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1. CN117088888 - PREPARATION METHOD OF
ALPRAZOLAM AND IMPURITY LAP THEREOF
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[ZH ]
A preparation method of alprazolam and its
impurity LAP
Technical Field
The present invention belongs to the technical field of chemical synthesis medicines,
and in particular relates to a method for preparing alprazolam and its impurity LAP.
Background Art
Alprazolam, also known as methyltriazolamide and 1-methyl-6-phenyl-8-chloro-4H-
(1,2,4-triazole [4,3-α] [1,4])-benzodiazepine, is a benzodiazepinetype hypnotic,
sedative, and anxiolytic. It is a third-generation central nervous system depressant drug
introduced in recent years and launched in the United States in 1981 for the treatment of
depression, insomnia, and other conditions. It acts on the benzodiazepine receptors (BZRs)
of the central nervous system, enhancing the binding of the central inhibitory
neurotransmitter γ-aminobutyric acid (GABA) to GABAA receptors, promoting the opening
of chloride channels, causing cell hyperpolarization, and increasing synaptic inhibition
mediated by GABAergic neurons, thereby reducing neuronal excitability.
The structural formula of alprazolam is as follows:
Related literature reports on the synthesis routes of alprazolam and optimizes them.
The main synthesis routes are as follows:
Synthesis Route 1: US Pat. No. 4,000,153 reports a complex nine-step synthesis using
(2-amino-5-chlorophenyl)-phenyl ketone and acetyl chloride as starting materials to

produce alprazolam. The specific synthesis route is shown in Synthesis Route 1 below. In the
fifth step, the intermediate undergoes oxidation of the quinoline ring with sodium periodate
and ruthenium oxide to form a triazole benzophenone. The benzene ring then undergoes
oxidation with formaldehyde to form a hydroxymethyl intermediate, which is then
chlorinated with thionyl chloride to form a chloromethyltriazole ring. Finally, the ring closes
with ammonia to produce alprazolam. The raw materials used in this route are not readily
available, resulting in high costs. Furthermore, several intermediates are difficult to
synthesize, resulting in a high number of byproducts and a lengthy synthesis route.
Synthesis Route 2: Patent ES8500944A1 reports a five-step synthesis using (2-amino-5chlorophenyl)-phenylmethanone as the starting material to synthesize a triazole ring,
followed by ring closure to form a triazole ring and a diazepine. The product, alprazolam, is
obtained through a five-step synthesis. The specific synthesis route is shown in Synthesis
Route 2 below. While this route shortens the synthesis cycle, some reactions suffer from
poor selectivity, low yield, high cost, and significant challenges in industrialization.
Synthesis Route 3: Currently, the commercial production of alprazolam mostly uses (2chloroacetamido-5-chlorophenyl)-benzophenone as the starting material to synthesize 7chloro-5-phenylbenzodiazepine. 7-Chloro-5-phenylbenzodiazepine is then subjected to
sulfidation, hydrazinolysis, and ring reduction to obtain alprazolam. The synthesis route is
shown in Synthesis Route 3 below. This route utilizes key raw materials with sufficient market
supply, reliable quality, and reasonable pricing. The process is simple to operate and has a
short reaction cycle, making it suitable for large-scale industrial production. However, the
use of phosphorus pentasulfide to thiolate the hydroxyl group during the reaction, followed
by ring closure with acetylhydrazine, easily generates hydrogen sulfide during the ring
closure process. Hydrogen sulfide is an acutely toxic substance, and inhaling even small
amounts of high-concentration hydrogen sulfide can be fatal within a short period of time.

During the research on the preparation process of alprazolam API, we discovered an
impurity LAP, and its content was >0.1%, exceeding the identification limit of impurities and
significantly exceeding the ICH requirements. At the same time, the applicant can prepare
the target product alprazolam according to the method of CN201410332777.8, but the
content of impurity LAP is generally between 0.2% and 0.5%, which cannot meet the
requirements of drug consistency evaluation. Combined with the reaction mechanism, it is
speculated that the cause of the generation of impurity LAP is: acetylhydrazine may undergo
enol isomerization under high temperature conditions, and react with thione cyclization
dehydration under high temperature conditions to obtain this impurity. The structure of
impurity LAP is as follows:
Impurity research is a crucial component of drug development, running through the
entire process and directly impacting drug safety, efficacy, and quality controllability. We
need to study the impurity LAP and its preparation method in anticipation of its application
in the quality research of alprazolam raw materials and their preparations. The applicant first
inferred the structure through HPLC-MS analysis, designed a synthetic route, and conducted
a targeted synthesis. The synthesis was performed using literature retrieval. During the
synthesis of this impurity, phosphorus pentasulfide was still used to thiolate and cyclize the
carbonyl group, inevitably producing the toxic substance hydrogen sulfide. Therefore, we
developed a method to avoid the introduction of thiolates.
Summary of the Invention
To address the above-mentioned issues, the present invention provides a method for
preparing high-purity alprazolam and its impurity LAP. This method uses 7-chloro-5phenylbenzodiazepine as a starting material, undergoes an acylation reaction with acetyl
chloride, and then undergoes a cyclization reaction with hydrazine hydrate to produce the
finished alprazolam product. The present invention features mild reaction conditions and
uses inexpensive and readily available raw materials, facilitating industrial production. This
method avoids the production of the LAP impurity and also avoids the use of phosphorus
pentasulfide and the risk of poisoning caused by hydrogen sulfide generated during the
reaction, greatly improving process safety. The present invention uses 7-chloro-5phenylbenzodiazepine as a starting material, reacts with chloroacetic acid, and then
undergoes a cyclization reaction with hydrazine hydrate under the catalysis of the
condensing agent N,N'-carbonylbis(1,2,4-triazole) to produce the impurity LAP. This method
can be widely used in quality research of alprazolam raw materials and their preparations,
thereby improving the safety, efficacy, and quality controllability of pharmaceuticals.
The technical solution of the present invention is: a method for preparing alprazolam,
which is characterized by comprising the following steps:
1) Preparation of Compound II: Compound I (7-chloro-5-phenylbenzodiazepine) is used
as a starting material, acetonitrile is used as a reaction solvent, and in the presence of an
acid-binding agent, it reacts with acetyl chloride to obtain Compound II;
2) Preparation of crude alprazolam: Compound II was reacted with water and hydrazine
using n-butanol as the reaction solvent. After the reaction, the temperature was lowered and
crystallization was performed to obtain crude alprazolam. The synthesis route is shown
below.

Preferably, the acid binding agent in step 1) is triethylamine, anhydrous sodium
carbonate, anhydrous potassium carbonate, sodium bicarbonate, etc., and triethylamine is
most preferred.
Preferably, the reaction temperature of step 1) is 0-10° C., and the reaction is kept warm
for 1-2 hours. After the reaction is completed, a solid is precipitated and then filtered to
obtain compound II.
Preferably, the reflux reaction in step 2) is carried out for 5 to 8 hours.
Preferably, the crystallization temperature in step 2) is -10 to 10°C, and most preferably
the crystallization temperature is -5 to 5°C.
Preferably, in step 1), the molar ratio of compound I, acid binding agent and acetyl
chloride is 1:1.05-1.5:1.05-1.2; and in step 2), the molar ratio of compound II and hydrazine
hydrate is 1:1.05-1.3.
Furthermore, the crude alprazolam product is further refined to obtain an alprazolam
product, specifically comprising the following steps: adding anhydrous ethanol to the crude
alprazolam product for slurrying, decolorizing with activated carbon; and then adopting a
gradient slow cooling process for crystallization to obtain the alprazolam product. The
cooling process adopts a gradient slow cooling process to prevent explosive precipitation,
specifically comprising the following steps: cooling to 50-70° C., adding seed crystals, and
maintaining the temperature for 0.5-2 hours (the most preferred temperature is 65-70° C.,
and the optimal holding time is 1 hour), then cooling to -5-0° C., maintaining the
temperature for 1-3 hours, filtering, and drying to obtain alprazolam.
The present invention also provides a method for preparing the impurity LAP, which is
characterized by comprising the following steps:
1) Preparation of Compound IIB: Compound I (7-chloro-5-phenylbenzodiazepine) is
used as a starting material and acetonitrile is used as a reaction solvent. The mixture is
reacted with chloroacetic acid in the presence of an acid-binding agent to obtain Compound
IIB.
2) Preparation of Impurity LAP: Using n-butanol as the reaction solvent, compound IIB
and hydrazine hydrate were subjected to a cyclization reaction catalyzed by the
condensation agent N,N'-carbonylbis(1,2,4-triazole) to obtain impurity LAP. The synthetic
route is as follows:
Preferably, the acid binding agent in step 1) is triethylamine, anhydrous sodium
carbonate, anhydrous potassium carbonate, sodium bicarbonate, etc., and most preferably
potassium bicarbonate.
Preferably, the reaction temperature in step 1) is 30-40° C., and the reaction is kept at
this temperature for 3-4 hours; then the temperature is lowered to 0-10° C. for crystallization
to obtain compound IIB.
Preferably, the reaction temperature in step 2) is 80-100°C, and the reaction is kept at
this temperature for 5-8 hours, followed by post-treatment to obtain the compound LAP.
The post-treatment comprises: quenching the reaction with water after completion, allowing
the reaction to stand, discarding the aqueous phase, slowly cooling the organic phase for
crystallization, filtering, and drying to obtain the impurity LAP.
Preferably, in step 1), the molar ratio of compound I, acid binding agent and
chloroacetic acid is 1:1.05-1.5:1.05-1.2;
Preferably, in step 2), the molar ratio of compound IIB, hydrazine hydrate and N,N'carbonylbis(1,2,4-triazole) is 1:1.05-1.3:1.05-1.5.
The advantages of the alprazolam preparation process of the present invention are:

1) The process route is short, the post-processing operation is simple, the production
energy consumption and cost are low, and it is conducive to large-scale industrial
production;
2) Avoid using expensive or dangerous raw materials, which is safe and environmentally
friendly and significantly reduces the cost of raw materials;
3) The present invention can avoid the generation of impurities LAP and hydrogen
sulfide, avoids the complicated impurity removal process, and the obtained product has
higher purity.
4) The process is short, produces less waste liquid, is environmentally friendly, and
saves costs;
In addition, the present invention also synthesizes the impurity LAP through a simple
method, which can be widely used in the quality research of alprazolam raw materials and
preparations thereof, thereby improving the safety, efficacy and quality controllability of
drugs.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a spectrum of related substances of alprazolam;
FIG2 is a mass spectrum of alprazolam impurity LAP;
Figure 3 is the hydrogen spectrum of alprazolam impurity LAP.
DETAILED DESCRIPTION
The following embodiments of the present invention are provided to further illustrate
the technical solutions and technical effects of the present invention, but are not intended to
limit the present invention.
Example 1:
1) Preparation of Intermediate II
Weigh 30 g of compound I, 120 g of acetonitrile and 13.4 g of triethylamine, cool to 010 ° C, add 9.5 g of acetyl chloride dropwise, and keep warm for 1-2 hours to react. Solid
precipitates and is then filtered. The filter cake is rinsed with 10 g of acetonitrile and dried to
obtain compound II with a dry weight of 32.7 g and a yield of 95.0%.
2) Preparation of crude alprazolam
30.0 g of compound II obtained above was added to 220.8 g of n-butanol and 5.5 g of
hydrazine hydrate, and the temperature was raised to reflux and kept for reaction for 6
hours. After the reaction was completed, the temperature was lowered to 0-10°C at a rate of
10°C/h, kept for 2 hours, and filtered to obtain crude alprazolam with a dry weight of 26.1 g,
a yield of 88.2%, and a purity of 99.2%.
3) Preparation of Alprazolam Finished Product
20 g of the crude alprazolam obtained above was added to 140 g of anhydrous ethanol,
the temperature was raised to reflux, and the temperature was maintained for 1 to 2 hours.
0.4 g of activated carbon was added and stirred for 30 minutes. After filtration, the filtrate
was cooled to 65°C, seed crystals were added, and the temperature was maintained for 1
hour. Then, the temperature was cooled to -5 to 0°C and maintained for 2 hours. The
finished alprazolam was filtered and dried at 60 to 70°C for 6 hours. The dry weight was 18.4
g, the yield was 92.0%, the total yield was 77.1%, and the purity was 99.98%. The results are
shown in Figure 1.
Example 2: Preparation of Impurity LAP
1) Preparation of intermediate IIB:
Weigh 10 g of compound I, 120 g of acetonitrile and 4.4 g of potassium bicarbonate,
cool to 0-10 ° C, add 3.8 g of chloroacetic acid dropwise, and after the addition is complete,
heat to 30-40 ° C, keep warm for 3-4 hours, cool to 0-10 ° C, filter, and rinse the filter cake
with 10 g of acetonitrile to obtain compound IIB with a wet weight of 15.0 g, which is
directly used in the next reaction.
2) Preparation of impurity LAP:
Compound IIB was added to 70 g of n-butanol, 2.2 g of hydrazine hydrate, and 7.3 g of
N,N"-carbonylbis(1,2,4-triazole). The temperature was raised to 90°C and maintained for 6 h.
The reaction was then cooled to 80°C, 40 g of purified water was added, and the mixture was
stirred for 20 min. The mixture was allowed to stand for 20 min, and the aqueous phase was
discarded. 40 g of purified water was added, and the mixture was stirred for 20 min. The
mixture was allowed to stand for 20 min, and the aqueous phase was discarded. The organic

phase was slowly cooled to crystallize, filtered, and dried to obtain 9.6 g of impurity LAP
with a yield of 80.0% and a purity of 95.46%.
MS(ESI+): 325.0([M+H] + ),327.0([M+2+H] + );
H-NMR(d-CDCl 3 ): 8.00-8.03 (d, 1H), 7.62-7.66 (dd, 1H), 7.34-7.53 (m, 6H), 5.44-5.48
(d, 1H), 4.09-4.32 (dd, 2H), 4.05-4.09 (d, 1H). Structural identification diagrams Figures 2-3.
1
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