CN104140423B - The process for purification of 9-hydroxy-risperidone - Google Patents
The process for purification of 9-hydroxy-risperidone Download PDFInfo
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- CN104140423B CN104140423B CN201310173582.9A CN201310173582A CN104140423B CN 104140423 B CN104140423 B CN 104140423B CN 201310173582 A CN201310173582 A CN 201310173582A CN 104140423 B CN104140423 B CN 104140423B
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- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title claims abstract description 23
- 238000005352 clarification Methods 0.000 claims abstract description 31
- 238000002425 crystallisation Methods 0.000 claims abstract description 30
- 230000008025 crystallization Effects 0.000 claims abstract description 28
- 238000007670 refining Methods 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 14
- 238000005360 mashing Methods 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 239000007787 solid Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- -1 piperazines Ketone Chemical class 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000002845 discoloration Methods 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 229940106887 risperdal Drugs 0.000 claims 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000003756 stirring Methods 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 239000007788 liquid Substances 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 206010013786 Dry skin Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003693 atypical antipsychotic agent Substances 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- JDQWAXVWEXPVQV-UHFFFAOYSA-N 3-fluoro-1,2-benzoxazole Chemical class C1=CC=C2C(F)=NOC2=C1 JDQWAXVWEXPVQV-UHFFFAOYSA-N 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010041243 Social avoidant behaviour Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 239000000706 filtrate Substances 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the process for purification of 9-hydroxy-risperidone.Specifically, 9-hydroxy-risperidone highly finished product are made by making 9-hydroxy-risperidone undergo the steps such as dissolving, reduction, dissolved clarification, crystallization, mashing, refined and filtering in the process for purification.The present invention process for purification have refining effect good, high income is simple to operate, and uncontrollability is low, it is economical and practical the advantages that.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to the process for purification of 9-hydroxy-risperidone, more precisely (±) -3-
[2- [4- (the fluoro- 1,2- benzoisoxazoles -3- bases of 6-) -1- piperidyls] ethyl] -6,7,8,9- tetrahydrochysene -9- hydroxy-2-methyls -
The process for purification of 4H- pyridos [1,2-a] pyrimidin-4-one.
Background technology
It is reported that in the world, just there is a people to suffer from schizophrenia, and essence the most serious in every 100 people
Refreshing disease type.Mainly include positive symptom（Illusion and illusion）And negative symptoms（Depressed, introversive and social withdrawal）And think
Dimension is disorderly.
It is also first currently the only atypical antipsychotic that 9-hydroxy-risperidone, which is, using OROS（Osmotic sustained release agent）Prolong
The 9-hydroxy-risperidone piece of long release tech allows medicine to be sustained release into blood plasma at 24 hours later.In addition, 9-hydroxy-risperidone delays
The extensive metabolism of liver will not be caused by releasing piece, and by kidney largely secrete without changing, and atypical treatment
Less generation involuntary movement specific to schizophrenia drug or tremble etc. side effect the characteristics of also have the medical instrument
Good prospect of the application.
The 9-hydroxy-risperidone that the Yang Sen companies of subsidiary of Johson ＆ Johnson develop（Paliperidone, Invega）In 2006
Year December by the approval of U.S. FDA, listed, Britain's listing on 08 01st, 2007 on 01 23rd, 2007 in the U.S., and
Listed on April 1st, 2008 in Australia.9-hydroxy-risperidone is that one kind treats schizoid atypical antipsychotic agents
Thing, and be over 2003 first it is approved be used for treat schizoid newtype drug.
On 07 20th, 2005, Alza Corp（The subsidiary of Johson ＆ Johnson）Apply for 9-hydroxy-risperidone controlled release tablet clinic rank
Section, gets the Green Light on 04 14th, 2006.It has been used as imported medicine by Yang Sen companies in Discussion on Chinese Listed（Data of issue：In September, 2008
No. 28, effective expired date September 27 in 2013）.
On 9-hydroxy-risperidone purifying and process for refining, existing pertinent literature report, but use alcohols solvent more, due to pa profit
The shortcomings of piperazine ketone dissolubility in alcohols solvent is poor, except oxidation impurities effect difference, therefore these methods are present that quantity of solvent is big, refined effect
The shortcomings of fruit difference.
The content of the invention
The present invention is directed to the deficiency of prior art, there is provided a kind of refining effect is good, and oxidation impurities control effect is preferable, yield
Height, simple to operate, uncontrollability is low, economical and practical 9-hydroxy-risperidone process for purification.
The present invention is achieved through the following technical solutions：
The process for purification of 9-hydroxy-risperidone, comprises the following steps：
（1）9-hydroxy-risperidone is dissolved in dichloromethane, adds reducing agent, two-phase reduction；Organic phase is extracted, is dried, filtering；
（2）The organic phase for filtering gained is concentrated, dissolved clarification solvent dissolved clarification is added, cooling crystallization, filters, dry；
（3）The organic phase for filtering gained is concentrated, mashing solvent mashing is added, cooling crystallization, filters, dry, get Pa Li
Piperazine ketone crude product；
（4）9-hydroxy-risperidone crude product is dissolved in refining solvent and refines, decolourize, is back to dissolved clarification, cools, crystallization, obtains I crystal
9-hydroxy-risperidone highly finished product.
Preferably, the volume mass ratio of the dichloromethane and 9-hydroxy-risperidone solid is 20~60:1, preferably 40:1.
Preferably, the reducing agent is selected from sodium borohydride, more preferably potassium borohydride, sodium borohydride；The drier is selected from
Sodium sulphate or magnesium sulfate.Preferably, the drier is sodium sulphate.
Preferably, the dissolved clarification solvent and mashing solvent are each independently selected from DMF and/or N, N-
Dimethyl acetamide, preferably DMF；The refining solvent is selected from ethanol.
Preferably, the step（2）Dissolved clarification temperature be 90-120 DEG C, more preferably 95-110 DEG C；The dissolved clarification time is 5-
30min；The volume of the dissolved clarification solvent is 5~10 times of 9-hydroxy-risperidone quality.
Preferably, the volume of the mashing solvent is 4~10 times of 9-hydroxy-risperidone quality.
Preferably, the volume of the refining solvent is 30~70 times of 9-hydroxy-risperidone quality.
Preferably, the recrystallization temperature after the dissolved clarification is 10~30 DEG C, more preferably 15-25 DEG C；
Preferably, the crystallization time after the dissolved clarification is 1~8h, more preferably 2.5-3.5h；
Preferably, it is 50~60 DEG C, more preferably 53-58 DEG C to be beaten temperature；
Preferably, beating time is 0.5~3h, more preferably 0.5-1.5h；
Preferably, the step（3）Mashing recrystallization temperature be 10~30 DEG C, more preferably 15-25 DEG C；
Preferably, the refining solvent is ethanol, more preferably ethanol；
Preferably, the step（4）Refined recrystallization temperature be 10~30 DEG C, more preferably 15-25 DEG C；
Preferably, the step（4）The refined crystallization time be 12~24h, more preferably 16-20h, most preferably 16-18h；
Preferably, the step（4）Discoloration method be activated carbon decolorizing, maintain the reflux for 0.5~2h, activated carbon dosage is
The 2%-10% of 9-hydroxy-risperidone quality, more preferably 5%；
Preferably, the step（1）Restoring method be：Dissolved with the dichloromethane of 30~60 times of 9-hydroxy-risperidone quality
Sample, with the sodium borohydride aqueous solution containing 100 times of molar equivalents and dichloromethane solution two-phase stirring reduction 0.5h.
Preferably, the step（2）Crystallization method after dissolved clarification is：With the N of 5 times of 9-hydroxy-risperidone quality, N- dimethyl
Formamide, 10min dissolved clarifications are stirred under the conditions of 100 DEG C, be cooled to 20 DEG C, insulation crystallization 3h.
Preferably, the step（3）Methods of beating be：With the DMF of 5 times of 9-hydroxy-risperidone quality,
1h is stirred under the conditions of 55 DEG C, is cooled to 20 DEG C, insulation crystallization 3h.
Preferably, the step（4）Refined Crystallization method be：With the ethanol of 30~70 times of 9-hydroxy-risperidone quality, 2%
The activated carbon of~10% times of 9-hydroxy-risperidone quality, maintain the reflux for 0.5~2h, 10~30 DEG C of 12~20h of crystallization.
Beneficial effect of the present invention is：
The present invention is in step 1）Middle to remove oxidation impurities using reducing agent, reduction effect is notable, can effectively remove oxygen before main peak
Change impurity.
Further use step 2）Middle DMF dissolved clarification crystallization, be advantageous to improve except oxidation impurities are imitated
Fruit, and have obvious refining effect.
Further use step 3）Middle DMF mashing, it is more beneficial for improving and removes oxidation impurities effect,
More there is obvious refining effect.
Further use step 4）Middle ethanol refines, and activated carbon decolorizing, decolorizing effect is notable, and can obtain required I
Crystal formation.
The inventive method, which also has, is adapted to industrial mass production, simple to operate, quality controllable, low cost and other advantages.
Embodiment
In order that technical problem solved by the invention, technical scheme and beneficial effect are more clearly understood, below will knot
Closing embodiment, the present invention will be described in further detail, but is not limitation of the present invention.It is every to be disclosed according to the present invention
The equal replacement of any this area that content is made, belongs to protection scope of the present invention.
Embodiment one
The process for refining of 9-hydroxy-risperidone：
Step 1：200L dichloromethane, 6.5kg 9-hydroxy-risperidone brown solids are added into 1000L reactors successively
（HPLC：93.45%；21.55min 0.72%）, stir dissolved clarification.200L sodium borohydride solutions are added to reactor（Containing 0.675kg
NaBH4）, stir, stand, separate organic layer.100L dichloromethane is added into kettle, is stirred, stands, separates organic layer, water layer
Discard.Merge organic layer, filtered after 25kg anhydrous sodium sulfate dryings 1h.
Step 2：The pure material eluent being collected into is sucked in 300L reactors, in 40~50 DEG C of bath temperature, vacuum
It is concentrated under reduced pressure under degree≤- 0.06MPa.Residue is gone in 50L reactors, 32.5L DMFs is added, opens
Open stirring.Interior 100 DEG C of dissolved clarifications of temperature are heated to, vacuum≤- 0.06MPa, stir 10min.After stirring terminates, temperature in the kettle is dropped
To 10~30 DEG C, 2~3h of stirring and crystallizing.After crystallization terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.Use 10L every time
The filter cake of acetone washing gained, washes twice, rejection filter, dries, obtain solid 5.5kg, mass yield 84.6%（HPLC：98.97%；
21.67min 0.09%）.
Step 3：27.5L DMFs are added into reactor, the material of step gained in addition, water-bath 50~
60 DEG C, vacuum≤- 0.06MPa, stir 1h, 2~3h of stirring and crystallizing after temperature in the kettle is down to 10~30 DEG C by stirring after terminating.
After crystallization terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.The filter cake of gained, washing two are washed with 10L acetone every time
It is secondary, rejection filter, dry, obtain solid 4.9kg, mass yield 89.1%（HPLC：99.83%；21.47min 0.06%）.
Step 4：Added into 500L reactors 220L absolute ethyl alcohols, on 4.9kg step gained solid, 245g activated carbons,
75~85 DEG C are heated in kettle, 45~60min of return stirring.Above-mentioned feed liquid is anti-to another 500L by filter element filtering successively
Answer in kettle.Temperature in the kettle is cooled to 15~25 DEG C, 12~24h of stirring and crystallizing.After crystallization terminates, feed liquid is put into centrifuge and got rid of
Filter, 10~20min of rejection filter after filter cake is washed with absolute ethyl alcohol 30L, 26~28h is dried in 45~55 DEG C of temperature ranges, obtain I crystalline substances
The 9-hydroxy-risperidone off-white powder 4.2kg of type, mass yield 85.7%（HPLC：99.86%；21.52min 0.02%）.
Embodiment two
The process for refining of 9-hydroxy-risperidone：
Step 1：200L dichloromethane, 6.5kg 9-hydroxy-risperidone brown solids are added into 1000L reactors successively
（HPLC：93.45%；21.35min 0.72%）, stir dissolved clarification.200L solution of potassium borohydride is added to reactor（Containing 0.961kg
KBH4）, stir, stand, separate organic layer.100L dichloromethane is added into kettle, is stirred, stands, separates organic layer, water layer is abandoned
Go.Merge organic layer, filtered after 25kg anhydrous sodium sulfate dryings 1h.
Step 2：The pure material eluent being collected into is sucked in 300L reactors, in 40~50 DEG C of bath temperature, vacuum
It is concentrated under reduced pressure under degree≤- 0.06MPa.Residue is gone in 50L reactors, 32.5L DMFs is added, opens
Open stirring.Interior 100 DEG C of dissolved clarifications of temperature are heated to, vacuum≤- 0.06MPa stirs 5min, and temperature in the kettle is down to by stirring after terminating
2~3h of stirring and crystallizing after 10~30 DEG C.After crystallization terminates, feed liquid is transferred to centrifuge rejection filter.Every time institute is washed with acetone 10L
The filter cake obtained, is washed twice, rejection filter, is dried, is obtained solid 5.1kg（HPLC：98.56%；21.37min 0.15%）.
Step 3：25.5L DMFs are added into reactor, the material of step gained in addition, water-bath 50~
60 DEG C, vacuum≤- 0.06MPa, 1h is stirred, stir and temperature in the kettle is down to 10~30 DEG C after terminating, 2~3h of stirring and crystallizing.
After crystallization terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.The filter cake of gained, washing two are washed with acetone 10L every time
It is secondary, 10~20min of rejection filter, dry, obtain solid 4.6kg, mass yield 90.2%（HPLC：99.67%；21.62min 0.08%）.
Step 4：Added into 500L reactors 207L absolute ethyl alcohols, on 4.6kg step gained solid, 230g activated carbons,
75~85 DEG C are heated in kettle, 45~60min of return stirring.Above-mentioned feed liquid is anti-to another 500L by filter element filtering successively
Answer in kettle.Temperature in the kettle is cooled to 15~25 DEG C, 12~24h of stirring and crystallizing.After crystallization terminates, feed liquid is put into centrifuge
Rejection filter, 10~20min of rejection filter after filter cake is washed with absolute ethyl alcohol 30L, 26~28h is dried in 45~55 DEG C of temperature ranges, obtains I
The 9-hydroxy-risperidone off-white powder 3.8kg of crystal formation, mass yield 82.6%（HPLC：99.78%；21.53min 0.02%）.
Embodiment three
The process for refining of 9-hydroxy-risperidone：
Step 1：200L dichloromethane, 6.5kg 9-hydroxy-risperidone brown solids are added into 1000L reactors successively
（HPLC：93.45%；21.55min 0.72%）, stir dissolved clarification.200L sodium borohydride solutions are added to reactor（Containing 0.675kg
NaBH4）, stir, stand, separate organic layer.100L dichloromethane is added into kettle, is stirred, stands, separates organic layer, water layer
Discard.Merge organic layer, filtered after 25kg anhydrous sodium sulfate dryings 1h.
Step 2：The pure material eluent being collected into is sucked in 300L reactors, in 40~50 DEG C of bath temperature, vacuum
It is concentrated under reduced pressure under degree≤- 0.06MPa.Residue is gone in 50L reactors, 32.5L DMFs is added, opens
Open stirring.Interior 100 DEG C of dissolved clarifications of temperature are heated to, vacuum≤- 0.06MPa stirs 10min, and stirring drops temperature in the kettle after terminating
2~3h of stirring and crystallizing after to 10~30 DEG C.After crystallization terminates, feed liquid is transferred to centrifuge rejection filter.Washed every time with acetone 10L
The filter cake of gained, is washed twice, rejection filter, is dried, is obtained solid 5.4kg（HPLC：98.80%；21.61min 0.08%）.
Step 3：27L DMFs are added into reactor, the material of gained, water-bath 50~60 are walked in addition
DEG C, vacuum≤- 0.06MPa, stir 1h, 2~3h of stirring and crystallizing after temperature in the kettle is down to 10~30 DEG C by stirring after terminating.Analysis
After crystalline substance terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.The filter cake of gained, washing two are washed with acetone 10L every time
It is secondary, 10~20min of rejection filter, dry, obtain solid 4.8kg, mass yield 88.9%（HPLC：99.81%；21.47min 0.08%）.
Step 4：Added into 500L reactors 240L isopropanols, on 4.8kg step gained solid, 240g activated carbons, kettle
75~85 DEG C are inside heated to, 45~60min of return stirring.Above-mentioned feed liquid is reacted by filter element filtering to another 500L successively
In kettle.Temperature in the kettle is cooled to 15~25 DEG C, 12~24h of stirring and crystallizing.After crystallization terminates, feed liquid is put into centrifuge and got rid of
Filter, rejection filter after filter cake is washed with absolute ethyl alcohol 30L, 26~28h is dried in 45~55 DEG C of temperature ranges, obtain the Pa Li of I crystal
Piperazine ketone white solid 4.1kg, mass yield 85.4%（HPLC：99.83%；21.61min 0.07%）.
Example IV
The process for refining of 9-hydroxy-risperidone：
Step 1：32.5L DMFs are added into 50L reactors, open stirring, add 6.5kg pas profit
Piperazine ketone brown solid（93.45%；21.55min 0.72%）.Interior 100 DEG C of dissolved clarifications of temperature are heated to, vacuum≤- 0.06MPa, are stirred
Mix 10min.After stirring terminates, temperature in the kettle is down to 10~30 DEG C, 2~3h of stirring and crystallizing.After crystallization terminates, feed liquid is shifted
To centrifuge rejection filter.The filter cake of gained is washed with acetone 10L every time, is washed twice, rejection filter, dries, obtains solid 5.9kg（HPLC：
97.66%；21.61min 0.36%）.
Step 2：30L DMFs are added into reactor, the material of gained, water-bath 50~60 are walked in addition
DEG C, vacuum≤- 0.06MPa, stir 1h.After stirring terminates, temperature in the kettle is down to 10~30 DEG C, 2~3h of stirring and crystallizing.Analysis
After crystalline substance terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.The filter cake of gained, washing two are washed with acetone 10L every time
It is secondary, 10~20min of rejection filter, dry, obtain solid 5.2kg, mass yield 88.1%（HPLC：97.83%；21.47min 0.27%）.
Step 3：Added into 500L reactors 260L ethanol, on 5.2kg step gained solid, 259g activated carbons, in kettle
75~85 DEG C are heated to, 45~60min of return stirring.By above-mentioned feed liquid successively by filter element filtering to another 500L reactor
In.Temperature in the kettle is cooled to 15~25 DEG C, 12~24h of stirring and crystallizing.After crystallization terminates, feed liquid is put into centrifuge and got rid of
Filter, rejection filter after filter cake is washed with absolute ethyl alcohol 30L, 26~28h is dried in 45~55 DEG C of temperature ranges, obtain the Pa Li of I crystal
Piperazine ketone white solid 4.5kg, mass yield 86.5%（HPLC：98.12%；21.61min 0.22%）.
Embodiment five
The process for refining of 9-hydroxy-risperidone：
Step 1：200L dichloromethane, 6.5kg 9-hydroxy-risperidone brown solids are added into 1000L reactors successively
（HPLC：93.45%；21.55min 0.72%）, stir dissolved clarification.200L sodium borohydride solutions are added to reactor（Containing 0.675kg
NaBH4）, stir, stand, separate organic layer.100L dichloromethane is added into kettle, is stirred, stands, separates organic layer, water layer
Discard.Merge organic layer, filtered after 25kg anhydrous sodium sulfate dryings 1h.
Step 2：The pure material eluent being collected into is sucked in 300L reactors, in 40~50 DEG C of bath temperature, vacuum
It is concentrated under reduced pressure under degree≤- 0.06MPa.Residue is gone in 50L reactors, 32.5L DMFs is added, opens
Open stirring.Interior 130 DEG C of dissolved clarifications of temperature are heated to, vacuum≤- 0.06MPa, 10min is stirred, after stirring terminates, temperature in the kettle is dropped
To 10~30 DEG C, 2~3h of stirring and crystallizing.After crystallization terminates, feed liquid is transferred to 10~20min of centrifuge rejection filter.Every time with third
The filter cake of ketone 10L washing gained, washes twice, rejection filter, dries, obtain solid 5.4kg, mass yield 83.1%（HPLC：98.16%；
21.63min 0.21%）.
Step 3：27L DMFs are added into reactor, walk resulting material in addition, 50~60 DEG C of water-bath,
Vacuum≤- 0.06MPa, stir 1h.After stirring terminates, temperature in the kettle is down to 10~30 DEG C, 2~3h of stirring and crystallizing.Crystallization
After end, feed liquid is transferred to 10~20min of centrifuge rejection filter.The filter cake of gained is washed with acetone 10L every time, is washed twice,
Rejection filter, dry, obtain solid 4.7kg, mass yield 87.0%（HPLC：99.32%；21.41min 0.13%）.
Step 4：Added into 500L reactors 211L absolute ethyl alcohols, on 4.7kg step gained solid, 235g activated carbons,
75~85 DEG C are heated in kettle, 45~60min of return stirring.Above-mentioned feed liquid is anti-to another 500L by filter element filtering successively
Answer in kettle.Temperature in the kettle is cooled to 15~25 DEG C, 12~24h of stirring and crystallizing.After crystallization terminates, feed liquid is put into centrifuge and got rid of
Filter, 10~20min of rejection filter after filter cake is washed with absolute ethyl alcohol 30L, 26~28h is dried in 45~55 DEG C of temperature ranges, obtain I crystalline substances
The 9-hydroxy-risperidone off-white powder 4.0kg of type, mass yield 85.1%（HPLC：99.68%；21.56min 0.05%）.
Comparative example one
390L methanol is added into reactor, adds 6.5kg 9-hydroxy-risperidones（Brown solid, HPLC：93.45%；
21.55min 0.72%）, it is heated to flowing back, stirs to dissolved clarification, add 325g activated carbons, stir 1h, filtering, filtrate is cooled to 10
~30 DEG C, stirring and crystallizing 12h, rejection filter, filtration cakes torrefaction, obtain 4.6kg off-white powders（HPLC：97.56%；21.54min,
0.43%）, mass yield 70.8%.
Claims (14)
1. the process for purification of 9-hydroxy-risperidone, it is characterised in that it comprises the following steps：
1) 9-hydroxy-risperidone is dissolved in dichloromethane, adds reducing agent sodium borohydride aqueous solution, two-phase reduction；Extract organic phase,
Dry, filtering；
2) organic phase for filtering gained is concentrated, adds dissolved clarification solvent dissolved clarification, cooling crystallization, filter, dry；
3) solid of gained will be filtered, adds mashing solvent, in 50~60 DEG C of mashing, cooling crystallization, filtering, dries get Pa Li piperazines
Ketone crude product, the recrystallization temperature are 15~25 DEG C；
4) 9-hydroxy-risperidone crude product is dissolved in refining solvent and refines, decolourizes, be back to dissolved clarification, cooled, crystallization, obtain the pa of I crystal
Risperdal highly finished product.
2. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the dichloromethane and 9-hydroxy-risperidone
The volume mass ratio of solid is 20~60:1.
3. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the dichloromethane and 9-hydroxy-risperidone
The volume mass ratio of solid is 40:1.
4. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that drier used be selected from sodium sulphate or
Magnesium sulfate.
5. the process for purification of 9-hydroxy-risperidone according to claim 4, it is characterised in that the drier is selected from sodium sulphate.
6. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the dissolved clarification solvent and mashing solvent
It is each independently selected from N,N-dimethylformamide and/or DMAC N,N' dimethyl acetamide；The refining solvent is selected from ethanol.
7. the process for purification of 9-hydroxy-risperidone according to claim 6, it is characterised in that the dissolved clarification solvent and mashing solvent
Selected from N,N-dimethylformamide.
8. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the dissolved clarification temperature of the step 2) is
90-120℃；The dissolved clarification time is 5-30min；The volume of the dissolved clarification solvent is 5~10 times of 9-hydroxy-risperidone quality.
9. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the volume of the mashing solvent is pa
4~10 times of Risperdal quality.
10. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the volume of the refining solvent is
30~70 times of 9-hydroxy-risperidone quality.
11. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the discoloration method is activated carbon
Decolourize, maintain the reflux for 0.5~2h, activated carbon dosage is the 2%-10% of 9-hydroxy-risperidone quality.
12. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the temperature of refined crystallization for 10~
30℃。
13. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that the time 12 of refined crystallization~
24h。
14. the process for purification of 9-hydroxy-risperidone according to claim 1, it is characterised in that mashing temperature is 53~58 DEG C.
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