CN115594614A - Method for preparing high-purity rivastigmine bitartrate - Google Patents
Method for preparing high-purity rivastigmine bitartrate Download PDFInfo
- Publication number
- CN115594614A CN115594614A CN202110771902.5A CN202110771902A CN115594614A CN 115594614 A CN115594614 A CN 115594614A CN 202110771902 A CN202110771902 A CN 202110771902A CN 115594614 A CN115594614 A CN 115594614A
- Authority
- CN
- China
- Prior art keywords
- rivastigmine
- filtering
- purity
- bitartrate
- crystallizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- GWHQHAUAXRMMOT-MBANBULQSA-N rivastigmine tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 GWHQHAUAXRMMOT-MBANBULQSA-N 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims abstract description 7
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims abstract description 16
- 229960004136 rivastigmine Drugs 0.000 claims abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 102100033639 Acetylcholinesterase Human genes 0.000 description 3
- 108010022752 Acetylcholinesterase Proteins 0.000 description 3
- 229950010673 rivastigmine hydrogen tartrate Drugs 0.000 description 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960004323 rivastigmine tartrate Drugs 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 2
- 229940124596 AChE inhibitor Drugs 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for purifying rivastigmine bitartrate, which is characterized by comprising the following steps: adding the crude rivastigmine into isopropanol solution, heating to dissolve, filtering while hot, cooling, stirring, crystallizing, controlling the temperature to 25-30 ℃ for crystallizing, filtering, and drying to obtain refined rivastigmine product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to purification of rivastigmine.
Background
Rivastigmine (rivastigmine), also known as rivastigmine, belongs to the second generation of central AChE inhibitor, has selective inhibition effect on AChE in cerebral cortex and hippocampus, has little influence on AChE in striatum and heart, and can slow down the formation of amyloid precursor (APP). The function of cholinergic-releasing neurons in the brain is increased by inhibition of acetylcholinesterase, thereby improving cognitive effects in alzheimer's patients, with highly selective effects in the hippocampal and cortical regions of the brain. It also slows the formation of the amyloid p-Amyloid Precursor Protein (APP) fragment.
Because the preparation route of the rivastigmine is short, and most of adopted intermediates are crude chemicals, rivastigmine impurity systems prepared by different processes are very different, such as the synthesis route in patent CN110668976 (A) is as follows.
This route requires the use of complexes and is multistep, with later removal of optical isomers. The synthesis cost of the rivastigmine raw material is higher, and the final yield is lower due to the longer route. Therefore, the search for a reaction condition for efficiently purifying the rivastigmine is very important for industrial production, and the quality of the product can be ensured to the maximum extent without great fluctuation caused by the change of materials. For example, in patent cn201810862323.X, the yield of rivastigmine bitartrate obtained after recrystallization is low. Aiming at the aspect, a large amount of experimental researches are carried out by I, and the results show that the rivastigmine is heated, dissolved and cleaned in an isopropanol solution, filtered while the solution is hot, cooled, stirred and crystallized, so that impurities can be effectively removed, and meanwhile, the yield of the product is ensured.
Disclosure of Invention
The invention relates to a method for purifying rivastigmine hydrogen tartrate, which is characterized by comprising the following steps: adding the crude rivastigmine into isopropanol solution, heating to dissolve, filtering while hot, cooling, stirring, crystallizing, controlling the temperature to 25-30 ℃ for crystallizing, filtering, and drying to obtain refined rivastigmine product.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1:
adding 4.0g of crude rivastigmine tartrate (with chemical purity of 98.0%) into 28.0ml of isopropanol solution, heating, filtering while hot, cooling to 25-30 ℃ for crystallization for 5h, filtering, and drying to obtain refined rivastigmine tartrate 3.6g, wherein the yield is 90.0%, the chemical purity is 99.8%, and the maximum single impurity content is 0.07%.
Example 2:
adding 4.0g of crude rivastigmine hydrogen tartrate (with the chemical purity of 98.0%) into 32.0ml of isopropanol solution, heating to dissolve the solution, carrying out suction filtration while the solution is hot, cooling to 25-30 ℃ for crystallization for 5h, carrying out suction filtration and drying to obtain 3.4g of refined rivastigmine hydrogen tartrate, wherein the yield is 85.0%, the chemical purity is 99.7%, and the maximum single impurity content is 0.09%.
Claims (2)
1. A method for purifying rivastigmine bitartrate is characterized in that: adding the crude rivastigmine into isopropanol solution, heating to dissolve, filtering while hot, cooling, stirring, crystallizing, controlling the temperature to 25-30 ℃ for crystallizing, filtering, and drying to obtain refined rivastigmine.
2. The process according to claim 1, wherein the ratio of rivastigmine to isopropanol solution is from 7ml/g to 8ml/g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110771902.5A CN115594614A (en) | 2021-07-08 | 2021-07-08 | Method for preparing high-purity rivastigmine bitartrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110771902.5A CN115594614A (en) | 2021-07-08 | 2021-07-08 | Method for preparing high-purity rivastigmine bitartrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115594614A true CN115594614A (en) | 2023-01-13 |
Family
ID=84841352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110771902.5A Pending CN115594614A (en) | 2021-07-08 | 2021-07-08 | Method for preparing high-purity rivastigmine bitartrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115594614A (en) |
-
2021
- 2021-07-08 CN CN202110771902.5A patent/CN115594614A/en active Pending
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| PB01 | Publication | ||
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