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Preparation method of omeprazole intermediate 2,3,5-trimethylpyridyl-N-oxide

CN 102942523 A
Abstract
The invention discloses a preparation method of an omeprazole intermediate 2,3,5-
trimethylpyridyl-N-oxide, which comprises the following steps: by using molybdophosphoric
acid or ammonium molybdate as a catalyst, oxidizing 2,3,5-trimethylpyridine with oxydol, and
concentrating and distilling under reduced pressure to obtain the 2,3,5-trimethylpyridyl-N-oxide.
The preparation method disclosed by the invention has the advantages of mild reaction, high
safety and higher yield, and is more suitable for industrial production; and the distilled water can
be directly discharged, thereby achieving zero pollution.
Claims(4) translated from Chinese
1. A method of preparing omeprazole intermediate 2,3,5-trimethyl pyridine -N- oxide,
characterized in that: the key to phosphorus acid or ammonium as a key catalyst for the use of
hydrogen peroxide 2,3 , 5-trimethyl pyridine oxide, and then concentrated under reduced
pressure by distillation, to give the 2,3,5-trimethyl pyridine -N- oxide.
2. An omeprazole prepared according to the method of Intermediate I 2,3,5-trimethyl pyridine
oxide -N- claim, characterized in that: comprising the steps of: (1) the I~ 3 parts by weight of
phosphorus acid or keyhole key ammonium phosphate dissolved in water to obtain key or key
solution of ammonium acid solution; (2) the key Phosphorus acid solution or keyhole, was added
to a solution of ammonium 180~220 parts by weight of 2, 3,5_ trimethyl pyridine, heated to
90~95 C, and a solution of 160~200 parts by weight of 50wt% hydrogen peroxide, and then
incubated at 92~95 C at 7 to 10 hours, to obtain a reaction solution; (3) The reaction solution
was concentrated under reduced pressure 85~90 C distilled after distillation of the intermediate
2,3,5-trimethyl pyridine omeprazole -N- oxide.
3. An omeprazole prepared according to the method of Intermediate 2 2,3,5-trimethyl pyridine
oxide -N- claim, wherein: said step (2), using a water bath heating, gradually warmed to 90~95
C.
4. A method of preparing a 2 or 3 wherein the intermediate omeprazole -N- 2,3,5-trimethyl
pyridine oxide as claimed in claim wherein: said step (2), The drop accelerated hydrogen
peroxide was 30~35kg / h.
Description translated from Chinese

- The method of producing 2,3,5-trimethyl pyridine omeprazole intermediate oxide -N-

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates,
particularly relates to a method for preparing omeprazole -N- intermediate 2,3,5-trimethyl
pyridine oxide.

Background

[0002] Currently, Omeprazole is widely used in diseases of the digestive system, it is one of the
better in recent years, widely used in the treatment of peptic ulcer drug efficacy, but there is no
pollution in the preparation of omeprazole intermediate nitrogen oxides environment and reacts
violently explosive and affect large-scale industrial production.
[0003] The traditional process commonly used hydrogen peroxide and acetic acid into Mr.
peracetic acid, peracetic acid and 2,3,5-tri-acetic acid oxidation reaction severe, difficult to
control, easy explosion, industrialization difficult to operate; low concentration of waste
generated by the reaction Acid containing peracetic acid refractory, the direct discharge of
contaminated groundwater, resulting in industrial production bottlenecks.

DISCLOSURE

[0004] The technical problem to be solved by the present invention is to provide a method for
preparing omeprazole intermediate 2,3,5_ trimethylpyridine -N- oxide, the reaction mild, safe,
without the use of organic lower cost of solvent, no pollution, simple operation suitable for
industrial production, thereby eliminating the above-described background art defect.

[0005] In order to solve the above problems, the technical aspect of the present invention are:

[0006] A method of preparing omeprazole intermediate 2,3,5-trimethyl pyridine -N- oxide,


which is key to phosphorous acid or ammonium as a key catalyst for the use of hydrogen
peroxide 2,3,5 - trimethyl pyridine oxidation, and then under reduced pressure, concentration,
distillation, to give the 2,3,5-trimethyl pyridine -N- oxide.

[0007] Omeprazole intermediate 2,3,5_ three -N- methylpyridine oxide production method,
comprising the steps of:

[0008] (I) I~3 parts by weight of phosphorus acid key key ammonium phosphate dissolved in
water to obtain key acid solution or a solution of ammonium or keys;

[0009] (2) a solution of an acid or a phosphorus-key key is added to the ammonium solution
prepared 2,3,5_ 180~220 parts by weight of trimethyl pyridine, heated to 90~95 C, and a
solution of 160~200 parts by weight of 50wt% hydrogen peroxide, incubated at 92~95 C 7 to
10 hours, to obtain a reaction solution;

[0010] (3) The reaction mixture was concentrated under reduced pressure 85~90 C distilled
water when evaporated substantially no end distillation; then cooling to 40~50 C, to give the
intermediate 2 omeprazole , 3,5_ three -N- methylpyridine-oxide.

Omeprazole Intermediate 2,3,5_ trimethylpyridine -N- dioxide [0011] obtained in the above
method purity 99% (GC), 98% yield ; its NMR and mass spectral data are as follows =
1HNMr (CDCI3) 8. 03 (s, 1), 6. 90 (s, 1H), 2. 47 (s, 3H), 2. 31 (s, 3H), 2. 24 (s, 3H) ; MS m /
z 138. 2 (M + H) +.

[0012] As an improvement, said step (2) using a water bath heated to 90~95 C, was slowly
warmed to achieve.

[0013] As a modification, the step (2), hydrogen peroxide is dropped, was 30~35kg / h.

[0014] As a result of the technical proposal, the beneficial effects of the present invention are:
[0015] I. Key phosphorus acid or ammonium as a key catalyst for the use of hydrogen peroxide
oxidation of 2,3,5-trimethyl pyridine, changed the traditional use of peracetic acid preparation
2,3,5_ trimethyl pyridine -N- oxide method avoids the use of peracetic acid prone to explosion,
uncontrollable problems, the present invention provides a method for preparing a reaction gentle,
safe, and yield is improved, more suitable for industrial production.

[0016] 2. The traditional process, a large amount of low-concentration waste acid water, since it
is difficult to handle and deal with high costs, restricted the industrial production; the production
method of the present invention provides, avoid the use of organic solvents, waste water
distillation, thermal decomposition of hydrogen peroxide, ammonium phosphate key acids and
key does not evaporate with the water, so distilled water can be discharged directly, achieve zero
pollution.

DETAILED DESCRIPTION

[0017] In order to achieve the technical means of the present invention, the creation of
characteristics, to achieve the purpose and effect is easy to understand to understand, below with
specific examples further illustrate the invention.

[0018] A method of preparing omeprazole intermediate 2,3,5-trimethyl pyridine -N- oxide,


which is key to phosphorous acid or ammonium as a key catalyst for the use of hydrogen
peroxide 2,3,5 - trimethyl pyridine oxidation, and then under reduced pressure, concentration,
distillation, to give the 2,3,5-trimethyl pyridine -N- said oxide.

[0019] The following specific examples.

[0020] Example I

[0021] Omeprazole intermediate 2,3,5-trimethyl pyridine oxide -N- preparation, comprising the
steps of:

[0022] (I) will be key Ikg phosphorus acid dissolved in water to obtain phosphorus key acid
solution;

[0023] (2) the key Phosphorus acid solution was added to 180kg of preparation of 2,3,5-trimethyl
pyridine, water bath heated to 900C, and a solution 160kg50wt% of hydrogen peroxide,
hydrogen peroxide to control the acceleration rate drops 30kg / h, incubation at 92 C for 7
hours to obtain a reaction solution;

[0024] (3) at 90 C the reaction was concentrated under reduced pressure distillation, when the
little end of the distillation distilled water; then cooled to 40 C, to give the intermediate 2,3,5
omeprazole - three -N- methylpyridine-oxide.

Omeprazole Intermediate 2,3,5-trimethyl pyridine -N- dioxide [0025] The present embodiment
obtained in a purity of 99. 0% (GC), a yield of 98%.
[0026] Example 2

[0027] Omeprazole intermediate 2,3,5-trimethyl pyridine oxide -N- preparation, comprising the
steps of:

[0028] (I) will be key 2kg of dissolved ammonium water solution of ammonium obtain key;

[0029] (2) the key is added to the prepared solution of ammonium 200kg of 2,3,5-trimethyl
pyridine, in a water bath heated to 930C, and 180kg50wt% hydrogen peroxide was added
dropwise, to control the acceleration rate of hydrogen peroxide drops 32kg / h, incubation at 92
C for 8 hours to obtain a reaction solution;

[0030] (3) at 85 C the reaction was concentrated under reduced pressure distillation, when the
little end of the distillation distilled water; then cooled to 45 C, to give the intermediate 2,3,5
omeprazole - three -N- methylpyridine-oxide.

Omeprazole Intermediate 2,3,5-trimethyl pyridine -N- dioxide [0031] The present embodiment
obtained in a purity of 99. 3% (GC), a yield of 98.7%.

[0032] Example 3

[0033] Omeprazole intermediate 2,3,5-trimethyl pyridine oxide -N- preparation, comprising the
steps of:

[0034] (I) the key water 3kg of ammonium phosphate dissolved prepared key or key solution of
ammonium acid solution;

[0035] (2) the key, was added to a solution of ammonium 220kg of 2,3,5-trimethyl pyridine,
water bath heated to 95 C, and a solution 200kg50wt% of hydrogen peroxide, hydrogen
peroxide drops acceleration control rate of 35kg / h, incubation at 95 C for 10 hours to obtain a
reaction solution;

[0036] (3) at 88 C the reaction was concentrated under reduced pressure distillation, when the
little end of the distillation distilled water; then cooled to 50 C, to give the intermediate 2,3,5
omeprazole - three -N- methylpyridine-oxide.

Omeprazole Intermediate 2,3,5-trimethyl pyridine -N- dioxide [0037] The present embodiment
obtained in a purity of 99. 2% (GC), a yield of 98. 3%

[0038] The present invention is not limited to the specific embodiments, all based on the
technical concept of the invention to improve the structure made on, all fall within the scope of
the present invention.