CN109748837A - A kind of preparation method of Esomeprazole - Google Patents
A kind of preparation method of Esomeprazole Download PDFInfo
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- CN109748837A CN109748837A CN201810457021.4A CN201810457021A CN109748837A CN 109748837 A CN109748837 A CN 109748837A CN 201810457021 A CN201810457021 A CN 201810457021A CN 109748837 A CN109748837 A CN 109748837A
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- esomeprazole
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Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of Esomeprazole.Esomeprazole provided by the present invention obtains lactone through intramolecular dehydration by 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid, and lactone reacts with ammonia water generation again.The preparation method of Esomeprazole provided by the invention has short reaction time, mild condition, production cost low, and the advantages such as product yield is high, quality is good, is suitble to industrialization large-scale production.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of preparation of Esomeprazole
Method.
Background technique
The present invention relates to a kind of synthesis of Esomeprazole (i.e. Oxiracetam).Oxiracetam
Molecular formula is C6H10N2O3, it is a kind of hydroxy-amino-butyric acid cyclic derivatives of synthesis, structural formula is as follows:
Oxiracetam is that one kind acts on the cholinergic nootropic of reticular formation of brain stem, is used for cerebral injury and caused nerve
Afunction, memory and the treatment of disturbance of intelligence, wide market.
Reported according to existing literature, the synthetic method of Oxiracetam mainly include the following types:
Japanese patent application JP53101367 is disclosed using 4- amino -3-hydroxybutyrate as starting material, through hydroxyl protection,
After cyclization, with 2- bromoacetate replace, deprotection, again ammonolysis the step of obtain target product.The shortcomings that route, is institute
Expensive, the high production cost with raw material and amino protecting agent is not suitable for industrialized production.
Chinese patent application CN1956953A is disclosed using chloro ethylene oxide as starting material, is substituted, open loop, water
Solution, esterification, 5 step of cyclization react to obtain Oxiracetam.Although the cost of material of this route is not high, the cyanogen using severe toxicity is needed
Compound, and side reaction is more, not only intermediate is difficult to purify, but also final products need ion exchange resin desalination, and total recovery is only
For 25-30%.
Chinese patent application CN1513836A discloses a kind of preparation process of Oxiracetam, with 4- haloacetyl acetic acid
Derivative is starting material, is reacted first with the azide of alkali or alkaline earth metal, and 4- nitrine acetoacetate is obtained
Derivative, then hydrogenated, cyclization, ammonification, obtain Oxiracetam, route is as follows:
Though the Esomeprazole starting material of existing technique synthesis is different, there are parts
The shortcomings that raw material, which uses, very big security risk, and reaction step is cumbersome, and total recovery is low, poor product quality.
Therefore develop that a kind of reaction time is short, and reaction condition is mild, production cost is low, and product yield is high, quality is good, is suitble to
The synthetic method of the Esomeprazole of industrialization large-scale production.
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of preparation sides of Esomeprazole
Method, reaction time is short, and reaction condition is mild.
To achieve the above object, the technical solution of the present invention is as follows:
Esomeprazole is dehydrated in molecular acid by 4- hydroxyl -2- oxo-1-pyrrolidine
Lactone is obtained, lactone occurs ammonolysis reaction and generates, and reaction equation is as follows:
As a preferred option, preparation method of the invention the following steps are included:
1) 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid is mixed with non-protonic solvent, insulation reaction obtains lactone；
2) it is added in ammonium hydroxide after dissolving lactone obtained by step 1) in polar organic solvent, reaction obtains 4- hydroxyl -2-
Oxo-1-pyrrolidine ethanamide.
Preferably, in step 1), the non-protonic solvent is selected from n,N-Dimethylformamide (DMF), N, N- dimethyl
Acetamide, dimethyl sulfoxide (DMSO), acetonitrile it is one or more.
Preferably, in step 1), the mass ratio of the non-protonic solvent and 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid
For 0.4-0.8:1.Further, preferably 0.5-0.6:1.
Preferably, in step 1), the 4- hydroxyl -2- oxo-1-pyrrolidine acetic acidreaction temperature is 100-160 DEG C, excellent
It is selected as 120-140 DEG C.Further, preferably 130-140 DEG C.
Preferably, in step 1), the 4- hydroxyl -2- oxo-1-pyrrolidine acetic acidreaction time is 1.5-2h.
Preferably, in step 1) after insulation reaction, cooling, reaction system is added to the water mashing, filters, and obtains described interior
Ester.
Further, temperature is 100-105 DEG C after cooling.
Preferably, in step 2), polar organic solvent be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol one kind or
It is a variety of.
Preferably, in step 2), the ammonium hydroxide refers to that mass fraction containing ammonia is the aqueous solution of 25%-28%.
Further, the quality of above-mentioned ammonium hydroxide is 4-5 times of lactone quality.
Preferably, in step 2), reaction temperature is 20-25 DEG C.
Preferably, in step 2), reaction time 10-12h.
Preferably, it after step 2), is precipitated and recrystallizes the Esomeprazole.
Further, it is precipitated and recrystallizes the process of Esomeprazole are as follows: solvent evaporated is added
Acetone crystallization obtains crude product, again with methanol recrystallize high-purity target product Esomeprazole.
The synthetic method of Esomeprazole provided by the invention is short reaction time, reaction condition
Mildly, production cost is low, is suitble to industrialization large-scale production.
The second object of the present invention is the 4- hydroxyl -2- oxo -1- pyrrole that a kind of method for providing purpose one is prepared
Cough up alkyl acetamide.
To achieve the above object, the technical solution of the present invention is as follows:
According to the preparation method of purpose one, Esomeprazole is prepared.
Preparation method according to the invention, Esomeprazole rubs in the product being prepared
For that yield up to 80% or more, purity reaches 99.9%.Product yield of the invention is high, high-quality.
The beneficial effects of the present invention are: the synthesis side of Esomeprazole provided by the invention
Method:
1) reaction time is short, and reaction condition is mild, and production cost is low, is suitble to industrialization large-scale production.
2) product yield of the invention is high, high-quality, and for yield up to 80% or more, purity reaches 99.9%.
Specific embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of actual conditions is not specified in preferred embodiment
Proved recipe method, usually according to normal condition, illustrated embodiment are but not to be to preferably be illustrated to the contents of the present invention
The contents of the present invention are only limitted to illustrated embodiment.So those skilled in the art are according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
Embodiment 1
(1) by 10g 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid (Hubei Yang Xin Pharmaceutical Technology Co., Ltd, similarly hereinafter) with
5g DMF mixing stirs the lower dissolved clarification that heats up, keeps the temperature 130-135 DEG C of reaction 2h, finish, 40g water is added it to after being cooled to 100 DEG C
Middle mashing filters to obtain lactone weight in wet base 9.5g.
(2) it is added in 40g 25% (ammonia mass fraction, similarly hereinafter) ammonium hydroxide, keeps the temperature after dissolving 9.5g lactone with 5g methanol
20-25 DEG C of reaction 12h finishes, solvent evaporated, and 20g acetone crystallization is added and obtains crude product 8.90g, again with methanol recrystallization, dry mesh
Mark product 8.2g:4- hydroxy-2-oxo-1-pyrrolidine acetamide molar yield 82.6%, HPLC purity 99.9%.
Embodiment 2
(1) 10g 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid is mixed with 5g DMSO, stirs the lower dissolved clarification that heats up, heat preservation
130-135 DEG C of reaction 2h finishes, adds it in 40g water and be beaten after being cooled to 102 DEG C, filter to obtain lactone weight in wet base 9.4g.
(2) it is added in 25% ammonium hydroxide of 46g after dissolving 9.4g lactone wet product with 5g ethyl alcohol, keeps the temperature 20-25 DEG C of reaction
12h finishes, solvent evaporated, and 15g acetone crystallization is added and obtains crude product, obtains target product 8.1g, molar yield after again with methanol recrystallization
81.5%, HPLC purity 99.9%.
Embodiment 3
(1) 20g 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid is mixed with 10g DMF, stirs the lower dissolved clarification that heats up, heat preservation
130-135 DEG C of reaction 2h finishes, adds it in 80g water and be beaten after being cooled to 100 DEG C, filter to obtain lactone weight in wet base 19.8g.
(2) it is added in 25% ammonium hydroxide of 100g after dissolving lactone wet product with 5g methanol, keeps the temperature 20-25 DEG C of reaction 13h,
Finish, solvent evaporated, 30g acetone crystallization is added and obtains crude product, again with methanol recrystallization obtains target product 4- hydroxyl -2- oxo -1- pyrrole
Cough up alkyl acetamide 8.13g, molar yield 81.8%, HPLC purity 99.9%.
Hydrogen nuclear magnetic resonance spectrum analysis is carried out to the product of embodiment 1, analysis result is as follows:
1H-NMR (300MHz, DMSO-d6) δ 2.10 (d, 1H), 2.57 (dd, 1H), 3.69 (d, 1H), 3.88 (d, 1H),
4.10 (d, 1H), 4.31 (m, 1H), 5.25 (s, 1H), 7.13 (s, 1H), 7.33 (s, 1H).
It is attached: the condition and method of HPLC method measurement Esomeprazole purity:
1. instrument: high performance liquid chromatograph
2. reagent and solution
Acetonitrile (HPLC), potassium dihydrogen phosphate (AR), phosphoric acid (AR), ammonium hydroxide (AR)；
The preparation of mobile phase: phosphate buffer (takes potassium dihydrogen phosphate 4.08g, ammonia quality is added after adding water 500ml to dissolve
Score is the ammonium hydroxide 5ml of 25-28%, 1000ml is diluted with water, with phosphoric acid tune PH to 3.5 ± 0.1)-acetonitrile (volume after mixing
Than being mobile phase for 26:74), filtering degassing is spare.
The preparation of test solution: weighing sample 50mg in 25ml measuring bottle, adds flowing phased soln and is diluted to scale, shakes
It is even.
3. chromatographic condition and system suitability are tested: being filler with amino bonded silica gel, with mixture of acetonitrile-phosphate buffer
(volume ratio 26:74) is mobile phase, flow velocity 1.0ml/min, Detection wavelength 210nm.
4. determination step: the blank solvent of (20ul), test solution high performance liquid chromatograph will be injected in equal volume respectively,
Chromatogram is recorded to 30min.It deducts blank solvent and presses area normalization method computer chromatography purity.
The product yield prepared as a result, using method of the invention is high, with high purity, high-quality.Preparation 4- hydroxyl of the invention
The method of base -2- oxo-1-pyrrolidine ethanamide is initially formed interior using 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid as starting material
Ester, then the target product of high-purity is obtained by ammonolysis.Method of the invention has reaction time short, and reaction condition is mild, raw
Advantage at low cost is produced, industrialized production is suitble to.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (10)
1. a kind of preparation method of Esomeprazole, which is characterized in that the 4- hydroxyl -2- oxygen
Generation -1- pyrrolidine acetamide by be dehydrated in 4- hydroxyl -2- oxo-1-pyrrolidine molecular acid lactone, lactone occur ammonolysis it is anti-
It should generate, reaction equation is as follows:
2. preparation method according to claim 1, which comprises the following steps:
1) 4- hydroxyl -2- oxo-1-pyrrolidine acetic acid is mixed with non-protonic solvent, insulation reaction obtains lactone；
2) it is added in ammonium hydroxide after dissolving lactone obtained by step 1) in polar organic solvent, reaction obtains 4- hydroxyl -2- oxo -
1- pyrrolidine acetamide.
3. preparation method according to claim 2, which is characterized in that in step 1), the non-protonic solvent is selected from N,
Dinethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, acetonitrile it is one or more.
4. preparation method according to claim 2, which is characterized in that in step 1), the non-protonic solvent and 4- hydroxyl
The mass ratio of base -2- oxo-1-pyrrolidine acetic acid is 0.4-0.8:1.
5. preparation method according to claim 2, which is characterized in that in step 1), the 4- hydroxyl -2- oxo -1- pyrrole
Coughing up alkane acetic acidreaction temperature is 100-160 DEG C, it is preferable that is 130-140 DEG C.
6. preparation method according to claim 2, which is characterized in that in step 1) after insulation reaction, cooling, reaction system
Be added to the water mashing, filters, obtains the lactone.
7. preparation method according to claim 2, which is characterized in that in step 2), polar organic solvent is methanol, second
Alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol it is one or more.
8. preparation method according to claim 2, which is characterized in that in step 2), the ammonium hydroxide refers to that ammonia mass fraction is
The aqueous solution of 25%-28%.
9. preparation method according to claim 2, which is characterized in that after step 2), be precipitated and with recrystallizing methanol, obtain
Esomeprazole.
10. the Esomeprazole that the described in any item preparation methods of claim 1-9 are prepared.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810457021.4A CN109748837B (en) | 2018-05-14 | 2018-05-14 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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| CN201810457021.4A CN109748837B (en) | 2018-05-14 | 2018-05-14 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN106496089A (en) * | 2016-02-05 | 2017-03-15 | 华润双鹤药业股份有限公司 | A kind of method for preparing Oxiracetam |
-
2018
- 2018-05-14 CN CN201810457021.4A patent/CN109748837B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN106496089A (en) * | 2016-02-05 | 2017-03-15 | 华润双鹤药业股份有限公司 | A kind of method for preparing Oxiracetam |
Non-Patent Citations (2)
| Title |
|---|
| NEIL BARNWELL，ET AL.: "Stereoselective synthesis of a dialkylhydantoin featuring an asymmetric Strecker reaction on an acyclic dialkyl ketone", 《TETRAHEDRON LETTERS》 * |
| WILLIAM W.LEE，ET AL.: "Synthesis of mustards from putrescine，cadaverine，and 1,3-diaminopropane", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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