USOO6278O14B1

(12) United States Patent (10) Patent No.: US 6,278,014 B1

Handal-Vega et al. (45) Date of Patent: Aug. 21, 2001

(54) SYNTHETIC PROCEDURE FOR THE (56) References Cited

MANUFACTURE OF ASPIRIN
U.S. PATENT DOCUMENTS
(75) Inventors: Erlinda Handal-Vega, San Salvador 3,373,187 3/1968 Edmunds et al. .
(SV); Andre Patrick Denis Loupy,
Gambauderie (FR); Jorge Manuel Primary Examiner Paul J. Killos
Collazo Garcia, San Salvador (SV) ASSistant Examiner John N. Calve
(73) Assignee: Manufacturas Humberto Buelee (74) Attorney, Agent, or Firm-Sughrue, Mion, Zinn,
Hijos, S.A. de C.V., San Salvador (SV) Macpeak & Seas, PLLC
(57) ABSTRACT
(*) Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35 The present invention provides a method for the synthesis of
U.S.C. 154(b) by 0 days. acetyl Salicylic acid comprising mixing acetic anhydride and
Salicylic acid in approximately or exactly Stoichiometric
(21) Appl. No.: 09/587,803 proportions and calcium oxide or Zinc oxide, obtaining a
yield of a mixture of acetyl Salicylic acid and calcium acetate
(22) Filed: Jun. 6, 2000 or Zinc acetate with 2% maximum of free Salicylic acid
content. The reaction is fast, exothermic, one-pot, non
Related U.S. Application Data pollutant of the environment due to the fact that it doesn’t
require elimination of acid residues nor requires the use of
(63) Continuation-in-part of application No. PCT/IB98/02083, any type of organic Solvent (other than Such Solvent activity
filed on Dec. 18, 1998.
provided by the reactants themselves), and doesn't require
(30) Foreign Application Priority Data recrystallization Since it yields a dense product which can be
Dec. 18, 1997 (SV) ......................................... O11997OOO108 mixed with the common excipients for acetyl Salicylic acid
and compressed into tablets immediately after the Synthesis
(51) Int. Cl." ................................................. C07C 69/00 proceSS.
(52) U.S. Cl. .............................................................. 560/143
(58) Field of Search ............................................... 560/143 13 Claims, 3 Drawing Sheets
U.S. Patent Aug. 21, 2001 Sheet 1 of 3 US 6,278,014 B1

CM
400.0

CM-1
400,0
U.S. Patent Aug. 21, 2001 Sheet 2 of 3 US 6,278,014 B1

SEERN
OOA
700,0nm 0001A
PEAK DETECTION
2 ABS
280,00,851
(0.500 242.02,025
/DIV)

-0.01A
200.0nm (100/DN) 700.0nm
FIG. 2(a)
SPECTRUM 700,0nm 0.008A
5.00A
PEAK DEECTION

(0.500
/DIV)

-0.01A
200,0nm (100/DM) 700,0mm
FIG. 2(b)
SPECTRUM 0.00A
1.10A
PEAK DETECTION
2 ABS
280,00,366
(3,200 241.01.078
/DIV)

0.01A
200,0nm (20/DM) 350,0nm
FIG. 2(C)
U.S. Patent Aug. 21, 2001 Sheet 3 of 3 US 6,278,014 B1

4600.0 3000.0 2000.0 1000.0 400.0

R SPECTRUM OF PRODUCT REACTION BEWEEN SAICYC ACID
AND ACEC ANHYDRIDE IN PRESENCE ON ZNC OXDE,
F.G. 3
 US 6,278,014 B1
1 2
SYNTHETIC PROCEDURE FOR THE U.S. Pat. No. 3,373,187 describes a method of synthesiz
MANUFACTURE OF ASPIRIN ing aspirin by the reaction of acetic anhydride and Salicylic
acid using a catalytic metal salt Such as Mg(OH). Reaction
This application is a continuation-in-part application of times of about 2 to 11 hours are shown. Typical catalytic
PCT/IB98/02083 filed Dec. 18, 1998, claiming priority from 5 salts in addition to the preferred Mg(OH), are said to be
S.V. O11997000108 filed Dec. 18, 1997. nickel hydroxide, calcium nitrate, cobalt nitrate and mag
BACKGROUND OF THE INVENTION
nesium acetate. A concentration range for the catalyst is
described as 25 to 500 p.p.m. The following chart depicts a
1. Field of the Invention partial comparison between the process of U.S. 3,373,187
The current invention relates to the field of pharmaceu and the inventive proceSS disclosed herein. In addition, the
tical Synthesis and the preparation of acetyl Salicylic acid. A CaO and/or ZnO used in the present invention forms sig
Synthetic procedure is shown which is elegant in its Sim nificant quantity of Caacetate and/or Zn acetate as a wanted
plicity and its ability to provide a product, which does not part of the reaction product.
require any purification of the final reaction product before 15
being used in pharmaceutical preparations. The reaction is
very fast, one-pot, non-polluting of the environment, and U.S. PAT NO. U.S. 3,373,187 INVENTIVE
provides 100% yield of product which contains 2% maxi REACTION SYSTEM REACTION SYSTEM
mum of free Salicylic acid. Stoichiometric synthesis
2. Background of the Art 1. Non-stoichiometric synthesis
2. Solvent is needed, such as acetic acid No solvent is needed
Acetyl Salicylic acid, commonly known as aspirin, has or toluene, benzene and xylene
been the most Successful pharmaceutical product in the 3. Reaction time of at least 2 hours Short, i.e., 20 minute, reaction
time
World. Its original benefits as an analgesic and fever reduc 4. Necessary to heat the reaction system External heat not required
ing agent continue to be recognized today, and new and even 5. Separation step required after product Not necessary to carry out a
more significant benefits have been found in recent years. 25 synthesis for obtaining desired product separation step after final
product synthesis
Acetyl Salicylic acid has been found to reduce the likelihood 6. Distillation, evaporation, needed for Final reaction product does not
of Strokes, reduce the likelihood of heart attacks, reduce the obtaining crystals of reaction product need to be distilled
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 In the process of the 187 patent, larger amounts of the
complications, it is the most widely used pharmaceutical preferred Mg(OH) catalyst would produce Significant quan
agent in the World, and its range of use continues to grow. tities of water and Mg acetate, which due to its deliqueScent
The original U.S. patent covering the compound acetyl character, would cause decomposition of the wanted aspirin
salicylic acid is U.S. Pat. No. 644,077, issued Feb. 27, 1900, reaction product.
in the name of Felix Hoffman. The Hoffman Patent describes 35 SUMMARY OF THE INVENTION
that the compound exhibits therapeutic properties. A Single
Synthetic procedure for its manufacture is taught, compris The present invention provides a method for the synthesis
ing refluxing Salicylic acid and acetic anhydride for about of acetyl Salicylic acid comprising reacting acetic anhydride
two hours at 150 degrees Celsius. and Salicylic acid in Stoichiometric proportions, along with
U.S. Pat. No. 671,769 describes a process of producing 40 calcium oxide or Zinc oxide, for obtaining a yield of acetyl
acetylsalicylic acid by Substituting the acetyl group for the Salicylic acid, and admixed calcium acetate or Zinc acetate,
hydrogen of the hydroxyl group of Salicylic acid and of its with 2% maximum of free salicylic acid content, even after
derivatives. The reaction is effected by the reciprocal action Storage. The Synthetic procedure comprises a method for
of Salicylic acid and acetic anhydride in the presence of a obtaining acetyl Salicylic acid comprising reacting acetic
condensing agent. The condensing agent shown is concen 45 anhydride, Salicylic acid and calcium oxide or Zinc oxide.
trated Sulfuric acid. The reaction is heterogeneous, fast, exothermic, one-pot,
U.S. Pat. No. 3,235,583 describes an improved method of non-pollutant of the environment due to the fact that it
Synthesizing acetyl Salicylic acid without resorting to the use doesn’t require elimination of acid residues nor requires the
of Strong agents. The proceSS is asserted to provide products use of any type of organic Solvents (other than Such Solvent
with high purity and near theoretical yields, without resort 50 activity provided by the reactants themselves), and doesn’t
ing to extreme or repeated recrystallization Steps. The pro require recrystallization Since it yields as product a dense
ceSS comprises a mixture of Salicylic acid and acetic anhy mixture of acetyl Salicylic acid and calcium acetate or Zinc
dride at 40 to 95 C. employing a molar excess of about 20% acetate which can be mixed with the conventional excipients
of acetic anhydride, reacting the mixture in a closed vacuum for acetyl Salicylic acid and compressed into tablets imme
equipped vessel at the elevated temperature, maintaining the 55 diately after the Synthesis process.
elevated temperature and reducing the internal pressure to a BRIEF DESCRIPTION OF THE FIGURES
partial vacuum within the range of about 1.5x10' to 2.2x
10' torr and thereafter gradually reducing the pressure to FIGS. 1a and 1b show the Infrared Spectrum of a) acetyl
range between about 3.9x10° torr and the minimum attain Salicylic acid and b) the product "as is of a synthetic
able preSSure, maintaining the elevated temperature and 60 procedure according to the present invention.
reduced pressure at the lower range for about 1 to 3 hours, FIGS. 2a and 2c show an UV spectrum of a) acetyl
and thereafter recovering crystalline acetyl Salicylic acid Salicylic acid, b) Salicylic acid, and c) a freshly Synthesized
from the reaction vessel. AS can be seen from the description product according to the present invention made with cal
provided in the 583 patent, Special reaction vessels are cium oxide.
needed, pressure within the vessel must be actively 65 FIG. 3 shows an Infrared Spectrum of a freshly synthe
controlled, and the process takes a number of hours to sized product according to the present invention made with
complete. Zinc oxide.
 US 6,278,014 B1
3 4
DETAILED DESCRIPTION OF THE B. the reaction System doesn’t need external heating,
INVENTION C. Solvents are not required in the Synthesis process,
The invention describes a novel method for the synthesis D. it is not necessary to add exceSS reactants to accelerate
of acetylsalicylic acid. Since 1900, when Hoffman received and/or increase the Synthesis yield,
the patent for the manufacture of acetyl Salicylic acid from E. the Synthesis is very fast, with a high yield,
acetic anhydride and Salicylic acid, there have been many F. the product obtained is a mixture of acetyl Salicylic acid
modifications of the synthesis: Ledeler (1901) added sulfuric and calcium acetate or Zinc acetate, with a maximum free
acid to the System in order to accelerate the process of Salicylic acid content of about 2%, in a single Synthesis
Step,
esterification. A. Bercy, (Nature, No. 2977, p.462, 1936) G. the Synthetic procedure may be performed in a single pot,
further proposed to make this Synthesis in the presence of
acetic acid as a Solvent, heating the System to 90° C. for H. with each of these features helping to contribute to a low
Some time and then cooling to 20 C. Other authors (e.g., cost proceSS for the production of acetyl Salicylic acid,
E.J.Perry, Chem. Abst. Vol. 10 No. 2121), proposed that I. the aqueous Solution of the Synthesis product, without
during the Synthesis process at those temperatures, the ester recrystallization, gives a pH less acid (pH 4.2) than that
o-AcOHCO-CHCOH is formed and then it is decom
15 presented by the aqueous Solution of Standard acetyl
posed into acetyl Salicylic acid and Salicylic acid. Salicylic acid alone (pH 2.6) and commercial acetyl
In Summary, the methods proposed So far for the Synthesis salicylic acid tablet (pH 2.9),
J. a tablet containing acetyl Salicylic acid with calcium or
of acetyl Salicylic acid include: use of an excess of acetic Zinc can be manufactured directly from the Synthetic
anhydride or addition of acetic acid to the System as Solvent, product without purification,
the addition of a strong acid (e.g., concentrated Sulfuric or K. recrystallization of the synthesis product would not be
concentrated phosphoric acid as a catalyst), a Subsequent needed for the Subsequent manufacture of the tablets, and
Stage of disposal of the Sulfuric acid (or phosphoric acid), L. the Synthesis is non-polluting of the environment by not
frequently recrystallization of the obtained product and producing waste material and by not using organic Sol
using metal Salt catalysts. Currently, the most used method 25 VentS.
of obtention at industrial level consists of mixing Salicylic It is possible to add various materials into the reaction
acid and acetic anhydride in exceSS in a preSSure reactor at mixture, but the addition of materials which might have to
a temperature of 98 C. for 2-3 hours, then the resultant be removed by purification should be avoided so that
solution is pumped to a filter and cooled to 0 C. to aid the additional purification StepS are not added back into the
crystallization of the product (e.g., possibly within the process. Thus, any additive should be incorporated after the
practice of U.S. Pat. No. 3,235,583). The suspension is reaction product is obtained.
centrifuged and the product crystallized and washed (cf. The final reaction product without any purification pro
Kirk Othmer Encyclopedia of Chemical Technology, 1997, ceSS or distilling operation comprises acetyl Salicylic acid
on line text, and acetylsalicylic acid 530-75-6). The and calcium acetate or Zinc acetate with less than 2% free
reported yield for the proposed methods is about 90%. 35 salicylic acid, preferably less than 1%, by weight of the
The present invention provides a method for the synthesis mixture.
of acetyl Salicylic acid comprising reacting acetic anhydride The direct reaction product compositions (the reaction
and Salicylic acid in about Stoichiometric proportions along product composition immediately after conclusion of the
with calcium oxide or Zinc oxide as a Support and acid Synthetic reaction and before any purification Step has been
neutralization agent. When CaO is used a yield of acetyl 40 performed) may also be characterized by the low contents of
salicylic acid of no less than 98-99% (2% maximum of free free Salicylic acid.
Salicylic acid content) and calcium acetate is obtained. The The CaO and/or ZnO is heat activated by calcination as
reaction is fast, exothermic, one-pot, non pollutant of the illustrated in the following examples, for removing water
environment due to the fact that it doesn't require elimina and possible impurities which might otherwise produce
tion of acid residues nor requires the use of any type of 45 excessive free Salicylic acid.
organic Solvent (other than Such solvent activity provided by
the reactants themselves), and doesn’t require recrystalliza EXAMPLES
tion Since it yields a dense product which can be mixed with
the excipients for acetyl Salicylic acid and compressed into EXAMPLE 1.
tablets immediately after the Synthesis process. Calcium in 50 In a 100 ml beaker, 1.3680 g acetic anhydride (13.4x10
the form of calcium acetate is one of the most bioassimilated mol) and 1.8492 g salicylic acid (13.4x10 mol) was
forms of this element by the human body and is a resultant thoroughly mixed by agitation with glass rod with 0.5628 g
product from this Synthetic route. calcium oxide (10.05x10 mol previously calcinated at a
CaO and/or ZnO is used in a molar proportion of 0.5 to temperature from 430 to 850 C. for one hour and Subse
0.8 moles per one mole of acetic anhydride. Preferably, 55 quently cooled at room temperature in a Silicagel desiccant).
acetic anhydride and Salicylic acid are used in exact Sto The calcium oxide was added to the acetic anhydride
ichiometric proportion to the degree obtainable on an indus Salicylic acid mixture with Vigorous agitation. A dense paste
trial Scale in practice. The reaction product contains about was formed at the beginning, which turned liquid for a
70% aspirin and about 30% Ca and/or Zn acetate by weight. couple of minutes and then Started to harden and fraction
One perspective of the value of the proceSS and products 60 alize into Small crystals (agitation was not Suspended at any
of the present invention from the technical and economic time). The reaction was exothermic, reaching 60-70° C. At
point of View and the advantages of the Synthesis method for the end of the reaction, the System went back to room
acetyl Salicylic acid as compared to previously reported temperature, and considerably increased in Volume
Synthetic procedures is understood from one or more of the (resulting in a volume of approximately three times with
following aspects: 65 reference to the initial volume of the mixture). Duration of
A. there is no need to add Sulfuric acid or phosphoric acid the Synthesis was 20 min. The Synthesis product was iden
to the reaction System as an acid catalyst of the Synthesis, tified by the record of UV and IR spectra, which were
 US 6,278,014 B1
S 6
compared to Similar spectrum corresponding to acetyl Sali synthesis was 30 min. The synthesis product was identified
cylic acid, calcium oxide and calcium acetate Standard by the record of UV and IR spectra, which were compared
Samples. The content of free Salicylic acid was measured by to Similar spectra corresponding to acetyl Salicylic acid, Zinc
colorimetry through the formation of a colored complex oxide and Zinc acetate Standard Samples. The content of free
with Fe. The proportion of free salicylic acid in the product Salicylic acid was measured by colorimetry through the
36 days after synthesis was about 0.9% by weight of the formation of colored complex with Fe (III). Content of free
composition. Salicylic acid in the product was about 1%.
FIG. 1 shows the IR Spectrum of a)acetyl salicylic acid FIG. 3 shows the spectra for the composition resulting
Standard; and b) product of this type of Synthesis "as it is, from this synthesis.
without any further crystallization. The reaction product Variations of the invention will be apparent to the skilled
contained about 70% aspirin and 30% Caacetate, by weight. artisan.
What is claimed is:
EXAMPLE 2 1. A Synthesis method to obtain a reaction product con
taining acetyl Salicylic acid and calcium and/or Zinc acetate
19.0648 g salicylic acid (1.38x10" mol) was weighed 15 comprising heterogeneously reacting acetic anhydride, Sali
and was mixed with 14.1 mL acetic anhydride (1.38x10 cylic acid and at least one of calcium oxide and Zinc oxide.
mol) in a 250 mL beaker. To the mixture, 3.7028 g calcium 2. The synthesis method of claim 1 wherein said acetic
oxide (6.6x10f mol, previously treated as in example 1) anhydride and Salicylic acid are heated by an exothermic
was added. The two components were thoroughly mixed. reaction between acetic anhydride, Salicylic acid and at least
The reaction was exothermic. After 25 minutes, the System one of calcium oxide and Zinc oxide.
returned to room temperature, had increased approximately 3. The method of claim 2 wherein the method is carried
three times its original Volume and appeared as a fine white, out in the absence of external heat.
loose and dense powder. The presence of acetyl Salicylic 4. The method of claim 2 wherein said acetic anhydride
acid was analyzed in the final product, by dissolving a and Said Salicylic acid are present in about Stoichiometric
sample in chloroform and recording the UV spectrum. The 25 proportions.
Spectrum was compared to that of Salicylic acid and acetyl 5. The method of claim 2 wherein the method is carried
Salicylic acid Standard Samples and mixture of both in a out in the absence of any added organic Solvents.
chloroform vehicle. IR spectra of the synthesis product were 6. The method of claim 1 wherein said CaO is heat
recorded and compared to Similar spectra of Standard activated CaO.
Samples. The content of Salicylic acid was measured by 7. The method of claim 3 wherein said ZnO is heat
colorimetry by the formation of colored complex with Fe. activated ZnO.
The content of free Salicylic acid in the product immedi 8. The method of claim 3 wherein said acetic anhydride
ately after synthesis was 0% and 138 days after synthesis and Salicylic acid are thoroughly mixed before addition of
was 1.9% by total weight of the composition. the at least one of calcium oxide and Zinc oxide.
FIG.2. shows the UV/Visible spectra of a) acetyl salicylic 35 9. The method of claim 3, wherein at least one of the CaO
acid standard; b) Salicylic acid Standard; and c)a freshly and ZnO is present as 0.5 to 0.8 molar proportion in
Synthesized product of the invention. relationship to the acetic anhydride.
10. The method of claim 4 wherein the reaction product
EXAMPLE 3 contains less than 2% free salicylic acid without further
40 purification.
In a 100 mL beaker, 1.3974 g acetic anhydride (1.37x10° 11. The synthesis method of claim 1, wherein calcium
mol) and 1.9060 g salicylic acid (1.37x10f mol) was oxide is used as a Support and acid neutralization agent in
thoroughly mixed by agitation with a glass rod. 0.8718g of two concomitant reactions by which acetyl Salicylic acid and
Zinc oxide (1.07x10f mol, previously calcinated at a tem calcium acetate are produced.
perature from 250 to 700° C. for one hour and Subsequently 45 12. The synthesis method of claim 1, wherein zinc oxide
cooled at room temperature in a silicagel desiccant), was is used as a Support and acid neutralization agent in two
added to the first composition with Vigorous agitation. A concomitant reactions by which acetyl Salicylic acid and
dense liquid was formed for ten minutes and then Started to Zinc acetate are produced.
harden. Agitation was not Suspended at any time. The 13. The synthesis method of claim 4, wherein an exact
reaction was exothermic, and at the end of the exothermic 50 Stoichrometric proportion is used.
period, the System was allowed to cool to room temperature
and considerably increased in Volume. Duration of the k k k k k
 UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION

PATENT NO. : 6,278,014 B1 Page 1 of 1

DATED : August 21, 2001
INVENTOR(S) : Erlinda Handal-Vega, Andre Patrick Denis Loupy and Jorge Manuel Collazo Garcia

It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:

Title page,
Item 73, ASSignee, delete “Buelee Hijos” and insert -- Bukelee Hijos --.

Signed and Sealed this

Tenth Day of September, 2002

Attest.

JAMES E ROGAN
Attesting Officer Director of the United States Patent and Trademark Office
 UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION

PATENT NO. : 6,278,014 B1 Page 1 of 1

DATED : August 21, 2001
INVENTOR(S) : Erlinda Handal-Vega, Andre Patrick Denis Loupy and Jorge Manuel Collazo Garcia

It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:

Title page,
Item 73, ASSignee, delete “Buelee Hijos” and insert -- Bukele e Hijos --.
This certificate Supersedes Certificate of Correction issued September 10, 2002

Signed and Sealed this

Twelfth Day of August, 2003

JAMES E ROGAN
Director of the United States Patent and Trademark Office