CN101815708A - Method for purification of dibenzoxepin compound - Google Patents
Method for purification of dibenzoxepin compound Download PDFInfo
- Publication number
- CN101815708A CN101815708A CN200880109944A CN200880109944A CN101815708A CN 101815708 A CN101815708 A CN 101815708A CN 200880109944 A CN200880109944 A CN 200880109944A CN 200880109944 A CN200880109944 A CN 200880109944A CN 101815708 A CN101815708 A CN 101815708A
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- Prior art keywords
- dibenzo
- oxa
- dihydro
- purification
- acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a method for purifying (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz- [b,e]oxepin-2-acetic acid represented by the formula [I] or an acid addition salt thereof, which comprises dissolving (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz- [b,e]oxepin-2-acetic acid or the acid addition salt thereof in a mixed solvent of water and a ketone solvent and causing a crystal to be precipitated from the solution. The method can purify (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrobenz[b,e]- oxepin-2-acetic acid, which is useful as a medicinal substance, or an acid addition salt thereof efficiently in an industrially advantageous manner.
Description
Technical field
The present invention relates to as the useful dibenzo oxa-of pharmaceuticals
The method of purification of compound in more detail, relates to (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The method of purification of-2-acetate or its acid salt.
Background technology
(Z)-and 11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate (popular name: Olopatatadine) be the compound shown in the following formula (I).Known in the special fair 7-116174 communique of special fair 5-86925 communique of Japan and Japan, this compound or its acid salt are the useful pharmaceuticals compounds of anti-allergy agent that is suitable for as to allergic rhinitis, urticaria etc.
At chemosynthesis dibenzo oxa-
During compound, the isomer (E type) that can contain with other is the impurity of representative, wants to improve purity and just is necessary to purify.
In the special fair 7-116174 communique of special fair 5-86925 communique of Japan and Japan, when having put down in writing with suitable-back mixing compound (EZ mixture) acquisition target compound, their separation can separate through vapor-phase chromatography, recrystallization etc.Yet, in these documents not to (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The purification of-2-acetate itself is put down in writing.
Summary of the invention
The object of the present invention is to provide efficient and at industrial (the Z)-11-(3-dimethylamino propylidene base)-6 that advantageously purifies, 11-dihydro-dibenzo [b, e] oxa-
The method of-2-acetate or its acid salt.
According to the present invention, by making the dibenzo oxa-shown in the formula (I)
Acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, and crystallization is separated out from the solution of gained, obtain the high crystallization of purity thus.
That is, the present invention relates to following content:
[1] a kind of (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The method of purification of-2-acetate or its acid salt is characterized in that, makes (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, and crystallization is separated out from the solution of gained,
[2] according to [1] described method of purification, wherein, make (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, concentrate by the solution of component distillation with gained, and crystallization is separated out from concentrated solution,
[3] according to [1] described method of purification, wherein, make (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, concentrate by the solution of component distillation with gained, then after the adding acid, crystallization are separated out in concentrated solution,
[4] according to [1] described method of purification, wherein, make (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, after the adding acid, crystallization are separated out in the solution that obtains,
[5] according to [3] or [4] described method of purification, wherein, acid is hydrogenchloride.
[6] according to each described method of purification in [1]～[4], wherein, ketone solvent is a methylethylketone.
Embodiment
Below, the present invention will be described.In addition, if % does not specify, mean weight %.
(Z)-11-shown in the following formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
After-2-acetate or its acid salt are added in the solvent, can make its dissolving by heating.As the acid salt of the Olopatatadine that uses among the present invention, can enumerate hydrochloride, vitriol etc., the preferably salt hydrochlorate.
As the solvent that uses among the present invention, make the mixed solvent of water and ketone solvent.The blending ratio of water and ketone solvent usually with the capacity proportional meter at water: in the scope of ketone solvent=1: 5～1: 20.As ketone solvent, can enumerate methyl iso-butyl ketone (MIBK), methylethylketone, pimelinketone, cyclopentanone, their mixture etc., preferred methylethylketone.The usage quantity of solvent is not particularly limited, but yield reduces in the time of too much, insoluble or the purity decline of crystallization when very few, therefore with respect to Olopatatadine 1kg, for example when using the mixed solvent of methylethylketone and water, the ratio of the about 10～20L of methylethylketone, the about 1～2L of water normally, the ratio of the preferred about 12～17L of methylethylketone, the about 1.2～1.7L of water.
Temperature when making Olopatatadine be dissolved in the mixed solvent of water and ketone solvent is about 40～90 ℃ usually, preferably is about 50～70 ℃.After the dissolving, can also add sorbent material (for example aluminum oxide, gac etc.), decolour, the absorption of impurity.The amount of sorbent material is about 10～70g with respect to Olopatatadine 1kg, preferably is about 20～50g.After adding sorbent material, sorbent material is eliminated through filtering.
After preferably making Olopatatadine be dissolved in above-mentioned solvent, through component distillation with the solution concentration that obtains.Component distillation can use known distillating method to carry out.When using the about 1～2L of the about 10～20L of ketone solvent, water with respect to Olopatatadine or its acid salt 1kg, the distillation amount of removing is about 3～15L, preferably is about 5～10L.After the distillation, because therefore the quantity of solvent deficiency preferably adds ketone solvent.Its additional amount is about 3～15L, preferably is about 5～10L.When carrying out concentration operation, crystalline for example separate out about 50～90 ℃, be generally 60～80 ℃ of beginnings, but, be advisable to continue to stir in order to make the crystallization slaking.
Solution is cooled to about 0～30 ℃, preferably is cooled to about 5～20 ℃,, it can be emanated by the crystallization that filtration is separated out.At this moment, about 5～20 ℃ of normally per 1 hour of speed of cooling, preferred per 1 hour about 5～15 ℃.Can when above-mentioned cooling or after the cooling solution be stirred.When after cooling solution being stirred, churning time being not particularly limited, for example is 1～100 hour.
Can when separating out, crystallization add acid.As acid, can enumerate hydrochloric acid, sulfuric acid etc., preferred hydrochloric acid.These acid may be used singly or in combination of two or more use.The period that adds acid can also can be in process of cooling, preferably before cooling before cooling.Acid addition with respect to Olopatatadine, in the proton equivalent, normally about 0.5～1.5 equivalent.For example when using 35% hydrochloric acid,, be about 100～400g usually, preferably be about 150～300g with respect to Olopatatadine 1kg.
When crystallization is emanated, can utilize known method such as filtration, washing, drying.
In addition, in the present invention, 11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate also is named as (11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-yl) acetate.
Embodiment
Below, the present invention will be described to use embodiment, but the invention is not restricted to these embodiment.
Embodiment 1
(Z)-and 11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The purification of-2-acetic acid hydrochloride
At purity 96.9%, E: Z=0.7: rough (Z)-11-of 99.3 (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
Add methylethylketone 1120ml among the-2-acetic acid hydrochloride 80.0g (0.21 mole), be heated to 70 ℃ while stirring.In this solution, drip water 112ml,, stir and make the crystallization dissolving after 20 minutes.Add gac 2.4g, after one and a half hours, remove by filter gac 70 ℃ of stirrings.Filtrate is heated to 75 ℃, carries out azeotropic dehydration, 560g is removed in distillation.Add methylethylketone 670ml, Dropwise 35 % hydrochloric acid 16g while stirring at 70 ℃.,, stirred 16 hours after 30 minutes 70 ℃ of slakings at 10 ℃ with 10 ℃ ratio cooling in per 1 hour.
After the filtering crystallization, with the acetone 320ml wash crystallization that is cooled to 10 ℃.With the crystallization drying under reduced pressure that obtains, obtain (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetic acid hydrochloride 70.5g.Purity is 99.92%, E: Z=0.01: 99.99.Apparent yield is 88%.Median size is 17.6 μ m.
Embodiment 2
(Z)-and 11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The purification of-2-acetate
At purity 96.2%, E: Z=0.8: rough (Z)-11-of 99.2 (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
Add methylethylketone 105L, water 10.5L and gac 0.2kg among-the 2-acetate 7.5kg (20.1 moles), be heated to about 70 ℃ while stirring.After stirring 30 minutes under the same temperature, the filter activity charcoal is used water 0.75L and methylethylketone 7.5L mixes and temperature is adjusted into 70 ℃ solvent gac is washed.Filtrate is cooled to 30 ℃ with per 1 hour ratio of 15 ℃, under reduced pressure carries out azeotropic dehydration under 30～35 ℃ temperature, 57.9kg is removed in distillation.Then, at 35 ℃ with adding methylethylketone 72.0L in 3 hours.After 30 minutes, be cooled to 10 ℃ in about 35 ℃ of stirrings, stirred 3 hours at 10 ℃ with per 1 hour ratio of 10 ℃.
After the crystallization that filtering is separated out, usefulness temperature is adjusted to 10 ℃ acetone 37.5L washing.With the crystallization drying under reduced pressure that obtains, obtain (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate (purity 100%) 6.0kg.Apparent yield is 80%.The crystalline median size is 17.5 μ m.
Industrial applicibility
Can provide efficient according to the present invention and advantageously purify as useful (the Z)-11-of pharmaceuticals (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-industrial
-2-acetic acid and acid-addition salts thereof.
Claims (6)
1. (Z)-11-(3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
The method of purification of-2-acetate or its acid salt is characterized in that, makes (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, and crystallization is separated out from the solution of gained,
2. method of purification according to claim 1 wherein, makes (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, concentrate by the solution of component distillation with gained, and crystallization is separated out from concentrated solution,
3. method of purification according to claim 1 wherein, makes (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, concentrate by the solution of component distillation with gained, then after the adding acid, crystallization are separated out in concentrated solution,
4. method of purification according to claim 1 wherein, makes (the Z)-11-shown in the formula (I) (3-dimethylamino propylidene base)-6,11-dihydro-dibenzo [b, e] oxa-
-2-acetate or its acid salt are dissolved in the mixed solvent of water and ketone solvent, after the adding acid, crystallization are separated out in the solution that obtains,
5. according to claim 3 or 4 described methods of purification, wherein, acid is hydrogenchloride.
6. according to each described method of purification in the claim 1～4, wherein, ketone solvent is a methylethylketone.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007267156 | 2007-10-12 | ||
| JP2007-267156 | 2007-10-12 | ||
| PCT/JP2008/068325 WO2009048086A1 (en) | 2007-10-12 | 2008-10-02 | Method for purification of dibenzoxepin compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101815708A true CN101815708A (en) | 2010-08-25 |
Family
ID=40549229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880109944A Pending CN101815708A (en) | 2007-10-12 | 2008-10-02 | Method for purification of dibenzoxepin compound |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5325517B2 (en) |
| CN (1) | CN101815708A (en) |
| CH (1) | CH700068B8 (en) |
| WO (1) | WO2009048086A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375060A (en) * | 2020-12-07 | 2021-02-19 | 广州健康元呼吸药物工程技术有限公司 | Post-treatment purification method of olopatadine hydrochloride |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102668626A (en) | 2010-01-07 | 2012-09-12 | 日本电气株式会社 | Wireless communication system, radio terminal, radio network, wireless communication method and program |
| JP2016010418A (en) | 2012-10-22 | 2016-01-21 | パナソニックヘルスケア株式会社 | Dental vibration application device and dental vibration application method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105234A2 (en) * | 2006-03-14 | 2007-09-20 | Usv Limited | A PROCESS FOR THE PREPARATION OF ISOMERS OF 11-[3-(DIMETHYLAMINO)PROPYLIDENE]-6, 11-DIHYDRODIBENZ [b, e] OXEPIN-2-ACETIC ACID HYDROCHLORIDE AND POLYMORPHS THEREOF |
| WO2007110761A2 (en) * | 2006-03-28 | 2007-10-04 | Universität Zürich | Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ20021849A3 (en) * | 1999-11-29 | 2002-08-14 | Aventis Pharma S. A. | Chemical derivatives and their use as anti-telomerase agents |
| TW200409746A (en) * | 2002-07-26 | 2004-06-16 | Theravance Inc | Crystalline β2 adrenergic receptor agonist |
| JP4279087B2 (en) * | 2003-08-22 | 2009-06-17 | 旭化成ケミカルズ株式会社 | Electrolytic solution for electrolytic capacitors |
| JP2005298405A (en) * | 2004-04-12 | 2005-10-27 | Kuraray Co Ltd | Production method for cis-1-amino-4-hydroxymethyl-2-cyclopentene or its salt |
| EP2228371A1 (en) * | 2005-12-22 | 2010-09-15 | Medichem, S.A. | New process for preparing olopatadine free base and/or its hydrochloride salt |
| JP5139104B2 (en) * | 2007-02-16 | 2013-02-06 | 住友化学株式会社 | Method for producing dibenzooxepin compound |
| ES2344242B1 (en) * | 2007-02-16 | 2011-06-06 | Sumitomo Chemical Company, Limited | METHOD FOR THE PRODUCTION OF A DIBENZOXEPINE COMPOUND. |
-
2008
- 2008-10-01 JP JP2008256257A patent/JP5325517B2/en active Active
- 2008-10-02 WO PCT/JP2008/068325 patent/WO2009048086A1/en active Application Filing
- 2008-10-02 CH CH00491/10A patent/CH700068B8/en not_active IP Right Cessation
- 2008-10-02 CN CN200880109944A patent/CN101815708A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105234A2 (en) * | 2006-03-14 | 2007-09-20 | Usv Limited | A PROCESS FOR THE PREPARATION OF ISOMERS OF 11-[3-(DIMETHYLAMINO)PROPYLIDENE]-6, 11-DIHYDRODIBENZ [b, e] OXEPIN-2-ACETIC ACID HYDROCHLORIDE AND POLYMORPHS THEREOF |
| WO2007110761A2 (en) * | 2006-03-28 | 2007-10-04 | Universität Zürich | Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| ETSUO OHSHIMA,ET AL.,: "Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 薛建英等，: "抗过敏药盐酸奥洛他定的合成工艺研究", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375060A (en) * | 2020-12-07 | 2021-02-19 | 广州健康元呼吸药物工程技术有限公司 | Post-treatment purification method of olopatadine hydrochloride |
| CN112375060B (en) * | 2020-12-07 | 2022-02-22 | 广州健康元呼吸药物工程技术有限公司 | Post-treatment purification method of olopatadine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CH700068B8 (en) | 2012-09-14 |
| JP2009108039A (en) | 2009-05-21 |
| CH700068B1 (en) | 2012-07-31 |
| JP5325517B2 (en) | 2013-10-23 |
| WO2009048086A1 (en) | 2009-04-16 |
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Application publication date: 20100825 |