CN106632233B - A kind of purification process preparing high-purity duloxetine hydrochloride intermediate - Google Patents
A kind of purification process preparing high-purity duloxetine hydrochloride intermediate Download PDFInfo
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- CN106632233B CN106632233B CN201610824935.0A CN201610824935A CN106632233B CN 106632233 B CN106632233 B CN 106632233B CN 201610824935 A CN201610824935 A CN 201610824935A CN 106632233 B CN106632233 B CN 106632233B
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- duloxetine hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Abstract
The present invention relates to high-purity duloxetine hydrochloride intermediate S- (-)-N, the purification process of N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine, by S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine recrystallizes condition by process control in a solvent and obtains purified product, wherein, solvent is the mixed solvent of first alcohol and water, process control recrystallizes condition concrete operations are as follows: first temperature rising reflux, reflux temperature is 72~74 DEG C, return time is 5~60 minutes, mixing speed is 0.5~15 rev/min, then cool down crystallization, temperature setting range is 72 DEG C~8 DEG C, time is 120~150 minutes, mixing speed is 6~15 revs/min.Purification process of the present invention, it is easy to operate, make isomer impurities purity less than 0.03%, is suitable for industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of to prepare high-purity duloxetine hydrochloride intermediate
The purification process of S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine.
Background technique
Duloxetine hydrochloride (Duloxetine hydrochloride), entitled (S)-N- methyl -3- (the 1- naphthalene oxygen of chemistry
Base) -3- (2- thienyl) -3- propylamin hydrochloride, 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 brush company, Germany, it is a kind of
Serotonin and norepinephrine reuptake double inhibitor (serotonin&norepinephrine reuptake
Inhibitors, SNRIs), it can be generated in high dose and inhibiting effect is absorbed to dopamine (DA), in September, 2002 obtains FDA approval
It is listed in the U.S., for treating major depression and anxiety disorder, trade name " Cymbalta (glad hundred reach) ", the FDA of in September, 2004
Approval enters for alleviating central pain, such as Diabetes Peripheral neuropathy pain and women's fibromyalgia, in April, 2007
China.Duloxetine is in global 20 best-selling prescription medicine lists in 2012 with 49.94 hundred million dollars of annual sales amount ranking the
9, opposite 2011 annual sales amounts have increased 16%.
Currently, duloxetine hydrochloride has there are many preparation methods reported in the literature, using 2- acetyl thiophene as starting material,
It carries out Mannich with dimethylamine hydrochloride to react, then by reduction, (S)-(+)-mandelic acid is split, and obtains intermediate S-
(-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is condensed in the presence of sodium hydride with 1- fluoronaphthalene as shown in formula (5),
Duloxetine hydrochloride most is obtained through N- demethylation afterwards, this is most basic in industrialized production, the synthesis of technology relative maturity
Route.
Its reaction equation is as follows:
Original grinds the duloxetine hydrochloride quality height in pharmaceutical factory at present, and for single contaminant purity less than 0.03%, total impurity is pure
Degree is less than 0.1%.We have discovered that being primarily due to impurity (S)-N- methyl -3- (1- naphthoxy) -3- (3- thienyl) -3-
Propylamin hydrochloride (as shown in formula (8)) is greater than 0.03%, and not can be removed this isomers miscellaneous by purification duloxetine hydrochloride
Matter, this impurity is by miscellaneous in chiral raw material S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine (as shown in formula (5))
Matter S- (-)-N, N- dimethyl -3- hydroxyl -3- (3- thiophene) propylamine (such as formula (9)) introduces.
Therefore, impurity S- in S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine (such as formula (5)) is 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.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a kind of high-purity duloxetine salts
The purification process of hydrochlorate intermediate S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine, keeps isomer impurities purity small
In 0.03%, it is applicable in industrialized production.
In order to solve the above technical problems, a kind of technical solution that the present invention takes is:
Structure is spent Lip river as shown in formula (5) by a kind of purification process for preparing high-purity duloxetine hydrochloride intermediate
Western spit of fland hydrochloride intermediate recrystallizes condition by process control in a solvent and obtains purified product,
Wherein, solvent is the mixed solvent of first alcohol and water, and process control recrystallizes condition concrete operations are as follows: first heats up back
Stream, reflux temperature are 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 are 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 use of above technical scheme, the invention has the following advantages over the prior art:
Duloxetine hydrochloride intermediate S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine of the present invention it is pure
Change method, it is easy to operate, make isomer impurities purity less than 0.03%, by using the high-purity intermediate after purification as original
Material, synthesis obtain the duloxetine hydrochloride of high-purity, single contaminant purity less than 0.03%, total impurity purity less than 0.1%,
It is suitble to 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 by the scope limitation of following embodiment.It is adopted in embodiment
Implementation condition can do further adjustment according to specific requirement, and the implementation condition being not specified is usually the item in routine experiment
Part.
The purifying of embodiment 1:S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine
30.1g S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is weighed to be added in 500mL four-hole boiling flask,
The mixed solvent 293.7g that the volume ratio for measuring first alcohol and water is 1/10 is added, and warming-in-water is to 72 DEG C, reflux, mixing speed 5
Rev/min, it stirs 5 minutes, by adjusting temperature regulating device slow cooling crystallization, interior temperature after 6 revs/min of revolving speed, 140 minutes of control
Suction filtration when being down to 8 DEG C, filter cake are dried in vacuo at 45 DEG C, obtain 26.8g off-white powder.Yield 89.1%, HPLC purity assay
It is 99.9%, isomer impurities formula (9) purity is less than 0.03%.Utilize S- (-)-N, N- dimethyl -3- hydroxyl -3- of the preparation
(2- thiophene) propylamine is condensed in the presence of sodium hydride with 1- fluoronaphthalene, most afterwards through N- demethylation, at being refining to obtain high-purity after salt
Duloxetine hydrochloride, single contaminant purity is less than 0.03%.
The purifying of embodiment 2:S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine
90.0g S- (-)-N, N- dimethyl -3- hydroxyl -3- (2- thiophene) propylamine is weighed to be added in 1000mL four-hole boiling flask,
The mixed solvent 881.1g that the volume ratio for measuring first alcohol and water is 1/10 is added, and warming-in-water is to 74 DEG C, reflux, mixing speed 4
Rev/min, it stirs 5 minutes, by adjusting temperature regulating device slow cooling crystallization, interior temperature after 6 revs/min of revolving speed, 150 minutes of control
Suction filtration when being down to 9 DEG C, filter cake are dried in vacuo at 45 DEG C, obtain 81.9g off-white powder.Yield 91.0%, HPLC purity assay
It is 99.9%, isomer impurities formula (9) purity is less than 0.03%.Utilize S- (-)-N, N- dimethyl -3- hydroxyl -3- of the preparation
(2- thiophene) propylamine is condensed in the presence of sodium hydride with 1- fluoronaphthalene, most afterwards through N- demethylation, at being refining to obtain high-purity 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 merely used to help understand method of the invention and
Its core concept, its object is to allow the personage for being familiar with this field technology to can understand the content of the present invention and implement it accordingly, and
The protection scope that the present invention cannot be limited in this way.Any equivalent change or modification in accordance with the spirit of the invention should all be contained
Lid is 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 shown recrystallizes condition by process control in a solvent and obtains purified product,
Wherein, solvent is the mixed solvent of first alcohol and water, and process control recrystallizes condition concrete operations are as follows: first temperature rising reflux returns
Flowing temperature is 72~74 DEG C, and return time is 5~60 minutes, and mixing speed is 0.5~15 rev/min, and then cool down crystallization, temperature
Spending setting range is 72 DEG C~8 DEG C, and the time is 120~150 minutes, and mixing speed is 6~15 revs/min, and last crystallization terminates
After filter, filter cake 45 DEG C be dried in vacuo.
2. the purification process of preparation high-purity duloxetine hydrochloride intermediate according to claim 1, it is characterised in that:
The volume ratio of the first alcohol and water is 1:10.
3. the purification process of preparation high-purity duloxetine hydrochloride intermediate according to claim 1, it is characterised in that:
The weight of the initial duloxetine hydrochloride intermediate and the weight ratio of the solvent are 1:9~1:10.
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| 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 |
| CN115286613B (en) * | 2022-10-08 | 2023-01-31 | 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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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 |
|---|
| Process for the purification of (S)-(+)-N,N-dimetil-3-(1-naphthalenoxy)-3-(2-tienyl) propanamine;Disclosed Anonymously;《IP.com》;20090918;No.IPCOM000187768D |
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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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