CN107365276B - A kind of preparation method of diazepam-D5 - Google Patents
A kind of preparation method of diazepam-D5 Download PDFInfo
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- CN107365276B CN107365276B CN201710670878.XA CN201710670878A CN107365276B CN 107365276 B CN107365276 B CN 107365276B CN 201710670878 A CN201710670878 A CN 201710670878A CN 107365276 B CN107365276 B CN 107365276B
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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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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention discloses the preparation methods of diazepam-D5 a kind of; with 6- chloro-2-methyl -4H-3; 1- benzoxazin-4-one (compound of formula I) is raw material, is reacted, hydrolyzed, is acylated, cyclization, methylation with deuterated bromobenzene Grignard Reagent, isolates and purifies to obtain diazepam-D5.Present invention process have reaction condition it is mild, it is easy to operate etc. a little, using diazepam-D5 standard items prepared by 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 producing the deuterated internal standard compound used when analysis detection diazepam.
Description
Technical field
The present invention relates to chemical analysis and testing areas, and in particular in forensic science field among deuterated diazepam standard items
The preparation method of body.
Background technique
Diazepam is Benzodiazepines central nervous depressant, can cause the inhibition of central nervous system different parts, with
The increasing of dosage, clinical manifestation can from slight calmness to hypnosis even go into a coma.In recent years, because of the throwing of such drug initiation
Poison, the criminal cases such as commit suiside, wrongly take happen occasionally.This requires judicial identification of public security organs departments to being related to the sample sample of such drug
This is detected.And in order to ensure detection method prepares, reliable means are to add internal standard compound when detecting, and it is corresponding deuterated
Object is then optimal internal standard compound, due to its purposes be it is non-civilian, band has specific characteristics, thus China for such commodity research with
Produce relatively fewer, and this kind of standard items are required and indispensable in analysis detection.Deuterated internal standard compound stability is poor,
China not yet breaks through the technical bottleneck of the deuterated object production in this restriction China, there is no the producer for producing the deuterated object of 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 seriously limit such standard items in addition it is expensive
Being widely used at home.
Summary of the invention
It is an object of the present invention to provide the preparation methods of diazepam-D5 a kind of.
In order to achieve the above objectives, the present invention adopts the following technical solutions:
A kind of preparation method of diazepam-D5, Formula V compound is dissolved in chloroform or DMF, is added under the conditions of ice salt bath
Na2CO3Or NaH, stirring add the chloroformic solution or DMF solution of iodomethane, are extracted after reaction with organic solvent, depressurize
Concentration, column chromatograph up to such as Formula IV compound, and specific reaction is as follows:
5.5g Formula V compound is dissolved in 30mL chloroform or DMF, ice salt bath cooling by the preparation method of above-mentioned diazepam-D5
To -5 DEG C, 2.12g Na is 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 chloroform or DMF and is added drop-wise to reaction system, is added dropwise, and reacts 30min；Then slowly add
Enter saturated ammonium chloride quenching reaction, after chloroform or ethyl acetate extract, merges organic phase, washing three times, after dry, is depressurized dense
Contracting, column chromatograph diazepam-D5 shown in Formula IV, recrystallizing methanol obtain white crystal.
The preparation method of above-mentioned diazepam-D5, Formula V compounds process for production thereof include the following steps:
(1) as the compound as shown in following formula I preparation such as Formula Il compound represented:
(2) following formula III compound represented is prepared by Formula II compound represented:
(3) following formula IV compound represented is prepared by formula III compound represented:
(4) following Formula V compound represented is prepared by formula IV compound represented:
The preparation method of above-mentioned diazepam-D5, in step (1): compound of formula I 6- chloro-2-methyl -4H-3,1- benzo
Oxazines -4- ketone and freshly prepd C6D5The THF solution of MgBr obtains in toluene in 0 DEG C of reaction: compound of formula I 2- acetamide -5-
Chlorobenzophenone -2', 3', 4', 5', 6'-d5.Freshly prepd C6D5MgBr is prepared as follows: Mg item (2.6g) is placed in
Anhydrous THF (50mL) is added in the there-necked flask of 250mL, and iodine grain (30mg) then is added, and it is molten to stir the lower THF that deuterated bromobenzene is added dropwise
C is made in liquid (the deuterated bromobenzene of 8.8g is added in 40mL THF)6D5The THF solution of MgBr；Compound of formula I and C6D5MgBr's rubs
You are than being 1:1.05.
The preparation method of above-mentioned diazepam-D5, in step (1): compound of formula I and C6D5The molar ratio of MgBr is 1:
1.05,1g compound of formula I toluene 5mL；After reaction, the dilute hydrochloric acid that concentration is 6mol/L is added, divides after stirring 30min
Liquid, organic phase are washed twice, are concentrated under reduced pressure after dry, and yellow oil is obtained, and gained crude product can be directly used for reacting in next step.
The preparation method of above-mentioned diazepam-D5, in step (2): Formula II compound being added in ethyl alcohol, is then added again
Enter NaOH solution, be heated to reflux and slough protecting group and obtain formula III compound 2- amino -5- chlorobenzophenone -2', 3', 4', 5',
6'-d5。
The preparation method of above-mentioned diazepam-D5, in step (2): NaOH solution concentration used is 3mol/L, NaOH dosage
Molar ratio with Formula II compound is 2:1；After reaction, methylene chloride extraction is added, after organic phase is dry, filtering, decompression
Concentration, column chromatograph to obtain product.
The preparation method of above-mentioned diazepam-D5, in the step (3): formula III compound and bromoacetyl bromide are in alkaline item
Reaction obtains formula IV compound 2- acetbromamide -5- chlorobenzophenone -2', 3', 4', 5', 6'-d in organic solvent under part5。
The preparation method of above-mentioned diazepam-D5, in the step (3): the molar ratio of bromoacetyl bromide and formula III compound
For 1.5:1；Alkali used is triethylamine, pyridine or DBU, and the molar ratio of triethylamine and formula III compound is 2:1；It is used organic molten
Agent is toluene, chloroform, methylene chloride or tetrahydrofuran, and the mass ratio of chloroform volume used and formula III compound is 8:1mL/g；
After reaction, add water quenching reaction, separate organic phase, water phase is extracted with organic solvent again, is merged organic phase and is used saturated carbon
After sour sodium washing, drying is simultaneously concentrated under reduced pressure, and obtains grease, is directly used in without purifying and is reacted 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
It receives.
The preparation method of above-mentioned diazepam-D5, in the step (4): formula IV compound being dissolved in methanol and is passed through ammonia
Gas obtains the chloro- 1,3- dihydro -5- (phenyl-d of Formula V compound 7- in 50 DEG C of reactions5) -2H-1,4- benzodiazepine -2- ketone.
The preparation method of above-mentioned diazepam-D5, 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, methanol is added, the total volume of methanol used and the mass ratio of formula IV compound are 5:
1mL/g；After methanol is added, sealed reaction vessel is passed through ammonia, ammonia pressure 1kg/cm2, 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, suitable water is added, ethyl acetate is added and extracts 3 times, merges organic phase, does
It is dry, it removes solvent rear pillar and chromatographs to obtain chloro- 1, the 3- dihydro -5- (phenyl-d of Formula V compound 7-5) -2H-1,4- benzodiazepine -
2- ketone.
Compound of formula I used in the present invention can be used following method and obtain:
Operating method is as follows: 15g 2- amino -5- chlorobenzoic acid formula A compound being placed in 100mL round-bottomed flask, is added
50mL Ac2O, flow back 1.5h, and TLC monitoring reaction to raw material disappears, and removes about 25mLAc under reduced pressure2O stands crystallization, depressurized
After filter, with a small amount of Ac2O washing, 55 DEG C of product are dried under reduced pressure 12h, obtain 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 analysis detection are provided；On the other hand, developed a kind of with certainly
The new process of the synthesis deuterated diazepam of d5- of main intellectual property, the technique have reaction condition mild, easy to operate, gained d5-
The advantages that deuterated diazepam good product quality, stability is good.
Detailed description of the invention
Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawing.
The synthetic route chart of Fig. 1 diazepam-D5.
Specific embodiment
Embodiment 1
Step (1): 2- acetamide -5- chlorobenzophenone -2', 3', 4', 5', 6'-d5The preparation of (Formula II compound)
Mg 2.6g is placed in the there-necked flask of 250mL, the anhydrous THF of 50mL is added, 30mg iodine grain is then added, stirs lower drop
Add the THF solution (the deuterated bromobenzene of 8.8g is added to 40mL THF) of deuterated bromobenzene, back flow reaction 1 hour, Grignard Reagent is made.
Raw material 10.0g 6- chloro-2-methyl -4H-3,1- benzoxazin-4-one (compound of formula I) is placed in 250mL single port
Toluene 50mL is then added in bottle, and ice bath is cooled to 0 DEG C hereinafter, above-mentioned Grignard Reagent is added dropwise, and time for adding is greater 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 to 0 DEG C, 100mL6mol/L is added
Dilute hydrochloric acid, stir liquid separation after 30min, water phase is extracted twice with toluene, merges organic phase, organic phase is washed twice, after dry
It is concentrated under reduced pressure, obtains the crude product that yellow oil is Formula II compound, which can be directly used for reacting in next step.
Step (2): 2- amino -5- chlorobenzophenone -2', 3', 4', 5', 6'-d5The preparation of (formula III compound)
The resulting crude mixture of step (1) is added in 40mL ethyl alcohol and be dissolved, be then added NaOH solution (3mol/L,
16mL), it is heated to reflux, TLC detection reaction to Formula II compound disappears, and is cooled to room temperature, and DCM (methylene chloride) extraction is organic
Mutually after drying, the yellow oil of reduced pressure is filtered, silica gel 400-500 mesh column chromatographs to 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 (2) two step of step 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- chlorobenzophenone -2', 3', 4', 5', 6'-d5The preparation of (formula IV compound):
7.08g formula III compound is placed in 250mL round-bottomed flask, the dissolution of 36mL chloroform is added, 6.06g is then added
Triethylamine, ice bath are cooled to 0 DEG C, and the chloroformic solution (3.9mL bromoacetyl bromide is added in 20mL chloroform) of bromoacetyl bromide is added dropwise,
TLC is monitored after the reaction was completed, adds water quenching reaction, and chloroform extracts organic phase (each 30mL amounts to 3 times), merges organic phase simultaneously
After being washed with saturated sodium carbonate, drying is simultaneously concentrated under reduced pressure, and obtains grease, the as crude product of formula IV compound, direct without purifying
For reacting in next step.
Step (4): the chloro- 1,3- dihydro -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine -2- ketone (Formula V compound)
Preparation:
Gained 11.6g crude product formula IV compound is transferred in closed reaction vessel after being dissolved with 18mL methanol, is added
40mL methanol, sealed reaction vessel are passed through ammonia, ammonia pressure 1kg/cm2, after being warming up to 50 DEG C of reactions 12 hours, take out
After methanol is recovered under reduced pressure, 50mL water is added in reaction mass, is added ethyl acetate and is extracted 3 times, and organic phase is merged, dry, is removed
Silica gel 400-500 mesh column chromatography (petroleum ether is 4:1 with ethyl acetate volume ratio) obtains white solid 5.79g Formula V after solvent
Close object, (4) two step yield 70% of step (3) and step.
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): d5Deuterated diazepam: the chloro- 1,3- dihydro -1- methyl -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine *
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, and Na is added2CO3(2.12g)
After continue stir 15min, at this point, system be in light yellow clear shape.By the chloroformic solution of iodomethane, (2.8g iodomethane is dissolved in 25mL
Chloroform) it is slowly dropped to reaction system, it is added dropwise, reacts 30min.It is then slowly added to saturated ammonium chloride quenching reaction, chlorine
After imitative extraction, merge organic phase, washing three times, after dry, is concentrated under reduced pressure, silica gel 400-500 mesh column chromatographs (PE/EA=4:1)
Deuterated diazepam (foamy white solid), recrystallizing methanol obtain 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- chlorobenzophenone -2', 3', 4', 5', 6'-d5The preparation of (formula IV compound):
7.08g formula III compound is placed in 250mL round-bottomed flask, the dissolution of 36mL toluene is added, 4.74g is then added
Pyridine, ice bath are cooled to 0 DEG C, and the toluene solution (3.9mL bromoacetyl bromide is added in 20mL chloroform) of bromoacetyl bromide, TLC is added dropwise
Monitoring after the reaction was completed, adds water quenching reaction, and toluene extracts organic phase (each 30mL, totally 3 times), merges organic phase and with being saturated
After sodium carbonate washing, drying is simultaneously concentrated under reduced pressure, and obtains grease, the as crude product of formula IV compound, is directly used in down without purifying
Single step reaction.
Step (4): the chloro- 1,3- dihydro -5- (phenyl-d of 7-5) -2H-1,4- benzodiazepine -2- ketone (Formula V compound)
Preparation:
Gained 11.6g crude product formula IV compound is transferred in closed reaction vessel after being dissolved with 18mL methanol, is added
40mL methanol, sealed reaction vessel are passed through ammonia, ammonia pressure 1kg/cm2, after being warming up to 50 DEG C of reactions 12 hours, take out
After methanol is recovered under reduced pressure, 50mL water is added in reaction mass, and ethyl acetate is added and extracts 3 times, merges organic phase, dry, is removed molten
(petroleum ether and ethyl acetate volume ratio chromatograph to obtain white solid 5.37g formula silica gel 400-500 mesh column chromatography for 4:1) column after agent
V compound, (4) two step yield 65% of step (3) and step.
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 the difference from embodiment 1 is that step (5): the chloro- 1,3- dihydro -1- methyl -5- of diazepam-D5:7-
(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, and NaH (0.48g) is added and continues afterwards
15min is stirred, at this point, 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 and (iodomethane be dissolved in DMF and be slowly added dropwise, purpose is avoiding generating upper two first
The by-product 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
Reaction of going out merges organic phase after ethyl acetate extraction, washes three times, after dry, is concentrated under reduced pressure, silica gel 400-500 mesh column chromatography
(petroleum ether is 4:1 with ethyl acetate volume ratio) obtains deuterated diazepam (foamy white solid), and 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 be only to clearly illustrate example of the present invention, and not be pair
The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is all to belong to this hair
The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.
Claims (9)
1. a kind of preparation method of diazepam-D5, which is characterized in that Formula V compound is dissolved in chloroform or DMF, ice salt bath item
Na is added under part2CO3Or NaH, stirring add the chloroformic solution or DMF solution of iodomethane, use organic solvent after reaction
Extraction is concentrated under reduced pressure, and column chromatographs up to such as Formula IV compound, and specific reaction is as follows:
Formula V compounds process for production thereof includes the following steps:
(1) as the compound as shown in following formula I preparation such as Formula Il compound represented:
(2) following formula III compound represented is prepared by Formula II compound represented:
(3) following formula IV compound represented is prepared by formula III compound represented:
(4) following Formula V compound represented is prepared by formula IV compound represented:
2. the preparation method of diazepam-D5 according to claim 1, which is characterized in that 5.5g Formula V compound to be dissolved in
30mL chloroform or DMF, ice salt bath are cooled to -5 DEG C, and 2.12g Na is added2CO3Or 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 chloroform or DMF and is added drop-wise to reaction system, is dripped
Finish, reacts 30min；It is then slowly added to saturated ammonium chloride quenching reaction and merges organic phase after chloroform or ethyl acetate extract,
Washing three times, after dry, is concentrated under reduced pressure, column chromatograph diazepam-D5 shown in Formula IV, recrystallizing methanol obtain white crystal.
3. the preparation method of diazepam-D5 according to claim 1 a kind of, which is characterized in that in step (1): Formulas I
Close object 6- chloro-2-methyl -4H-3,1- benzoxazin-4-one and freshly prepd C6D5The THF solution of MgBr is anti-in 0 DEG C in toluene
It should obtain: Formula II compound 2- acetamide -5- chlorobenzophenone -2', 3', 4', 5', 6'-d5。
4. the preparation method of diazepam-D5 according to claim 3 a kind of, which is characterized in that in step (1): Formulas I
Close object and C6D5The molar ratio of MgBr is 1:1.05,1g compound of formula I toluene 5mL；After reaction, it is 6mol/ that concentration, which is added,
The dilute hydrochloric acid of L, stirs liquid separation after 30min, and organic phase washes twice, is concentrated under reduced pressure after dry, obtains yellow oil, gained crude product
It can be directly used for reacting in next step.
5. the preparation method of diazepam-D5 according to claim 1 a kind of, which is characterized in that in step (2): by formula
II compound is added in ethyl alcohol, then adds NaOH solution, is heated to reflux and is sloughed protecting group and obtain formula III compound 2- ammonia
Base -5- chlorobenzophenone -2', 3', 4', 5', 6'-d5。
6. the preparation method of diazepam-D5 according to claim 5 a kind of, which is characterized in that in step (2): used
NaOH solution concentration is 3mol/L, and the molar ratio of NaOH dosage and Formula II compound is 2:1；After reaction, dichloromethane is added
Alkane extraction, after organic phase is dry, filtering is concentrated under reduced pressure, and column chromatographs to obtain product.
7. the preparation method of diazepam-D5 according to claim 1 a kind of, which is characterized in that in the step (3):
Formula III compound reacts to obtain formula IV compound 2- acetbromamide -5- under alkaline condition in organic solvent with bromoacetyl bromide
Chlorobenzophenone -2', 3', 4', 5', 6'-d5。
8. the preparation method of diazepam-D5 according to claim 7 a kind of, which is characterized in that in the step (3):
The molar ratio of bromoacetyl bromide and formula III compound is 1.5:1；Alkali used is triethylamine, pyridine or DBU, triethylamine and formula III
The molar ratio for closing object is 2:1；Organic solvent used is toluene, chloroform, methylene chloride or tetrahydrofuran, chloroform volume and formula used
The mass ratio of III compound is 8:1mL/g；After reaction, add water quenching reaction, separate organic phase, water phase is used organic molten again
Agent extraction, after merging organic phase and being washed with saturated sodium carbonate, drying is simultaneously concentrated under reduced pressure, and obtains grease, is directly used without purifying
It is reacted in next step.
9. the preparation method of diazepam-D5 according to claim 1 a kind of, which is characterized in that in the step (4): institute
It obtains after crude product formula IV compound is dissolved with a small amount of methanol and is transferred in closed reaction vessel, methanol, the totality of methanol used is added
The long-pending mass ratio with formula IV compound is 5:1mL/g；After methanol is added, sealed reaction vessel is passed through ammonia, and ammonia pressure is
1kg/cm2, after being warming up to 50 DEG C of reactions 12 hours, reaction mass is taken out, after methanol is recovered under reduced pressure, suitable water is added, be added
Ethyl acetate extracts 3 times, merges organic phase, dry, removes solvent rear pillar and chromatographs to obtain chloro- 1, the 3- dihydro -5- of Formula V compound 7-
(phenyl-d5) -2H-1,4- benzodiazepine -2- ketone.
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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 |
| 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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