Synthetic procedure for the manufacture of aspirin

Details Synthetic procedure for the manufacture of aspirin Synthetic procedure for the manufacture of aspirin

2000-06-06

2001-08-21

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06278014

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The current invention relates to the field of pharmaceutical synthesis and the preparation of acetyl salicylic acid. A synthetic procedure is shown which is elegant in its simplicity and its ability to provide a product, which does not require any purification of the final reaction product before being used in pharmaceutical preparations. The reaction is very fast, one-pot, non-polluting of the environment, and provides 100% yield of product which contains 2% maximum of free salicylic acid.
2. Background of the Art
Acetyl salicylic acid, commonly known as aspirin, has been the most successful pharmaceutical product in the world. Its original benefits as an analgesic and fever reducing agent continue to be recognized today, and new and even more significant benefits have been found in recent years. Acetyl salicylic acid has been found to reduce the likelihood of strokes, reduce the likelihood of heart attacks, reduce the complications of a stroke or heart attack when administered after the cardiovascular incident, and reduce the likelihood of second heart attack. With only minimal side effects or complications, it is the most widely used pharmaceutical agent in the world, and its range of use continues to grow.
The original U.S. patent covering the compound acetyl salicylic acid is U.S. Pat. No. 644,077, issued Feb. 27,1900, in the name of Felix Hoffman. The Hoffman Patent describes that the compound exhibits therapeutic properties. A single synthetic procedure for its manufacture is taught, comprising refluxing salicylic acid and acetic anhydride for about two hours at 150 degrees Celsius.
U.S. Pat. No. 671,769 describes a process of producing acetylsalicylic acid by substituting the acetyl group for the hydrogen of the hydroxyl group of salicylic acid and of its derivatives. The reaction is effected by the reciprocal action of salicylic acid and acetic anhydride in the presence of a condensing agent. The condensing agent shown is concentrated sulfuric acid.
U.S. Pat. No. 3,235,583 describes an improved method of synthesizing acetyl salicylic acid without resorting to the use of strong agents. The process is asserted to provide products with high purity and near theoretical yields, without resorting to extreme or repeated recrystallization steps. The process comprises a mixture of salicylic acid and acetic anhydride at 40 to 95° C. employing a molar excess of about 20% of acetic anhydride, reacting the mixture in a closed vacuum equipped vessel at the elevated temperature, maintaining the elevated temperature and reducing the internal pressure to a partial vacuum within the range of about 1.5×10
−1
to 2.2×10
−1
torr and thereafter gradually reducing the pressure to range between about 3.9×10
−2
torr and the minimum attainable pressure, maintaining the elevated temperature and reduced pressure at the lower range for about 1 to 3 hours, and thereafter recovering crystalline acetyl salicylic acid from the reaction vessel. As can be seen from the description provided in the '583 patent, special reaction vessels are needed, pressure within the vessel must be actively controlled, and the process takes a number of hours to complete.
U.S. Pat. No. 3,373,187 describes a method of synthesizing aspirin by the reaction of acetic anhydride and salicylic acid using a catalytic metal salt such as Mg(OH)
2
. Reaction times of about 2 to 11 hours are shown. Typical catalytic salts in addition to the preferred Mg(OH)
2
, are said to be nickel hydroxide, calcium nitrate, cobalt nitrate and magnesium acetate. A concentration range for the catalyst is described as 25 to 500 p.p.m. The following chart depicts a partial comparison between the process of U.S. 3,373,187 and the inventive process disclosed herein. In addition, the CaO and/or ZnO used in the present invention forms significant quantity of Ca acetate and/or Zn acetate as a wanted part of the reaction product.
U.S. PAT. NO. U.S. 3,373,187
INVENTIVE
REACTION SYSTEM
REACTION SYSTEM
1. Non-stoichiometric synthesis
Stoichiometric synthesis
2. Solvent is needed, such as acetic acid
No solvent is needed
or toluene, benzene and xylene
3. Reaction time of at least 2 hours
Short, i.e., 20 minute, reaction
time
4. Necessary to heat the reaction system
External heat not required
5. Separation step required after product
Not necessary to carry out a
synthesis for obtaining desired product
separation step after final
product synthesis
6. Distillation, evaporation, needed for
Final reaction product does not
obtaining crystals of reaction product
need to be distilled
In the process of the '187 patent, larger amounts of the preferred Mg(OH)
2
catalyst would produce significant quantities of water and Mg acetate, which due to its deliquescent character, would cause decomposition of the wanted aspirin reaction product.
SUMMARY OF THE INVENTION
The present invention provides a method for the synthesis of acetyl salicylic acid comprising reacting acetic anhydride and salicylic acid in stoichiometric proportions, along with calcium oxide or zinc oxide, for obtaining a yield of acetyl salicylic acid, and admixed calcium acetate or zinc acetate, with 2% maximum of free salicylic acid content, even after storage. The synthetic procedure comprises a method for obtaining acetyl salicylic acid comprising reacting acetic anhydride, salicylic acid and calcium oxide or zinc oxide. The reaction is heterogeneous, fast, exothermic, one-pot, non-pollutant of the environment due to the fact that it doesn't require elimination of acid residues nor requires the use of any type of organic solvents (other than such solvent activity provided by the reactants themselves), and doesn't require recrystallization since it yields as product a dense mixture of acetyl salicylic acid and calcium acetate or zinc acetate which can be mixed with the conventional excipients for acetyl salicylic acid and compressed into tablets immediately after the synthesis process.


REFERENCES:
patent: 3373187 (1968-03-01), Edmunds et al.

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