CN106146501A - A kind of preparation method of unformed inhibitors of kinases - Google Patents
A kind of preparation method of unformed inhibitors of kinases Download PDFInfo
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- CN106146501A CN106146501A CN201510138060.4A CN201510138060A CN106146501A CN 106146501 A CN106146501 A CN 106146501A CN 201510138060 A CN201510138060 A CN 201510138060A CN 106146501 A CN106146501 A CN 106146501A
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- idelalisib
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Abstract
The present invention relates to the preparation method of a kind of unformed inhibitors of kinases, including: Idelalisib is dissolved in good solvent, is then instilled poor solvent, stirring and crystallizing, obtain Idelalisib unformed.The method simple operation.
Description
Technical field
The invention belongs to pharmaceutical formulating art, be specifically related to the preparation method of a kind of unformed inhibitors of kinases.
Background technology
Transmit via the cell signal of 3 '-phosphorylation phosphoinositide and have been directed to multiple cell processes, such as, vicious transformation, life
The transmission of long factor signal, inflammation and immunity.For summary, see Rameh etc., J.Biol.Chem., 274:8347-8350 (1999).
The enzyme being responsible for producing these phosphorylation signal transmission product is phosphatidyl-inositol 3-kinase (PI 3-kinases；PI3K).PI3K initially reflects
It is set to and viral oncoprotein and phosphorylation phosphatidylinositols (PI) and the life of phosphorylated derivative thereof at 3 '-hydroxyl of inositol ring
The activity that growth factor receptor body tyrosine kinase is relevant.See Panayotou etc., Trends Cell Biol.2:358-60 (1992).
It is believed that PI 3-kinase activator relates to various kinds of cell response, including cell growth, differentiation and apoptosis.See Parker etc.,
Curr.Biol.,5:577-99(1995)；Yao etc., Science, 267:2003-05 (1995).PI 3-kinases also demonstrates and relates to leukocyte
The many aspects activated.See, e.g., Pages etc., Nature, 369:327-29 (1994)；Rudd, Immunity,
4:527-34(1996)；Fraser etc., Science, 251:313-16 (1991).
Phosphatidyl-inositol 3-kinase (PI3K) includes I class and II class kinases, and I class PISK can be divided into IA (PI3K α,
β, δ) and IB (PI3K γ) two groups.The activation of PI3K can make film phosphoinositide phosphorylation, 3 hydroxyls on catalysis inositol ring
Base generate phosphatidylinositol diphosphate PIP2), acyl inositoltriphosphoric acid (PIP3), they all can be as second message,second messenger in cell
Transmission signal, and then activate egg kinase b (Akt)；The Akt activated is mainly by promoting that stream substrates phosphorylation plays extensively
Biological effect, including apoptosis, promote the function such as cells survival.
Idelalisib, is the inhibitor of a kind of phosphatidyl-inositol 3-kinase (PI3K) δ, for the treatment of haematological tumours, can make
For single therapy recurrent follicular B cells non-Hodgkin lymphoma and recurrent small lymphocyte lymphoma (SLL), it is possible to and profit
Appropriate former times monoclonal antibody (Rituxan), the chronic lymphocytic leukemia (CLL) of bendamustine therapeutic alliance recurrence.Wherein, China
Chronic lymphocytic leukemia (CLL) sickness rate is 0.05/10 ten thousand, accounts for leukemic 2%.And non-Hodgkin lymphoma (NHL)
It is divided into about more than 30 kind hypotypes；According to tumor growth rate, NHL can be divided into again 3 types, the most poky inertia lymph
Tumor, grow aggressive lymphomas and grow very fast Highly invasive lymphoma, wherein in indolent lymphoma more faster
Commonly follicular lymphoma, accounts for the 25%～30% of NHL.China's NHL sickness rate 7/,100,000, accounts for lymphadenomatous 90
About %.
Idelalisib chemical constitution is as follows:
Patent CO7071131 reports a kind of method preparing crystal formation, molten is then added water clearly in the backflow of methanol/water system by API,
It is cooled to 30-35 DEG C of crystallize.
Summary of the invention
The invention provides a kind of unformed preparation method of inhibitors of kinases Idelalisib, the method has process stabilizing, can grasp
The property made is strong, yield advantages of higher.
A kind of unformed preparation method of Idelalisib, including: Idelalisib is dissolved in good solvent, then is added dropwise to not
In good solvent, stirring and crystallizing, prepare Idelalisib unformed.
Described good solvent means the organic solvent having dissolved Idelalisib, and preferably water-soluble solvent, such as dimethyl sulfoxide, N, N-
Dimethylformamide or alcohol, more preferably methanol, ethanol or isopropanol.
Described poor solvent means the solvent to Idelalisib poor dissolution, preferably aqueous solvent, such as water.
Further, the volume of described poor solvent is more than 5 times of described good solvent, preferably 5-6 times.
Further, described stirring and crystallizing temperature is 0～25 DEG C, preferably 0～15 DEG C.
Further, the time of described stirring and crystallizing is 0.5～3 hour, preferably 2 hours.
Present inventor have discovered that employing forward charging (being joined by poor solvent in Idelalisib solution) prepares Idelalisib without fixed
During type, being easily created that grease is viscous to be difficult to reclaim on the wall, be not suitable for amplifying and produce, yield is the highest.Through anti-
Multiple exploration, the inventors discovered that employing reversely charging (Idelalisib solution is added poor solvent), reacts and become to be easily controlled,
Wall sticking phenomenon will not occur, and yield is the highest.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram of the white powder product of embodiment 1.
Detailed description of the invention
The unformed preparation of embodiment 1:Idelalisib
Weigh Idelalisib (5g), add in methanol (80ml), stir molten clearly, gained solution is instilled 0 DEG C of water (480ml)
In, stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 4.5g white powder product, measure through XRPD, collection of illustrative plates
As shown in Figure 1, i.e. unformed for Idelalisib.
The unformed preparation of embodiment 2:Idelalisib
Weigh Idelalisib (5g), add in methanol (80ml), stir molten clearly, gained solution is instilled 15 DEG C of water (480ml)
In, stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 4.4g white powder product, measure through XRPD, collection of illustrative plates
The most as shown in Figure 1, i.e. unformed for Idelalisib.
The unformed preparation of embodiment 3:Idelalisib
Weigh Idelalisib (5g), add in methanol (80ml), stir molten clearly, gained solution is instilled 25 DEG C of water (480ml)
In, stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 4.2g white powder product, measure through XRPD, collection of illustrative plates
The most as shown in Figure 1, i.e. unformed for Idelalisib.
The unformed preparation of embodiment 4:Idelalisib
Weigh Idelalisib (5g), add in DMF (50ml), stir molten clearly, gained solution is instilled 0
In DEG C water (250ml), stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 3.7g white powder product, through XRPD
Measuring, collection of illustrative plates is the most as shown in Figure 1, i.e. unformed for Idelalisib.
The unformed preparation of embodiment 5:Idelalisib
Weigh Idelalisib (5g), add in DMF (50ml), stir molten clearly, gained solution is instilled
In 15 DEG C of water (250ml), stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 3.6g white powder product, warp
XRPD measures, and collection of illustrative plates is the most as shown in Figure 1, i.e. unformed for Idelalisib.
The unformed preparation of embodiment 6:Idelalisib
Weigh Idelalisib (5g), add in DMF (50ml), stir molten clearly, gained solution is instilled
In 25 DEG C of water (250ml), stirring and crystallizing 2h, filters, 55 DEG C of forced air drying 12h, obtains 3.5g white powder product, warp
XRPD measures, and collection of illustrative plates is the most as shown in Figure 1, i.e. unformed for Idelalisib.
Comparative example: weigh Idelalisib (5g), adds in methanol (80ml), stir molten clearly, under agitation by 0 DEG C of water (480ml)
Joining gained methanol solution, separate out oily solid, continue stirring, grease adheres on bottle wall, transfer difficulty, it is difficult to amplify
Produce.
Claims (10)
- The unformed preparation method of 1.Idelalisib, including: Idelalisib is dissolved in good solvent, is then instilled not Good solvent, stirring and crystallizing, obtain Idelalisib unformed.
- Preparation method the most according to claim 1, it is characterised in that: described good solvent is water-soluble solvent.
- Preparation method the most according to claim 1, it is characterised in that: described good solvent be alcohol, dimethyl sulfoxide or N,N-dimethylformamide.
- Preparation method the most according to claim 3, it is characterised in that: described good solvent is methanol, ethanol or isopropyl Alcohol.
- Preparation method the most according to claim 1, it is characterised in that: described poor solvent is aqueous solvent.
- Preparation method the most according to claim 1, it is characterised in that: described poor solvent is water.
- 7. according to the preparation method described in any one of claim 1-6, it is characterised in that: the temperature of described stirring and crystallizing is 0-25 ℃。
- Preparation method the most according to claim 7, it is characterised in that: described temperature is 0-15 DEG C.
- 9. according to the preparation method described in claim 7 or 8, it is characterised in that: the time of described stirring and crystallizing is that 0.5-3 is little Time, preferably 2 hours.
- 10. according to the preparation method described in any one of claim 1-6, it is characterised in that: the volume of described poor solvent is More than 5 times of described good solvent, preferably 5-6 times.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510138060.4A CN106146501A (en) | 2015-03-26 | 2015-03-26 | A kind of preparation method of unformed inhibitors of kinases |
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| CN201510138060.4A CN106146501A (en) | 2015-03-26 | 2015-03-26 | A kind of preparation method of unformed inhibitors of kinases |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104066722A (en) * | 2012-02-01 | 2014-09-24 | 克莱斯托生物药业有限公司 | Novel therapeutic agents |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
| CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
| CN104334560A (en) * | 2012-03-05 | 2015-02-04 | 吉利德卡利斯托加有限责任公司 | Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one |
| CN104379169A (en) * | 2012-08-14 | 2015-02-25 | Ibc药品公司 | T-cell redirecting bispecific antibodies for treatment of disease |
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
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- 2015-03-26 CN CN201510138060.4A patent/CN106146501A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104066722A (en) * | 2012-02-01 | 2014-09-24 | 克莱斯托生物药业有限公司 | Novel therapeutic agents |
| CN104334560A (en) * | 2012-03-05 | 2015-02-04 | 吉利德卡利斯托加有限责任公司 | Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one |
| CN104379169A (en) * | 2012-08-14 | 2015-02-25 | Ibc药品公司 | T-cell redirecting bispecific antibodies for treatment of disease |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
| CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
| CN104402946A (en) * | 2014-11-17 | 2015-03-11 | 连云港恒运医药科技有限公司 | Invokana intermediate and preparation method thereof in amorphous form |
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| 韩修林: "《中医药基础化学实验》", 31 August 2009 * |
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