CN103804310A - Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one - Google Patents
Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one Download PDFInfo
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- CN103804310A CN103804310A CN201310580899.4A CN201310580899A CN103804310A CN 103804310 A CN103804310 A CN 103804310A CN 201310580899 A CN201310580899 A CN 201310580899A CN 103804310 A CN103804310 A CN 103804310A
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- 0 CC(CC1C#CC1C1)C(C)C*(CC(C2=*C3=CC3C=CC2)=NCC2)=C1N*2O Chemical compound CC(CC1C#CC1C1)C(C)C*(CC(C2=*C3=CC3C=CC2)=NCC2)=C1N*2O 0.000 description 2
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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
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
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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
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
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Abstract
The invention relates to a method for preparing a high-purity important intermediate of alprazolam, namely 7-chloro-5-phenyl-benzodiazepine-2-one. The method comprises the following steps: after a ring-closure reaction taking 2-chloroacetylamino-5-chloro-diphenyl ketone and hexamethylenetetramine as main raw materials, performing vacuum concentration to dryness, and directly adding a refining solvent for clear dissolution; then, washing and layering, and dropwise adding dilute acid for salifying; adding alkaline water into the separated salt in purified water, and freeing to obtain 7-chloro-5-phenyl-benzodiazepine-2-one of which the HPLC (high performance liquid chromatography) purity is not lower than 99.0%. In the method, the end point of the concentration operation after complete reaction is easy to control, the HPLC purity of the product is remarkably increased, and the interference of unavoidable impurities on later preparation of alprazolam is avoided.
Description
Technical field
The present invention relates to a kind of method of preparing the chloro-5-phenyl-benzodiazepine-2-of high purity alprazolam important intermediate 7-ketone, belong to pharmacy synthesis technology field.
Background technology
The chloro-5-phenyl-benzodiazepine-2-of 7-ketone is the key intermediate of the benzodiazepines sedative hypnotic drugs such as synthetic alprazolam, diazepam.The chemistry chloro-1-methyl-6-of 8-phenyl-4H-［ 1,2,4 ］ triazolo ［ 4,3-α ］ benzodiazepine by name of alprazolam is the cental system Depressant of development in recent years.Because of the triazole ring that contains a metabolic stability in its molecule, make the Benzodiazepines that its physiologically active is more general strong, calm and syngignoscism is respectively 25～30 times and 3.5～11.3 times of diazepam, and also has obvious anti-epileptic and antidepressant effect.The synthesis technique of existing alprazolam exists that intermediate purity is not high, the final quality detection meeting of product alprazolam occurs repeatedly doing over again refining phenomenon because related substance detection transfinites.Because the refinement mother liquor of alprazolam is difficult to process qualified, so not only affect production schedule, also make production cost unprecedented soaring.By analyzing, the purity of the intermediate especially purity of the chloro-5-phenyl-benzodiazepine-2-of 7-ketone is larger on the reaction process impact of subsequent handling, is therefore necessary existing synthesis technique to carry out further perfect.
The existing synthesis technique of the chloro-5-phenyl-benzodiazepine-2-of intermediate 7-ketone adopts conventionally take the chloro-benzophenone of 2-chloro acetylamino-5-and hexamethylenetetramine as main raw material, industrial alcohol are as solvent, under volatile salt or bicarbonate of ammonia exist, carries out ring-closure reaction.Reaction finishes to obtain crude product through concentrating under reduced pressure, cooling, filtration drying, and crude product obtains intermediate fine work and is applied to subsequent reactions and obtains finished product alprazolam in ethanol after recrystallizing and refining; Document " chemosynthesis of alprazolam " (Zhengzhou University's journal medicine, 2008,43,791-793), report the synthesis process that comprises the chloro-5-phenyl-benzodiazepine-2-of intermediate 7-ketone crude product and finished product alprazolam, in document, do not mentioned the process for refining process of intermediate.The intermediate HPLC purity preparing according to document technique is not high, does not carry out further refinement treatment, brings a large amount of impurity into subsequent handling, finally can cause the related substance detection in finished product alprazolam quality index to transfinite.Subject matter in intermediate preparation process is: in reaction process, often there will be the phenomenon that causes blockage of condenser because of the distillation of bicarbonate of ammonia or volatile salt, exist potential safety hazard; The striking point that reaction finishes is wayward, the solvent amount of steaming very few direct affect cyclization yield, the amount of steaming many can be easy to occur material be glue can not separate due to the situation of discharging difficulty; The HPLC purity of the chloro-5-phenyl-benzodiazepine-2-of gained intermediate 7-ketone crude product is only 85% left and right; Intermediate solubleness in ethanol is little, it is undesirable that in etoh solvent, recrystallization is removed impurity effect, the HPLC purity of fine work can only reach 95% left and right, the impurity wherein comprising is brought subsequent reactions into, there is impurity scale effect step by step, easily cause finished product alprazolam quality and stablize not, occur being forced to because finished product related substance detection exceeds standard the refining phenomenon of doing over again.
Summary of the invention
Object of the present invention is exactly the defect for prior art, and the chloro-5-phenyl-benzodiazepine-2-of a kind of alprazolam important intermediate 7-preparation method of ketone is provided.The reaction process of being prepared the chloro-5-phenyl-benzodiazepine-2-of 7-ketone (I) crude product and fine work by the chloro-benzophenone of 2-chloro acetylamino-5-(II) and hexamethylenetetramine (III) is as follows:
Method provided by the invention, for do not add volatile salt or bicarbonate of ammonia in ring-closure reaction, adopts and adds the mode of hydrochloric acid as catalyzer, avoids occurring the phenomenon of blockage of condenser; After reaction finishes, directly solvent is concentrated near doing, after directly lowering the temperature without discharging, adds refining solvent to stir molten clear rear layering washing, avoided the phenomenon of loss of material and discharging difficulty; Be added dropwise to diluted acid to refining solvent layer and carry out salt-forming reaction, after filtration filter cake is suspended in purified water again, separate out off-white color material to dripping buck in suspension, filter, purified water washing, dryly obtain the chloro-5-phenyl-benzodiazepine-2-of 7-ketone, its HPLC purity is more than 99.0% after testing.
For reaching above-mentioned purpose, the measure that the present invention takes is as follows:
Prepare a method for the chloro-5-phenyl-benzodiazepine-2-of high purity alprazolam important intermediate 7-ketone, chloro-2-chloro acetylamino-5-benzophenone, industrial alcohol, hexamethylenetetramine, hydrochloric acid are dropped in reaction vessel, temperature rising reflux reaction is to complete.Be evaporated to closely dry, cooling adds refining solvent to stir molten clear after washing layering, carries out salt-forming reaction to being added dropwise to diluted acid in refining solvent layer.After salt-forming reaction completely, filter, gained filter cake is suspended in purified water, adjust pH to 7.2～7.5 to separate out gradually off-white color material to dripping buck in suspension, filter, purified water washing, the dry chloro-5-phenyl-benzodiazepine-2-of the 7-ketone that obtains.
Refining solvent used is trichloromethane.
The volume of refining solvent used is 15～20 times of the chloro-benzophenone quality of 2-chloro acetylamino-5-.
The solution of diluted acid used after for mass percent concentration be 68% refining nitric acid and purified water mixed diluting.
The volumetric molar concentration of diluted acid used is 3 mol/L.
The mol ratio of diluted acid and the chloro-benzophenone of 2-chloro acetylamino-5-is 1.1～1.3:1.
Buck used is the saturated aqueous solution of sodium bicarbonate.
Preparation method of the present invention has improved the HPLC purity of the chloro-5-phenyl-benzodiazepine-2-of alprazolam important intermediate 7-ketone, then the high purity intermediate obtaining by this preparation method carries out the preparation of finished product alprazolam.Wherein can adopt any means of prior art by the method that the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone is prepared finished product alprazolam.
Compared with prior art, the present invention has the following advantages:
1. in ring-closure reaction process, do not add volatile salt or bicarbonate of ammonia, adopt and add hydrochloric acid to carry out as the mode of catalyzer.So both guaranteed completing smoothly of ring-closure reaction, avoid again occurring blockage of condenser phenomenon, eliminated potential safety hazard;
Ring-closure reaction completely solvent is concentrated near dry after, cooling adds refining solvent to stir molten adding water again after clear to carry out layering washing.So do not exist in former technique aftertreatment concentration process the solvent amount of steaming very fewly to affect cyclization yield, the amount of steaming is easy to occur that material is gluey indissociable difficulty more, has avoided the phenomenon of loss of material and discharging difficulty;
3. be added dropwise to after diluted acid salt-forming reaction to refining solvent layer, gained filter cake be suspended in purified water, add again the free chloro-5-phenyl-benzodiazepine-2-of the high purity 7-ketone that obtains of buck after filtration.This preparation method has not only omitted the baking operation of former technique before refining, and the HPLC purity of the chloro-5-phenyl-benzodiazepine-2-of gained 7-ketone reaches more than 99.0%, for the follow-up alprazolam of preparing has been exempted the impurity that is difficult to remove and disturbed.
Accompanying drawing explanation
Fig. 1 is the purity HPLC detection figure that the chloro-5-phenyl-benzodiazepine-2-of important intermediate 7-ketone crude product retention time that formula I prepared by existing traditional technology represents is 4.657min;
Fig. 2 is the purity HPLC detection figure that the chloro-5-phenyl-benzodiazepine-2-of important intermediate 7-ketone fine work retention time that formula I prepared by existing traditional technology represents is 4.653min;
Fig. 3 is the purity HPLC detection figure that the chloro-5-phenyl-benzodiazepine-2-of important intermediate 7-ketone retention time that formula I prepared by the embodiment of the present invention 1 represents is 4.164min;
Fig. 4 is the purity HPLC detection figure that the chloro-5-phenyl-benzodiazepine-2-of important intermediate 7-ketone retention time that formula I prepared by the embodiment of the present invention 2 represents is 4.201min;
Fig. 5 is the purity HPLC detection figure that the chloro-5-phenyl-benzodiazepine-2-of important intermediate 7-ketone retention time that formula I prepared by the embodiment of the present invention 3 represents is 3.998min;
As shown in Figure 1, the chloro-5-phenyl-benzodiazepine-2-of the important intermediate 7-ketone crude product that formula I prepared by existing traditional technology represents, retention time is 4.657min, purity is 88.0431%, illustrates that it is only 85% left and right that existing traditional technology is prepared the intermediate crude product purity that formula I represents;
As shown in Figure 2, the chloro-5-phenyl-benzodiazepine-2-of the important intermediate 7-ketone fine work that formula I prepared by existing traditional technology represents, retention time is 4.653min, purity is 93.5255%, illustrates that existing traditional technology prepares intermediate crude product fine work purity after ethyl alcohol recrystallization is refining that formula I represents and can only reach 95% left and right;
As shown in Figure 3, the chloro-5-phenyl-benzodiazepine-2-of the important intermediate 7-ketone fine work that formula I prepared by the embodiment of the present invention 1 represents, retention time is 4.164min, and purity is 99.7913%, illustrates that method of the present invention prepares purity >=99.0% of the intermediate that formula I represents;
As shown in Figure 4, the chloro-5-phenyl-benzodiazepine-2-of the important intermediate 7-ketone fine work that formula I prepared by the embodiment of the present invention 2 represents, retention time is 4.201min, and purity is 99.4702%, illustrates that method of the present invention prepares purity >=99.0% of the intermediate that formula I represents;
As shown in Figure 5, the chloro-5-phenyl-benzodiazepine-2-of the important intermediate 7-ketone fine work that formula I prepared by the embodiment of the present invention 3 represents, retention time is 3.998min, and purity is 99.8094%, illustrates that method of the present invention prepares purity >=99.0% of the intermediate that formula I represents.
Embodiment
With example, the present invention is illustrated below, these examples are intended to help to understand technique means of the present invention.But should be understood that these embodiment are exemplary, the present invention is not limited thereto.
Embodiment mono-
Successively by chloro-to industrial alcohol 400ml, 2-chloro acetylamino-5-benzophenone 40g(0.130mol), after hexamethylenetetramine 34g drops into and stirs in reaction flask, it is more than 35% refining hydrochloric acid 15ml that room temperature drips mass percent concentration.Finish temperature rising reflux reaction 7 hours.Be evaporated to closely dry, add trichloromethane 600ml after being cooled to room temperature, stir molten clear.With washing purified water 100ml × 3, the following rare nitric acid 48ml(0.144mol to being added dropwise to 3mol/L in chloroform soln of 20 ℃ of temperature controls after branch vibration layer), separate out gradually yellow solid particle.Finish, continue at 20 ℃～25 ℃ stirring reactions 2 hours.Filter, filter cake is dropped in purified water 400ml and stirred 1 hour, be cooled to 10 ℃ of following pure water solutions that drip saturated sodium bicarbonate, adjust pH to 7.2～7.5.Finish, continue to be cooled to below 5 ℃, leave standstill more than 2 hours.Filter purified water washing, the dry chloro-5-phenyl-benzodiazepine-2-of 7-ketone 29.3g, 214.4～214.6 ℃ of fusing points, HPLC purity >=99.0% of obtaining.
Embodiment bis-
Successively by chloro-to industrial alcohol 300ml, 2-chloro acetylamino-5-benzophenone 30g(0.097mol), after hexamethylenetetramine 25.5g drops into and stirs in reaction flask, it is more than 35% refining hydrochloric acid 12ml that room temperature drips mass percent concentration.Finish temperature rising reflux reaction 7 hours.Be evaporated to closely dry, add trichloromethane 600ml after being cooled to room temperature, stir molten clear.With washing purified water 75ml × 3, the following rare nitric acid 42ml(0.126mol to being added dropwise to 3mol/L in chloroform soln of 20 ℃ of temperature controls after branch vibration layer), separate out gradually yellow solid particle.Finish, continue at 20 ℃～25 ℃ stirring reactions 2 hours.Filter, filter cake is dropped in purified water 300ml and stirred 1 hour, be cooled to 10 ℃ of following pure water solutions that drip saturated sodium bicarbonate, adjust pH to 7.2～7.5.Finish, continue to be cooled to below 5 ℃, leave standstill more than 2 hours.Filter purified water washing, the dry chloro-5-phenyl-benzodiazepine-2-of 7-ketone 22.4g, 214.3～214.9 ℃ of fusing points, HPLC purity >=99.0% of obtaining.
Embodiment tri-
Successively by chloro-to industrial alcohol 500ml, 2-chloro acetylamino-5-benzophenone 50g(0.162mol), after hexamethylenetetramine 42.5g drops into and stirs in reaction flask, it is more than 35% refining hydrochloric acid 19ml that room temperature drips mass percent concentration.Finish temperature rising reflux reaction 7 hours.Be evaporated to closely dry, add trichloromethane 875ml after being cooled to room temperature, stir molten clear.With washing purified water 125ml × 3, the following rare nitric acid 65ml(0.195mol to being added dropwise to 3mol/L in chloroform soln of 20 ℃ of temperature controls after branch vibration layer), separate out gradually yellow solid particle.Finish, continue at 20 ℃～25 ℃ stirring reactions 2 hours.Filter, filter cake is dropped in purified water 500ml and stirred 1 hour, be cooled to 10 ℃ of following pure water solutions that drip saturated sodium bicarbonate, adjust pH to 7.2～7.5.Finish, continue to be cooled to below 5 ℃, leave standstill more than 2 hours.Filter purified water washing, the dry chloro-5-phenyl-benzodiazepine-2-of 7-ketone 37.4g, 215.2～215.4 ℃ of fusing points, HPLC purity >=99.0% of obtaining.
Claims (6)
1. a method of preparing the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone (I), is characterized in that, preparation method's processing step is:
Chloro-2-chloro acetylamino-5-benzophenone (II), industrial alcohol, hexamethylenetetramine (III), hydrochloric acid are dropped in reaction vessel, and temperature rising reflux reaction is to complete; Be evaporated near dry, cooling add refining solvent stir molten clear after, with purifying washing, the backward refining solvent layer of branch vibration layer is added dropwise to diluted acid and carries out salt-forming reaction; After salt-forming reaction completely, filter, gained filter cake is suspended in purified water, adjust pH to 7.2～7.5 to separate out gradually off-white color material to dripping buck in suspension, filter, purified water washing, dryly obtain HPLC purity and be not less than 99.0% the chloro-5-phenyl-benzodiazepine-2-of 7-ketone (I);
The structural formula of above-mentioned formula I, (II), (III) is as follows:
2. one according to claim 1 is prepared the method for the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone (I), it is characterized in that: described refining solvent is trichloromethane.
3. one according to claim 1 and 2 is prepared the method for the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone (I), it is characterized in that: the volume of refining solvent is 15～20 times of the chloro-benzophenone of 2-chloro acetylamino-5-(II) quality.
4. one according to claim 1 is prepared the method for the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone (I), it is characterized in that: described diluted acid is that mass percent concentration is the solution after 68% refining nitric acid and purified water mixed diluting, and the volumetric molar concentration of diluted acid is 3 mol/L.
5. the method for preparing the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone (I) according to the one described in claim 1 or 4, is characterized in that: the mol ratio of diluted acid and the chloro-benzophenone of 2-chloro acetylamino-5-(II) is 1.1～1.3:1.
6. a kind of method of preparing the chloro-5-phenyl-benzodiazepine-2-of high purity 7-ketone according to claim 1, is characterized in that: the saturated aqueous solution that buck used is sodium bicarbonate.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130201A (en) * | 2014-07-14 | 2014-11-05 | 河南豫辰精细化工有限公司 | Preparation method of benzodiazothioketone serving as intermediate of alprazolam |
| CN109721556A (en) * | 2018-12-05 | 2019-05-07 | 许昌豫通生物科技有限公司 | A kind of production technology of thioketones |
| CN112608283A (en) * | 2020-12-22 | 2021-04-06 | 华中药业股份有限公司 | Preparation method of nitrazepam |
| CN115322160A (en) * | 2022-08-04 | 2022-11-11 | 温州医科大学 | Preparation method of 5-aryl-1,4-benzodiazepine-2-one compound |
| CN116023342A (en) * | 2021-10-26 | 2023-04-28 | 江苏昱林生物科技有限公司 | Preparation method of high-purity clonazepam |
| CN116023342B (en) * | 2021-10-26 | 2024-06-25 | 江苏昱林生物科技有限公司 | Preparation method of high-purity clonazepam |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130201A (en) * | 2014-07-14 | 2014-11-05 | 河南豫辰精细化工有限公司 | Preparation method of benzodiazothioketone serving as intermediate of alprazolam |
| CN104130201B (en) * | 2014-07-14 | 2016-06-01 | 河南豫辰药业股份有限公司 | The preparation method of a kind of alprazolam intermediate benzodiazepine thioketones |
| CN109721556A (en) * | 2018-12-05 | 2019-05-07 | 许昌豫通生物科技有限公司 | A kind of production technology of thioketones |
| CN112608283A (en) * | 2020-12-22 | 2021-04-06 | 华中药业股份有限公司 | Preparation method of nitrazepam |
| CN116023342A (en) * | 2021-10-26 | 2023-04-28 | 江苏昱林生物科技有限公司 | Preparation method of high-purity clonazepam |
| CN116023342B (en) * | 2021-10-26 | 2024-06-25 | 江苏昱林生物科技有限公司 | Preparation method of high-purity clonazepam |
| CN115322160A (en) * | 2022-08-04 | 2022-11-11 | 温州医科大学 | Preparation method of 5-aryl-1,4-benzodiazepine-2-one compound |
| CN115322160B (en) * | 2022-08-04 | 2024-05-31 | 温州医科大学 | Preparation method of 5-aryl-1, 4-benzodiazepine-2-ketone compound |
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Application publication date: 20140521 |