CN106008436A - Preparation method of alpha crystal form of Iguratimod - Google Patents
Preparation method of alpha crystal form of Iguratimod Download PDFInfo
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- CN106008436A CN106008436A CN201610468273.8A CN201610468273A CN106008436A CN 106008436 A CN106008436 A CN 106008436A CN 201610468273 A CN201610468273 A CN 201610468273A CN 106008436 A CN106008436 A CN 106008436A
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- ailamode
- crystal form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an alpha crystal form of Iguratimod. A preparation process is optimized with the method, an ethanol/DMF mixed solvent with better solubility is used, the use quantity of the solvent is reduced, production time is shortened, the cost is reduced, and the method can be applied to industrial production.
Description
Technical field
The present invention relates to medicine manufacture field, particularly relate to the preparation method of the crystal formation α of antirheumatic Ailamode.
Background technology
Ailamode (Iguratimod, T-614), be by Japan folic hill and the exploitation of Wei Cai drugmaker joint research and development a kind of novel, alleviate state of an illness medicine (DMARDs) for treating rheumatic arthritis.In JIUYUE, 2003 is registered in Japanese publication, within 06 29th, 2012, is approved listing, and South Africa, Britain and Korea S are carrying out clinical trial.Ailamode lists the most at home, is used for treating rheumatism.
US20070287844 discloses XRD figure spectrum and the manufacture method of four kinds of Ailamode crystal formations；Japan Patent 5-97840 and 5-125072 discloses and obtains alpha-crystal form with acetone crystallization, but the dissolubility of acetone is poor, and 1g Ailamode raw material needs about 80ml solvent, is unfavorable for industrialization；Patent CN1944420A discloses five kinds of crystal formations of Ailamode, wherein alpha-crystal form is prepared by alcohol crystal, crystallization 10g Ailamode product needed 1000-1500ml ethanol, through overtesting, crystallization 1000g Ailamode (backflow, outer temperature 90 DEG C) product needs 250-300L ethanol, and rate of dissolution is slower, long-time return stirring, the use of a large amount of alcohol solvents is needed to be susceptible to danger, be unfavorable for industrialized production.
Summary of the invention
In order to solve ethanol large usage quantity, being unfavorable for industrialized shortcoming, the present invention uses mixed solvent and other solvent crystallizations, has obtained alpha-crystal form, has greatly reduced solvent load, beneficially industrial operation.
Take Ailamode highly finished product, be dissolved in the DMF of reflux state and the mixed solvent of ethanol, after half an hour of refluxing, cooling crystallization, obtain the alpha-crystal form of Ailamode.Solvent load is less, is beneficial to produce；XRD figure spectrum display, the method has been similarly obtained alpha-crystal form.
According to experimental result, under counterflow condition, the quantity of solvent needed for dissolving 1g is as shown in the table:
As seen from the above table, DMF/ alcohol mixed solvent crystallizes Ailamode, crystallizes compared to straight alcohol, can greatly reduce solvent load, beneficially industrialized production, and all obtain can be used for the alpha-crystal form of pharmaceutical production.
Accompanying drawing illustrates: Fig. 1 is self-control Ailamode highly finished product nuclear magnetic data；
Fig. 2 is self-control Ailamode highly finished product mass spectrometric data；
Fig. 3 is the XRD data of the alpha-crystal form of US20070287844 patent disclosure；
Fig. 4 is self-control Ailamode highly finished product XRD data；
Fig. 5 is that 1:10DMF/ ethanol solution crystallizes the XRD data obtained；
Fig. 6 is that 1:6DMF/ ethanol solution crystallizes the XRD data obtained；
Fig. 7 is that 1:4DMF/ ethanol solution crystallizes the XRD data obtained；
Fig. 8 is that 1:1DMF/ ethanol solution crystallizes the XRD data obtained；
Fig. 9 is that alcohol solvent crystallizes the XRD data obtained.
Present disclosure is described in further detail by form more by the following examples, but should not be only limitted to following example in being interpreted as the above-mentioned subject area of the present invention with regard to this.Without departing under the present invention above-mentioned technology premise, replace accordingly or the amendment of change according to what ordinary skill knowledge and customary means were made, be included within the scope of the present invention。
Embodiment 1: raw material preparation method
200g formamido methyl-2-hydroxyl-4-methylsulfonyl amido-5-Phenoxyphenyl ketone and N,N-dimethylformamide (DMF) 300mL are added in 1L reaction bulb.Under agitation it is sequentially added into 200gN, N-diformamide dimethylacetal, 33.2g glacial acetic acid, DMF200mL.It is stirred at room temperature, reacts 7 hours.After reaction terminates, transfer the material in 10L glass beaker, stirring, in reactor, it is sequentially added into 1L dichloromethane, 1.5L purified water, with 6N hydrochloric acid regulation system pH value to pH4；Adjust pH complete, continue stirring and make fluffy solid separate out completely.Separating out complete, filter, to dripping without continuous drop, discharging, filter cake with dichloromethane, purified water, dehydrated alcohol, respectively stirs and washes 3～5 minutes successively, filters, and vacuum drying obtains Ailamode crude product.Crude product crystallizes through acetonitrile, obtains Ailamode highly finished product, and its nuclear-magnetism, mass spectrum and XRD data are as shown in Figure 1, Figure 2, Figure 4 shows.
The research of following crystal formation is applied the Ailamode that the present embodiment prepares.
Embodiment 2
Take Ailamode highly finished product 10g, add in 250mL eggplant type flask；Adding 1:1DMF/ alcohol mixed solvent 90ml, 90 DEG C are refluxed 30 minutes, stand crystallize (room temperature, about 25 DEG C), sucking filtration, it is vacuum dried (50 DEG C, vacuum ＜-0.1Mpa) 12 hours, obtain Ailamode crystallized product, its XRD data are as shown in Figure 5.
Embodiment 3
Take Ailamode highly finished product 10g, add in 1000mL eggplant type flask；Adding 1:4DMF/ alcohol mixed solvent 350ml, 90 DEG C are refluxed 30 minutes, stand crystallize (in refrigerator, about-5 DEG C), sucking filtration, it is vacuum dried (50 DEG C, vacuum ＜-0.1Mpa) 12 hours, obtain Ailamode crystallized product, its XRD data are as shown in Figure 6.
Embodiment 4
Take Ailamode highly finished product 5g, add in 1000mL eggplant type flask；Adding 1:6DMF/ alcohol mixed solvent 380ml, 90 DEG C are refluxed 30 minutes, stand crystallize (in refrigerator, about-5 DEG C), sucking filtration, it is vacuum dried (50 DEG C, vacuum ＜-0.1Mpa) 12 hours, obtain Ailamode crystallized product, its XRD data are as shown in Figure 7.
Embodiment 5
Take Ailamode highly finished product 5g, add in 1000mL eggplant type flask；Adding 1:10DMF/ alcohol mixed solvent 520ml, 90 DEG C are refluxed 30 minutes, stand crystallize (room temperature, about 25 DEG C), sucking filtration, it is vacuum dried (50 DEG C, vacuum ＜-0.1Mpa) 12 hours, obtain Ailamode crystallized product, its XRD data are as shown in Figure 8.
Embodiment 6
Take Ailamode highly finished product 2g, add in 1000mL eggplant type flask；Adding ethanol 600ml, 90 DEG C of return stirrings 30 minutes, stand crystallize (room temperature, about 25 DEG C), sucking filtration, vacuum drying (50 DEG C, vacuum ＜-0.1Mpa) 12 hours, obtain Ailamode crystallized product, its XRD data are as shown in Figure 9.
Claims (4)
1. the method preparing Ailamode alpha-crystal form: take Ailamode highly finished product, is dissolved in the DMF of reflux state and the mixed solvent of ethanol, after half an hour, cooling crystallization, obtains Ailamode alpha-crystal form.
The method preparing Ailamode alpha-crystal form the most according to claim 1, the diffraction maximum of Ailamode alpha-crystal form is 4.865,6.849,9.723,10.875,13.769,14.613,15.385,17.572,18.896,19.530,20.716,21.269,21.840.
The method preparing Ailamode alpha-crystal form the most according to claim 1, wherein mixed solvent is characterised by that DMF is 1:1 ~ 1:10 with the ratio of ethanol.
The method preparing Ailamode alpha-crystal form the most according to claim 1, wherein cooling crystallization step is characterised by, recrystallization temperature is-5 ~ 25 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610468273.8A CN106008436A (en) | 2016-06-25 | 2016-06-25 | Preparation method of alpha crystal form of Iguratimod |
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| CN201610468273.8A CN106008436A (en) | 2016-06-25 | 2016-06-25 | Preparation method of alpha crystal form of Iguratimod |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109512786A (en) * | 2018-11-12 | 2019-03-26 | 北京化工大学 | A kind of preparation method of Ailamode Nano medication particle |
| JP2021109849A (en) * | 2020-01-10 | 2021-08-02 | 株式会社トクヤマ | Iguratimod having a novel crystal structure and its manufacturing method |
| CN115703772A (en) * | 2021-08-09 | 2023-02-17 | 天地恒一制药股份有限公司 | Iguratimod eutectic crystal, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1604986A1 (en) * | 2003-03-14 | 2005-12-14 | Toyama Chemical Co., Ltd. | Novel crystal of n- 3-(formylamino)-4-oxo-6-phenoxy-4h-crome ne-7-yl methanesulfonamide |
| CN1931159A (en) * | 2005-09-16 | 2007-03-21 | 天津药物研究院 | Superfine Iguratimod powder and quick released oral prepn |
| CN102050810A (en) * | 2009-11-05 | 2011-05-11 | 天津太平洋制药有限公司 | Medicine for treating rheumatoid arthritis and preparation method thereof |
-
2016
- 2016-06-25 CN CN201610468273.8A patent/CN106008436A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1604986A1 (en) * | 2003-03-14 | 2005-12-14 | Toyama Chemical Co., Ltd. | Novel crystal of n- 3-(formylamino)-4-oxo-6-phenoxy-4h-crome ne-7-yl methanesulfonamide |
| CN1931159A (en) * | 2005-09-16 | 2007-03-21 | 天津药物研究院 | Superfine Iguratimod powder and quick released oral prepn |
| CN102050810A (en) * | 2009-11-05 | 2011-05-11 | 天津太平洋制药有限公司 | Medicine for treating rheumatoid arthritis and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 王青松等: "艾拉莫德两种晶型的体内外比较研究", 《中国药科大学学报》 * |
| 赵临襄: "化学合成药物的工艺研究", 《化学制药工艺学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109512786A (en) * | 2018-11-12 | 2019-03-26 | 北京化工大学 | A kind of preparation method of Ailamode Nano medication particle |
| JP2021109849A (en) * | 2020-01-10 | 2021-08-02 | 株式会社トクヤマ | Iguratimod having a novel crystal structure and its manufacturing method |
| JP7426832B2 (en) | 2020-01-10 | 2024-02-02 | 株式会社トクヤマ | Iguratimod with a novel crystal structure and its production method |
| CN115703772A (en) * | 2021-08-09 | 2023-02-17 | 天地恒一制药股份有限公司 | Iguratimod eutectic crystal, and preparation method and application thereof |
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