CN104447714A - Production process of paroxetine hydrochloride - Google Patents
Production process of paroxetine hydrochloride Download PDFInfo
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- CN104447714A CN104447714A CN201410658867.6A CN201410658867A CN104447714A CN 104447714 A CN104447714 A CN 104447714A CN 201410658867 A CN201410658867 A CN 201410658867A CN 104447714 A CN104447714 A CN 104447714A
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- CN
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- Prior art keywords
- paroxetine hydrochloride
- paroxetine
- reaction
- production technique
- vinyl acetate
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- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960005183 paroxetine hydrochloride Drugs 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000007670 refining Methods 0.000 claims abstract description 9
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 8
- 230000017858 demethylation Effects 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- AGQKYUPKNZGEQS-UHFFFAOYSA-N C(C)(=O)OC=C.C(O)(=O)Cl Chemical compound C(C)(=O)OC=C.C(O)(=O)Cl AGQKYUPKNZGEQS-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000011549 crystallization solution Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000000843 powder Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- MOJZPKOBKCXNKG-YJBOKZPZSA-N N-methylparoxetine Chemical compound C1([C@@H]2CCN(C[C@H]2COC=2C=C3OCOC3=CC=2)C)=CC=C(F)C=C1 MOJZPKOBKCXNKG-YJBOKZPZSA-N 0.000 abstract 1
- -1 compound paroxetine hydrochloride Chemical class 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 abstract 1
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 11
- 229960002296 paroxetine Drugs 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000003153 cholinolytic effect Effects 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010010 raising Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a production process of paroxetine hydrochloride and belongs to the technical field of medicines. The compound paroxetine hydrochloride has the following structure as shown in the specification. According to the invention, the demethylation reaction of N-methyl paroxetine is mainly studied in detail and the refining process of paroxetine hydrochloride is relevantly inspected. Industrially available vinyl chloroformate is adopted as a demethylation reagent, reaction conditions are mild and the total yield is above 90%. By adopting acetone of which the use amount is 10 times amount of a paroxetine hydrochloride crude product as a refining solvent, a majority of impurities can be well removed to obtain pure white crystalline powder of which the content is above 99.8%.
Description
Technical field
The invention belongs to medical art, particularly a kind of production technique of paroxetine hydrochloride.
Background technology
Paroxetine, (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy group) phenoxy group] methyl]-piperidines.This product is a kind of selectivity 5-HT reuptake inhibitor, during common dose, has no significant effect other mediators.Improve the concentration of 5-HT in nerve synapse gap by stoping absorbing again of 5-HT, thus produce antidepressant effect.Paroxetine plays drug effect by suppressing the former 5-TH re-uptake of cranial nerve, and selectivity comparatively fluoxetine, Sertraline or chlorimipramine is strong.Low to the avidity of cholinergic, histamine or adrenergic receptor, cholinolytic, cardiovascular adverse effects are less than tricyclic antidepressants.Without cognitive function or psychomotor disturbance.Short-term or long-term treatment hematology, biological chemistry and urinary system parameter, without special change.
US Patent No. 4007196 first disclose this compound with and uses thereof, European patent EP 0223403 again discloses its synthetic route subsequently.But the difficult point that the committed step process from N-paroxetine methanesulfonate to paroxetine is synthesized always.Although relevant patent documentation is also studied this reaction, totally all present yield on the low side, the problems such as the reaction of N-paroxetine methanesulfonate is incomplete.
Summary of the invention
Main purpose of the present invention is for the N-paroxetine methanesulfonate reaction existed in prior art not exclusively, and then causes the problem that paroxetine hydrochloride yield is low, provides the new production technique that a kind of paroxetine hydrochloride yield is high.The present invention has also carried out the screening operation of system to the process for refining of paroxetine crude product simultaneously
In order to realize foregoing invention object, the invention provides following technical scheme:
A production technique for paroxetine hydrochloride, comprises the following steps:
N-paroxetine methanesulfonate and demethylation reagent are reacted, hydrolysis, hcl acidifying salify obtains paroxetine hydrochloride crude product, then obtains by crystal refining the paroxetine hydrochloride finished product meeting medicinal standard.Its reaction equation is as follows:
Described demethylation reagent is chloroformic acid vinyl acetate, reacts for anhydrous response, and reaction solvent is toluene, and the reagent of hydrolysis reaction is potassium hydroxide, and hydrolysis time is 20 ~ 24 hours, and acidizing reagent is the hydrochloric acid of 8-10N.
The mol ratio of described N-paroxetine methanesulfonate and chloroformic acid vinyl acetate is 1:1.5 ~ 1:2, according to reaction ratio design, demethylation reagent is slightly excessive, ensures the complete of reaction, prevent the N-paroxetine methanesulfonate not having demethylating because of unreacted from becoming impurity, affect later crystallization purification process.The ingredient proportion of N-paroxetine methanesulfonate and toluene is 1:8 ~ 1:15.
The reaction times of N-paroxetine methanesulfonate and chloroformic acid vinyl acetate is 6 ~ 8 hours, preferably 7 ~ 8 hours.Temperature of reaction is 80 ~ 90 DEG C, preferred 83-88 DEG C, ensures being swift in response completely of chloroformic acid vinyl acetate.
Described hydrolysis drops into potassium hydroxide and is hydrolyzed, and it is 2 ~ 3 times of equivalents that potassium hydroxide feeds intake, and hydrolysis time is 20 ~ 48 hours, is preferably 20 ~ 24 hours.After being hydrolyzed, adding salt acid for adjusting pH, solution ph is adjusted to 1 ~ 3, make paroxetine change paroxetine hydrochloride into.
Obtain meeting in the paroxetine hydrochloride Finished product processThe of medicinal standard at crystal refining, the crystallization solution of paroxetine hydrochloride crude product refining process is acetone.The charging capacity of acetone is 10 ~ 15 times of equivalents, preferably 10 times amount.Appropriate acetone solution crude product paroxetine can ensure dissolution rate, raises the efficiency, and the concentration simultaneously also controlling paroxetine in the solution after dissolving completely is suitable for, and quick and completely can separate out, reduce unnecessary crystallization loss when decrease temperature crystalline.
The temperature of the molten clear paroxetine crude product of acetone is 60 ~ 70 DEG C, should avoid too high molten clear temperature, reduce unnecessary side reaction, avoids going bad and brings new impurity.Preferably, crude product complete molten clear after add 2% ~ 5% activated carbon decolorizing 30 ~ 60 minutes, preferred, add reflux decolour after gac.
Crude product paroxetine, after acetone treatment, carries out crystallization, and recrystallization temperature is 0 ~ 5 DEG C, recrystallization temperature should not be too low, although lower recrystallization temperature can accelerate the speed of separating out of paroxetine, foreign matter content in the refining paroxetine obtained also can be caused greatly to increase, most preferably 0-4 DEG C.
Compared with prior art, beneficial effect of the present invention:
Paroxetine hydrochloride production technique of the present invention, by adopting chloroformic acid vinyl acetate as demethylation reagent, and filtered out concrete processing parameter, all very large raisings of the yield of reaction and purity.And in follow-up treating process, crystallization solvent, crystallization condition have done optimizing and revising of system, improve productive rate and the purity of paroxetine hydrochloride, 20 ~ 25% are improved compared to prior art total recovery, and the purity of product also has great lifting, top grade purity can be reached, ensure stay in grade and the safety control of pharmaceutical preparation.
The chloroformic acid vinyl acetate that the present invention adopts industrialization to be easy to get is demethylation reagent, and reaction conditions is gentle, and total recovery reaches more than 90%.And then after employing acetone refining, can be good at getting rid of most of impurity, obtain lily crystal powder, paroxetine hydrochloride content reaches more than 99.8%.
Embodiment
Below in conjunction with test example and embodiment, the present invention is described in further detail.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on content of the present invention all belong to scope of the present invention.Liquid reactions ratio of reagents not specified in the present invention is volume ratio.Lexical or textual analysis: the dilute hydrochloric acid of 1N hydrochloric acid=1mol/L.The charging capacity of acetone is 10 ~ 15 times of equivalents, relative to 10 times of volume mass ratios (ml/g) of paroxetine hydrochloride crude product.
Embodiment 1
N-paroxetine methanesulfonate 20g, toluene 200ml is added in there-necked flask, the mixed solution of chloroformic acid vinyl acetate 9.4g and toluene 20ml is slowly dripped under room temperature, drip off rear 80 DEG C of reactions TLC (methylene dichloride: methyl alcohol=5:1) monitoring in 6 hours until react completely, 200ml water is added in reaction solution, stir, layering, retain organic layer, water layer with 100ml methylbenzene extraction once, merge organic layer, use 200ml water washing respectively three times.Get organic layer concentrating under reduced pressure, obtain oily matter 22.2g, yield 95%.
Embodiment 2
The oily matter 20g that embodiment 1 obtains is added, toluene 200ml, potassium hydroxide 6g in there-necked flask, 80 DEG C are reacted 24 hours, and TLC monitoring, to react completely (methylene dichloride: ethyl acetate=5:1), adds water stratification, collected organic layer, water layer with 100ml methylbenzene extraction once, merge organic layer, wash three times with 200ml respectively, get under organic layer stirs and add concentrated hydrochloric acid, a large amount of light yellow crystal is had to separate out, suction filtration, dry faint yellow paroxetine hydrochloride crude product 18g, yield 95%.
Embodiment 3
Paroxetine hydrochloride crude product 18g is added in there-necked flask, adds the acetone of 180ml.Heat up 66 DEG C, add the gac of 2%, reflux decolour 30 minutes.Suction filtration, filtrate stirring is cooled to 0 DEG C, suction filtration, dry paroxetine hydrochloride finished product 16.5g.
Claims (5)
1. a production technique for paroxetine hydrochloride, comprises the following steps:
N-paroxetine methanesulfonate and chloroformic acid vinyl acetate are reacted, then be hydrolyzed, acidifying salify obtains paroxetine hydrochloride crude product, then obtains by crystal refining the paroxetine hydrochloride finished product meeting medicinal standard, its reaction equation is as follows:
2. the production technique of paroxetine hydrochloride according to claim 1, it is characterized in that: described demethylation reagent is chloroformic acid vinyl acetate, reaction is anhydrous response, reaction solvent is toluene, the reagent of hydrolysis reaction is potassium hydroxide, hydrolysis time is 20 ~ 24 hours, and acidizing reagent is the hydrochloric acid of 10N.
3. the production technique of paroxetine hydrochloride according to claim 1, is characterized in that: described crystallization solution is acetone.
4. the production technique of paroxetine hydrochloride according to claim 2, is characterized in that: the mol ratio of described N-paroxetine methanesulfonate and chloroformic acid vinyl acetate is 1:1.5 ~ 1:2.
5. the production technique of paroxetine hydrochloride according to claim 3, is characterized in that: the charging capacity of acetone is 10 ~ 15 times of equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410658867.6A CN104447714A (en) | 2014-11-18 | 2014-11-18 | Production process of paroxetine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410658867.6A CN104447714A (en) | 2014-11-18 | 2014-11-18 | Production process of paroxetine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104447714A true CN104447714A (en) | 2015-03-25 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410658867.6A Pending CN104447714A (en) | 2014-11-18 | 2014-11-18 | Production process of paroxetine hydrochloride |
Country Status (1)
| Country | Link |
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| CN (1) | CN104447714A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831736A (en) * | 2017-02-15 | 2017-06-13 | 浙江华海药业股份有限公司 | A kind of method for preparing Paxil impurity |
| CN116348110A (en) * | 2020-10-12 | 2023-06-27 | 浙江华海药业股份有限公司 | Paroxetine hydrochloride purification method |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223403A2 (en) * | 1985-10-25 | 1987-05-27 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
| WO2002006275A1 (en) * | 2000-07-17 | 2002-01-24 | Smithkline Beecham P.L.C. | Novel processes for the preparation of 4-phenylpiperidine derivatives |
| CN101560207A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医学技术有限公司 | Preparation method of paroxetine hydrochloride and intermediate thereof |
| CN102718756A (en) * | 2012-07-02 | 2012-10-10 | 浙江尖峰药业有限公司 | Paroxetine hydrochloride compound and synthetic method thereof |
-
2014
- 2014-11-18 CN CN201410658867.6A patent/CN104447714A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223403A2 (en) * | 1985-10-25 | 1987-05-27 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| EP0810225A1 (en) * | 1996-05-31 | 1997-12-03 | Asahi Glass Company Ltd. | Process for producing paroxetine |
| WO2002006275A1 (en) * | 2000-07-17 | 2002-01-24 | Smithkline Beecham P.L.C. | Novel processes for the preparation of 4-phenylpiperidine derivatives |
| CN101560207A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医学技术有限公司 | Preparation method of paroxetine hydrochloride and intermediate thereof |
| CN102718756A (en) * | 2012-07-02 | 2012-10-10 | 浙江尖峰药业有限公司 | Paroxetine hydrochloride compound and synthetic method thereof |
Non-Patent Citations (1)
| Title |
|---|
| MIREIA SEGURA，ET AL.: ""Synthesis of the major metabolites of Paroxetine"", 《BIOORGANIC CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831736A (en) * | 2017-02-15 | 2017-06-13 | 浙江华海药业股份有限公司 | A kind of method for preparing Paxil impurity |
| CN116348110A (en) * | 2020-10-12 | 2023-06-27 | 浙江华海药业股份有限公司 | Paroxetine hydrochloride purification method |
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Application publication date: 20150325 |