CN107522667B - diazepam-D8 and preparation method thereof - Google Patents
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000000126 substance Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 13
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 deuterated Bromobenzene Grignard reagent Chemical class 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000012074 organic phase Substances 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
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- 125000006239 protecting group Chemical group 0.000 claims description 2
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- 125000003944 tolyl group Chemical group 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims 1
- 230000006837 decompression Effects 0.000 claims 1
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- 229960003529 diazepam Drugs 0.000 abstract description 2
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 1
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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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了地西泮‑D8及其制备方法，以6‑氯‑2‑甲基‑4H‑3,1‑苯并噁嗪‑4‑酮(式I化合物)为原料，经与氘代溴苯格氏试剂反应、水解、酰化、环合、甲基化，分离纯化得到氘代地西泮‑D8。本发明工艺具有反应条件温和、操作简单等有点，采用本发明制备的氘代地西泮‑D8标准品，化学纯度高，产品质量好，稳定性好，可方便用于分析用标准品的配制。本发明制备方法可用于生产分析检测地西泮时使用的氘代内标物。
The invention discloses diazepam-D8 and a preparation method thereof. The 6-chloro-2-methyl-4H-3, 1-benzoxazine-4-ketone (compound of formula I) is used as a raw material, and deuterated Bromobenzene Grignard reagent reaction, hydrolysis, acylation, cyclization, methylation, separation and purification to obtain deuterated diazepam-D8. The process of the invention has the advantages of mild reaction conditions and simple operation. The deuterated diazepam-D8 standard product prepared by the invention has high chemical purity, good product quality and good stability, and can be conveniently used for the preparation of the standard product for analysis. . The preparation method of the invention can be used for producing the deuterated internal standard substance used in the analysis and detection of diazepam.
Description
Technical Field
The invention relates to the field of chemical analysis and detection, in particular to a preparation method of a deuterated diazepam standard intermediate in the field of forensic science.
Background
Diazepam (compound VIa in formula) is a benzodiazepine central nerve inhibitor, can cause inhibition of different parts of a central nervous system, and can be clinically shown from mild sedation to hypnosis and even coma with increasing dosage. In recent years, criminal cases such as drug administration, suicide and misuse caused by the drugs occur frequently. This requires the police department of justice to test sample samples related to this class of drugs. The internal standard substance is added during detection in order to ensure the preparation and reliable means of the detection method, and the corresponding deuterated substance is the optimal internal standard substance, and the application of the deuterated substance is non-civil and has particularity, so that the research and production of the commodity in China are relatively less, and the standard substance is necessary and indispensable in analysis and detection. The stability of the deuterated internal standard substance is poor, China has not broken through the technical bottleneck restricting the production of the deuterated substance in China, no manufacturer producing the deuterated substance involved in the case is available, and the product can only be imported. For a long time, the deuterated internal standard substances used in China all depend on import, and in addition, the deuterated internal standard substances are addedThe price is high, and the wide use of the standard products in China is severely limited. And currently only d is foreign5The sale of deuterated diazepam and no other related deuterates.
The literature does not report the synthesis of diazepam-D8 at present, but diazepam-D8 can be used as a deuterated standard.
Disclosure of Invention
An object of the present invention is to provide a method for preparing diazepam-D8 which can be used as a deuterated standard.
In order to achieve the purpose, the invention adopts the following technical scheme: diazepam-D8, wherein the compound is of formula VII:
a preparation method of diazepam-D8 comprises dissolving compound of formula V in DMF or chloroform, adding NaH and Na under ice salt bath condition2CO3、K2CO3Or triethylamine is stirred, DMF or chloroform solution of methyl iodide is added, after the reaction is finished, organic solvent is used for extraction, reduced pressure concentration and column chromatography are carried out, and the compound shown in the formula VI is obtained, wherein the specific reaction is as follows:
when the solvent used in the preparation method of diazepam-D8 is DMF: dissolving 5.5g of a compound shown as a formula V in 30mL of DMF, cooling the solution in an ice salt bath to-5 ℃, adding 0.48g of NaH, continuously stirring the solution for 15min to obtain a light yellow transparent system, slowly dropwise adding a solution formed by dissolving 2.9g of deuterated iodomethane in 25mL of DMF into the reaction system, reacting the solution for 30min after dropwise adding, then adding saturated ammonium chloride to quench the reaction, extracting the solution with ethyl acetate, combining organic phases, washing the organic phases for three times with water, drying the organic phases, concentrating the organic phases under reduced pressure, and performing column chromatography (PE/EA is 4:1) to obtain deuterated diazepam, formazanRecrystallizing with alcohol to obtain white crystal 4.2 g; when chloroform is used as the solvent: 5.5g of the compound of formula V are dissolved in 30mL of chloroform, cooled to-5 ℃ in an ice-salt bath and 2.12g of Na are added2CO3And then continuously stirring for 15min, wherein the system is light yellow and transparent, a solution formed by dissolving 2.9g of deuterated iodomethane in 25mL of chloroform is dropwise added into the reaction system, the dropwise addition is finished, the reaction is carried out for 30min, then saturated ammonium chloride is added to quench the reaction, after chloroform extraction, organic phases are combined, water washing is carried out for three times, drying, reduced pressure concentration and column chromatography are carried out, deuterated diazepam is obtained, and 3.6g of white crystals are obtained after methanol recrystallization.
The preparation method of the diazepam-D8 compound shown in the formula V comprises the following steps:
(1) preparing a compound represented by formula II below from a compound represented by formula I below:
(2) preparing a compound represented by the following formula III from a compound represented by formula II:
(3) preparing a compound of formula IV below from a compound of formula III:
(4) preparing a compound represented by formula V from a compound represented by formula IV:
the preparation method of diazepam-D8 comprises the following steps of (1): compounds of formula I6-chloro-2-methyl-4H-3, 1-benzoxazin-4-one and newly prepared C6D5MgBr in THF was reacted in toluene at 0 ℃ to give: the compound of formula I2-acetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5. New preparation of C6D5MgBr was prepared as follows: placing the Mg strip (2.6g) in a 250mL three-necked flask, adding anhydrous THF (50mL), followed by addition of iodonium particles (30Mg), and dropwise adding a THF solution of deuterated bromobenzene with stirring (8.8g deuterated bromobenzene was added to 40mL THF) gave C6D5A THF solution of MgBr; a compound of the formula I and C6D5The molar ratio of MgBr was 1: 1.05.
The preparation method of diazepam-D8 comprises the following steps of (1): a compound of the formula I and C6D5The molar ratio of MgBr is 1:1.05, and 1g of the compound shown in the formula I is added with 5mL of toluene; after the reaction is finished, adding dilute hydrochloric acid with the concentration of 6mol/L, stirring for 30min, separating liquid, washing an organic phase twice, drying, concentrating under reduced pressure to obtain yellow oily matter, and directly using the obtained crude product for the next reaction.
The preparation method of diazepam-D8 comprises the following steps of (2): adding the compound shown in the formula II into ethanol, then adding NaOH solution, heating and refluxing to remove a protecting group to obtain the compound shown in the formula III, namely 2-amino-5-chlorobenzophenone-2 ',3',4',5',6' -d5。
The preparation method of diazepam-D8 comprises the following steps of (2): the concentration of the NaOH solution is 3mol/L, and the molar ratio of the amount of NaOH to the compound in the formula II is 2: 1; after the reaction is finished, dichloromethane is added for extraction, an organic phase is dried, filtered, decompressed and concentrated, and the product is obtained through column chromatography.
The preparation method of diazepam-D8, wherein in the step (3): reacting the compound shown in the formula III with bromoacetyl bromide in an organic solvent under the alkaline condition to obtain a compound shown in the formula IV, namely 2-bromoacetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5。
The preparation method of diazepam-D8, wherein in the step (3): the molar ratio of bromoacetyl bromide to the compound of formula III is 1.5: 1; the base is triethylamine, pyridine or DBU, and the molar ratio of the triethylamine to the compound in the formula III is 2: 1; the organic solvent is toluene, chloroform, dichloromethane or tetrahydrofuran, and the mass ratio of the volume of the chloroform to the compound of the formula III is 8:1 mL/g; after the reaction is finished, adding water to quench the reaction, separating out an organic phase, extracting a water phase with an organic solvent, combining the organic phases, washing with saturated sodium carbonate, drying, decompressing and concentrating to obtain an oily substance, and directly using the oily substance in the next reaction without purification. Triethylamine is preferably used as the base, and the triethylamine has the highest yield and the best effect; the organic solvent is preferably chloroform, and the chloroform has good reaction effect, high yield and easy recovery.
The preparation method of diazepam-D8 comprises the following steps in step (4): dissolving the compound shown in the formula IV in methanol, introducing ammonia gas, and reacting at 50 ℃ to obtain the compound shown in the formula V, namely 7-chloro-1, 3-dihydro-5- (phenyl-d)5) -2H-1, 4-benzodiazepin-2-one.
The preparation method of diazepam-D8 comprises the following steps in step (4): dissolving the obtained crude compound shown in the formula IV by using a small amount of methanol, transferring the dissolved crude compound into a closed reaction container, and adding methanol, wherein the mass ratio of the total volume of the methanol to the compound shown in the formula IV is 5:1 mL/g; after methanol was added, the reaction vessel was sealed, and ammonia gas was introduced under a pressure of 1kg/cm2Heating to 50 deg.C for reaction for 12 hr, taking out the reaction mass, recovering methanol under reduced pressure, adding appropriate amount of water, extracting with ethyl acetate for 3 times, mixing the organic phases, drying, removing solvent, and performing column chromatography to obtain compound 7-chloro-1, 3-dihydro-5- (phenyl-d) of formula V5) -2H-1, 4-benzodiazepin-2-one.
The compounds of formula I used in the present invention can be obtained by the following method:
the operation method comprises the following steps: 15g of 2-amino-5-chlorobenzoic acid A compound was placed in a 100mL round bottom flask and 50mL of Ac was added2O, refluxing for 1.5h, TLC monitoring the reaction until the starting material disappeared, and reduced pressure evaporation to remove about 25ml of LAc2O, standing for crystallization, filtering under reduced pressure, and adding a small amount of Ac2And O washing, and drying the product at 55 ℃ under reduced pressure for 12h to obtain the white crystal compound of the formula I.
The invention has the following beneficial effects:
in one aspect, an internal standard for analytical testing is provided; on the other hand, a new process for synthesizing diazepam-D8 with independent intellectual property rights is developed, and the process has the advantages of mild reaction conditions, simplicity in operation, good quality of the obtained D8-deuterated diazepam product, good stability and the like.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a synthetic scheme for diazepam-D8.
Detailed Description
Example 1
Step (1): 2-acetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5(Compound of formula II)
2.6g of the Mg strip was placed in a 250mL three-necked flask, 50mL of anhydrous THF was added, followed by addition of 30Mg of iodine pellets, followed by dropwise addition of a THF solution of deuterated bromobenzene (8.8g of deuterated bromobenzene was added to 40mL of THF) with stirring, and the reaction was refluxed for 1 hour to prepare a Grignard reagent.
10.0g of raw material 6-chloro-2-methyl-4H-3, 1-benzoxazine-4-ketone (compound shown in formula I) is placed in a 250mL single-neck bottle, then 50mL of toluene is added, the temperature is reduced to below 0 ℃ in an ice bath, and the Grignard reagent is added dropwise for more than 45 min. After the addition is finished, stirring for 30min at 0 ℃, then raising the temperature to room temperature, stirring overnight, cooling the reaction to 0 ℃, adding 100mL of 6mol/L diluted hydrochloric acid, stirring for 30min, separating liquid, extracting the water phase twice with toluene, combining organic phases, washing the organic phases twice, drying, and concentrating under reduced pressure to obtain yellow oily matter, namely the crude product of the compound of the formula II, wherein the crude product can be directly used for the next reaction.
Step (2): 2-amino-5-chlorobenzophenone-2 ',3',4',5',6' -d5Preparation of (Compound of formula III)
Dissolving the crude mixture obtained in the step (1) in 40mL of ethanol, adding NaOH solution (3mol/L,16mL), heating and refluxing, detecting by TLC until the compound of the formula II disappears, cooling to room temperature, extracting by DCM (dichloromethane), drying the organic phase, filtering the yellow oily matter concentrated under reduced pressure, and carrying out silica gel 400-500-mesh column chromatography to obtain a yellow product (PE/EA is 15:1, namely the volume ratio of petroleum ether to ethyl acetate is 15:1) to obtain 10.3g of a light yellow solid, namely the compound of the formula III, wherein the yield of the two steps of the step (1) and the step (2) is 72%.
1H NMR(300MHz,DMSO-d6)δ6.91(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)。
And (3): 2-bromoacetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5Preparation of (Compound of formula IV):
placing 7.08g of the compound shown in the formula III in a 250mL round-bottom flask, adding 36mL of chloroform for dissolution, then adding 6.06g of triethylamine, cooling to 0 ℃ in an ice bath, dropwise adding a bromoacetyl bromide chloroform solution (3.9mL of bromoacetyl bromide is added into 20mL of chloroform), adding water for quenching reaction after TLC monitoring reaction is completed, extracting an organic phase (30mL each time and 3 times in total) by using chloroform, combining the organic phases, washing by using saturated sodium carbonate, drying and concentrating under reduced pressure to obtain an oily substance which is a crude product of the compound shown in the formula IV, and directly using the oily substance in the next reaction without purification.
And (4): 7-chloro-1, 3-dihydro-5- (phenyl-d)5) -preparation of 2H-1, 4-benzodiazepin-2-one (compound of formula V):
dissolving 11.6g of the crude compound of formula IV with 18mL of methanol, transferring into a closed reaction container, adding 40mL of methanol, sealing the reaction container, introducing ammonia gas with the pressure of 1kg/cm2Heating to 50 ℃ for reaction for 12 hours, taking out the reaction mass, recovering methanol under reduced pressure, adding 50mL of water, adding ethyl acetate for extraction for 3 times, combining organic phases, drying, removing the solvent, and performing silica gel 400-500 mesh column chromatography (the volume ratio of petroleum ether to ethyl acetate is 4:1) to obtain 5.79g of the compound shown in the formula V as a white solid, wherein the yield of the two steps of the step (3) and the step (4) is 70%.
1H NMR(300MHz,DMSO-d6)δ4.15(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)。
And (5): d8-deuterated diazepam: 7-chloro-1, 3-dihydro-1- (methyl-d)3) -5- (phenyl-d)5) -preparation of 2H-1, 4-benzodiazepin-2-one (compound of formula VII):
the compound of formula V (5.5g) was dissolved in DMF (30mL), the ice salt bath was cooled to-5 deg.C, NaH (0.48g) was added and stirring continued for 15min, at which time the system was light yellow and transparent. The DMF solution of deuterated iodomethane (2.9g deuterated iodomethane dissolved in 25mL DMF) is slowly dripped into the reaction system, and the reaction is carried out for 30min after the dripping is finished. Then slowly adding saturated ammonium chloride to quench reaction, extracting with ethyl acetate, merging organic phases, washing with water for three times, drying, concentrating under reduced pressure, performing silica gel 400-500 mesh column chromatography (PE/EA is 4:1) to obtain deuterated diazepam (foamy white solid), and recrystallizing with methanol to obtain white crystals 4.2g, wherein the yield is 72% and the HPLC purity is more than 99%.
White crystals; m.p.124.2-125.0 deg.C;1H NMR(300MHz,DMSO-d6)δ3.78(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)δ39.5(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.
example 2 (preparation of Compound of formula V)
The steps (1) and (2) are the same as in example 1.
And (3): 2-bromoacetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5Preparation of (Compound of formula IV):
placing 7.08g of the compound of the formula III in a 250mL round-bottom flask, adding 36mL of toluene to dissolve the compound, then adding 4.74g of pyridine, cooling to 0 ℃ in an ice bath, dropwise adding a bromoacetyl bromide toluene solution (3.9mL of bromoacetyl bromide is added into 20mL of chloroform), adding water to quench the reaction after TLC monitoring reaction is completed, extracting an organic phase (30mL each time and 3 times in total) with toluene, combining the organic phases, washing with saturated sodium carbonate, drying and concentrating under reduced pressure to obtain an oily substance which is a crude product of the compound of the formula IV, and directly using the oily substance in the next reaction without purification.
And (4): 7-chloro-1, 3-dihydro-5- (phenyl-d)5) -preparation of 2H-1, 4-benzodiazepin-2-one (compound of formula V):
dissolving 11.6g of the crude compound of formula IV with 18mL of methanol, transferring into a closed reaction container, adding 40mL of methanol, sealing the reaction container, introducing ammonia gas with the pressure of 1kg/cm2Heating to 50 ℃ for reaction for 12 hours, taking out the reaction mass, recovering methanol under reduced pressure, adding 50mL of water, adding ethyl acetate for extraction for 3 times, combining organic phases, drying, removing the solvent, and then carrying out silica gel 400-500 mesh column chromatography (the volume ratio of petroleum ether to ethyl acetate is 4:1) to obtain 5.37g of the compound shown in the formula V as a white solid, wherein the yield of the two steps of the step (3) and the step (4) is 65%.
1H NMR(300MHz,DMSO-d6)δ4.15(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)。
Example 3
This example differs from example 1 in the preparation method of step (5): the compound of formula V (5.5g) was dissolved in chloroform (30mL), cooled to-5 ℃ in an ice salt bath and Na was added2CO3(2.12g) stirring was continued for 15min, at which time the system was light yellow transparent. Slowly dropwise adding a chloroform solution of deuterated iodomethane (2.9g of deuterated iodomethane dissolved in 25mL of chloroform) into the reaction system, and reacting for 30min after dropwise adding. The reaction was then quenched by slow addition of saturated ammonium chlorideExtracting with chloroform, mixing organic phases, washing with water for three times, drying, concentrating under reduced pressure, performing silica gel 400-500 mesh column chromatography (volume ratio of petroleum ether to ethyl acetate is 4:1) to obtain deuterated diazepam (foamy white solid), recrystallizing with methanol to obtain white crystal 3.6g, yield 62%, and HPLC purity>99％。
White crystals; m.p.124.2-125.0 deg.C;1H NMR(300MHz,DMSO-d6)δ3.78(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)δ39.5(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.
it should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.
Claims (8)
1. The preparation method of diazepam-D8 is characterized in that the compound shown in the formula V is dissolved in DMF or chloroform, and NaH and Na are added under the condition of ice salt bath2CO3、K2CO3Or triethylamine is stirred, then DMF or chloroform solution of deuterium with iodomethane is added, after the reaction is finished, organic solvent is used for extraction, decompression concentration and column chromatography are carried out, and the compound shown in the formula VI is obtained, and the specific reaction is as follows:
the preparation method of the compound of the formula V comprises the following steps:
(1) preparing a compound represented by formula II below from a compound represented by formula I below:
(2) preparing a compound represented by the following formula III from a compound represented by formula II:
(3) preparing a compound of formula IV below from a compound of formula III:
(4) preparing a compound represented by formula V from a compound represented by formula IV:
2. the method of claim 1, wherein the solvent used is DMF: dissolving 5.5g of a compound shown in the formula V in 30mL of DMF, cooling the solution in an ice salt bath to-5 ℃, adding 0.48g of NaH, continuously stirring the solution for 15min to obtain a light yellow transparent system, slowly dropwise adding a solution formed by dissolving 2.9g of deuterated iodomethane in 25mL of DMF into the reaction system, reacting the solution for 30min after the dropwise addition is finished, then adding saturated ammonium chloride to quench the reaction, extracting the solution with ethyl acetate, combining organic phases, washing the organic phases for three times with water, drying the organic phases, concentrating the organic phases under reduced pressure, carrying out column chromatography (PE/EA is 4:1) to obtain deuterated diazepam, and recrystallizing the methanol to obtain 4.2g of white crystals; when chloroform is used as the solvent: 5.5g of the compound of formula V are dissolved in 30mL of chloroform, cooled to-5 ℃ in an ice-salt bath and 2.12g of Na are added2CO3Stirring for 15min, adding dropwise a solution of 2.9g deuterated iodomethane dissolved in 25mL chloroform into the reaction system, reacting for 30min, adding saturated ammonium chloride, quenching, extracting with chloroform, mixing organic phases, washing with water for three times, and dryingDrying, concentrating under reduced pressure, performing column chromatography to obtain diazepam-D8, and recrystallizing with methanol to obtain white crystal 3.6 g.
3. The method for preparing diazepam-D8 as claimed in claim 1, wherein in step (1): compounds of formula I6-chloro-2-methyl-4H-3, 1-benzoxazin-4-one and newly prepared C6D5MgBr in THF was reacted in toluene at 0 ℃ to give: the compound of formula I2-acetamide-5-chlorobenzophenone-2 ',3',4',5',6' -d5。
4. The method for preparing diazepam-D8 according to claim 3, wherein in step (1): a compound of the formula I and C6D5The molar ratio of MgBr is 1:1.05, and 1g of the compound shown in the formula I is added with 5mL of toluene; after the reaction is finished, adding dilute hydrochloric acid with the concentration of 6mol/L, stirring for 30min, separating liquid, washing an organic phase twice, drying, concentrating under reduced pressure to obtain yellow oily matter, and directly using the obtained crude product for the next reaction.
5. The method for preparing diazepam-D8 as claimed in claim 1, wherein in step (2): adding the compound shown in the formula II into ethanol, then adding NaOH solution, heating and refluxing to remove a protecting group to obtain the compound shown in the formula III, namely 2-amino-5-chlorobenzophenone-2 ',3',4',5',6' -d5。
6. The method for preparing diazepam-D8 according to claim 5, wherein in the step (2): the concentration of the NaOH solution is 3mol/L, and the molar ratio of the amount of NaOH to the compound in the formula II is 2: 1; after the reaction is finished, dichloromethane is added for extraction, an organic phase is dried, filtered, decompressed and concentrated, and the product is obtained through column chromatography.
7. The method for preparing diazepam-D8 according to claim 1, wherein in the step (3): reacting the compound shown in the formula III with bromoacetyl bromide in an organic solvent under the alkaline condition to obtain a compound shown in the formula IV, namely 2-bromoacetamide-5-chlorobenzophenone-2 ',3',4',5',6'-d5。
8. the method for preparing diazepam-D8 according to claim 7, wherein in said step (3): the molar ratio of bromoacetyl bromide to the compound of formula III is 1.5: 1; the base is triethylamine, pyridine or DBU, and the molar ratio of the triethylamine to the compound in the formula III is 2: 1; the organic solvent is toluene, chloroform, dichloromethane or tetrahydrofuran, and the mass ratio of the volume of the chloroform to the compound of the formula III is 8:1 mL/g; after the reaction is finished, adding water to quench the reaction, separating out an organic phase, extracting a water phase by using an organic solvent, combining the organic phases, washing the organic phase by using saturated sodium carbonate, drying, decompressing and concentrating to obtain an oily substance, and directly using the oily substance in the next reaction without purification; in the step (4): dissolving the obtained crude compound shown in the formula IV by using a small amount of methanol, transferring the dissolved crude compound into a closed reaction container, and adding methanol, wherein the mass ratio of the total volume of the methanol to the compound shown in the formula IV is 5:1 mL/g; after methanol was added, the reaction vessel was sealed, and ammonia gas was introduced under a pressure of 1kg/cm2Heating to 50 deg.C for reaction for 12 hr, taking out the reaction mass, recovering methanol under reduced pressure, adding appropriate amount of water, extracting with ethyl acetate for 3 times, mixing the organic phases, drying, removing solvent, and performing column chromatography to obtain compound 7-chloro-1, 3-dihydro-5- (phenyl-d) of formula V5) -2H-1, 4-benzodiazepin-2-one.
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