CN106831736A - A kind of method for preparing Paxil impurity - Google Patents
A kind of method for preparing Paxil impurity Download PDFInfo
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- CN106831736A CN106831736A CN201710081183.8A CN201710081183A CN106831736A CN 106831736 A CN106831736 A CN 106831736A CN 201710081183 A CN201710081183 A CN 201710081183A CN 106831736 A CN106831736 A CN 106831736A
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- paxil
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- 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
- C07D405/14—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 three or more hetero rings
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Abstract
The invention provides a kind of easy method for preparing Paxil impurity, including by Paxil or its salt in action solvent, under acid system with aldehyde solution reaction and be isolated to the methylene Paxil dimer of target product 4,4 '.Paxil impurity preparation method provided by the present invention is simple to operate, and product yield is high, purity is good and low cost.
Description
Technical field
The present invention relates to medical manufacturing technology field, more particularly to a kind of side for rapidly and efficiently preparing Paxil dimer
Method.
Background technology
Paxil (paroxetine), chemical name：(3S, 4S) -4- (4- fluorophenyls) -3- [[(3,4- methylene epoxide) benzene
Epoxide] methyl] piperidines, molecular formula C19H20FNO3, molecular weight is 329.36, and its structural formula is as follows：
Paxil trade name Sai Erte (English names), 1991 the U.S. listing, 1996
Discussion on Chinese Listed, for treating depression, is adapted to patients with depression of the treatment with anxiety disorder, acts on faster than TCAs, and at a specified future date
Curative effect is better than imipramine, also can be used for the former treatment for fearing obstacle, social phobia and obsession.Because advanced information society work and
Rhythm of life causes stress excessive soon, has a depression and have the number of Depression trend in recent years constantly rising, therefore, Paro
Xi Ting and its related preparations product have broad application prospects and researching value.
During Paxil finished product is prepared, it has been found that 4 in finished product, 4 '-methylene Paxil dimer
(impurity F is named as in European Pharmacopoeia) is one of major impurity in Paxil production process, and its structural formula is as follows：
Content of the impurity in Paxil finished product is relatively large, generally in 0.05-0.10% or so, and its
Finished product Crystallization Procedure is difficult to remove；In product inspection, it would be desirable to this impurity in finished product is carried out with the standard items of the impurity
Position and quantitative, be so accomplished by using substantial amounts of contamination levels product, and the standard items can only be from Paxil mother liquor at present
Middle separation, because the impurity content is less than 0.5% in mother liquor, separating effect is poor, it is necessary to repeatedly be enriched with preparation with liquid phase is prepared
This contamination levels product can be just obtained, overall yield is less than 0.1%.As can be seen here, the standard items quantity for obtaining in aforementioned manners
It is very limited, therefore research prepares the method for this impurity very with practical significance.
We have consulted all open source informations on 4,4 '-methylene Paxil dimer, except in European Pharmacopoeia
In be included by outside the structural information of impurity F, only in document CHIRALITY, 2003,15 (7):Mentioned in 600-604 one on
The report of this impurity, this article develops a kind of separation 4 kinds of Paxil chiral isomers, methoxyl group Paxils and 4,4 '-Asia
Paroxetine methanesulfonate dimer etc., by optimizing different chiral column and mobile phases, is finally established about the analysis method of material
Analysis method, it is ensured that these impurity can be efficiently separated, but simply refer to impurity structure in this article, this is not had been reported that
How impurity is largely prepared.
The content of the invention
The invention provides a kind of easy preparation 4, the method for 4 '-methylene Paxil dimer, its structural formula is such as
Shown in lower,
Comprise the following steps：
A () adds the salt that Paxil or Paxil and acid are formed in action solvent, be subsequently added into appropriate organic
Acid or inorganic acid, add appropriate aldehyde solution, and the aldehyde is selected from：Formaldehyde, two polyformaldehyde, metaformaldehyde or paraformaldehyde；
B () is heated to 35~100 DEG C and reacts 0.5~36 hour；
C () then separates and obtains target product 4,4 '-methylene Paxil dimer.
Preferably, step (a) Paxil is selected from paroxetine hydrochloride or Paxil first sulphur with the salt that acid is formed
Hydrochlorate.
Preferably, the action solvent described in step (a) is water, and polar organic solvent, or water is combined with polar organic solvent
Mixture.It is sub- that the polar organic solvent is selected from acetonitrile, methyl alcohol, ethanol, isopropanol, N,N-dimethylformamide, dimethyl
Sulfone.
Preferably, the mol ratio 0.1~10 of step (a) organic acid or inorganic acid and Paxil molecule：1, enter one
Step is preferably 0.5~2.5：1.Step (a) organic acid or inorganic acid are selected from formic acid, acetic acid, watery hydrochloric acid, dilute sulfuric acid or trifluoro
Acetic acid.
Preferably, step (a) aldehyde and the mol ratio of Paxil molecule are 0.2~10：1, preferably 1~5：1.Institute
The aldehyde solution more preferably formalin stated.
Preferably, the heating-up temperature described in step (b) is 55~75 DEG C, and the reaction time is 12~24 hours.
Preferably, the separation method described in step (c) includes thin-layered chromatography, column chromatography and preparative liquid chromatography.
Through HPLC purity detectings, its content is about 35-65% to the completely reacted sample solution of step (b).
Step (c) preparative separation target product well out detects its purity up to more than 98.8% through HPLC.
Target product prepared by the present invention determines that its structure is through proton nmr spectra and carbon spectrum detection by structural characterization
4,4 '-methylene Paxil dimer is shown in Fig. 1 and Fig. 2, and compound number is shown in Fig. 3.
The proton nmr spectra parsing of the target product that table 1 is prepared for the present invention.
Table 1
| Proton type | Chemical shift (ppm) | Peak type | Ownership H numberings | Proton number |
| C-H | 1.78,2.02 | m | 8/8' | 4 |
| C-H | 2.49 | m | H-11/11' | 2 |
| C-H | 2.65 | t | H-7/7' | 2 |
| C-H | 2.89,3.38 | m | H-9/9' | 4 |
| C-H | 2.93,3.51 | m | H-10/10' | 4 |
| C-H | 3.44,3.64 | m | H-12/12' | 4 |
| C-H | 3.72 | s | H-20 | 2 |
| C-H | 5.89 | s | H-16/16' | 4 |
| C-H | 6.51 | s | H-14/14' | 2 |
| C-H | 6.53 | s | H-18/18' | 2 |
| C-H | 7.08 | d | H-3/3'/5/5' | 4 |
| C-H | 7.09 | d | H-2/2'/6/6' | 4 |
The target product carbon-13 nmr spectra parsing that table 2 is prepared for the present invention.
Table 2
Target product prepared by this hair is combined instrument (HPLC-HRMS) and detects through efficient liquid phase-high resolution mass spectrum, its [M+H+] accurate molecular weight be 671.2930, see Fig. 4.
The following following advantage of the method for preparation 4,4 '-methylene Paxil dimer that the present invention is provided：
1. reaction dissolvent be other polar organic solvents such as water, methyl alcohol, ethanol or polar organic solvent and water mixing it is molten
Agent, be not directed to be of little use or costliness organic solvent, product chiral centre stabilization, will not occur isomery in acid condition
Change.
2. by target product 4,4 '-methylene Paxil dimer content in the reaction solution of reaction up to 35-65%
Between, remaining component is mainly the complete Paxil of unreacted, and separating difficulty is substantially reduced, and yield is greatly improved；As right
Than original preparation method raw material Paxil mother liquor target impurity content only has 0.5% or so, and mother liquor also has more a lot
The interference impurity of individual similar amount.
3. in whole preparation process, without using special installation and raw material, manufacturing cycle is shorter, it is easy to operate, cost
It is low.
Brief description of the drawings
The proton nmr spectra spectrogram (1H-NMR) of target product prepared by Fig. 1 present invention.
The carbon-13 nmr spectra spectrogram (13C-NMR) of target product prepared by Fig. 2 present invention.
The formula atom numbering of target product prepared by Fig. 3 present invention.
The efficient liquid phase of target product prepared by Fig. 4 present invention-high resolution mass spectrum combination spectrogram.
Specific embodiment
Embodiment 1：
By in 1.0g paroxetine hydrochlorides addition 12ml water, the hydrochloric acid of 0.1ml 36% is added, stirring then adds to after dissolving
Enter in the formalins of 1.0ml 30%, be heated to 60 DEG C and react 18 hours, reaction solution is monitored with HPLC, targeted
The purity of compound is 65%, and then with column chromatography method, [HP-Silica purification on normal-phase silica gel, eluant, eluent is dichloromethane：Methyl alcohol=
(10:1, V/V] isolated 4,4 '-methylene Paxil dimer 0.48g, HPLC purity are carried out to target product
99.1%, yield 52%.
Embodiment 2：
By in 1.0g paroxetine hydrochlorides addition 10ml water, 0.2ml glacial acetic acid is added, stirring is subsequently added into after dissolving
In the formalins of 0.8ml 30%, it is heated to 60 DEG C and reacts 18 hours, reaction solution is monitored with HPLC, target chemical combination
The purity of thing is 55%, then adjusts reaction solution pH to 8 or so with sodium carbonate liquor, freezes and removes moisture, and the solid for obtaining is used
[HP-Silica purification on normal-phase silica gel, eluant, eluent is dichloromethane to column chromatography method：Methyl alcohol=(20:1, V/V)] target product is carried out
Isolated 4,4 '-methylene Paxil dimer 0.44g, HPLC purity 99.9%, yield 48%.
Embodiment 3：
1.0g paroxetine hydrochlorides are added into 24ml water-methanol mixture (water：Methyl alcohol volume ratio is 1:1) in, add
0.3ml trifluoroacetic acids, stirring is subsequently added into 0.25g metaformaldehyde solids to after dissolving, and is heated to 60 DEG C of reactions 24 small
When, reaction solution is monitored with HPLC, the purity of target compound is 64%, then adjusts reaction solution pH with sodium carbonate liquor
To 8 or so, freeze and remove solvent, [HP-Silica purification on normal-phase silica gel, eluant, eluent is dichloromethane to the solid for obtaining with column chromatography method
Alkane：Methyl alcohol=(15:1, V/V) isolated 4,4 '-methylene Paxil dimer 0.51g, HPLC] are carried out to target product
Purity 99.2%, yield 56%.
Embodiment 4：
1.0g methanesulfonic acids Paxil is added into 18ml water-dimethyl sulfoxide mixed liquor (water：Dimethyl sulfoxide volume ratio is 1:
1) 0.35ml glacial acetic acid, is added, stirring is subsequently added into the formalins of 0.9ml 30% to after dissolving, and is heated to 60 DEG C
Reaction 18 hours, is monitored with HPLC to reaction solution, and the purity of target compound is 42%, is then adjusted with sodium carbonate liquor
Reaction solution pH is freezed and is removed solvent, the solid for obtaining column chromatography method (model to 8 or so：HP-Silica purification on normal-phase silica gel, washes
De- agent is dichloromethane：Methyl alcohol=20:1, V/V) target product separate and obtain 4,4 '-methylene Paxil dimer
0.28g, HPLC purity 99.1%, yield 35%.
Embodiment 5：
1.0g methanesulfonic acids Paxil is added into 24ml water-ethanol mixed liquor (water：Ethanol volume ratio is 1:1), add
0.8ml trifluoroacetic acids, stirring is subsequently added into the formalins of 0.7ml 30% to after dissolving, and is heated to 70 DEG C of reactions 18
Hour, reaction solution is monitored with HPLC, the purity of target compound is 39%, then adjusts reaction solution with sodium carbonate liquor
PH is freezed and is removed solvent, the solid for obtaining column chromatography method (model to 8 or so：HP-Silica purification on normal-phase silica gel, eluant, eluent is
Dichloromethane：Methyl alcohol=20:1, V/V) isolated 4,4 '-methylene Paxil dimer 0.25g are carried out to target product,
HPLC purity 99.0%, yield 32%.
Embodiment 6：
By in 1.0g Paxils free alkali addition 12ml water, 0.4ml formic acid is added, stirring is subsequently added into after dissolving
In the formalins of 1.2ml 30%, it is heated to 75 DEG C and reacts 12 hours, reaction solution is monitored with HPLC, target chemical combination
The purity of thing is 52%, then adjusts reaction solution pH to 8 or so with sodium carbonate liquor, freezes and removes moisture, and the solid for obtaining is used
Column chromatography method (model：HP-Silica purification on normal-phase silica gel, eluant, eluent is dichloromethane：Methyl alcohol=20:1, V/V) to target product
Carry out isolated 4,4 '-methylene Paxil dimer 0.47g, HPLC purity 99.2%, yield 46%.
Embodiment 7：
By in 200mg paroxetine hydrochlorides addition 12ml methyl alcohol, 0.1ml glacial acetic acid is added, stirring then adds to after dissolving
Enter in the formalins of 0.15ml 30%, be heated to 65 DEG C and react 14 hours, reaction solution is monitored with HPLC, target
The purity of compound is 38%, then adjusts reaction solution pH to 8 or so with sodium carbonate liquor, freezes and removes solvent, and what is obtained consolidates
Body thin-layer chromatography method (model：GF254 purification on normal-phase silica gel, eluant, eluent is dichloromethane：Methyl alcohol=10:1, V/V) target is produced
Thing carries out isolated 4,4 '-methylene Paxil dimer 57mg, HPLC purity 99.0%, yield 31%.
Embodiment 8：
By in 200mg paroxetine hydrochlorides addition 12ml water, 0.15ml trifluoroacetic acids are added, after stirring to dissolving, then
Add in the formalins of 0.2ml 30%, be heated to 55 DEG C and react 24 hours, reaction solution is monitored with HPLC, target
The purity of compound is 62%, then adjusts reaction solution pH to 8 or so with sodium carbonate liquor, freezes and removes moisture, and what is obtained consolidates
Body thin-layer chromatography method (model：GF254 purification on normal-phase silica gel, eluant, eluent is dichloromethane：Methyl alcohol=12:1, V/V) target is produced
Thing carries out isolated 4,4 '-methylene Paxil dimer 90mg, HPLC purity 99.6%, yield 49%.
It is above-mentioned that only the preferred embodiments of the present invention are elaborated, it is any right the invention is not restricted to above-described embodiment
Conversion of the invention and modification all belong to protection scope of the present invention.
Claims (10)
1. one kind 4, the preparation method of 4 '-methylene Paxil dimer, its structural formula is as follows,
Comprise the following steps：
(a) will during Paxil or Paxil and the salt that acid is formed adds action solvent, be subsequently added into appropriate organic acid or
Inorganic acid, adds appropriate aldehyde solution, and the aldehyde is selected from：Formaldehyde, two polyformaldehyde, metaformaldehyde or paraformaldehyde；
B () is heated to 35~100 DEG C and reacts 0.5~36 hour；
C () then separates and obtains target product 4,4 '-methylene Paxil dimer.
2. preparation method according to claim 1, it is characterised in that：The salt that step (a) Paxil is formed with acid is selected from
Paroxetine hydrochloride or salts of paroxetine.
3. preparation method according to claim 1, it is characterised in that：Action solvent described in step (a) is water, and polarity has
Machine solvent, or the mixture that water is combined with polar organic solvent.
4. preparation method according to claim 3, it is characterised in that：Step (a) polar organic solvent be selected from acetonitrile,
Methyl alcohol, ethanol, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide (DMSO).
5. preparation method according to claim 1, it is characterised in that：Step (a) organic acid or inorganic acid and Paro
The mol ratio 0.1~10 of western spit of fland molecule：1, preferably 0.5~2.5：1.
6. preparation method according to claim 1, it is characterised in that：Step (a) organic acid or inorganic acid are selected from first
Acid, acetic acid, watery hydrochloric acid, dilute sulfuric acid or trifluoroacetic acid.
7. preparation method according to claim 1, it is characterised in that：Step (a) aldehyde rubs with Paxil molecule
You are than being 0.2~10：1, preferably 1~5：1.
8. preparation method according to claim 1, it is characterised in that：Aldehyde solution described in step (a) is formalin.
9. preparation method according to claim 1, it is characterised in that：Heating-up temperature described in step (b) is 55~75 DEG C,
Reaction time is 12~24 hours.
10. preparation method according to claim 1, it is characterised in that：Separation method described in step (c) includes thin layer color
Spectrometry, column chromatography and preparative liquid chromatography.
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| CN201710081183.8A CN106831736A (en) | 2017-02-15 | 2017-02-15 | A kind of method for preparing Paxil impurity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325034A (en) * | 2017-06-23 | 2017-11-07 | 浙江华海药业股份有限公司 | A kind of method for preparing Ropinirole dimer |
| CN113045545A (en) * | 2021-03-23 | 2021-06-29 | 济南同路医药科技发展有限公司 | Preparation method of mizolastine related substance A |
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|---|---|---|---|---|
| CN1341113A (en) * | 1999-02-23 | 2002-03-20 | 里科达蒂化学药物公司 | Process for production of paroxetine |
| CN1179961C (en) * | 1997-04-28 | 2004-12-15 | 安瑟希夫制药公司 | Sulfonamides for treatment of endothelin-mediated disorders |
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN104447714A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Production process of paroxetine hydrochloride |
-
2017
- 2017-02-15 CN CN201710081183.8A patent/CN106831736A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1179961C (en) * | 1997-04-28 | 2004-12-15 | 安瑟希夫制药公司 | Sulfonamides for treatment of endothelin-mediated disorders |
| CN1341113A (en) * | 1999-02-23 | 2002-03-20 | 里科达蒂化学药物公司 | Process for production of paroxetine |
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN104447714A (en) * | 2014-11-18 | 2015-03-25 | 成都医路康医学技术服务有限公司 | Production process of paroxetine hydrochloride |
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| Title |
|---|
| EDQM: "《European Pharmacopoeia 7.0》", 31 January 2011 * |
| 潘才元著: "《高分子化学》", 31 July 2012, 合肥 中国科学技术大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325034A (en) * | 2017-06-23 | 2017-11-07 | 浙江华海药业股份有限公司 | A kind of method for preparing Ropinirole dimer |
| CN113045545A (en) * | 2021-03-23 | 2021-06-29 | 济南同路医药科技发展有限公司 | Preparation method of mizolastine related substance A |
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