CN105481854B - A kind of preparation method of the brilliant III type material of Risperidone - Google Patents
A kind of preparation method of the brilliant III type material of Risperidone Download PDFInfo
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- CN105481854B CN105481854B CN201510906848.5A CN201510906848A CN105481854B CN 105481854 B CN105481854 B CN 105481854B CN 201510906848 A CN201510906848 A CN 201510906848A CN 105481854 B CN105481854 B CN 105481854B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention provides a kind of preparation method of the brilliant III type material of Risperidone, and Risperidone crude product, water, ethanol, propane diols, adsorbent are mixed, 10~60 minutes is incubated at 5~60 DEG C, is then filtered to remove adsorbent while hot；Then gained filtrate is placed in precooling 3~10 hours at 40~25 DEG C rapidly；Maintained 1~4 hour under the conditions of being warming up to 23~15 DEG C；It is warming up at 10~0 DEG C and maintains 1~4 hour；It is warming up at 10~30 DEG C and maintains 2~6 hours again；Finally it is warming up at 40~80 DEG C and maintains 2~4 hours, prepares the brilliant III type material of Risperidone.The purification of Risperidone crude product is carried out using the mixed solvent of water and ethanol and propane diols, nontoxic solvent, recyclable recycling, control crystallization using stage heating and dry, it can be very good to control the growth of crystal grain and the formation of crystal formation, gained III type Risperidone purity of crystalline substance is up to 99.59%.
Description
Technical field
The present invention relates to a kind of preparation method of the brilliant III type material of Risperidone, belong to field of medicine and chemical technology.
Background technology
Risperidone belongs to benzo Isoxazole derivative in chemical constitution, and its chemical name is 3- [2- [4- (6- fluoro- 1,2-
Benzo isoxazole -3- bases) -1- piperidyls] ethyl] -6,7,8,9- tetrahydrochysene -2- methyl -4H- pyridos [1,2- α] pyrimidine -4-
Ketone, its molecular formula are C23H27FN4O2, its structural formula is as follows：
Risperidone is developed for 1984 by Belgian Yang Sen drugmakers, trade name " Risperidal " (Risperdal).Mainly
For treating acute and chronic schizophrenia, particularly to positive and negative symptoms and its affective symptom to occur together (such as anxiety,
Depression etc.) there is the effect of preferable.Also the affective symptom relevant with schizophrenia can be mitigated.For the effective trouble of acute stages treated
Person, in the treatment of the phase of maintenance, Risperidone can continue to play its clinical efficacy.
Chinese patent CN2011101283971 provides a kind of preparation method of the brilliant III type material of Risperidone, using acetone
Brilliant III type Risperidone is prepared with recrystallization after n-butanol, pyridine, isopropanol, the dissolving of acetonitrile mixed solvent, research finds brilliant III type
The product that Risperidone is developed as active component by oral administration after biological absorption effect, more brilliant I types and brilliant II type Risperidone come
Saying has more preferable advantage function.But the solvent of poisonous acetone, pyridine, acetonitrile etc. has been used in preparation process, to life
Production personnel bring certain harm.
The content of the invention
The present invention is solves the problems, such as to provide a kind of new preparation side of III type material of Risperidone crystalline substance in above-mentioned background technology
Method, this method is nontoxic using solvent safety, and products therefrom purity is higher.
The present invention is further solves the problems, such as to provide a kind of preparation of III type material of Risperidone crystalline substance in above-mentioned background technology
Method, the preparation process of Risperidone III type material of crystalline substance are：1. purifying：Risperidone crude product, water, ethanol, propane diols, adsorbent are mixed
Close, be incubated 10~60 minutes at 5~60 DEG C, be then filtered to remove adsorbent while hot；Mixed from ethanol and propane diols with water
The system of composition can be very good scattered Risperidone crude product；The weight ratio of the purge process material is Risperidone crude product：Water：Second
Alcohol：Propane diols：Adsorbent=1：5~10：3~6：0.3~0.6：0.005~0.03.
2. desolventizing：The first step, gained filtrate is placed in precooling 3~10 hours at -40~-25 DEG C rapidly；Second step
Maintained 1~4 hour under the conditions of being warming up to -23~-15 DEG C；3rd step, it is warming up at -10~0 DEG C and maintains 1~4 hour；4th
Step, is warming up at 10~30 DEG C and maintains 2~6 hours；5th step, it is warming up at 40~80 DEG C and maintains 2~4 hours to prepare profit
The brilliant III type material of ketone is trained, is characterized using powder x-ray diffraction, 2 θ angles characteristic peak occur in 21.5 °, 25.0 °, 27.5 °, 33.0 °.
Further still, it is preferred that the weight ratio of material is Risperidone crude product：Water：Ethanol：Propane diols：Adsorbent=1：7~
8：3.5~4.5：0.35~0.45：0.008~0.02.
Further still, it is preferred that the weight ratio of material is Risperidone crude product：Water：Ethanol：Propane diols：Adsorbent=1：7.5：
4：0.4：0.01.
Further, the adsorbent is diatomite and/or molecular sieve, preferably molecular sieve, and molecular sieve can be more preferable
Adsorb the impurity in Risperidone crude product.
Further, the purge process is preferably to be incubated 20~50 minutes at 10~50 DEG C, preferably at 40 DEG C
Insulation 30 minutes, Risperidone is completely dissolved, and adsorbent adsorbing contaminant effect is best.
Further, in removing process, first step precooling temperature is preferably -30 DEG C, and the precooling time is preferably 6 small
When；Second step heating is preferably -20 DEG C, 3 hours；The heating of 3rd step is preferably -5 DEG C, 3 hours；The heating of 4th step is preferably 20
DEG C, 4 hours；The heating of 5th step is preferably 65 DEG C, 3 hours.
Further, the temperature-rise period heating rate in removing process is 5 DEG C/min.
Except it is described above present invention solves the technical problem that, form technical scheme technical characteristic and by these
Outside advantage caused by the technical characteristic of technical scheme, other technologies problem that the present invention can solve, wrap in technical scheme
Advantage caused by the other technical characteristics contained and these technical characteristics, will be described in further detail.
The present invention has the advantages and positive effects of：Because the present invention is using as above technical scheme, i.e., using water and second
The mixed solvent of alcohol and propane diols carries out the purification of Risperidone crude product, nontoxic solvent, recyclable recycling, green, section
About cost, in addition by the way of heating rate is controlled, control crystallization using stage heating and dry, can be very good to control
The growth of combinations grain and the formation of crystal formation, gained III type Risperidone purity of crystalline substance is up to 99.59%.
Embodiment
The embodiment of the present invention is described further below.Herein it should be noted that for these implementations
The explanation of mode is used to help understand the present invention, but does not form limitation of the invention.In addition, invention described below
As long as the technical characteristic being related in each embodiment does not form conflict each other, can is mutually combined.
Embodiment 1
Risperidone crude product 100g, water 750g, ethanol 400g, propane diols 40g, molecular sieve 10g, under being stirred after mixing, heating
To at 40 DEG C, 30 minutes are incubated, molecular sieve is filtered to remove while hot, gained filtrate is then placed in precooling 6 hours at -30 DEG C,
It is warming up to -20 DEG C to maintain 3 hours, heating is put -5 DEG C and maintained 3 hours, then is warming up to 20 DEG C and maintains 4 hours, is finally warming up to 65 DEG C
Maintain 3 hours, heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.59%.
Embodiment 2
Risperidone crude product 100g, water 700g, ethanol 350g, propane diols 45g, diatomite 8g, under being stirred after mixing, at 5 DEG C,
Insulation 60 minutes, is filtered to remove diatomite, gained filtrate then is placed in into precooling 10 hours at -40 DEG C, be warming up to -23 DEG C of dimensions
Hold 4 hours, heating sets to 0 DEG C maintenance 1 hour, then is warming up to 30 DEG C and maintains 2 hours, is finally warming up to 80 DEG C and maintains 2 hours, heating
Speed is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.16%.
Embodiment 3
Risperidone crude product 100g, water 800g, ethanol 450g, propane diols 35g, diatomite 20, under being stirred after mixing, 60 DEG C
Under, 10 minutes are incubated, diatomite is filtered to remove, gained filtrate is then placed in precooling 3 hours at -25 DEG C, is warming up to -15 DEG C
Maintaining 1 hour, heating is put -10 DEG C and maintained 4 hours, then is warming up to 10 DEG C and maintains 6 hours, is finally warming up to 40 DEG C and maintains 4 hours,
Heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.25%.
Embodiment 4
Risperidone crude product 100g, water 500g, ethanol 300g, propane diols 60g, molecular sieve 5g, under being stirred after mixing, it is warming up to
At 40 DEG C, 30 minutes are incubated, molecular sieve is filtered to remove while hot, gained filtrate is then placed in precooling 6 hours at -30 DEG C, risen
Extremely -20 DEG C of temperature maintains 3 hours, and heating is put -5 DEG C and maintained 3 hours, then is warming up to 20 DEG C and maintains 4 hours, is finally warming up to 65 DEG C of dimensions
Hold 3 hours, heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 98.38%.
Embodiment 5
Risperidone crude product 100g, water 1kg, ethanol 600g, propane diols 30g, diatomite 30g, under being stirred after mixing, at 5 DEG C,
Insulation 60 minutes, is filtered to remove diatomite, gained filtrate then is placed in into precooling 10 hours at -40 DEG C, be warming up to -23 DEG C of dimensions
Hold 4 hours, heating sets to 0 DEG C maintenance 1 hour, then is warming up to 30 DEG C and maintains 2 hours, is finally warming up to 80 DEG C and maintains 2 hours, heating
Speed is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.24%.
Embodiment 6
Risperidone crude product 100g, water 750g, ethanol 400g, propane diols 40g, molecular sieve 10g, under being stirred after mixing, heating
To at 40 DEG C, 30 minutes are incubated, molecular sieve is filtered to remove while hot, gained filtrate is then placed in precooling 6 hours at -30 DEG C,
It is warming up to -20 DEG C to maintain 3 hours, heating is put -5 DEG C and maintained 3 hours, then is warming up to 20 DEG C and maintains 4 hours, is finally warming up to 65 DEG C
Maintain 3 hours, heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.52%.
Embodiment 7
Risperidone crude product 100g, water 700g, ethanol 350g, propane diols 45g, diatomite 8g, under being stirred after mixing, at 5 DEG C,
Insulation 60 minutes, is filtered to remove diatomite, gained filtrate then is placed in into precooling 10 hours at -40 DEG C, be warming up to -23 DEG C of dimensions
Hold 4 hours, heating sets to 0 DEG C maintenance 1 hour, then is warming up to 30 DEG C and maintains 2 hours, is finally warming up to 80 DEG C and maintains 2 hours, heating
Speed is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.21%.
Embodiment 8
Risperidone crude product 100g, water 800g, ethanol 450g, propane diols 35g, diatomite 20, under being stirred after mixing, 60 DEG C
Under, 10 minutes are incubated, diatomite is filtered to remove, gained filtrate is then placed in precooling 3 hours at -25 DEG C, is warming up to -15 DEG C
Maintaining 1 hour, heating is put -10 DEG C and maintained 4 hours, then is warming up to 10 DEG C and maintains 6 hours, is finally warming up to 40 DEG C and maintains 4 hours,
Heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.33%.
Embodiment 9
Risperidone crude product 100g, water 500g, ethanol 300g, propane diols 60g, molecular sieve 5g, under being stirred after mixing, it is warming up to
At 40 DEG C, 30 minutes are incubated, molecular sieve is filtered to remove while hot, gained filtrate is then placed in precooling 6 hours at -30 DEG C, risen
Extremely -20 DEG C of temperature maintains 3 hours, and heating is put -5 DEG C and maintained 3 hours, then is warming up to 20 DEG C and maintains 4 hours, is finally warming up to 65 DEG C of dimensions
Hold 3 hours, heating rate is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 98.64%.
Embodiment 10
Risperidone crude product 100g, water 1kg, ethanol 600g, propane diols 30g, diatomite 30g, under being stirred after mixing, at 5 DEG C,
Insulation 60 minutes, is filtered to remove diatomite, gained filtrate then is placed in into precooling 10 hours at -40 DEG C, be warming up to -23 DEG C of dimensions
Hold 4 hours, heating sets to 0 DEG C maintenance 1 hour, then is warming up to 30 DEG C and maintains 2 hours, is finally warming up to 80 DEG C and maintains 2 hours, heating
Speed is set as that for 5 DEG C/min, gained III type Risperidone purity of crystalline substance be 99.12%.
Embodiments of the present invention are explained in detail above, but the present invention is not limited to described embodiment.
For the ordinary skill in the art, without departing from the principles and spirit of the present invention to these embodiments
A variety of changes, modification, replacement and deformation is carried out to still fall within the scope of the present invention.
Claims (7)
- A kind of 1. preparation method of the brilliant III type material of Risperidone, it is characterised in that：Its preparation process is：(1) purify：By Risperidone Crude product, water, ethanol, propane diols, adsorbent mixing, 5 ~ 60o10 ~ 60 minutes are incubated under C, is then filtered to remove absorption while hot Agent；The system for mixing composition with water from ethanol and propane diols can be very good scattered Risperidone crude product；The purge process thing The weight ratio of material is Risperidone crude product：Water：Ethanol：Propane diols：Adsorbent=1：5~10：3~6：0.3~0.6：0.005~0.03；(2) desolventizing：The first step, gained filtrate is placed in -40 ~ -25 rapidlyoPrecooling 3 ~ 10 hours under C；Second step heats up To -23 ~ -15oMaintained 1 ~ 4 hour under the conditions of C；3rd step, is warming up to -10 ~ 0oMaintained 1 ~ 4 hour under C；4th step, is warming up to 10~30oMaintained 2 ~ 6 hours under C；5th step, is warming up to 40 ~ 80oMaintain to prepare within 2 ~ 4 hours the brilliant III type thing of Risperidone under C Matter, characterized using powder x-ray diffraction, 2 θ corner characteristics peaks are 21.5o、25.0o、27.5o、33.0o。
- 2. preparation method according to claim 1, it is characterised in that：The weight ratio of material is Risperidone crude product：Water：Second Alcohol：Propane diols：Adsorbent=1：7~8：3.5~4.5：0.35~0.45：0.008~0.02.
- 3. preparation method according to claim 2, it is characterised in that：The weight ratio of material is Risperidone crude product：Water：Second Alcohol：Propane diols：Adsorbent=1：7.5：4：0.4：0.01.
- 4. preparation method according to claim 1, it is characterised in that：The adsorbent is diatomite and/or molecular sieve.
- 5. preparation method according to claim 1, it is characterised in that：The purge process is preferably 10 ~ 50oIt is incubated under C 20 ~ 50 minutes.
- 6. preparation method according to claim 1, it is characterised in that：Further, in removing process, first step precooling It is preferably -30 to freeze temperatureoC, precooling time are preferably 6 hours；Second step heating is preferably -20oC, 3 hours；3rd step heats up Preferably -5oC, 3 hours；The heating of 4th step is preferably 20oC, 4 hours；The heating of 5th step is preferably 65oC, 3 hours.
- 7. the preparation method according to claim 1 or 6, it is characterised in that：Temperature-rise period heating speed in removing process Rate is 5oC/min。
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Citations (6)
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|---|---|---|---|---|
| WO2004020439A2 (en) * | 2002-08-30 | 2004-03-11 | Sunil Sadanand Nadkarni | Improved process for preparation of risperidone |
| CN102718762A (en) * | 2012-07-02 | 2012-10-10 | 天津市嘉凡生物科技有限公司 | Risperidone crystal form A and preparation method of risperidone crystal form A |
| WO2012147035A1 (en) * | 2011-04-26 | 2012-11-01 | Torrent Pharmaceuticals Limited | Acid addition salts of risperidone and pharmaceutical compositions thereof |
| CN102786521A (en) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | Risperidone crystal III substance, its preparation method and its applications in medicines and healthcare products |
| CN104557923A (en) * | 2015-01-04 | 2015-04-29 | 东南大学 | Paliperidone hydrochloride crystal |
| CN104557915A (en) * | 2014-12-01 | 2015-04-29 | 浙江京新药业股份有限公司 | Method for preparing high-purity paliperidone II crystal form |
-
2015
- 2015-12-08 CN CN201510906848.5A patent/CN105481854B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004020439A2 (en) * | 2002-08-30 | 2004-03-11 | Sunil Sadanand Nadkarni | Improved process for preparation of risperidone |
| WO2012147035A1 (en) * | 2011-04-26 | 2012-11-01 | Torrent Pharmaceuticals Limited | Acid addition salts of risperidone and pharmaceutical compositions thereof |
| CN102786521A (en) * | 2011-05-18 | 2012-11-21 | 中国医学科学院药物研究所 | Risperidone crystal III substance, its preparation method and its applications in medicines and healthcare products |
| CN102718762A (en) * | 2012-07-02 | 2012-10-10 | 天津市嘉凡生物科技有限公司 | Risperidone crystal form A and preparation method of risperidone crystal form A |
| CN104557915A (en) * | 2014-12-01 | 2015-04-29 | 浙江京新药业股份有限公司 | Method for preparing high-purity paliperidone II crystal form |
| CN104557923A (en) * | 2015-01-04 | 2015-04-29 | 东南大学 | Paliperidone hydrochloride crystal |
Non-Patent Citations (1)
| Title |
|---|
| An Improved and Efficient Process for the Production of Highly Pure Paliperidone, a Psychotropic Agent, via DBU Catalyzed N-Alkylation;Pavankumar V. Solanki 等;《ACS Sustainable Chemistry & Engineering》;20121231;第1卷;第243-248页 * |
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