dimethyl sulfoxide (DMSO) again, stirring at room temperature makes it fully dissolve in 17 minutes, powder cesium carbonate 326mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 160 degrees Celsius, stirring reaction 1 hour, close oil bath, cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 20 milliliters, water, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and the volume ratio of the mixture 20mL(propyl carbinol from t-butyl methyl ether to this separating funnel and t-butyl methyl ether that add propyl carbinol and is 1:1.3), after abundant concussion shakes up, stratification, after separating organic layer, the mixture (volume ratio of propyl carbinol and t-butyl methyl ether is 1:1.3) of water layer continuation 20mL propyl carbinol and t-butyl methyl ether shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 99.1% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 99.1% to transfer in organic phase), the organic phase solution obtained three times merges, filter after 2 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is V(trichloromethane): V(methyl alcohol)=8.5:1, now obtain the display of white powder solid deuterated triazolam 153.5mg(liquid phase analysis: the purity of deuterated triazolam is 99.5%, can directly use as standard substance), yield 89%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Embodiment 5
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (858mg, 2.5mmol), add 40mL dimethyl sulfoxide (DMSO) again, stirring at room temperature makes it fully dissolve in 17 minutes, powder cesium carbonate 1630mg and deuterochloroform 5 milliliters is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 160 degrees Celsius, stirring reaction 1 hour, close oil bath, cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 100 milliliters, water, now mixed solution in there-necked flask is transferred in 500mL separating funnel, and the volume ratio of the mixture 100mL(propyl carbinol from t-butyl methyl ether to this separating funnel and t-butyl methyl ether that add propyl carbinol and is: 2:1), after abundant concussion shakes up, stratification, after separating organic layer, (volume ratio of propyl carbinol and t-butyl methyl ether is the mixture of water layer continuation 100mL propyl carbinol and t-butyl methyl ether: 2:1) shake up concussion extraction, (liquid phase analysis display extraction efficiency is 99.9% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 99.9% to transfer in organic phase), the organic phase solution obtained three times merges, filter after 2 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is V(trichloromethane): V(methyl alcohol)=7:1, now obtain the display of white powder solid deuterated triazolam 845mg(liquid phase analysis: the purity of deuterated triazolam is 99.7%, can directly use as standard substance), yield 98%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Embodiment 6
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, 171mg is added, the chloro-6-of 0.5mmol8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine, add 10mLN again, dinethylformamide, stirring at room temperature makes it fully dissolve in 30 minutes, powder salt of wormwood 138mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 120 degrees Celsius, stirring reaction 2 hours, close oil bath, cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 20 milliliters, water, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add ethyl acetate 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating ethyl acetate layer, water layer continuation 20mL ethyl acetate shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 92.3% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 92.3% to transfer in ethyl acetate), the ethyl acetate solution obtained three times merges, filter after 3 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, ethyl acetate filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, being separated silica gel is 200-300 order, moving phase is V(methylene dichloride): V(methyl alcohol)=15:1, now obtain the display of white powder solid deuterated triazolam 140mg(liquid phase analysis: the purity of deuterated triazolam is 92%), yield 81%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H)。
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)
Embodiment 7
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 10mLN again, dinethylformamide, stirring at room temperature makes it fully dissolve in 30 minutes, powder salt of wormwood 138mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is in stirred at ambient temperature after 24 hours, 20 milliliters, water is added in there-necked flask, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add ethyl acetate 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating ethyl acetate layer, water layer continuation 20mL ethyl acetate shakes up concussion extraction, so repeatedly extract 3 times, the ethyl acetate solution obtained three times merges, filter after 3 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, ethyl acetate filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, this material column chromatography is further purified, being separated silica gel is 200-300 order, moving phase is V(methylene dichloride): V(methyl alcohol)=15:1, obtain white powder solid 160mg, nuclear-magnetism is accredited as the chloro-6-of raw material 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine, substantially the deuterated triazolam of target product is not had to generate.
Embodiment 8
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 10mLN again, dinethylformamide, stirring at room temperature makes it fully dissolve in 30 minutes, powder salt of wormwood 138mg and deuterochloroform 0.5 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 120 degrees Celsius, stirring reaction 6 hours, close oil bath, 20 milliliters, water is added in there-necked flask, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add ethyl acetate 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating ethyl acetate layer, water layer continuation 20mL ethyl acetate shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 91.8% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 91.8% to transfer in ethyl acetate), the ethyl acetate solution obtained three times merges, filter after 3 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, ethyl acetate filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, being separated silica gel is 200-300 order, moving phase is V(methylene dichloride): V(methyl alcohol)=15:1, obtain the display of white powder solid product deuterated triazolam 119mg(liquid phase analysis: the purity of deuterated triazolam is 91%), yield 69%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Embodiment 9
In the 100mL there-necked flask of a band reflux condensing tube, put into stirrer, adopt magnetic agitation, then in there-necked flask, add the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine (171mg, 0.5mmol), add 10mLN again, dinethylformamide, stirring at room temperature makes it fully dissolve in 30 minutes, powder salt of wormwood 69mg and deuterochloroform 1 milliliter is added again in there-necked flask, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 120 degrees Celsius, stirring reaction 8 hours, close oil bath, cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 20 milliliters, water, now mixed solution in there-necked flask is transferred in 100mL separating funnel, and add ethyl acetate 20mL to this separating funnel, after abundant concussion shakes up, stratification, after separating ethyl acetate layer, water layer continuation 20mL ethyl acetate shakes up concussion extraction, (liquid phase analysis display extraction efficiency is 93.2% so repeatedly to extract 3 times, namely the deuterated triazolam of the target product in mixed solution has 93.2% to transfer in ethyl acetate), the ethyl acetate solution obtained three times merges, filter after 3 hours with anhydrous sodium sulfate drying, removing solid sodium sulfate, ethyl acetate filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, being separated silica gel is 200-300 order, moving phase is V(methylene dichloride): V(methyl alcohol)=15:1, now obtain the display of white powder solid deuterated triazolam 112mg(liquid phase analysis: the purity of deuterated triazolam is 92.7%), yield 65%(supposes 8-chloro-6-(2-chloro-phenyl-)-1-methyl-4H-[1, 2, 4] triazole also [4, 3-a] [1, 4] benzodiazepine complete reaction calculates).
1HNMR(400MHz,DMSO-d6):δ7.915-7.893(d,1H),7.851-7.823(dd,1H)，7.664-7.632(m,1H),7.541-7.496(m,2H),7.483-7.441(m,1H),7.144-7.138(d,1H),2.545(s,3H).
LC-MS:m/z(%)calcdfor[C17H12Cl2N4]
+342.04,found344.9;
LC-MS:100%(λ=214nm),100%(λ=254nm)。
Claims (4)
1. the preparation method of deuterated triazolam, is characterized in that, comprises the steps:
(1) by chloro-for 8-6-(2-chloro-phenyl-)-1-methyl-4H-[1,2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine join in dimethyl sulfoxide (DMSO) or DMF, mixing, stir;
(2) add cesium carbonate or salt of wormwood as catalyzer, and add deuterochloroform, be heated to 60-160 degree Celsius, stir;
(3) first the mixture obtained in step (2) is extracted, extraction agent is the mixture of propyl carbinol, t-butyl methyl ether or propyl carbinol and t-butyl methyl ether, then extraction agent is removed, last column chromatography purification, the stationary phase of column chromatography is 300-400 object neutral alumina, moving phase is the mixture of methylene dichloride and methyl alcohol or the mixture of trichloromethane and methyl alcohol, trichloromethane is more than or equal to 6 with the ratio of the ratio of the volume of both methyl alcohol and is less than or equal to 8.5, and methylene dichloride is more than or equal to 10 with the ratio of the ratio of the volume of both methyl alcohol; Be separated to obtain the deuterated triazolam that is shown below:
2. the preparation method of deuterated triazolam according to claim 1, it is characterized in that, in step (1): the chloro-6-of 8-(2-the chloro-phenyl-)-1-methyl-4H-[1 often adding 171mg, 2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine time, the add-on of dimethyl sulfoxide (DMSO) or DMF is 5mL-20mL.
3. the preparation method of deuterated triazolam according to claim 1, it is characterized in that, in step (2): the chloro-6-of 8-(2-the chloro-phenyl-)-1-methyl-4H-[1 often adding 171mg, 2,4] triazole also [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine time, the add-on of cesium carbonate or salt of wormwood is 69mg-652mg, and the add-on of deuterochloroform is 0.5mL-3mL.
4., according to the preparation method of the arbitrary described deuterated triazolam of claim 1-3, it is characterized in that, comprise the steps:
(1) in the 100mL there-necked flask of band reflux condensing tube, put into stirrer, adopt magnetic agitation, then the chloro-6-of 8-(2-chloro-phenyl-)-1-methyl-4H-[1,2, the 4] triazole adding 858mg in there-necked flask also [4,3-a] [1,4] benzodiazepine, then add 40mL dimethyl sulfoxide (DMSO), stirring at room temperature makes it fully dissolve in 17 minutes;
(2) in there-necked flask, powder cesium carbonate 1630mg and deuterochloroform 5 milliliters is added again, now by there-necked flask nitrogen replacement three times, to remove air and moisture in there-necked flask, after this there-necked flask is positioned in oil bath, be warmed up to 160 degrees Celsius, stirring reaction 0.5-1 hour, closes oil bath;
(3) cool under reaction flask being positioned over room temperature, to be cooledly after room temperature, in there-necked flask, add 100 milliliters, water, now mixed solution in there-necked flask is transferred in 500mL separating funnel, and add the mixture 100mL of propyl carbinol and t-butyl methyl ether as extraction agent to this separating funnel, after abundant concussion shakes up, stratification, after separating organic layer, water layer continuation 100mL extraction agent shakes up concussion extraction, so repeatedly extract 3 times, the organic phase obtained three times merges, with anhydrous sodium sulfate drying, filter after dry 2 hours, removing solid sodium sulfate, filtrate is solvent removed by evaporation at reduced pressure on a rotary evaporator, obtain thick faint yellow solid, room temperature becomes Powdered faint yellow solid after placing 2 hours, this Powdered faint yellow solid column chromatography is further purified, Separation of Neutral aluminum oxide is 300-400 order, moving phase is the mixture of trichloromethane and methyl alcohol, the ratio of the ratio of trichloromethane and the volume both methyl alcohol is 6 ~ 8.5.
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| CN102539765A (en) * | 2010-12-29 | 2012-07-04 | 北京宝瑞源科技孵化有限公司 | Triazolam detection kit and preparation method thereof |
| CN103204856A (en) * | 2013-04-15 | 2013-07-17 | 公安部物证鉴定中心 | Deuterated alprazolam and preparation method thereof |
| CN103204849A (en) * | 2013-04-27 | 2013-07-17 | 黑龙江大学 | Method for preparing thiabendazole |
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| CN102539765A (en) * | 2010-12-29 | 2012-07-04 | 北京宝瑞源科技孵化有限公司 | Triazolam detection kit and preparation method thereof |
| CN103204856A (en) * | 2013-04-15 | 2013-07-17 | 公安部物证鉴定中心 | Deuterated alprazolam and preparation method thereof |
| CN103204849A (en) * | 2013-04-27 | 2013-07-17 | 黑龙江大学 | Method for preparing thiabendazole |
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| Title |
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| Axial-Selective H/D Exchange of Glycine-Derived 1H-Benzo[e][1,4]diazepin-2(3H)-ones: Kinetic and Computational Studies of Enantiomerization;Paul R. Carlier，等;《J. Org. Chem.》;20100909;第75卷(第19期);第6588-6594页 * |
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