U.S. patent application number 13/945011 was filed with the patent office on 2013-11-14 for new process for the preparation of nitroorotic acid.
This patent application is currently assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. The applicant listed for this patent is Rolf DACH, Xiangrui JIANG, Jingshan SHEN, Jin SUO, Yi ZHU. Invention is credited to Rolf DACH, Xiangrui JIANG, Jingshan SHEN, Jin SUO, Yi ZHU.
Application Number | 20130303760 13/945011 |
Document ID | / |
Family ID | 42125911 |
Filed Date | 2013-11-14 |
United States Patent
Application |
20130303760 |
Kind Code |
A1 |
DACH; Rolf ; et al. |
November 14, 2013 |
New Process For The Preparation Of Nitroorotic Acid
Abstract
Subject of the present invention is a new improved process for
the preparation of nitroorotic acid via nitration of orotic
acid.
Inventors: |
DACH; Rolf; (Gau-Algesheim,
DE) ; JIANG; Xiangrui; (Shanghai, CN) ; SHEN;
Jingshan; (Shanghai, CN) ; SUO; Jin;
(Shanghai, CN) ; ZHU; Yi; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DACH; Rolf
JIANG; Xiangrui
SHEN; Jingshan
SUO; Jin
ZHU; Yi |
Gau-Algesheim
Shanghai
Shanghai
Shanghai
Shanghai |
|
DE
CN
CN
CN
CN |
|
|
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim am Rhein
DE
|
Family ID: |
42125911 |
Appl. No.: |
13/945011 |
Filed: |
July 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13201486 |
Oct 24, 2011 |
8513413 |
|
|
PCT/EP2010/052188 |
Feb 22, 2010 |
|
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|
13945011 |
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Current U.S.
Class: |
544/256 |
Current CPC
Class: |
C07D 239/557 20130101;
C07D 487/04 20130101 |
Class at
Publication: |
544/256 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 23, 2009 |
CN |
200910007568.5 |
Claims
1. A process for making dipyridamol using nitroorotic acid as an
intermediate, wherein the nitroorotic acid is prepared by nitrating
orotic acid at a temperature of about 40-80.degree. C., using a
mixture of concentrated sulphuric acid and concentrated, but not
fuming nitric acid.
2. The process according to claim 1 wherein the concentration of
the nitric acid is about 65%.
3. The process according to claim 1 wherein the nitration is
carried out at a temperature of about 40-60 .degree. C.
4. The process according to claim 3 wherein the nitration is
carried out at a temperature of about 50-60 .degree. C.
5. The process according to claim 1 wherein the molar ratio between
sulphuric acid and nitric acid is between 1:1 and 6:1.
6. The process according to claim 5 wherein the molar ratio between
sulfuric acid and nitric acid is about 3:1.
7. The process according to claim 1 wherein orotic acid is added
portionwise to the mixture of sulphuric acid and nitric acid.
8. The process according to claim 1 wherein the reaction mixture
does not contain any ethanol.
9. The process according to claim 1 for large scale industrial
production.
Description
[0001] Subject of the present invention is a new process for the
preparation of nitroorotic acid (II), which is obtained by
nitration of orotic acid (I) according to the following reaction
scheme:
##STR00001##
[0002] Reaction Scheme 1
[0003] Nitroorotic acid is a key intermediate in the synthesis of
dipyridamole, which is an active ingredient in Persantin.RTM. (sole
active ingredient) and Aggrenox.RTM. (in combination with
acetylsalicylic acid). Persantin.RTM. is a medicament used for
preventing thrombosis and embolic events, Aggrenox.RTM. is a
medicament used for the prevention of stroke.
[0004] Several other processes for preparing nitroorotic acid are
known from the prior art.
[0005] A synthesis of the potassium salt of nitroorotic acid
starting from orotic acid is described by M. Bachstez in
Ber.dtsch.chem.Ges. 63 (1930) 1000. The synthesis was done only in
a small laboratory scale, using a mixture of nitric and sulphuric
acid as reagent. Most of the educt did either not react or
decomposed, so that as a consequence, the yield of the product was
very low.
[0006] In Ann. 456 (1924) 165, H. Biltz and E. Kramer describe the
preparation of nitroorotic acid in form of yellow needles
decomposing at 236.degree. C. by reacting orotic acid with fuming
nitric acid, without giving any details about the reaction
conditions or the yield.
[0007] F. G. Fischer and J. Roch (Ann. 572 (1951) 217) describe a
laboratory scale process for preparing the potassium salt of
nitroorotic acid using 4-methyl-2-thiouracil as starting material.
They obtained the product in a yield of 50-55%.
[0008] Both R. Behrend and O. Roosen (Ann. 251 (1889) 238) and H.
Biltz and M. Heyn (Ann. 413 (1916) 110) describe the synthesis of
the potassium salt of nitroorotic acid starting from methyluracil
in laboratory scale.
[0009] Presently, the nitroorotic acid needed for the manufacture
of Persantin is produced by a large scale process based on
nitration and oxidation of 6-methyluracil using fuming nitric acid.
For the nitration step, the reaction temperature has to be
maintained in a range of between 20.degree. C. and 30.degree. C.
The oxidation step requires a temperature of up to 100.degree.
C.
[0010] Due to the high reaction temperature during the oxidation
step, the whole reaction system may become instable, if the
temperature is not controlled properly. The technical measurements,
which are needed to regulate the system and to control the
temperature in order to avoid e.g. decomposition, are highly
expensive. The maximum yield of the current process is about 80% of
the theory. A byproduct of this process is nitrogen dioxide, a
toxic gas. For each mole of the starting material 6-methyluracil, 6
moles of nitrogen dioxide are set free, which have to be disposed
of properly.
AIM OF THE INVENTION
[0011] The aim of the present invention is to overcome the problems
linked to the present process for producing nitroorotic acid, to
improve the known process for preparing nitroorotic acid,
particularly with respect to both economic (yield, costs and
availability of starting material) and ecologic (protection of the
environment) aspects of a large scale process, and to enhance the
safety (protection of employees) of the process.
SUBJECT OF THE INVENTION
[0012] Subject of the present invention is a new improved process
for the preparation of nitroorotic acid via nitration of orotic
acid according to reaction scheme
[0013] Surprisingly, it has been found that the process according
to the invention solves the problems related to the present
synthetic route.
[0014] Most importantly, the development of toxic nitrous fumes
such as nitrogen dioxide can completely be avoided by using the
process according to the invention, because instead of fumed nitric
acid as according to the prior art, 65% nitric acid is used. This
reduces pollution as well as risks, and is an advantage with
respect to safety and environment protection.
[0015] Furthermore, the educt is readily available in good quality
and at a reasonable price, because it is widely used (several 100
tons per year) as an ingredient for animal food. The reagents are
very common and in expensive chemicals, too, so that the costs of
goods are low.
[0016] Energy costs are reduced, since the reaction temperature is
significantly lower than in the process known from the prior art.
Furthermore, due to the lower reaction temperature particularly
during the oxidation step, no expensive technical measurements for
system regulation and temperature control are needed.
[0017] Bothe, the yield of the product (about 90%) and its purity
are high resp. very high. This enhances the profitability of the
process, and simultaneously reduces the efforts needed for
purification.
[0018] Contrary to the known process, even at production scale, the
process of invention does not require any special equipment for
controlling the reaction due to safety issues.
[0019] Another advantage of the process according to the invention
is that it can be conducted as a semi-batch process, i.e. that the
educt (orotid acid) does not need to be added all at once, but may
be added portionwise to the mixture of sulphuric and nitric acid.
The next portion of orotic is added to the reaction mixture only
after the previous portion was transformed into the product. This
procedure, which was not possible according to the old method,
helps to control the reaction in a simple, but effective way.
Energy (and temperature) peaks can thus be avoided.
[0020] Additionally, after quenching the reaction mixture in water,
the nitroorotic acid can be isolated as free acid, and thus, does
not need to be set free from its salt prior to the next reaction
step in the synthesis of dipyridamole, thereby avoiding additional
working steps and saving time.
[0021] Furthermore, after quenching the reaction mixture in water,
the water-containing product thus obtained may be used directly in
the next step without that it is necessary to dry it previously,
thereby saving time and costs. Due to the very high purity, the
product of the subsequent step in the synthesis of dipyridamole
does not need to be isolated.
[0022] Finally, the sulphuric acid used in the reaction can be
recycled directly, after concentration. This is both reducing costs
and protecting the environment.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Nitroorotic acid (II) is produced by nitration of orotic
acid (I) according to reaction scheme 1.
[0024] As the reagent, a mixture of concentrated sulphuric acid and
concentrated (but not fuming) nitric acid is used. Preferably, the
concentration of the sulphuric acid is 98% and the concentration of
the nitric acid is 65%. Usually, sulphuric acid and nitric acid are
mixed in a molar ratio of between 1:1 and 6:1. Preferably, the
ratio of sulfuric acid to nitric acid is about 3:1 (in mole).
[0025] The nitration is carried out at a temperature of about
40-80.degree. C. The preferred reaction temperature is about
40-60.degree. C.; even more preferred is a reaction temperature of
about 50-60.degree. C.
[0026] No ethanol is added to the reaction mixture.
[0027] The nitroorotic acid such produced is susceptible to form
hydrates.
EXAMPLE
[0028] Nitroorotic acid (obtained via nitration of orotic acid)
With cooling below 50.degree. C., 420 ml (7.68 mol) concentrated
sulphuric acid (H.sub.2SO.sub.4, approx. 98%) were added to 169 ml
(2.56 mol) 65% nitric acid (HNO.sub.3). Then, 200 g orotic acid
(1.28 mol; purity 99.64%) were added portionwise. The reaction
mixture was heated to 50-55 .degree. C. under stirring for 3
hours.
[0029] After completion of the nitration, the reaction mixture was
allowed to cool down to ambient temperature (about 10-15 .degree.
C.), and was then poured into 800 ml of water under cooling below
30.degree. C. While the resulting mixture was cooled to about 0-10
.degree. C., it was stirred slowly. The precipitated product was
filtered off and washed with a small amount of cold water, and then
dried at about 50-60 .degree. C.
[0030] Yield: 230 g (90%) based on waterfree material
[0031] Purity: 98.89% (HPLC)
[0032] Decomposition above 230.degree. C.
[0033] MS (ESI): 202 (MH.sup.+)
[0034] .sup.13C-NMR (500 MHz, D.sub.2O, ppm): 122.6, 150.1, 151.7,
158.3, 162.7
* * * * *