CN106632233A - Purification method for preparing high-purity duloxetine hydrochloride intermediate - Google Patents
Purification method for preparing high-purity duloxetine hydrochloride intermediate Download PDFInfo
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- CN106632233A CN106632233A CN201610824935.0A CN201610824935A CN106632233A CN 106632233 A CN106632233 A CN 106632233A CN 201610824935 A CN201610824935 A CN 201610824935A CN 106632233 A CN106632233 A CN 106632233A
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- C07—ORGANIC CHEMISTRY
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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Abstract
The invention relates to a purification method for preparing high-purity duloxetine hydrochloride intermediate (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine; (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is subjected to program-controlled recrystallization in a solvent to obtain a purified product, wherein the solvent is a mixed solvent of methanol and water, and program-controlled recrystallization includes the specific steps of heating and refluxing at 72-74 DEG C for 5-60 min, stirring at a speed of 0.5-15 r/min, cooling for crystallization at a temperature range of 72-80 DEG C for 120-150 min, and stirring at a speed of 6-15 r/min. The purification method is simple to perform, purity of isomer impurity is less than 0.03%, and the purification method is suitable for industrial production.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to one kind prepares high-purity duloxetine hydrochloride intermediate
The purification process of S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine.
Background technology
Duloxetine hydrochloride (Duloxetine hydrochloride), entitled (S)-N- methyl -3- (the 1- naphthalene oxygen of chemistry
Base) -3- (2- thienyls) -3- propylamin hydrochlorides, shown in structural formula such as formula (1),
It is the novel antidepressant researched and developed jointly by Lilly Co., Eli. and Bo Linyinge writing brushes company of Germany, and it is a kind of
Serotonin and norepinephrine reuptake double inhibitor (serotonin＆norepinephrine reuptake
Inhibitors, SNRIs), can produce in high dose and inhibitory action is absorbed to dopamine (DA), in September, 2002 obtains FDA approvals
In U.S.'s listing, for treating major depression and anxiety disorder, trade name " Cymbalta (glad hundred reach) ", in September, 2004 FDA
Ratify for alleviating central pain, such as Diabetes Peripheral neuropathy pain and women's fibromyalgia, in April, 2007 enters
China.Duloxetine is with 49.94 hundred million dollars of annual sales amount ranking the in global 20 best-selling prescription medicine lists in 2012
9, the annual sales amount with respect to 2011 has risen 16%.
At present, the preparation method for having document report of duloxetine hydrochloride has various, with 2- acetyl thiophenes as initiation material,
Mannich reactions are carried out with dimethylamine hydrochloride, then through reduction, (S)-(+)-mandelic acid splits, and obtains intermediate S-
(-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine, as shown in formula (5), is condensed in the presence of sodium hydride with 1- fluoronaphthalenes,
Jing N- demethylations obtain duloxetine hydrochloride after most, and this is most basic in industrialized production, the synthesis of technology relative maturity
Route.
Its reaction equation is as follows：
At present original grinds the duloxetine hydrochloride quality height in pharmaceutical factory, and single contaminant purity is less than 0.03%, and total impurity is pure
Degree is less than 0.1%.We have discovered that and be primarily due to impurity (S)-N- methyl -3- (1- naphthoxys) -3- (3- thienyls) -3-
Propylamin hydrochloride (as shown in formula (8)) is more than 0.03%, and it is miscellaneous to remove this isomers by refined duloxetine hydrochloride
Matter, this impurity is miscellaneous in N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine (as shown in formula (5)) by chiral raw material S- (-)-N
Matter S- (-)-N, N- dimethyl -3- hydroxyl -3- (3- thiophene) propylamine (such as formula (9)) are introduced.
Therefore, S- (-)-N, impurity S- in N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine (such as formula (5)) are prepared
(-)-N, N- dimethyl -3- hydroxyl -3- (3- thiophene) propylamine (such as formula (9)) purity is most important less than 0.03%, and exploitation is gone to work
The process for refining of industry becomes research hot topic.
The content of the invention
The technical problem to be solved is to overcome the deficiencies in the prior art, there is provided a kind of high-purity duloxetine salts
The purification process of hydrochlorate intermediate S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine, makes isomer impurities purity little
In 0.03%, industrialized production is suitable for.
To solve above technical problem, a kind of technical scheme that the present invention takes is：
A kind of purification process for preparing high-purity duloxetine hydrochloride intermediate, by degree Lip river of the structure as shown in formula (5)
Western spit of fland hydrochloride intermediate recrystallizes condition and obtains purified product by programme-control in a solvent,
Wherein, solvent is the mixed solvent of first alcohol and water, and programme-control recrystallization condition concrete operations are：First heat up back
Stream, reflux temperature is 72～74 DEG C, and return time is 5～60 minutes, and mixing speed is 0.5～15 rev/min, then cooling analysis
Crystalline substance, temperature setting range is 72 DEG C～8 DEG C, and the time is 120～150 minutes, and mixing speed is 6～15 revs/min.
Preferably, the volume ratio of first alcohol and water is 1:10.
Preferably, the weight of the initial duloxetine hydrochloride intermediate and the weight ratio of the solvent are 1:9～1：
10。
Due to the employing of above technical scheme, the present invention has the advantage that compared with prior art：
Duloxetine hydrochloride intermediate S- (-)-N of the present invention, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine it is pure
Change method, it is simple to operate, isomer impurities purity is made less than 0.03%, by being used as original with the high-purity intermediate after refined
Material, synthesis obtains highly purified duloxetine hydrochloride, and single contaminant purity is less than 0.03%, and total impurity purity is less than 0.1%,
Suitable industrialized production, quality index is fully equivalent to original and grinds pharmaceutical factory product quality.
Specific embodiment
The present invention is described in further details below in conjunction with specific embodiment.It should be understood that these embodiments are for saying
The bright basic principles, principal features and advantages of the present invention, and the present invention is not limited by the scope of following examples.Adopt in embodiment
Implementation condition can do further adjustment according to specific requirement, and not marked implementation condition is usually the bar in normal experiment
Part.
Embodiment 1：S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is purified
30.1g S- (-)-N are weighed, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is added in 500mL four-hole boiling flasks,
The volume ratio for measuring first alcohol and water is that 1/10 mixed solvent 293.7g is added, and warming-in-water flows back to 72 DEG C, mixing speed 5
Rev/min, stir 5 minutes, by adjusting temperature regulating device slow cooling crystallization, control 6 revs/min of rotating speed, interior temperature after 140 minutes
Suction filtration when being down to 8 DEG C, filter cake obtains 26.8g off-white powders in 45 DEG C of vacuum drying.Yield 89.1%, HPLC purity assays
For 99.9%, isomer impurities formula (9) purity is less than 0.03%.Using S- (-)-N of the preparation, N- dimethyl -3- hydroxyl -3-
(2- thiophene) propylamine in the presence of sodium hydride with 1- fluoronaphthalenes be condensed, most after Jing N- demethylations, be refining to obtain high-purity into after salt
Duloxetine hydrochloride, single contaminant purity is less than 0.03%.
Embodiment 2：The purifying of S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine
90.0g S- (-)-N are weighed, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is added in 1000mL four-hole boiling flasks,
The volume ratio for measuring first alcohol and water is that 1/10 mixed solvent 881.1g is added, and warming-in-water flows back to 74 DEG C, mixing speed 4
Rev/min, stir 5 minutes, by adjusting temperature regulating device slow cooling crystallization, control 6 revs/min of rotating speed, interior temperature after 150 minutes
Suction filtration when being down to 9 DEG C, filter cake obtains 81.9g off-white powders in 45 DEG C of vacuum drying.Yield 91.0%, HPLC purity assays
For 99.9%, isomer impurities formula (9) purity is less than 0.03%.Using S- (-)-N of the preparation, N- dimethyl -3- hydroxyl -3-
(2- thiophene) propylamine in the presence of sodium hydride with 1- fluoronaphthalenes be condensed, most after Jing N- demethylations, be refining to obtain high-purity into after salt
Duloxetine hydrochloride, single contaminant purity is less than 0.03%.
The present invention is described in detail above, the explanation of embodiment be only intended to help understand the method for the present invention and
Its core concept, its object is to allow the personage for being familiar with this art will appreciate that present disclosure and implement according to this, and
Can not be limited the scope of the invention with this.All equivalence changes made according to spirit of the invention or modification, all should contain
Cover within protection scope of the present invention.
Claims (3)
1. a kind of purification process for preparing high-purity duloxetine hydrochloride intermediate, it is characterised in that：By structure such as formula (5) institute
The duloxetine hydrochloride intermediate for showing recrystallizes condition and obtains purified product by programme-control in a solvent,
Wherein, solvent is the mixed solvent of first alcohol and water, and programme-control recrystallization condition concrete operations are：First temperature rising reflux, returns
Stream temperature is 72～74 DEG C, and return time is 5～60 minutes, and mixing speed is 0.5～15 rev/min, crystallization of then lowering the temperature, temperature
Degree setting range is 72 DEG C～8 DEG C, and the time is 120～150 minutes, and mixing speed is 6～15 revs/min.
2. it is according to claim 1 prepare high-purity duloxetine hydrochloride intermediate purification process, it is characterised in that：
The volume ratio of the first alcohol and water is 1:10.
3. it is according to claim 1 prepare high-purity duloxetine hydrochloride intermediate purification process, it is characterised in that：
The weight of the initial duloxetine hydrochloride intermediate is 1 with the weight ratio of the solvent:9～1：10.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113929657A (en) * | 2020-07-14 | 2022-01-14 | 浙江晖石药业有限公司 | Duloxetine hydrochloride impurity, its preparation and analysis method |
| CN115286613A (en) * | 2022-10-08 | 2022-11-04 | 潍坊市海欣药业有限公司 | Preparation method of duloxetine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007077580A2 (en) * | 2006-01-06 | 2007-07-12 | Msn Laboratories Limited | Improved process for pure duloxetine hydrochloride |
| CN101389621A (en) * | 2006-02-21 | 2009-03-18 | 特瓦制药工业有限公司 | Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate |
| CN102392059A (en) * | 2011-11-10 | 2012-03-28 | 连云港宏业化工有限公司 | Synthetic method of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine |
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2016
- 2016-09-14 CN CN201610824935.0A patent/CN106632233B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007077580A2 (en) * | 2006-01-06 | 2007-07-12 | Msn Laboratories Limited | Improved process for pure duloxetine hydrochloride |
| CN101389621A (en) * | 2006-02-21 | 2009-03-18 | 特瓦制药工业有限公司 | Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate |
| CN102392059A (en) * | 2011-11-10 | 2012-03-28 | 连云港宏业化工有限公司 | Synthetic method of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thiophene)propylamine |
Non-Patent Citations (1)
| Title |
|---|
| DISCLOSED ANONYMOUSLY: "Process for the purification of (S)-(+)-N,N-dimetil-3-(1-naphthalenoxy)-3-(2-tienyl) propanamine", 《IP.COM》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113929657A (en) * | 2020-07-14 | 2022-01-14 | 浙江晖石药业有限公司 | Duloxetine hydrochloride impurity, its preparation and analysis method |
| CN115286613A (en) * | 2022-10-08 | 2022-11-04 | 潍坊市海欣药业有限公司 | Preparation method of duloxetine hydrochloride |
| CN115286613B (en) * | 2022-10-08 | 2023-01-31 | 潍坊市海欣药业有限公司 | Preparation method of duloxetine hydrochloride |
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Effective date of registration: 20180727 Address after: 215151 No. 122, Hu Qing Road, Hu Guan Town, Suzhou, Jiangsu Applicant after: Suzhou Tianma Pharmaceutical Co., Ltd. Address before: 215000 Huayuan East Road, Mu Du Town, Wuzhong District, Suzhou, Jiangsu 199-1 Applicant before: Suzhou Tianma Fine Chemical Product Co., Ltd. |
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Address after: 215151 No. 122, Hu Qing Road, Hu Guan Town, Suzhou, Jiangsu Patentee after: Suzhou Zhengji Pharmaceutical Co.,Ltd. Address before: 215151 No. 122, Hu Qing Road, Hu Guan Town, Suzhou, Jiangsu Patentee before: SUZHOU TIANMA PHARMACEUTICAL Co.,Ltd. |
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