WO2017134617A1 - Procédé de préparation de dasatinib amorphe - Google Patents
Procédé de préparation de dasatinib amorphe Download PDFInfo
- Publication number
- WO2017134617A1 WO2017134617A1 PCT/IB2017/050596 IB2017050596W WO2017134617A1 WO 2017134617 A1 WO2017134617 A1 WO 2017134617A1 IB 2017050596 W IB2017050596 W IB 2017050596W WO 2017134617 A1 WO2017134617 A1 WO 2017134617A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dasatinib
- preparation
- amorphous
- methanol
- mixture
- Prior art date
Links
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 239000002067 L01XE06 - Dasatinib Substances 0.000 title claims abstract description 27
- 229960002448 dasatinib Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- SFQIIVMLXKSXGJ-UHFFFAOYSA-N N-(2-chloro-6-methylphenyl)-2-[2-[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methyl-3H-pyridin-4-ylidene]hydrazinyl]-1,3-thiazole-5-carboxamide Chemical compound ClC1=C(C(=CC=C1)C)NC(=O)C1=CN=C(S1)NN=C1CC(=NC(=C1)N1CCN(CC1)CCO)C SFQIIVMLXKSXGJ-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present application provides process for the preparation of amorphous form of dasatinib.
- the drug compound having the adopted name "dasatinib” has a chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyridiminyl]amino]-5-thiazolecarboxamide, and is structurally represented by Formula I.
- Dasatinib is sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatemant and Philadelphia chromosome- positive acute lymphoblasticjeukemia (Ph+ ALL).
- CML chronic myelogenous leukemia
- Ph+ ALL Philadelphia chromosome- positive acute lymphoblasticjeukemia
- the PCT application WO2005077945 discloses several crystalline forms of Dasatinib which are designated as monohydrate, butanol solvate, ethanol solvate, crystalline neat form (N-6) and crystalline neat form (T1H1-7).
- US patent no. 7973045 discloses anhydrous form and various other solvates of dasatinib.
- US '045 also discloses process for the preparation of amorphous dasatinib by evaporating the solvent from the suspension.
- the solvents used in the process were selected from dimethylformamide, 1, 2-dichlorobenzene, propylene glycol, ethylene glycol and glycerole.
- the process suffers from major drawbacks such as high boiling point of solvent and the amount of residual solvents in the product. Such a process is not well suited for use in a large scale commercial preparation.
- US20140343073A1 discloses process for the preparation of amorphous form of dasatinib by milling.
- the inventors of the present invention have surprisingly found a process for the preparation of amorphous dasatinib that eliminates the problems encountered in the process of prior art.
- the present application provides a process for the preparation of amorphous form of dasatinib, comprising the steps of: a) mixing dasatinib in an organic solvent system;
- Figure 1 illustrates the PXRD pattern of amorphous dasatinib, obtained by the process of Example 1.
- Figure 2 illustrates the PXRD pattern of amorphous dasatinib, obtained by the process of Example 2.
- the present application provides a process for the preparation of amorphous form of dasatinib, comprising the steps of: a) mixing dasatinib in an organic solvent system;
- Organic solvent used in step a) may be selected from but not limited to petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether or the like; N,N- dimethylacetamide, methanol, methanol-water, acetone, ethanol, acetonitrile, isopropyl alcohol, n-butanol, N-methyl-pyrrolidine, tetrahydrofuran, dimethyl sulfoxide or N, N- dimethylformamide or mixtures thereof.
- step b) of the process preferably either concentrated HC1 or an organic solution of HC1 is added to the mixture from step a).
- the organic solution of HC1 in step b) is prepared by passing HC1 gas through the organic solvent.
- the organic solvent used in preparing the organic solution of HC1 is selected from the group comprising a C 1 -4 alcohol, ethyl acetate and acetonitrile or mixtures thereof.
- the C 1 -4 alcohol is one or more of methanol, ethanol, isopropanol and n-butanol or mixtures thereof.
- Isolation of the amorphous form may involve methods such as removal of solvent by filtration, distillation under vacuum, spray drying or freeze drying.
- the isolated material may optionally be dried. Drying may be suitably carried out using any equipment such as a gravity oven, tray dryer, vacuum oven, Biichi® Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressures. In an embodiment, the drying may be carried out at a temperature of about 120°C, at a temperature of about 115°C, at a temperature of about 110°C or at a temperature of about 105°C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
- Example 2 preparation of amorphous dasatinib
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Procédé de préparation de Dasatinib amorphe.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201641003815 | 2016-02-03 | ||
| IN201641003815 | 2016-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2017134617A1 true WO2017134617A1 (fr) | 2017-08-10 |
Family
ID=59500621
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2017/050596 WO2017134617A1 (fr) | 2016-02-03 | 2017-02-03 | Procédé de préparation de dasatinib amorphe |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2017134617A1 (fr) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019008555A1 (fr) * | 2017-07-07 | 2019-01-10 | Biocon Limited | Formes polymorphes de dasatinib |
| WO2019209908A1 (fr) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Formes cristallines de dasatinib |
| CN111217807A (zh) * | 2018-11-26 | 2020-06-02 | 安礼特（上海）医药科技有限公司 | 一种达沙替尼无定型及其制备方法 |
| US10799459B1 (en) | 2019-05-17 | 2020-10-13 | Xspray Microparticles Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10940149B1 (en) | 2018-06-15 | 2021-03-09 | Handa Oncology, Llc | Kinase inhibitor salts and compositions thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009053854A2 (fr) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphes de dasatinib et leur procédé de préparation |
| CN104327067A (zh) * | 2014-10-11 | 2015-02-04 | 深圳市浩瑞实业发展有限公司 | 无定形达沙替尼的制备方法 |
| WO2015049645A2 (fr) * | 2013-10-04 | 2015-04-09 | Alembic Pharmaceuticals Limited | Procédé perfectionné de préparation de dasatinib |
-
2017
- 2017-02-03 WO PCT/IB2017/050596 patent/WO2017134617A1/fr active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009053854A2 (fr) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphes de dasatinib et leur procédé de préparation |
| WO2015049645A2 (fr) * | 2013-10-04 | 2015-04-09 | Alembic Pharmaceuticals Limited | Procédé perfectionné de préparation de dasatinib |
| CN104327067A (zh) * | 2014-10-11 | 2015-02-04 | 深圳市浩瑞实业发展有限公司 | 无定形达沙替尼的制备方法 |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020526528A (ja) * | 2017-07-07 | 2020-08-31 | バイオコン・リミテッド | ダサチニブの多形形態 |
| WO2019008555A1 (fr) * | 2017-07-07 | 2019-01-10 | Biocon Limited | Formes polymorphes de dasatinib |
| US11059813B2 (en) | 2017-07-07 | 2021-07-13 | Biocon Limited | Polymorphic forms of Dasatinib |
| WO2019209908A1 (fr) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Formes cristallines de dasatinib |
| US11440908B2 (en) | 2018-04-25 | 2022-09-13 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
| US10940149B1 (en) | 2018-06-15 | 2021-03-09 | Handa Oncology, Llc | Kinase inhibitor salts and compositions thereof |
| US11160805B2 (en) | 2018-06-15 | 2021-11-02 | Handa Onocology, Llc | Kinase inhibitor salts and compositions thereof |
| US11052088B2 (en) | 2018-06-15 | 2021-07-06 | Handa Oncology, Llc | Kinase inhibitor salts, and compositions thereof |
| US11007195B2 (en) | 2018-06-15 | 2021-05-18 | Handa Oncology, Llc | Kinase inhibitor salts, and compositions thereof |
| CN111217807A (zh) * | 2018-11-26 | 2020-06-02 | 安礼特（上海）医药科技有限公司 | 一种达沙替尼无定型及其制备方法 |
| US10799459B1 (en) | 2019-05-17 | 2020-10-13 | Xspray Microparticles Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10894017B1 (en) | 2019-05-17 | 2021-01-19 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10894018B1 (en) | 2019-05-17 | 2021-01-19 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10874613B1 (en) | 2019-05-17 | 2020-12-29 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10874614B1 (en) | 2019-05-17 | 2020-12-29 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10869837B1 (en) | 2019-05-17 | 2020-12-22 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US11344500B2 (en) | 2019-05-17 | 2022-05-31 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US10869836B1 (en) | 2019-05-17 | 2020-12-22 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
| US11833249B2 (en) | 2019-05-17 | 2023-12-05 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
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