CN108250091A - A kind of preparation method of alprazolam intermediate - Google Patents
A kind of preparation method of alprazolam intermediate Download PDFInfo
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- CN108250091A CN108250091A CN201711435134.6A CN201711435134A CN108250091A CN 108250091 A CN108250091 A CN 108250091A CN 201711435134 A CN201711435134 A CN 201711435134A CN 108250091 A CN108250091 A CN 108250091A
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- alprazolam
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of preparation methods of alprazolam intermediate.This method sequentially adds methanol and paranitrochlorobenzene in sodium hydrate aqueous solution, and then stirring is lower is added dropwise benzene acetonitrile, is added dropwise and is reacted after at 40 ± 5 DEG C, post-treated to obtain intermediate (II)；Intermediate (II) is dissolved in ethyl alcohol, is flowed back after adding in iron powder, and flow back 1h again after dropwise addition sulfuric acid, post-treated to obtain intermediate (III).The present invention replaces the dangerous way of alcohol reflux dissolved solid sodium hydroxide in synthetic intermediate (II) using sodium hydrate aqueous solution, and adds a small amount of methanol in the reaction system, successfully solves the problems, such as two phase reaction.The present invention replaces the hydrochloric acid of effumability in synthetic intermediate (III) with sulfuric acid, effectively shortens the reaction time, improves reaction efficiency.The method operation of the present invention is safer, and the reaction time is shorter, is more suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, in particular relate to a kind of alprazolam intermediate (2- amino -5- chlorine
Benzophenone) preparation method.
Background technology
Alprazolam (Alprazolam), chemical name：Chloro- 1- methyl -6- phenyl -4H- [1,2, the 4] triazols of 8- [4,3,
α] benzodiazepine, structural formula is as follows.Alprazolam is the cental system depressant developed in recent years, is usually used in treating
The Spirit nerve symptoms of disease such as insomnia, anxiety, melancholy.Triazole ring containing 1 metabolic stability in alprazolam molecule, therefore its physiology is lived
Property more general benzodiazepine strong drug action, sedation is stable 25~30 times, syngignoscism be stabilize 3.5~
11.3 times, and also apparent anti-epileptic and anti-melancholy effect.
At present, preparation method of many about alprazolam has been reported.Method 1：First synthesize diazepine ring, Ran Houzai
Triazole ring in parallel；Method 2：It is first to synthesize triazole ring, then cyclization forms triazole ring and diazepine again；Method 3：With to chlorine nitre
Base benzene is raw material, first synthesizes the chloro- 5- phenyl-Isosorbide-5-Nitrae-benzodiazepine -2- ketone (compound V) of 7-, then obtain through vulcanization, hydrazinolysis
To chemical compounds I, alprazolam (the chemical synthesis Zhengzhou University journal (doctor of the alprazolams such as Yao Xinjian is can obtain after cyclization
Learn version), the 4th phase volume 43 in 2008).The synthetic route of method 3 is as follows.
Wherein, the synthesis step having in first two method is more, and some expensive starting materials, yield are low, of high cost, should not adopt
With.In 3 intermediate of method (II) building-up process, due to the poor solubility of sodium hydroxide in ethanol, alcohol reflux is employed
Mode dissolved solid sodium hydroxide, this step operation is dangerous and solute effect is poor；In intermediate (III) building-up process, salt is added in
Back flow reaction can cause hydrochloric acid largely to volatilize after acid, lose hydrochloric acid, cause reaction effect poor.To sum up, the intermediate of method 3
(II), (III) synthesizes that this two-step reaction is cumbersome, and safety is poor, is unsuitable for industrialized production.Therefore, a peace is found
Complete economic and environment-friendly and simple and practicable preparation of industrialization intermediate (II), (III) method be this field technology urgently to be resolved hurrily
One of problem.
Invention content
In order to overcome above-mentioned the deficiencies in the prior art, the present invention provides a kind of safety and environmental protection, it is more suitable for industrializing
The preparation method of the alprazolam intermediate of production.This method is replaced in synthetic intermediate (II) using sodium hydrate aqueous solution
The dangerous way of alcohol reflux dissolved solid sodium hydroxide, and a small amount of methanol is added in the reaction system, successfully solve two
Phase reaction problem improves the safety of reaction.The hydrochloric acid of effumability is replaced with sulfuric acid in synthetic intermediate (III), is had
Effect shortens the reaction time, improves reaction efficiency.
The technical scheme is that：A kind of preparation method of alprazolam intermediate, it is characterized in that,
(1) methanol and paranitrochlorobenzene are sequentially added in sodium hydrate aqueous solution, then stirring is lower is added dropwise benzene acetonitrile, drop
It adds to finish and be reacted after at 40 ± 5 DEG C；Reaction complete after through cool down crystallization, be filtered, washed and drying intermediate
(II) --- the chloro- 3- phenyl-benzo isoxazoles of 5-；
(2) intermediate (II) is dissolved in ethyl alcohol, flowed back after adding in iron powder, reflux 1h ± 10min after sulfuric acid, reaction is added dropwise
After plus alkali adjust pH to 7-8, then through the crystallization that decolourizes, cools down, suction filtration, wash and be dried to obtain intermediate (III) --- 2-
Amino -5- chloro benzophenones.
Reaction equation is as follows：
Preferably, in the step (1) sodium hydrate aqueous solution a concentration of 20%~40% (w/v), preferred concentration is
30% (w/v).
Preferably, the time for adding of benzene acetonitrile is 10~30 minutes in the step (1), and preferably time for adding is 10 points
Clock.
Preferably, paranitrochlorobenzene in the step (1), benzene acetonitrile molar ratio be 1：1.0~1.2；Preferred molar ratio
It is 1:1.10.
Preferably, preferred reaction temperature is 40 DEG C in the step (1).
Preferably, methanol in the step (1), sodium hydroxide solution volume ratio be 1：8~12, preferably 1：10.
Preferably, the reaction time is 1~3 hour in the step (1), and the preferred reaction time is 2 hours.
Preferably, in the step (2) sulfuric acid a concentration of 4-8mol/L, preferred a concentration of 6mol/L, with intermediate
(II) molar ratio is 5~10：1.
In the above method 3 in alprazolam intermediate (II) preparation process, sodium hydroxide dissolves under alcohol reflux environment,
Benzene acetonitrile is added dropwise after adding in paranitrochlorobenzene reaction.It is above-mentioned by the way of alcohol reflux dissolved solid sodium hydroxide, operation danger
Danger and solute effect is poor.The present invention directly replaces alcohol reflux to dissolve sodium hydroxide using sodium hydrate aqueous solution, due to hydrogen-oxygen
Changing sodium, solubility is good in water, does not need to flow back, makes operation more safety and environmental protection.But due to using sodium hydrate aqueous solution generation
After sodium hydroxide ethanol solution, two phase reaction problem is produced, therefore the present invention adds on a small quantity in sodium hydroxide solution
Methanol successfully solves the problems, such as two-phase；After benzene acetonitrile are added dropwise, 40 DEG C or so reactions are warming up to, shorten the reaction time,
Improve production efficiency.
In the above method 3 in alprazolam intermediate (III) preparation process, the hydrochloric acid used is volatile acid, is being flowed back
The loss of hydrochloric acid can be caused in the process, cause reaction effect bad.The present invention uses sulphur acid instead of HCl, and the boiling point of sulfuric acid is
338 DEG C, and its dosage is few, can successfully replace hydrochloric acid, solve sour volatilization problems, the reaction time is shortened after replacement,
Improve reaction efficiency.
Compared with prior art, the present invention has the following advantages：
(1) present invention replaces sodium hydroxide ethanol solution using sodium hydrate aqueous solution, avoids molten at reflux
Sodium hydroxide is solved, makes operation safer, reduces the pollution to environment, it is also more friendly to environment.
(2) present invention will add a small amount of methanol in the reaction system, successfully solve the problems, such as two phase reaction, improve life
Produce efficiency.
(3) after benzene acetonitrile of the present invention is added dropwise, 40 DEG C or so reactions are warming up to, the reaction time is made to shorten half, are improved
Production efficiency.
(4) present invention replaces the hydrochloric acid of effumability with sulfuric acid, effectively shortens the reaction time, improves reaction effect
Rate.
In short, compared with prior art, the present invention in the case where ensureing product yield, obtain it is a kind of operate it is safer, during reaction
Between it is shorter, be more suitable for the production technology of industrialized production.
Specific embodiment
The present invention is further described by following embodiment, althoughs note that the scope of the present invention not by these embodiments
Any restrictions.
Embodiment 1
(1) 25g sodium hydrate solids are put into 100ml purified waters, be cooled at 30 DEG C, put into methanol 12ml, stir
Lower addition paranitrochlorobenzene 10g is mixed, reacts 0.5h, 7.4g benzene acetonitriles are added dropwise, 15min is added dropwise.After being added dropwise, it is warming up to
40 DEG C, react 1.5h.It is cooled to 0-5 DEG C after completion of the reaction, filters.With 0-5 DEG C of purifying water washing to neutrality, dry faint yellow
Solid, as alprazolam intermediate (II), weighing obtain 12.9g, and yield 88.5%, it is 114-116 DEG C to measure fusing point.
(2) 10.0g intermediates (II) is taken to add in there-necked flask, 50ml ethyl alcohol, 4.8g iron powders, flow back 0.5h, and 1ml sulphur is added dropwise
Sour (5mol/L), drips back flow reaction 1h after finishing, and adds in NaOH solution after completion of the reaction and adjusts pH to 8, be cooled to 50 DEG C, adds in
0.2g activated carbons, flow back 0.5h, and in heat filter to crystallization bottle, decrease temperature crystalline filters, and ethyl alcohol washes material, dry intermediate (III)
9.35g, yield 93.2%, fusing point are 96.2-98.0 DEG C.
Embodiment 2
(1) 30g sodium hydrate solids are put into 100ml purified waters, be cooled at 30 DEG C, put into methanol 10ml, stir
Lower addition paranitrochlorobenzene 10g is mixed, reacts 0.5h, 8.2g benzene acetonitriles are added dropwise, 10min is added dropwise.After being added dropwise, it is warming up to
40 DEG C, react 2h.It is cooled to 0-5 DEG C after completion of the reaction, filters.With 0-5 DEG C of purifying water washing to neutrality, pale yellow colored solid is dried to obtain
Body, as alprazolam intermediate (II), weighing obtain 13.2g, and total recovery 90.5%, it is 114-117 DEG C to measure fusing point.
(2) 10.0g intermediates (II) is taken to add in there-necked flask, 50ml ethyl alcohol, 4.8g iron powders, flow back 0.5h, and 1ml sulphur is added dropwise
Sour (6mol/L), drips back flow reaction 1h after finishing, and adds in NaOH solution after completion of the reaction and adjusts pH to 8, be cooled to 50 DEG C, adds in
0.2g activated carbons, flow back 0.5h, and in heat filter to crystallization bottle, decrease temperature crystalline, ethyl alcohol washes material, dry intermediate (III) 9.60g,
Yield is 95.1%, and fusing point is 96.3-98.2 DEG C.
Embodiment 3
(1) 35g sodium hydrate solids are put into 100ml purified waters, be cooled at 30 DEG C, put into methanol 10ml, stir
Lower addition paranitrochlorobenzene 10g is mixed, reacts 0.5h, 8.6g benzene acetonitriles are added dropwise, 15min is added dropwise.After being added dropwise, it is warming up to
40 DEG C, react 2.5h.It is cooled to 0-5 DEG C after completion of the reaction, filters.With 0-5 DEG C of purifying water washing to neutrality, dry faint yellow
Solid, as alprazolam intermediate (II), weighing obtain 13.1g, and total recovery 89.7%, it is 113-115 DEG C to measure fusing point.
(2) 10.0g intermediates (II) is taken to add in there-necked flask, 50ml ethyl alcohol, 4.8g iron powders, flow back 0.5h, and 1ml sulphur is added dropwise
Sour (6.5mol/L), drips back flow reaction 1h after finishing, and adds in NaOH solution after completion of the reaction and adjusts pH to 8, be cooled to 50 DEG C, adds in
0.2g activated carbons, flow back 0.5h, and in heat filter to crystallization bottle, decrease temperature crystalline, ethyl alcohol washes material, dry intermediate (III) 9.28g,
Yield is 92.5%, and fusing point is 96.0-97.8 DEG C.
Embodiment 1-3 and the prior art (《Zhengzhou University's journal (medicine)》, the 4th phase of volume 43 in 2008) product receive
The results are shown in Table 1 for rate, fusing point.As can be seen from Table 1：The product yield of intermediate (II) maintains an equal level with the prior art, intermediate
(III) yield is slightly improved than the prior art；But the reaction time of the present invention is obviously shortened, and reduce security risk.
The product yield of 1 embodiment 1-3 of table table compared with the prior art
Although some exemplary embodiments of the present invention have shown and described, those skilled in the art should know
Dawn in the case where not departing from the principle of the invention and spirit, can make a change these embodiments, the scope of the present invention is by weighing
Profit and its equivalent limit.
Claims (10)
1. a kind of preparation method of alprazolam intermediate, it is characterized in that, include the following steps：
(1) methanol and paranitrochlorobenzene are sequentially added in sodium hydrate aqueous solution, then stirring is lower is added dropwise benzene acetonitrile, drips
Finish and reacted after at 40 ± 5 DEG C；Reaction complete after through cool down crystallization, be filtered, washed and drying obtain the chloro- 3- phenyl of 5--
Benzo isoxazole；
(2) the chloro- 3- phenyl-benzo isoxazoles of 5- are dissolved in ethyl alcohol, flowed back after adding in iron powder, the 1h that flows back again after dropwise addition sulfuric acid ±
10min, after completion of the reaction plus alkali adjusts pH to 7-8, then through the crystallization that decolourizes, cools down, suction filtration, wash and be dried to obtain alprazolam
Intermediate 2-amino -5- chloro benzophenones.
2. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, hydrogen in the step (1)
The mass volume ratio a concentration of 20%~40% of aqueous solution of sodium oxide.
3. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, hydrogen in the step (1)
The mass volume ratio a concentration of 30% of aqueous solution of sodium oxide.
4. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, in the step (1)
Reaction temperature is 40 DEG C.
5. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, first in the step (1)
Alcohol, sodium hydroxide solution volume ratio be 1：8~12.
6. a kind of preparation method of alprazolam intermediate as claimed in claim 5, it is characterized in that, first in the step (1)
Alcohol, sodium hydroxide solution volume ratio be 1：10.
7. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, it is anti-in the step (1)
It is 1~3 hour between seasonable.
8. a kind of preparation method of alprazolam intermediate as claimed in claim 7, it is characterized in that, it is anti-in the step (1)
It is 2 hours between seasonable.
9. a kind of preparation method of alprazolam intermediate as described in claim 1, it is characterized in that, it is right in the step (1)
Nitro-chlorobenzene, benzene acetonitrile molar ratio be 1：1.0~1.2.
10. a kind of preparation method of alprazolam intermediate as described in any one in claim 1-9, it is characterized in that, institute
State a concentration of 4-8mol/L of sulfuric acid in step (2).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111196770A (en) * | 2018-11-19 | 2020-05-26 | 新发药业有限公司 | Simple preparation method of bromfenac sodium |
| CN112552154A (en) * | 2020-12-18 | 2021-03-26 | 河南省科学院化学研究所有限公司 | Preparation method of 1-bromofluorenone |
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| CN1686999A (en) * | 2005-04-20 | 2005-10-26 | 江苏省原子医学研究所 | 1-carboxy-1-(3,5-dimethoxy phenyl)-2-(4-R group phenyl) ethano and preparation method thereof |
| WO2015048370A1 (en) * | 2013-09-27 | 2015-04-02 | Auspex Pharmaceuticals, Inc. | Benzoquinolone inhibitors of vmat2 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111196770A (en) * | 2018-11-19 | 2020-05-26 | 新发药业有限公司 | Simple preparation method of bromfenac sodium |
| CN111196770B (en) * | 2018-11-19 | 2023-04-07 | 新发药业有限公司 | Simple preparation method of bromfenac sodium |
| CN112552154A (en) * | 2020-12-18 | 2021-03-26 | 河南省科学院化学研究所有限公司 | Preparation method of 1-bromofluorenone |
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Effective date of registration: 20200226 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Applicant after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Applicant before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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