CN104072391A - Synthesis process of rivastigmine hydrogen tartrate - Google Patents
Synthesis process of rivastigmine hydrogen tartrate Download PDFInfo
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- rivastigmine
- hydrogentartrate
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- 229950010673 rivastigmine hydrogen tartrate Drugs 0.000 title claims abstract description 85
- 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 85
- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 26
- 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 95
- 229960004136 rivastigmine Drugs 0.000 claims abstract description 92
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 150
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 135
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 128
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 102
- 239000000243 solution Substances 0.000 claims description 70
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 238000002425 crystallisation Methods 0.000 claims description 42
- 230000008025 crystallization Effects 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 42
- GQZXRLWUYONVCP-UHFFFAOYSA-N 3-[1-(dimethylamino)ethyl]phenol Chemical compound CN(C)C(C)C1=CC=CC(O)=C1 GQZXRLWUYONVCP-UHFFFAOYSA-N 0.000 claims description 37
- 238000010992 reflux Methods 0.000 claims description 28
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 24
- 239000012312 sodium hydride Substances 0.000 claims description 24
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 24
- -1 amido formyl chloride Chemical compound 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000001953 recrystallisation Methods 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 19
- 230000002194 synthesizing effect Effects 0.000 claims description 19
- 238000005352 clarification Methods 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 238000007670 refining Methods 0.000 claims description 12
- 238000005194 fractionation Methods 0.000 claims description 11
- YQCGEGQXFHSZHK-UHFFFAOYSA-N 4-formyloxy-2,3-dihydroxy-4-oxobutanoic acid Chemical compound OC(=O)C(O)C(O)C(=O)OC=O YQCGEGQXFHSZHK-UHFFFAOYSA-N 0.000 claims description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
- 238000012545 processing Methods 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 239000002994 raw material Substances 0.000 abstract description 16
- 230000003287 optical effect Effects 0.000 abstract description 5
- 230000006340 racemization Effects 0.000 abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 2
- 238000000926 separation method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 8
- 238000007605 air drying Methods 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000005265 energy consumption Methods 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- HZZOUWBMMWVPTR-UHFFFAOYSA-N 2-[[6-[bis(carboxymethyl)amino]-1,4-dioxocan-6-yl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C1(N(CC(O)=O)CC(O)=O)CCOCCOC1 HZZOUWBMMWVPTR-UHFFFAOYSA-N 0.000 description 1
- 229910018507 Al—Ni Inorganic materials 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 206010008096 Cerebral atrophy Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 238000006824 Eschweiler-Clarke methylation reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- VYWQTJWGWLKBQA-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;chloride Chemical class Cl.NC(N)=O VYWQTJWGWLKBQA-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000007074 memory dysfunction Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention aims to solve the technical problem that during industrial production, the yield of rivastigmine hydrogen tartrate is low, and provides a synthesis process of rivastigmine hydrogen tartrate. A racemized raw material is adopted to firstly synthesize racemized rivastigmine, and then direct separation is performed to obtain an optically pure S-shaped isomer, so that racemization in the reaction process is effectively avoided, the optical purity is controllable, and further the product quality is controllable. Through simplified process flow, the optimal reaction solvent, reaction time and reaction temperature can be discovered via exploration, and the method for preparing rivastigmine hydrogen tartrate, which is high in yield, low in cost and simple to operate, has easily accessible raw materials and is suitable for being realized in industrial production, is found.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of synthesis technique of anti senile dementia drug rivastigmine-hydrogentartrate.
Background technology
Rivastigmine-hydrogentartrate (Rivastigmine Hydrogen Tartrate) is-(S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate, hydrogen-(2R, 3R)-tartaric popular name, its structural formula is
Rivastigmine-hydrogentartrate can be used as treating light, moderate dementia of the Alzheimer type.Alzheimer's disease (Alzheimer ' s Disease) be carrying out property of a kind of central nervous system degenerative disease, the multiple the elderly who is born in more than 60 years old.First its clinical manifestation is recent memory dysfunction, produces subsequently persistence hypophrenia, judging and deducing Disability, aphasia, dyskinesia etc.Main pathological characters is cerebral atrophy, senile plaque and the formation of cerebrovascular throw out, neurofibrillary tangles in cerebral tissue.It is expected that, after 25 years, the whole world will have 2,200 ten thousand people to suffer from alzheimer's disease, to the year two thousand fifty patients with Alzheimer disease will increase to 4,500 ten thousand people.Become the nervous system disorders that China and developed country have a strong impact on life of elderly person quality, how to prevent and treat is the emphasis of current brain science area research.The medicine administrative protection that import drugs rivastigmine-hydrogentartrate capsule obtained in China on June 24th, 1999, in expiration of time limit on December 24 in 2006, existing many companies have completed the preparation of rivastigmine-hydrogentartrate by many routes.But the shortcomings such as ubiquity complex synthetic route, prices of raw and semifnished materials costliness, equipment requirements is high, yield is low.
As document " synthesizing of rivastigmine-hydrogentartrate " (" Nanfang Medical Univ's journal ", 2007:27 (2)), a kind of new synthetic process of rivastigmine-hydrogentartrate is disclosed.Taking 3-hydroxy acetophenone as raw material, through Oximation, the reduction of Al-Ni alloy as catalyst, Eschweiler-clarke N-methylation reaction obtains important intermediate 3-[1-(dimethylamino) ethyl] phenol, be connected with another side chain first and second urea chlorides, synthetic racemic rivastigmine, splits through DDTA again, with tartrate salify, finally obtain target product again.There is following shortcoming in the synthesis technique in document: (1) material proportion is unreasonable; (2) each intermediate is of low quality; (3) overall yield only has 4.17%, and yield is low.
Summary of the invention
The present invention, in order to solve the low technical problem of suitability for industrialized production rivastigmine-hydrogentartrate productive rate, provides a kind of synthesis technique of rivastigmine-hydrogentartrate.By the technical process of simplifying, the reaction solvent of exploration discovery the best, reaction times, temperature of reaction, find that a kind of yield is high, cost is low, simple to operate, raw material is easy to get, the method for preparing rivastigmine-hydrogentartrate that is adapted at realizing in suitability for industrialized production.
For achieving the above object, the present invention adopts following technical scheme:
A synthesis technique for rivastigmine-hydrogentartrate, is characterized in that: processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol are added in reactor, stir to clarify, be cooled to below 20 DEG C, add in batches sodium hydride, be cooled to 0-10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 20-30 DEG C of stirring reaction 16-24h, aftertreatment, obtains racemic rivastigmine;
The fractionation of B, racemize rivastigmine
In reactor, add racemic rivastigmine, D-(+)-to methyldiphenyl formyl tartrate and methanol solution, stir, reflux, to solution clarification, stops heating, is cooled to 0-10 DEG C, and stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt of rivastigmine, DTTA salt is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration of rivastigmine;
Synthesizing of C, rivastigmine-hydrogentartrate
The rivastigmine of S configuration and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, is cooled to 0-20 DEG C, and stirred crystallization has a large amount of white solids to separate out, and filters, the dry rivastigmine-hydrogentartrate crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 0-20 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate.
The present invention adopts the first rivastigmine of synthesising racemation of raw material of racemization, then resolution obtains optically pure S type isomer, effectively avoids the racemization in reaction process, makes that optical purity is controlled and then quality product is controlled.By Optimizing Technical, improve yield, reduce costs, make to operate advantages of simple more.
The aftertreatment of A step of the present invention refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Preferably, described hydrochloric acid is adjusted pH to 1-2, and product is well dissolved into water.
Preferably, adopt 30% sodium hydroxide solution tune pH to 10-11, product is dissolved in organic layer well.Acid-base neutralisation exothermic heat of reaction is obvious, so adopt 30% sodium hydroxide solution.
Preferably, described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9-10:1, has ensured the dissolving to each reactive component, and raw material is fully reacted completely.
Preferably, described A step, by mole number, sodium hydride: N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.Sodium hydride, these low cost raw materials of N-ethyl-N-methyl amido formyl chloride are excessive 20%, have ensured that 3-(1-(dimethylamino) ethyl) phenol reactant is complete; And these excessive raw material reactions are complete easily to be removed afterwards, and the impurity of generation is few, and product purity is high.
Preferably, described B step, methanol solution is that massfraction is 67% methanol aqueous solution, the methanol solution of this concentration can ensure under reflux conditions molten clear solute, can in the time of crystallization, well remove again impurity.
Preferably, described B step, racemic rivastigmine and D-(+)-be 1:0.5-0.9 to the tartaric mol ratio of methyldiphenyl formyl, the D-(+) of this ratio-methyldiphenyl formyl tartrate is enough to ensure the fractionation to racemic rivastigmine, without being added to 1:1, save cost.
Preferably, the recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, is cooled to 0-10 DEG C of stirred crystallization 50-70h at every turn, filters, and dries, and obtains the DTTA salt of rivastigmine.
The present invention is by the refining optical purity qualified product completely that can obtain for three times; Extend the crystallization time, can improve product yield, but crystallization overlong time can increase energy consumption, reduce production efficiency.
Preferably, described B step, regulates pH value to 10-11.The consumption of alkali affects hydrolysis reaction process, under such pH value condition, just can, by complete the DTTA salt hydrolysis of rivastigmine, its structure not had to any impact, and does not have too many impurity generation, and the purity of hydrolysate is high.
Beneficial effect of the present invention is:
1, technique of the present invention is taking 3-(1-(dimethylamino) ethyl) phenol and N-ethyl-N-methyl amido formyl chloride as raw material, synthetic rivastigmine-hydrogentartrate, adopt the first rivastigmine of synthesising racemation of raw material of racemization, resolution obtains optically pure S type isomer again, effectively avoid the racemization in reaction process, make that optical purity is controlled and then quality product is controlled.On the other hand, the present invention reasonably controls material proportion, by best reaction solvent, reaction times, temperature of reaction, explore an optimum operational path, thereby the quality of intermediate is carried out to strict control, improved dramatically yield, reduced cost, made to operate advantages of simple more, and reaction conditions gentleness, controllability is strong; In suitability for industrialized production, the high yield of realizing rivastigmine-hydrogentartrate greatly reduces cost and energy consumption pollution.
2, the building-up reactions of racemize rivastigmine, stirring reaction 16-24h at 20-30 DEG C, temperature is room temperature, reaction conditions gentleness, stable reaction, has greatly reduced energy consumption, has further reduced the cost of technique; The mol ratio of controlling sodium hydride and N-ethyl-N-methyl amido formyl chloride, 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1, sodium hydride, these low cost raw materials excessive 20% of N-ethyl-N-methyl amido formyl chloride, ensure that 3-(1-(dimethylamino) ethyl) phenol reactant is complete, and these excessive raw material reactions are complete easily to be removed afterwards, the impurity producing is few, and product purity is high.
3, in the fractionation of racemize rivastigmine, the present invention's methanol solution recrystallization three times, be cooled to 0-10 DEG C of stirred crystallization 50-70h at every turn, by the refining optical purity qualified product completely that can obtain for three times, extend the crystallization time, can improve product yield, but crystallization overlong time can increase energy consumption, reduce production efficiency; When DTTA salt hydrolysis, regulate pH value to 10-11, under such pH value condition, just can, by complete the DTTA salt hydrolysis of rivastigmine, its structure not had to any impact, and do not have too many impurity generation, the purity of hydrolysate is high.
4, rivastigmine-hydrogentartrate synthetic and refining in, adopt Virahol as solvent, ensured the yield of rivastigmine-hydrogentartrate.
Brief description of the drawings
Fig. 1 is the infrared analysis result data table of the rivastigmine-hydrogentartrate of synthesis technique of the present invention.
Fig. 2 is the rivastigmine-hydrogentartrate of synthesis technique of the present invention
1h NMR and COSY test data.
Embodiment
Below in conjunction with embodiment, essentiality content of the present invention is described in further detail.
Embodiment 1
A synthesis technique for rivastigmine-hydrogentartrate, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol are added in reactor, stir to clarify, be cooled to 20 DEG C, add in batches sodium hydride, be cooled to 10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 30 DEG C of stirring reaction 16h, aftertreatment, obtains racemic rivastigmine;
The fractionation of B, racemize rivastigmine
In reactor, add racemic rivastigmine, D-(+)-to methyldiphenyl formyl tartrate and methanol solution, stir, reflux, to solution clarification, stops heating, is cooled to 10 DEG C, and stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt of rivastigmine, DTTA salt is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration of rivastigmine.
Synthesizing of C, rivastigmine-hydrogentartrate
The rivastigmine of S configuration and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, is cooled to 20 DEG C, and stirred crystallization, has a large amount of white solids to separate out, and filters, the dry rivastigmine-hydrogentartrate crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 20 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate.
Embodiment 2
A synthesis technique for rivastigmine-hydrogentartrate, processing step is as follows:
Synthesizing of A, racemize rivastigmine (II)
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol (I) are added in reactor, stir to clarify, be cooled to 0 DEG C, add in batches sodium hydride, be cooled to 0 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 20 DEG C of stirring reaction 24h, aftertreatment, obtains racemic rivastigmine (II);
The fractionation of B, racemize rivastigmine (II)
To adding racemic rivastigmine (II), D-(+)-to methyldiphenyl formyl tartrate (D-(+) DTTA in reactor) and methanol solution, reflux stirred, to solution clarification, stop heating, be cooled to 0 DEG C, stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt (III) of rivastigmine, DTTA salt (III) is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration (IV) of rivastigmine.
Synthesizing of C, rivastigmine-hydrogentartrate (V) crude product
The rivastigmine of S configuration (IV) and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, be cooled to 0 DEG C, stirred crystallization, has a large amount of white solids to separate out, filter dry rivastigmine-hydrogentartrate (V) crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate (V)
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 0 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate (V).
Embodiment 3
A synthesis technique for rivastigmine-hydrogentartrate, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol are added in reactor, stir to clarify, be cooled to 10 DEG C, add in batches sodium hydride, be cooled to 5 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 25 DEG C of stirring reaction 20h, aftertreatment, obtains racemic rivastigmine;
The fractionation of B, racemize rivastigmine
In reactor, add racemic rivastigmine, D-(+)-to methyldiphenyl formyl tartrate and methanol solution, stir, reflux, to solution clarification, stops heating, is cooled to 5 DEG C, and stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt of rivastigmine, DTTA salt is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration of rivastigmine.
Synthesizing of C, rivastigmine-hydrogentartrate
The rivastigmine of S configuration and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, is cooled to 10 DEG C, and stirred crystallization, has a large amount of white solids to separate out, and filters, the dry rivastigmine-hydrogentartrate crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 8 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate.
Embodiment 4
A synthesis technique for rivastigmine-hydrogentartrate, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol are added in reactor, stir to clarify, be cooled to 8 DEG C, add in batches sodium hydride, be cooled to 6 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 26 DEG C of stirring reaction 22h, aftertreatment, obtains racemic rivastigmine;
The fractionation of B racemize rivastigmine
In reactor, add racemic rivastigmine, D-(+)-to methyldiphenyl formyl tartrate and methanol solution, stir, reflux, to solution clarification, stops heating, is cooled to 8 DEG C, and stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt of rivastigmine, DTTA salt is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration of rivastigmine.
Synthesizing of C, rivastigmine-hydrogentartrate
The rivastigmine of S configuration and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, is cooled to 12 DEG C, and stirred crystallization, has a large amount of white solids to separate out, and filters, the dry rivastigmine-hydrogentartrate crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 5 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate.
Embodiment 5
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Embodiment 6
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 2.
Embodiment 7
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.
Adopt 30% sodium hydroxide solution tune pH to 10.
Embodiment 8
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.5.
Adopt 30% sodium hydroxide solution tune pH to 11.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9:1.
Embodiment 9
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.2.
Adopt 30% sodium hydroxide solution tune pH to 10.5.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 10:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Embodiment 10
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.6.
Adopt 30% sodium hydroxide solution tune pH to 10.6.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.5:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Embodiment 11
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.8.
Adopt 30% sodium hydroxide solution tune pH to 10.2.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.8:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Described B step, racemic rivastigmine and D-(+)-be 1:0.5 to the tartaric mol ratio of methyldiphenyl formyl.
Embodiment 12
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.8.
Adopt 30% sodium hydroxide solution tune pH to 10.8.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.6:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Described B step, racemic rivastigmine and D-(+)-be 1:0.9 to the tartaric mol ratio of methyldiphenyl formyl.
The recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, is cooled to 0 DEG C of stirred crystallization 70h at every turn, filters, and dries, and obtains the DTTA salt of rivastigmine;
Embodiment 13
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.5.
Adopt 30% sodium hydroxide solution tune pH to 10.3.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.6:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Described B step, racemic rivastigmine and D-(+)-be 1:0.7 to the tartaric mol ratio of methyldiphenyl formyl.
The recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, is cooled to 10 DEG C of stirred crystallization 50h at every turn, filters, and dries, and obtains the DTTA salt of rivastigmine;
Described B step, regulates pH value to 10.
Embodiment 14
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.4.
Adopt 30% sodium hydroxide solution tune pH to 10.6.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.5:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Described B step, racemic rivastigmine and D-(+)-be 1:0.6 to the tartaric mol ratio of methyldiphenyl formyl.
The recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, is cooled to 5 DEG C of stirred crystallization 60h at every turn, filters, and dries, and obtains the DTTA salt of rivastigmine;
Described B step, regulates pH value to 11.
Embodiment 15
The present embodiment is substantially the same manner as Example 4, on this basis:
The aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), adds water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjusts pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
Described hydrochloric acid is adjusted pH to 1.6.
Adopt 30% sodium hydroxide solution tune pH to 10.2.
Described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9.8:1.
Described A step, the mol ratio of sodium hydride and N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
Described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
Described B step, racemic rivastigmine and D-(+)-be 1:0.75 to the tartaric mol ratio of methyldiphenyl formyl.
The recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, is cooled to 6 DEG C of stirred crystallization 65h at every turn, filters, and dries, and obtains the DTTA salt of rivastigmine;
Described B step, regulates pH value to 10.5.
Embodiment 16
The synthesis technique of rivastigmine-hydrogentartrate of the present invention, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) 9.7kg and 3-(1-(dimethylamino) ethyl) phenol 1lg are added in reactor, stirring at room temperature makes molten clear, be cooled to 20 DEG C and add below sodium hydride, after finishing, sodium hydride is cooled to 0-10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, control reacting liquid temperature lower than 10 DEG C, drip finish after in 20-30 DEG C of stirring reaction 16-24h, TLC (developping agent: methylene chloride/methanol=8/1) monitoring 3-(1-(dimethylamino) ethyl) phenol raw material reaction is complete.Aftertreatment is complete, and obtaining oily matter is racemic rivastigmine 1395g, yield 92.1%.
The fractionation of B, racemize rivastigmine
To 67% methanol aqueous solution that adds upper step gained oily matter 1395g, D-(+)-to methyldiphenyl formyl tartrate 1506g and 13.8L in reactor, stir, be heated to reflux, solution clarification, stop heating, be cooled to 0-10 DEG C of stirred crystallization 60h, filter, 60 DEG C of air blast are dried 5h and are obtained white solid 1300g, by 67% methanol aqueous solution recrystallization three times for gained white solid, be cooled to 0-10 DEG C of stirred crystallization 60h at every turn, filter, 8h is dried in 60 DEG C of air blast, obtains white solid 1127g.White solid 1127g and water 3.5L are added in there-necked flask, stirring makes molten clear, with 30% aqueous sodium hydroxide solution adjusting PH to 10-11, add 1.8L methylene dichloride, stir separatory, (the each 1000ml of purified water washing for dichloromethane layer, washed twice), concentrating under reduced pressure goes methylene dichloride to obtain oily matter (rivastigmine) 398g, yield 89.8% at 50 DEG C.
Synthesizing of C, rivastigmine-hydrogentartrate
In there-necked flask, add rivastigmine 398g, 2000ml Virahol and 239g L-(+)-tartrate, be heated to reflux, stir, reaction solution clarification, stops heating, be cooled to 0-20 DEG C, stirred crystallization 4h, has a large amount of white solids to separate out, and filters, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate crude product 512g, yield 80.4%.
Refining of D, rivastigmine-hydrogentartrate
In there-necked flask, add 512g rivastigmine-hydrogentartrate crude product, 2050ml Virahol, be heated to reflux, reaction solution is molten clear, stops heating, is cooled to 0-20 DEG C, stirred crystallization 8h, have a large amount of white solids to separate out, filter, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate 456g, yield 89.1%, purity is 99.8%.
Embodiment 17
The synthesis technique of rivastigmine-hydrogentartrate of the present invention, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) 9.7kg and 3-(1-(dimethylamino) ethyl) phenol 1lg are added in reactor, stirring at room temperature makes molten clear, be cooled to 20 DEG C and add below sodium hydride, after finishing, sodium hydride is cooled to 0-10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, control reacting liquid temperature lower than 10 DEG C, drip finish after in 20-30 DEG C of stirring reaction 16-24h, TLC (developping agent: methylene chloride/methanol=8/1) monitoring 3-(1-(dimethylamino) ethyl) phenol raw material reaction is complete.Aftertreatment is complete, and obtaining oily matter is racemic rivastigmine 1408g, yield 92.7%.
The fractionation of B, racemize rivastigmine
To 67% methanol aqueous solution that adds upper step gained oily matter 1408g, D-(+)-to methyldiphenyl formyl tartrate 1520g and 13.9L in reactor, stir, be heated to reflux, solution clarification, stop heating, be cooled to 0-10 DEG C of stirred crystallization 60h, filter, 60 DEG C of air blast are dried 5h and are obtained white solid 1299g, by 67% methanol aqueous solution recrystallization three times for gained white solid, be cooled to 0-10 DEG C of stirred crystallization 60h at every turn, filter, 8h is dried in 60 DEG C of air blast, obtains white solid 1131g.White solid 1131g and water 3.4L are added in there-necked flask, stirring makes molten clear, with 30% aqueous sodium hydroxide solution adjusting PH to 10-11, add 1.8L methylene dichloride, stir separatory, (the each 1000ml of purified water washing for dichloromethane layer, washed twice), concentrating under reduced pressure goes methylene dichloride to obtain oily matter (rivastigmine) 401g, yield 90.3% at 50 DEG C.
Synthesizing of C, rivastigmine-hydrogentartrate
In there-necked flask, add rivastigmine 401g, 2000ml Virahol and 240g L-(+)-tartrate, be heated to reflux, stir, reaction solution clarification, stops heating, be cooled to 0-20 DEG C, stirred crystallization 4h, has a large amount of white solids to separate out, and filters, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate crude product 515g, yield 80.3%.
Refining of D, rivastigmine-hydrogentartrate
In there-necked flask, add 515g rivastigmine-hydrogentartrate crude product, 2060ml Virahol, be heated to reflux, reaction solution is molten clear, stops heating, is cooled to 0-20 DEG C, stirred crystallization 8h, have a large amount of white solids to separate out, filter, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate 456g, yield 88.6%, purity is 99.2%.
Embodiment 18
The synthesis technique of rivastigmine-hydrogentartrate of the present invention, processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) 9.7kg and 3-(1-(dimethylamino) ethyl) phenol 1lg are added in reactor, stirring at room temperature makes molten clear, be cooled to 20 DEG C and add below sodium hydride, after finishing, sodium hydride is cooled to 0-10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, control reacting liquid temperature lower than 10 DEG C, drip finish after in 20-30 DEG C of stirring reaction 16-24h, TLC (developping agent: methylene chloride/methanol=8/1) monitoring 3-(1-(dimethylamino) ethyl) phenol raw material reaction is complete.Aftertreatment is complete, and obtaining oily matter is racemic rivastigmine 1415g, yield 94%.
The fractionation of B, racemize rivastigmine
To 67% methanol aqueous solution that adds upper step gained oily matter 1415g, D-(+)-to methyldiphenyl formyl tartrate 1525g and 13.9L in reactor, stir, be heated to reflux, solution clarification, stop heating, be cooled to 0-10 DEG C of stirred crystallization 60h, filter, 60 DEG C of air blast are dried 5h and are obtained white solid 1303g, by 67% methanol aqueous solution recrystallization three times for gained white solid, be cooled to 0-10 DEG C of stirred crystallization 60h at every turn, filter, 8h is dried in 60 DEG C of air blast, obtains white solid 1136g.White solid 1136g and water 3.4L are added in there-necked flask, stirring makes molten clear, with 30% aqueous sodium hydroxide solution adjusting PH to 10-11, add 1.8L methylene dichloride, stir separatory, (the each 1000ml of purified water washing for dichloromethane layer, washed twice), concentrating under reduced pressure goes methylene dichloride to obtain oily matter (rivastigmine) 410g, yield 82.2% at 50 DEG C.
Synthesizing of C, rivastigmine-hydrogentartrate
In there-necked flask, add rivastigmine 410g, 2000ml Virahol and 240g L-(+)-tartrate, be heated to reflux, stir, reaction solution clarification, stops heating, be cooled to 0-20 DEG C, stirred crystallization 4h, has a large amount of white solids to separate out, and filters, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate crude product 533g, yield 81.3%.
Refining of D, rivastigmine-hydrogentartrate
In there-necked flask, add 533g rivastigmine-hydrogentartrate crude product, 2071ml Virahol, be heated to reflux, reaction solution is molten clear, stops heating, is cooled to 0-20 DEG C, stirred crystallization 8h, have a large amount of white solids to separate out, filter, 60 DEG C of forced air drying 12h obtain rivastigmine-hydrogentartrate 480g, yield 90.1%, purity is 99.5%.
Raw material sources of the present invention
3-(1-(dimethylamino) ethyl) phenol: Beijing Ke Tuoqihua Glass Co., Ltd..
N-ethyl-N-methyl amido formyl chloride: Beijing Ke Tuoqihua Glass Co., Ltd..
Claims (10)
1. a synthesis technique for rivastigmine-hydrogentartrate, is characterized in that: processing step is as follows:
Synthesizing of A, racemize rivastigmine
Tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol are added in reactor, stir to clarify, be cooled to below 20 DEG C, add in batches sodium hydride, be cooled to 0-10 DEG C, drip N-ethyl-N-methyl amido formyl chloride, in 20-30 DEG C of stirring reaction 16-24h, aftertreatment, obtains racemic rivastigmine;
The fractionation of B, racemize rivastigmine
In reactor, add racemic rivastigmine, D-(+)-to methyldiphenyl formyl tartrate and methanol solution, stir, reflux, to solution clarification, stops heating, is cooled to 0-10 DEG C, and stirred crystallization, filters, and dries to obtain white solid; By gained white solid methanol solution recrystallization, filter, dry, obtain the DTTA salt of rivastigmine, DTTA salt is dissolved in the water, add aqueous sodium hydroxide solution to regulate pH value, add methylene dichloride, stir, separatory, dichloromethane layer washs by purified water, and concentrating under reduced pressure removes methylene dichloride, obtains the S configuration of rivastigmine;
Synthesizing of C, rivastigmine-hydrogentartrate
The rivastigmine of S configuration and L-(+)-tartrate are dissolved in Virahol, and reflux, after stirring to clarify, is cooled to 0-20 DEG C, and stirred crystallization has a large amount of white solids to separate out, and filters, the dry rivastigmine-hydrogentartrate crude product that obtains;
Refining of D, rivastigmine-hydrogentartrate
By rivastigmine-hydrogentartrate dissolving crude product, in Virahol, reflux, to reaction solution clarification, is cooled to 0-20 DEG C, and stirred crystallization, filters, and is dried to obtain rivastigmine-hydrogentartrate.
2. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, it is characterized in that: the aftertreatment of described A step refers to, after reacting completely, concentrating under reduced pressure is removed tetrahydrofuran (THF), add water, adjust pH with hydrochloric acid, washed with dichloromethane, water intaking phase, adjust pH with sodium hydroxide, dichloromethane extraction, washing, dry, filter, and obtaining oily matter is racemic rivastigmine.
3. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 2, is characterized in that: described hydrochloric acid is adjusted pH to 1-2.
4. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 2, is characterized in that: adopt 30% sodium hydroxide solution tune pH to 10-11.
5. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, is characterized in that: described A step, the mass ratio of tetrahydrofuran (THF) and 3-(1-(dimethylamino) ethyl) phenol is 9-10:1.
6. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, it is characterized in that: described A step, by mole number, sodium hydride: N-ethyl-N-methyl amido formyl chloride: 3-(1-(dimethylamino) ethyl) phenol is 1.2:1.2:1.
7. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, is characterized in that: described B step, methanol solution is that massfraction is 67% methanol aqueous solution.
8. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, is characterized in that: described B step, and racemic rivastigmine and D-(+)-be 1:0.5-0.9 to the tartaric mol ratio of methyldiphenyl formyl.
9. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, it is characterized in that: the recrystallization of described B step refers to, by methanol solution recrystallization three times of gained white solid, be cooled to 0-10 DEG C of stirred crystallization 50-70h at every turn, filter, dry, obtain the DTTA salt of rivastigmine.
10. the synthesis technique of a kind of rivastigmine-hydrogentartrate according to claim 1, is characterized in that: described B step, regulates pH value to 10-11.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439906A (en) * | 2015-12-08 | 2016-03-30 | 哈药集团三精制药有限公司 | Method for synthesizing rivastigmine hydrogen tartrate |
| CN110790682A (en) * | 2018-08-01 | 2020-02-14 | 万特制药(海南)有限公司 | Method for preparing high-purity rivastigmine bitartrate |
| CN110790681A (en) * | 2018-08-01 | 2020-02-14 | 万特制药(海南)有限公司 | Resolution method of racemic rivastigmine |
| CN115594614A (en) * | 2021-07-08 | 2023-01-13 | 北京万全德众医药生物技术有限公司（Cn） | A method for preparing high-purity rivastigmine bitartrate |
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| US20080306280A1 (en) * | 2007-06-11 | 2008-12-11 | Apotex Pharmachem Inc. | Novel process for the preparation of phenylcarbamates |
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| US20080306280A1 (en) * | 2007-06-11 | 2008-12-11 | Apotex Pharmachem Inc. | Novel process for the preparation of phenylcarbamates |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439906A (en) * | 2015-12-08 | 2016-03-30 | 哈药集团三精制药有限公司 | Method for synthesizing rivastigmine hydrogen tartrate |
| CN110790682A (en) * | 2018-08-01 | 2020-02-14 | 万特制药(海南)有限公司 | Method for preparing high-purity rivastigmine bitartrate |
| CN110790681A (en) * | 2018-08-01 | 2020-02-14 | 万特制药(海南)有限公司 | Resolution method of racemic rivastigmine |
| CN115594614A (en) * | 2021-07-08 | 2023-01-13 | 北京万全德众医药生物技术有限公司（Cn） | A method for preparing high-purity rivastigmine bitartrate |
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