CN107365276A - A kind of diazepam D5 preparation method - Google Patents
A kind of diazepam D5 preparation method Download PDFInfo
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- CN107365276A CN107365276A CN201710670878.XA CN201710670878A CN107365276A CN 107365276 A CN107365276 A CN 107365276A CN 201710670878 A CN201710670878 A CN 201710670878A CN 107365276 A CN107365276 A CN 107365276A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a kind of diazepam D5 preparation method; with the methyl 4H 3 of 6 chlorine 2; the ketone of 1 benzoxazine 4 (compound of formula I) is raw material, through with the reaction of deuterated bromobenzene RMgBr, hydrolysis, acylation, cyclization, methylate, isolate and purify to obtain diazepam D5.Present invention process have reaction condition it is gentle, it is simple to operate etc. a little, the diazepam D5 standard items prepared using the present invention, chemical purity is high, and good product quality, stability is good, can be conveniently used for the preparation of analysis standard items.Preparation method of the present invention can be used for the deuterated internal standard compound used during production analysis detection diazepam.
Description
Technical field
The present invention relates to chemical analysis detection field, and in particular in forensic science field among deuterated diazepam standard items
The preparation method of body.
Background technology
Diazepam is Benzodiazepines central nervous depressant, can cause the suppression of central nervous system different parts, with
The increasing of dosage, clinical manifestation can even be gone into a coma from slight calmness to hypnosis.In recent years, because of the throwing of such medicine initiation
Poison, the criminal case such as commit suiside, wrongly take happen occasionally.This requires judicial identification of public security organs department to being related to the sample sample of such medicine
This is detected.And in order to ensure detection method prepares, reliable means are to add internal standard compound in detection, and it is corresponding deuterated
Thing is then optimal internal standard compound, and because its purposes is non-civilian, band has specific characteristics, for this research of the China for such commodity and
Produce it is relatively fewer, and this kind of standard items analysis detect in be must and it is indispensable.Deuterated internal standard compound stability is poor,
China not yet breaks through the technical bottleneck of the deuterated thing production in this restriction China, there is no the producer for the deuterated thing for producing case-involving poisonous substance,
The use of the product is only capable of relying on import.For a long time, deuterated internal standard compound used in China is to rely on import, and external import
It is d5The methanol solution of-diazepam, rather than solid powder, it is expensive plus its, seriously limit such standard items
Widely using at home.
The content of the invention
It is an object of the present invention to provide a kind of diazepam-D5 preparation method.
To reach above-mentioned purpose, the present invention uses following technical proposals：
A kind of diazepam-D5 preparation method, Formula V compound is dissolved in chloroform or DMF, added under the conditions of ice salt bath
Na2CO3Or NaH, stirring, the chloroformic solution or DMF solution of iodomethane are added, reacts and is extracted after terminating with organic solvent, is depressurized
Concentration, column chromatography are produced such as Formula IV compound, specifically reacted as follows：
Above-mentioned diazepam-D5 preparation method, 5.5g Formula V compounds are dissolved in 30mL chloroforms or DMF, ice salt bath cooling
To -5 DEG C, 2.12g Na are added2CO3Or continue to stir 15min after 0.48g NaH, system is in light yellow clear shape.By 2.8g iodine
Methane is dissolved in the solution formed in 25mL chloroforms or DMF and is added drop-wise to reaction system, is added dropwise, and reacts 30min；Then slowly add
Enter saturated ammonium chloride and reaction is quenched, after chloroform or ethyl acetate extract, merge organic phase, three times, after drying, decompression is dense for washing
Contracting, column chromatography obtain diazepam-D5 shown in Formula IV, recrystallizing methanol, obtain white crystal.
Above-mentioned diazepam-D5 preparation method, Formula V compounds process for production thereof comprise the following steps：
(1) compound as shown in Formula Il is prepared as the compound as shown in following formula I：
(2) compound shown in following formula III is prepared as the compound shown in Formula II：
(3) compound shown in following formula IV is prepared as the compound shown in formula III：
(4) compound shown in following Formula V is prepared as the compound shown in formula IV：
Above-mentioned diazepam-D5 preparation method, in step (1)：Compound of formula I 6- chloro-2-methyl -4H-3,1- benzos
Oxazine -4- ketone and freshly prepd C6D5MgBr THF solution obtains in toluene in 0 DEG C of reaction：Compound of formula I 2- acetamides -5-
Chlorobenzophenone -2', 3', 4', 5', 6'-d5.Freshly prepd C6D5MgBr is prepared as follows：Mg bars (2.6g) are placed in
250mL there-necked flask, anhydrous THF (50mL) is added, then add iodine grain (30mg), it is molten to stir the lower THF that deuterated bromobenzene is added dropwise
C is made in liquid (the deuterated bromobenzenes of 8.8g are added in 40mL THF)6D5MgBr THF solution；Compound of formula I and C6D5MgBr's rubs
You are than being 1:1.05.
Above-mentioned diazepam-D5 preparation method, in step (1)：Compound of formula I and C6D5MgBr mol ratio is 1:
1.05,1g compound of formula I toluene 5mL；After reaction terminates, the watery hydrochloric acid that concentration is 6mol/L is added, is divided after stirring 30min
Liquid, organic phase are washed twice, are concentrated under reduced pressure after drying, and obtain yellow oil, and gained crude product can be directly used for reacting in next step.
Above-mentioned diazepam-D5 preparation method, in step (2)：Formula II compound is added in ethanol, then added again
Enter NaOH solution, be heated to reflux sloughing protection group and obtain formula III compound 2- amino -5- chlorobenzophenone -2', 3', 4', 5',
6'-d5。
Above-mentioned diazepam-D5 preparation method, in step (2)：NaOH solution concentration used is 3mol/L, NaOH dosages
Mol ratio with Formula II compound is 2:1；After reaction terminates, dichloromethane extraction is added, after organic phase is dried, filtering, decompression
Concentration, column chromatography obtain product.
Above-mentioned diazepam-D5 preparation method, in the step (3)：Formula III compound is with bromoacetyl bromide in alkaline bar
Reaction obtains formula IV compound 2- acetbromamide -5- chlorobenzophenones -2', 3', 4', 5', 6'-d in organic solvent under part5。
Above-mentioned diazepam-D5 preparation method, in the step (3)：Bromoacetyl bromide and the mol ratio of formula III compound
For 1.5:1；Alkali used is triethylamine, pyridine or DBU, and the mol ratio of triethylamine and formula III compound is 2:1；It is used organic molten
Agent is toluene, chloroform, dichloromethane or tetrahydrofuran, and the mass ratio of chloroform volume used and formula III compound is 8:1mL/g；
After reaction terminates, add water quenching to go out reaction, separate organic phase, aqueous phase is extracted with organic solvent again, and merging organic phase simultaneously uses saturated carbon
After sour sodium washing, dry and be concentrated under reduced pressure, obtain grease, be directly used in without purifying and react in next step.Alkali used preferably three second
Amine, the yield highest of triethylamine, effect are best；The preferred chloroform of organic solvent used, haloform reaction effect is good, high income, easily returns
Receive.
Above-mentioned diazepam-D5 preparation method, in the step (4)：Formula IV compound is dissolved in methanol and is passed through ammonia
Gas obtains the chloro- 1,3- dihydros -5- (phenyl-d of Formula V compound 7- in 50 DEG C of reactions5) -2H-1,4- benzodiazepine -2- ketone.
Above-mentioned diazepam-D5 preparation method, in the step (4)：Gained crude product formula IV compound is molten with a small amount of methanol
It is transferred to after solution in closed reaction vessel, adds methanol, the cumulative volume of methanol used is 5 with the mass ratio of formula IV compound:
1mL/g；After methanol adds, sealed reaction vessel, ammonia, ammonia pressure 1kg/cm are passed through2, it is warming up to 50 DEG C and reacts 12 hours
Afterwards, reaction mass is taken out, after methanol is recovered under reduced pressure, adds appropriate water, ethyl acetate is added and extracts 3 times, merge organic phase, do
Dry, column chromatography obtains chloro- 1, the 3- dihydros -5- (phenyl-d of Formula V compound 7- after removing solvent5) -2H-1,4- benzodiazepines -
2- ketone.
Compound of formula I used in the present invention can obtain with the following method：
Operating method is as follows：15g 2- amino -5- chlorobenzoic acid formula A compounds are placed in 100mL round-bottomed flasks, added
50mL Ac2O, flow back 1.5h, and TLC monitoring reaction to raw material disappears, and removes about 25mLAc under reduced pressure2O, crystallization is stood, was depressurized
After filter, with a small amount of Ac2O is washed, and 55 DEG C of product is dried under reduced pressure 12h, obtains white crystal compound of formula I.
Beneficial effects of the present invention are as follows：
On the one hand a kind of internal standard compound standard items for analyzing detection are provided；On the other hand, developed a kind of with certainly
The new technology of the deuterated diazepams of synthesis d5- of main intellectual property, the technique have that reaction condition is gentle, simple to operate, gained d5-
Deuterated diazepam good product quality, the advantages that stability is good.
Brief description of the drawings
The embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 diazepams-D5 synthetic route chart.
Embodiment
Embodiment 1
Step (1)：2- acetamide -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5The preparation of (Formula II compound)
Mg bars 2.6g is placed in 250mL there-necked flask, the anhydrous THF of 50mL is added, then adds 30mg iodine grains, stirs lower drip
Add the THF solution (the deuterated bromobenzenes of 8.8g are added to 40mL THF) of deuterated bromobenzene, back flow reaction 1 hour, RMgBr is made.
Raw material 10.0g 6- chloro-2-methyl -4H-3,1- benzoxazine -4- ketone (compound of formula I) is placed in 250mL single port
Bottle, toluene 50mL is then added, ice bath is cooled to less than 0 DEG C, above-mentioned RMgBr is added dropwise, and time for adding is more than 45min.Add
Bi Hou, stirs 30min at 0 DEG C, is then warmed to room temperature after being stirred overnight, and reaction is cooled into 0 DEG C, adds 100mL6mol/L
Watery hydrochloric acid, stir liquid separation after 30min, aqueous phase is extracted twice with toluene, merges organic phase, organic phase is washed twice, after drying
It is concentrated under reduced pressure, obtains the crude product that yellow oil is Formula II compound, the crude product can be directly used for reacting in next step.
Step (2)：2- amino -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5The preparation of (formula III compound)
Crude mixture obtained by step (1) is added in 40mL ethanol and dissolved, then add NaOH solution (3mol/L,
16mL), it is heated to reflux, TLC detections reaction to Formula II compound disappears, and is cooled to room temperature, and DCM (dichloromethane) extractions are organic
After mutually drying, the yellow oil being concentrated under reduced pressure is filtered, silica gel 400-500 mesh column chromatographies obtain yellow product (petroleum ether and acetic acid
The volume ratio of ethyl ester is 15:1) faint yellow solid 10.3g, as formula III compound are obtained, step (1) and the step of step (2) two are received
Rate 72%.
1H NMR(300MHz,DMSO-d6) δ 6.91 (d, J=8.9Hz, 1H), 7.18 (d, J=2.5Hz, 1H), 7.23 (s,
2H), 7.32 (dd, J=2.5,8.9Hz, 1H).
Step (3)：2- acetbromamide -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5The preparation of (formula IV compound)：
7.08g formula III compounds are placed in 250mL round-bottomed flasks, the dissolving of 36mL chloroforms is added, then adds 6.06g
Triethylamine, ice bath are cooled to 0 DEG C, and the chloroformic solution (3.9mL bromoacetyl bromides are added in 20mL chloroforms) of bromoacetyl bromide is added dropwise,
After the completion of TLC monitoring reactions, water quenching is added to go out reaction, chloroform extraction organic phase (each 30mL, altogether 3 times), merging organic phase is simultaneously
After being washed with saturated sodium carbonate, dry and be concentrated under reduced pressure, obtain the crude product of grease, as formula IV compound, it is direct without purifying
For reacting in next step.
Step (4)：The chloro- 1,3- dihydros -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine -2- ketone (Formula V compound)
Prepare：
Gained 11.6g crude product formula IV compounds are transferred in closed reaction vessel after being dissolved with 18mL methanol, are added
40mL methanol, sealed reaction vessel, it is passed through ammonia, ammonia pressure 1kg/cm2, be warming up to 50 DEG C reaction 12 hours after, take out
Reaction mass, after methanol is recovered under reduced pressure, 50mL water is added, add ethyl acetate and extract 3 times, merge organic phase, dry, remove
(petroleum ether is 4 with ethyl acetate volume ratio to silica gel 400-500 mesh column chromatography after solvent:1) white solid 5.79g Formula V is obtained
Compound, step (3) and the step yield 70% of step (4) two.
1H NMR(300MHz,DMSO-d6) δ 4.15 (s, 2H), 7.19 (d, J=2.5Hz, 1H), 7.28 (d, J=8.7Hz,
1H), 7.63 (dd, J=2.5,8.7Hz, 1H), 10.67 (s, 1H).
Step (5)：d5- deuterated diazepam：The chloro- 1,3- dihydros -1- methyl -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine *s
The preparation of miscellaneous -2- ketone (Formula IV compound)：
Formula V compound (5.5g) is dissolved in chloroform (30mL), ice salt bath is cooled to -5 DEG C or so, adds Na2CO3(2.12g)
After continue stir 15min, now, system is in light yellow clear shape.By the chloroformic solution of iodomethane, (2.8g iodomethane is dissolved in 25mL
Chloroform) reaction system is slowly dropped to, it is added dropwise, reacts 30min.It is then slowly added to saturated ammonium chloride and reaction, chlorine is quenched
After imitative extraction, merge organic phase, washing three times, after drying, is concentrated under reduced pressure, silica gel 400-500 mesh column chromatographies (PE/EA=4:1)
Deuterated diazepam (foamy white solid) is obtained, recrystallizing methanol, obtains white crystal 3.4g, yield 60%, HPLC purity>
99%.
m.p.123.5-123.9℃；1H NMR(300MHz,CDCl3) δ 3.38 (s, 3H), 3.76 (d, J=10.8Hz,
1H), 4.82 (d, J=10.8Hz, 1H), 7.27-7.30 (m, 2H), 7.50 (dd, J=2.5,8.8Hz, 1H)；13C NMR
(75MHz,CDCl3) δ 34.8,56.9,122.5,128.4 (dt, J=23.4,37.9Hz, 1C) 128.7,129.0,129.2,
129.8,130.0,131.4,137.9,142.5,168.8,169.9；HRMS(ESI)C16H8ClD5N2NaO[M+Na]+
312.0922,found:312.0914.
Embodiment 2 (Formula V compounds process for production thereof)
Step (1), (2) are same as Example 1.
Step (3)：2- acetbromamide -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5The preparation of (formula IV compound)：
7.08g formula III compounds are placed in 250mL round-bottomed flasks, the dissolving of 36mL toluene is added, then adds 4.74g
Pyridine, ice bath are cooled to 0 DEG C, and the toluene solution (3.9mL bromoacetyl bromides are added in 20mL chloroforms) of bromoacetyl bromide, TLC is added dropwise
After the completion of monitoring reaction, water quenching is added to go out reaction, toluene extraction organic phase (each 30mL, totally 3 times), merging organic phase simultaneously uses saturation
After sodium carbonate washing, dry and be concentrated under reduced pressure, obtain the crude product of grease, as formula IV compound, be directly used in down without purifying
Single step reaction.
Step (4)：The chloro- 1,3- dihydros -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine -2- ketone (Formula V compound)
Prepare：
Gained 11.6g crude product formula IV compounds are transferred in closed reaction vessel after being dissolved with 18mL methanol, are added
40mL methanol, sealed reaction vessel, it is passed through ammonia, ammonia pressure 1kg/cm2, be warming up to 50 DEG C reaction 12 hours after, take out
Reaction mass, after methanol is recovered under reduced pressure, 50mL water is added, add ethyl acetate and extract 3 times, merge organic phase, dry, remove molten
(petroleum ether is 4 with ethyl acetate volume ratio to silica gel 400-500 mesh column chromatography after agent:1) column chromatography obtains white solid 5.37g formulas
V compounds, step (3) and the step yield 65% of step (4) two.
1H NMR(300MHz,DMSO-d6) δ 4.15 (s, 2H), 7.19 (d, J=2.5Hz, 1H), 7.28 (d, J=8.7Hz,
1H), 7.63 (dd, J=2.5,8.7Hz, 1H), 10.67 (s, 1H).
Embodiment 3
The present embodiment and the difference of embodiment 1 are step (5)：Diazepam-D5：The chloro- 1,3- dihydros -1- methyl -5- of 7-
(phenyl-d5) -2H-1,4- benzodiazepine -2- ketone (Formula IV compound) preparation：
Formula V compound (5.5g) is dissolved in DMF (30mL), ice salt bath is cooled to -5 DEG C, adds NaH (0.48g) and continues afterwards
15min is stirred, now, system is in light yellow clear shape.By the DMF solution of iodomethane, (2.8g iodomethane is dissolved in 25mL DMF
In) be slowly dropped to reaction system (iodomethane is dissolved in DMF and is slowly added dropwise, purpose avoiding produce on two first
The accessory substance of base, to isolate and purify difficult and yield low), it is added dropwise, reacts 30min.Saturated ammonium chloride is then slowly added to quench
Go out reaction, after ethyl acetate extraction, merge organic phase, washing three times, after drying, is concentrated under reduced pressure, silica gel 400-500 mesh column chromatographies
(petroleum ether is 4 with ethyl acetate volume ratio:1) deuterated diazepam (foamy white solid) is obtained, recrystallizing methanol, obtains white crystalline substance
Body 4.3g, yield 75%, HPLC purity>99%.
m.p.123.5-123.9℃；1H NMR(300MHz,CDCl3) δ 3.38 (s, 3H), 3.76 (d, J=10.8Hz,
1H), 4.82 (d, J=10.8Hz, 1H), 7.27-7.30 (m, 2H), 7.50 (dd, J=2.5,8.8Hz, 1H)；13C NMR
(75MHz,CDCl3) δ 34.8,56.9,122.5,128.4 (dt, J=23.4,37.9Hz, 1C) 128.7,129.0,129.2,
129.8,130.0,131.4,137.9,142.5,168.8,169.9；HRMS(ESI)C16H8ClD5N2NaO[M+Na]+
312.0922,found:312.0914.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair
The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description
To make other changes in different forms, all embodiments can not be exhaustive here, it is every to belong to this hair
Row of the obvious changes or variations that bright technical scheme is extended out still in protection scope of the present invention.
Claims (10)
1. a kind of diazepam-D5 preparation method, it is characterised in that Formula V compound is dissolved in chloroform or DMF, ice salt bath bar
Na is added under part2CO3Or NaH, stirring, the chloroformic solution or DMF solution of iodomethane are added, reacts and uses organic solvent after terminating
Extraction, is concentrated under reduced pressure, and column chromatography is produced such as Formula IV compound, is specifically reacted as follows：
2. diazepam-D5 according to claim 1 preparation method, it is characterised in that be dissolved in 5.5g Formula V compounds
30mL chloroforms or DMF, ice salt bath are cooled to -5 DEG C, add 2.12g Na2CO3Or continue to stir 15min, system after 0.48g NaH
In light yellow clear shape.2.8g iodomethane is dissolved in the solution formed in 25mL chloroforms or DMF and is added drop-wise to reaction system, is dripped
Finish, react 30min；It is then slowly added to saturated ammonium chloride and reaction is quenched, after chloroform or ethyl acetate extract, merges organic phase,
Washing three times, after drying, is concentrated under reduced pressure, column chromatography obtains diazepam-D5 shown in Formula IV, recrystallizing methanol, obtains white crystal.
3. diazepam-D5 according to claim 1 or 2 preparation method, it is characterised in that Formula V compounds process for production thereof
Comprise the following steps：
(1) compound as shown in Formula Il is prepared as the compound as shown in following formula I：
(2) compound shown in following formula III is prepared as the compound shown in Formula II：
(3) compound shown in following formula IV is prepared as the compound shown in formula III：
(4) compound shown in following Formula V is prepared as the compound shown in formula IV：
4. a kind of diazepam-D5 according to claim 3 preparation method, it is characterised in that in step (1)：Formulas I
Compound 6- chloro-2-methyl -4H-3,1- benzoxazine -4- ketone and freshly prepd C6D5MgBr THF solution is anti-in 0 DEG C in toluene
It should obtain：Compound of formula I 2- acetamide -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5。
5. a kind of diazepam-D5 according to claim 4 preparation method, it is characterised in that in step (1)：Formulas I
Compound and C6D5MgBr mol ratio is 1:1.05,1g compound of formula I toluene 5mL；After reaction terminates, addition concentration is 6mol/
L watery hydrochloric acid, stirs liquid separation after 30min, and organic phase is washed twice, is concentrated under reduced pressure after drying, obtains yellow oil, gained crude product
It can be directly used for reacting in next step.
6. a kind of diazepam-D5 according to claim 3 preparation method, it is characterised in that in step (2)：By formula
II compounds are added in ethanol, then add NaOH solution, are heated to reflux sloughing protection group and are obtained formula III compound 2- ammonia
Base -5- chlorobenzophenones -2', 3', 4', 5', 6'-d5。
7. a kind of diazepam-D5 according to claim 6 preparation method, it is characterised in that in step (2)：It is used
NaOH solution concentration is 3mol/L, and the mol ratio of NaOH dosages and Formula II compound is 2:1；After reaction terminates, dichloromethane is added
Alkane extracts, and after organic phase is dried, filters, is concentrated under reduced pressure, column chromatography obtains product.
8. a kind of diazepam-D5 according to claim 3 preparation method, it is characterised in that in the step (3)：
Reaction obtains formula IV compound 2- acetbromamides -5- to formula III compound in organic solvent in the basic conditions with bromoacetyl bromide
Chlorobenzophenone -2', 3', 4', 5', 6'-d5。
9. a kind of diazepam-D5 according to claim 8 preparation method, it is characterised in that in the step (3)：
The mol ratio of bromoacetyl bromide and formula III compound is 1.5:1；Alkali used is triethylamine, pyridine or DBU, triethylamine and formula III
The mol ratio of compound is 2:1；Organic solvent used is toluene, chloroform, dichloromethane or tetrahydrofuran, chloroform volume and formula used
The mass ratio of III compounds is 8:1mL/g；After reaction terminates, add water quenching to go out reaction, separate organic phase, aqueous phase is again with organic molten
Agent extracts, and after merging organic phase and being washed with saturated sodium carbonate, dries and is concentrated under reduced pressure, obtain grease, is directly used without purifying
Reacted in next step.
10. a kind of diazepam-D5 according to claim 3 preparation method, it is characterised in that in the step (4)：Institute
Obtain after crude product formula IV compound is dissolved with a small amount of methanol and be transferred in closed reaction vessel, add methanol, the totality of methanol used
The mass ratio of product and formula IV compound is 5:1mL/g；After methanol adds, sealed reaction vessel is passed through ammonia, and ammonia pressure is
1kg/cm2, be warming up to 50 DEG C reaction 12 hours after, take out reaction mass, after methanol is recovered under reduced pressure, add appropriate water, add
Ethyl acetate extracts 3 times, merges organic phase, dries, and column chromatography obtains chloro- 1, the 3- dihydros -5- of Formula V compound 7- after removing solvent
(phenyl-d5) -2H-1,4- benzodiazepine -2- ketone.
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Cited By (4)
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| CN112920128A (en) * | 2021-03-08 | 2021-06-08 | 成都大学 | Novel method for synthesizing D5-diazepam |
| CN113072508A (en) * | 2021-03-25 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Novel method for preparing 7-amino-clonazepam compound |
| CN113149915A (en) * | 2021-03-01 | 2021-07-23 | 中国科学院成都有机化学有限公司 | Method for synthesizing clonazepam compound |
| CN114031566A (en) * | 2021-08-05 | 2022-02-11 | 谱同生物医药科技(常州)有限公司 | Preparation method of stable isotope labeled diazepam internal standard reagent |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113149915A (en) * | 2021-03-01 | 2021-07-23 | 中国科学院成都有机化学有限公司 | Method for synthesizing clonazepam compound |
| CN113149915B (en) * | 2021-03-01 | 2024-03-15 | 中国科学院成都有机化学有限公司 | Method for synthesizing clonazepam compound |
| CN112920128A (en) * | 2021-03-08 | 2021-06-08 | 成都大学 | Novel method for synthesizing D5-diazepam |
| CN113072508A (en) * | 2021-03-25 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Novel method for preparing 7-amino-clonazepam compound |
| CN114031566A (en) * | 2021-08-05 | 2022-02-11 | 谱同生物医药科技(常州)有限公司 | Preparation method of stable isotope labeled diazepam internal standard reagent |
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| CN107365276B (en) | 2019-09-24 |
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