Hallo guys, 
I have already seen that in this forum the following synthesis route is discussed:
"New and mild method for the synthesis of alprazolam..."
To a vigorously stirred of 2-amino-5-chloro benzophenone (0.232 g, 1 mmol) in a pear-shaped flask (10-50 ml), chloroacetyl chloride (1.2 mL, 2 mmol) was added drop wise at room temperature under solvent-free conditions during 30 min and the progress of reaction was monitored by TLC. After completion of the reaction, NH4OAc (0.23 g, 3 mmol) and K2CO3 (0.42 g, 3 mmol) were added to the mixture at room temperature under solvent-free conditions and stirred for 2.5 h. When the reaction was completed, as it was shown by TLC, the water (30 mL) was added and the product was filtered off via paper filter, washed with more distilled water (2 x 100 mL) and dried in vacuum desiccator. The product was obtained in high yield and purity (94% yield) and was used in the next step without any purification. m.p. = 212–214 °C.
Synthesis of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]-diazepin-2(3H)-one (Step 2)
To a vigorously stirred mixture of nordiazepam (1) (0.27 g, 1 mmol) in a pear-shaped flask (10-50 ml), a powder mixture of K2CO3 (0.55 g, 4 mmol)/KOH (0.22 g, 4 mmol) and acetic anhydride (0.18 mL, 2 mmol) was added. The progress of the reaction was monitored by TLC. After completion of the reaction (3 h), water (3 x 10 mL) was added and the 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2) was easily isolated by a simple filtration in more than 80% yield with high purity. The product was used in the next step without any purification. m.p. = 163–165 °C.
Synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (Alprazolam, Xanax) (Step 3)
A solution of 1 mmol (0.31 g) of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2), hydrazine hydrate N2H5OH (4 mmol, 0.2 mL) and NaOAc (4 mmol, 0.2 mL) in 25 ml of AcOH was refluxed for 12 h in a pear-shaped flask (100 ml) with a reflux condenser. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was cooled and the product was filtered, washed with water, dried, and crystallized from EtOH. (75% yield); m.p. = 228–230 °C.
I tryed the first Step of it, without success, my problem was to mix everything correctly because it was getting a sticky mass afer
putting the 2-Amino-5-chloro benzophenone together with the chloroacetyl chloride.
Has anybody an good experience with this synthesis.
Or can we together change it to make it more sucessfull.
Maybe by using solvents.
It would be great, if we can work out a detailled step by step manual for Alprazolam
I have already seen that in this forum the following synthesis route is discussed:
"New and mild method for the synthesis of alprazolam..."
Synthesis of 7-chloro-5-phenyl-1H benzo[e][1,4]diazepin-2(3H)-one (nordiazepam) (Step 1)To a vigorously stirred of 2-amino-5-chloro benzophenone (0.232 g, 1 mmol) in a pear-shaped flask (10-50 ml), chloroacetyl chloride (1.2 mL, 2 mmol) was added drop wise at room temperature under solvent-free conditions during 30 min and the progress of reaction was monitored by TLC. After completion of the reaction, NH4OAc (0.23 g, 3 mmol) and K2CO3 (0.42 g, 3 mmol) were added to the mixture at room temperature under solvent-free conditions and stirred for 2.5 h. When the reaction was completed, as it was shown by TLC, the water (30 mL) was added and the product was filtered off via paper filter, washed with more distilled water (2 x 100 mL) and dried in vacuum desiccator. The product was obtained in high yield and purity (94% yield) and was used in the next step without any purification. m.p. = 212–214 °C.
Synthesis of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]-diazepin-2(3H)-one (Step 2)
To a vigorously stirred mixture of nordiazepam (1) (0.27 g, 1 mmol) in a pear-shaped flask (10-50 ml), a powder mixture of K2CO3 (0.55 g, 4 mmol)/KOH (0.22 g, 4 mmol) and acetic anhydride (0.18 mL, 2 mmol) was added. The progress of the reaction was monitored by TLC. After completion of the reaction (3 h), water (3 x 10 mL) was added and the 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2) was easily isolated by a simple filtration in more than 80% yield with high purity. The product was used in the next step without any purification. m.p. = 163–165 °C.
Synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (Alprazolam, Xanax) (Step 3)
A solution of 1 mmol (0.31 g) of 1-acetyl-7-chloro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (2), hydrazine hydrate N2H5OH (4 mmol, 0.2 mL) and NaOAc (4 mmol, 0.2 mL) in 25 ml of AcOH was refluxed for 12 h in a pear-shaped flask (100 ml) with a reflux condenser. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was cooled and the product was filtered, washed with water, dried, and crystallized from EtOH. (75% yield); m.p. = 228–230 °C.
I tryed the first Step of it, without success, my problem was to mix everything correctly because it was getting a sticky mass afer
putting the 2-Amino-5-chloro benzophenone together with the chloroacetyl chloride.
Has anybody an good experience with this synthesis.
Or can we together change it to make it more sucessfull.
Maybe by using solvents.
It would be great, if we can work out a detailled step by step manual for Alprazolam