CN107522667A - Diazepam D8 and preparation method thereof - Google Patents
Diazepam D8 and preparation method thereof Download PDFInfo
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- CN107522667A CN107522667A CN201710670606.XA CN201710670606A CN107522667A CN 107522667 A CN107522667 A CN 107522667A CN 201710670606 A CN201710670606 A CN 201710670606A CN 107522667 A CN107522667 A CN 107522667A
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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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Abstract
The invention discloses diazepam D8 and preparation method thereof; 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 deuterated diazepam D8.Present invention process have reaction condition it is gentle, it is simple to operate etc. a little, the deuterated diazepam D8 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 (formula compound VIa) is Benzodiazepines central nervous depressant, and central nervous system can be caused different
The suppression at position, with the increasing of dosage, clinical manifestation can even be gone into a coma from slight calmness to hypnosis.In recent years, because of such
What medicine triggered poison, commit suiside, wrongly taking etc., and criminal case happens occasionally.This requires judicial identification of public security organs department to being related to such
The sample sample of medicine is detected.And in order to ensure detection method prepares, reliable means are to add internal standard compound in detection,
And corresponding deuterated thing is then optimal internal standard compound, because its purposes is non-civilian, band has specific characteristics, and for this, China is for such
The research of commodity is relatively fewer with producing, and this kind of standard items are required and indispensable in analysis detects.In deuterated
Mark thing stability is poor, and China not yet breaks through the technical bottleneck of the deuterated thing production in this restriction China, there is no the case-involving poisonous substance of production
The producer of deuterated thing, the use of the product are only capable of relying on import.For a long time, deuterated internal standard compound used in China be rely on into
Mouthful, it is expensive plus its, seriously limit the widely using at home of such standard items.And only d external at present5-
The sale of the sale of deuterated diazepam, not other related deuterated things.
Document is there is presently no report diazepam-D8 synthesis, and diazepam-D8 can be used as deuterated standard items.
The content of the invention
It is an object of the present invention to provide it is a kind of can be as the diazepam-D8 of deuterated standard items preparation method.
To reach above-mentioned purpose, the present invention uses following technical proposals：Diazepam-D8, it is characterised in that such as Formula VII institute
Show compound：
Diazepam-D8 preparation method, Formula V compound is dissolved in DMF or chloroform, under the conditions of ice salt bath add NaH,
Na2CO3、K2CO3Or triethylamine, stirring, the DMF or chloroformic solution of iodomethane are added, reacts and is extracted after terminating with organic solvent
Take, be concentrated under reduced pressure, column chromatography is produced such as Formula IV compound, is specifically reacted as follows：
Above-mentioned diazepam-D8 preparation method, when solvent for use is DMF：5.5g Formula V compounds are dissolved in 30mL DMF,
Ice salt bath is cooled to -5 DEG C, continues to stir 15min after adding 0.48g NaH, system is in light yellow clear shape, by the deuterated iodine of 2.9g
Methane is dissolved in the solution formed in 25mL DMF and is slowly dropped to reaction system, is added dropwise, and reacts 30min, then adds full
Reaction is quenched with ammonium chloride, after ethyl acetate extraction, merges organic phase, washing three times, after drying, is concentrated under reduced pressure, column chromatography
(PE/EA=4:1) deuterated diazepam is obtained, recrystallizing methanol, obtains white crystal 4.2g；When solvent for use is chloroform：By 5.5g Formula V
Compound is dissolved in 30mL chloroforms, and ice salt bath is cooled to -5 DEG C, adds 2.12g Na2CO3After continue to stir 15min, system is in pale yellow
Color transparence, the solution that the deuterated iodomethane of 2.9g is dissolved in the formation of 25mL chloroforms are added drop-wise to reaction system, are added dropwise, reacts
30min, then add saturated ammonium chloride and reaction is quenched, after chloroform extraction, merge organic phase, three times, after drying, decompression is dense for washing
Contracting, column chromatography obtain deuterated diazepam, recrystallizing methanol, obtain white crystal 3.6g.
Above-mentioned diazepam-D8 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-D8 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-D8 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-D8 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-D8 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-D8 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-D8 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 a kind of diazepam-D8 preparation method, in the step (4)：Formula IV compound is dissolved in methanol and led to
Enter ammonia and obtain the chloro- 1,3- dihydros -5- (phenyl-d of Formula V compound 7- in 50 DEG C of reactions5) -2H-1,4- benzodiazepines -2-
Ketone.
Above-mentioned diazepam-D8 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
Synthesis diazepam-the D8 of main intellectual property new technology, the technique have reaction condition gentle, simple to operate, and gained d8- is 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-D8 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 100mL 6mol/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 (PE/EA=15:1,
I.e. the volume ratio of petroleum ether and ethyl acetate is 15:1) faint yellow solid 10.3g, as formula III compound, step (1) are obtained
With the step yield 72% of step (2) two.
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)：d8- deuterated diazepam：The chloro- 1,3- dihydros -1- (methyl-d of 7-3) -5- (phenyl-d5) -2H-1,4- benzene
And the preparation of diaza -2- ketone (Formula VII compound)：
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 deuterated iodomethane, (the deuterated iodomethane of 2.9g is dissolved in
25mL DMF) reaction system is slowly dropped to, it is added dropwise, reacts 30min.Saturated ammonium chloride is then slowly added to be quenched instead
Should, after ethyl acetate 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 4.2g, yield 72%, HPLC
Purity>99%.
White crystal；m.p.124.2-125.0℃；1H NMR(300MHz,DMSO-d6) δ 3.78 (d, J=10.7Hz,
1H), 4.58 (d, J=10.7Hz, 1H), 7.21 (d, J=2.4Hz, 1H), 7.60 (d, J=8.8,1H), 7.50 (dd, J=
2.3,8.8Hz,1H)；13C NMR(75MHz,CDCl3) δ 39.5 (sep, J=20.9Hz, 1C), 56.6,123.8,127.7,
127.9,128.4,128.8,129.4,131.4,137.7,142.5,168.0,169.2；HRMS(ESI)C16H5ClD8N2NaO[M
+Na]+315.1111,found:315.1115.
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) white solid 5.37g Formula V chemical combination is obtained
Thing, 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 is that the preparation method of step (5) is different from the difference of embodiment 1：Formula V compound (5.5g) is molten
In chloroform (30mL), ice salt bath is cooled to -5 DEG C, adds Na2CO3Continue to stir 15min after (2.12g), now, system is in pale yellow
Color transparence.The chloroformic solution (the deuterated iodomethane of 2.9g is dissolved in 25mL chloroforms) of deuterated iodomethane is slowly dropped to reactant
System, is added dropwise, and reacts 30min.It is then slowly added to saturated ammonium chloride and reaction is quenched, after chloroform extraction, merges organic phase, water
Wash three times, after drying, be concentrated under reduced pressure, (petroleum ether is 4 with ethyl acetate volume ratio to silica gel 400-500 mesh column chromatography:1) obtain deuterated
Diazepam (foamy white solid), recrystallizing methanol, obtain white crystal 3.6g, yield 62%, HPLC purity>99%.
White crystal；m.p.124.2-125.0℃；1H NMR(300MHz,DMSO-d6) δ 3.78 (d, J=10.7Hz,
1H), 4.58 (d, J=10.7Hz, 1H), 7.21 (d, J=2.4Hz, 1H), 7.60 (d, J=8.8,1H), 7.50 (dd, J=
2.3,8.8Hz,1H)；13C NMR(75MHz,CDCl3) δ 39.5 (sep, J=20.9Hz, 1C), 56.6,123.8,127.7,
127.9,128.4,128.8,129.4,131.4,137.7,142.5,168.0,169.2；HRMS(ESI)C16H5ClD8N2NaO[M
+Na]+315.1111,found:315.1115.
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. diazepam-D8, it is characterised in that the compound as shown in Formula VII：
2. diazepam-D8 preparation method, it is characterised in that Formula V compound is dissolved in DMF or chloroform, under the conditions of ice salt bath
Add NaH, Na2CO3、K2CO3Or triethylamine, stirring, the DMF or chloroformic solution of iodomethane are added, is reacted after terminating with organic
Solvent extraction, it is concentrated under reduced pressure, column chromatography is produced such as Formula IV compound, is specifically reacted as follows：
3. diazepam-D8 according to claim 2 preparation method, it is characterised in that when solvent for use is DMF：Will
5.5g Formula V compounds are dissolved in 30mL DMF, and ice salt bath is cooled to -5 DEG C, continue to stir 15min, system after adding 0.48g NaH
In light yellow clear shape, the deuterated iodomethane of 2.9g is dissolved in the solution formed in 25mL DMF and is slowly dropped to reaction system, dripped
Complete, reaction 30min is added, saturated ammonium chloride is then added and reaction is quenched, after ethyl acetate extraction, merge organic phase, wash three
It is secondary, after drying, it is concentrated under reduced pressure, column chromatography (PE/EA=4:1) deuterated diazepam is obtained, recrystallizing methanol, obtains white crystal 4.2g；
When solvent for use is chloroform：5.5g Formula V compounds are dissolved in 30mL chloroforms, ice salt bath is cooled to -5 DEG C, adds 2.12g Na2CO3
After continue stir 15min, system be in light yellow clear shape, by the deuterated iodomethane of 2.9g be dissolved in 25mL chloroforms formation solution dropwise addition
To reaction system, it is added dropwise, reacts 30min, then adds saturated ammonium chloride and reaction is quenched, after chloroform extraction, merge organic
Phase, washing three times, after drying, are concentrated under reduced pressure, column chromatography obtains diazepam-D8, recrystallizing methanol, obtains white crystal 3.6g.
4. the preparation method of the diazepam-D8 according to Claims 2 or 3, 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：
5. a kind of diazepam-D8 according to claim 4 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。
6. a kind of diazepam-D8 according to claim 5 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.
7. a kind of diazepam-D8 according to claim 4 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。
8. a kind of diazepam-D8 according to claim 7 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.
9. a kind of diazepam-D8 according to claim 4 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。
10. a kind of diazepam-D8 according to claim 9 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；In the step (4)：Gained crude product formula IV compound is transferred to closed reaction and held after being dissolved with a small amount of methanol
In device, methanol is added, the cumulative volume of methanol used is 5 with the mass ratio of formula IV compound:1mL/g；After methanol adds, sealing is anti-
Container is answered, is passed through ammonia, ammonia pressure 1kg/cm2, be warming up to 50 DEG C reaction 12 hours after, take out reaction mass, depressurize back
After receiving methanol, appropriate water is added, ethyl acetate is added and extracts 3 times, merge organic phase, dry, column chromatography obtains after removing solvent
To the chloro- 1,3- dihydros -5- (phenyl-d of Formula V compound 7-5) -2H-1,4- benzodiazepine -2- ketone.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113072509A (en) * | 2021-03-01 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Method for synthesizing 7-amino clonazepam compound |
| 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 |
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| CN113072509A (en) * | 2021-03-01 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Method for synthesizing 7-amino clonazepam compound |
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| 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 |
| 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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