CN106831731B - A kind of synthetic method of Selinexor bulk pharmaceutical chemicals - Google Patents
A kind of synthetic method of Selinexor bulk pharmaceutical chemicals Download PDFInfo
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Abstract
The present invention provides a kind of synthetic methods of Selinexor bulk pharmaceutical chemicals, comprising the following steps: mixes compound 6, methylene chloride and ethyl acetate, compound 4, T are added at low temperature3P and DIPEA is added water after reaction and ethyl acetate, liquid separation, organic phase is evaporated to obtain 7 crude product of compound；Compound 7, glacial acetic acid and sodium iodide are mixed, heated up, reaction；After reaction, water and methylene chloride is added in cooling, is washed through stratification, organic phase, is distilled after dry and is obtained compound 8；After compound 1, DBACO, DMF are mixed, the DMF solution of compound 8, reaction is added dropwise；After completion of the reaction, water is added and ethyl acetate, organic phase are recrystallized to give compound 5 after is evaporated.Synthetic method of the invention overcomes the problem of traditional synthesis technology is easy to produce trans- impurity, reduces synthesis step, improves yield, provides a kind of new technique for the synthesis of Selinexor bulk pharmaceutical chemicals.
Description
Technical field
The present invention relates to biomedicine technical fields, particularly, are related to a kind of synthetic method of Selinexor bulk pharmaceutical chemicals.
Background technique
Selinexor is a kind of oral bio effective as selective core output protein inhibitor, first enters within 2012 and faces
Bed, has carried out 21 clinical tests altogether so far, and indication includes chronic myelogenous leukemia, acute myeloid leukaemia, acute
Lymphocytic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, at neuroblastoma, gynecological tumor, more
Unrestrained property large B cell lymphoid tumor, squamous cell carcinoma, carcinoma of the rectum etc..In May, 2014, it is acute myelogenous that FDA authorizes Selinexor treatment
The Orphan drug title of leukaemia and diffusivity large B cell lymphoid tumor, in June, 2014, EMA are equally granted by Selinexor treatment
The Orphan drug title of both diseases.It obtains FDA and treats the identification of Huppert's disease Orphan drug in January, 2015.
Currently, the synthesis technology having disclosed, reaction equation are as follows:
Wherein, compound 5 is Selinexor bulk pharmaceutical chemicals.
But in this method, it is easy to overturn from 1 to 2 double bond of intermediate, trans- impurity is easy to produce when being synthetically produced,
Compare it is difficult remove, influence yield；In intermediate 3 and 4 synthesis material medicine 5 of intermediate, ultralow temperature is needed, and product needed column
Purifying, yield is only 20%.
Summary of the invention
It is an object of that present invention to provide a kind of synthetic methods of Selinexor raw material drug compound 5, are asked with solution technology
Topic.
A kind of synthetic method of Selinexor bulk pharmaceutical chemicals, comprising the following steps:
A, the synthesis of compound 7
Compound 6, methylene chloride and ethyl acetate are mixed, after stirring and dissolving, compound 4, T are added at low temperature3P
(n-propyl phosphoric anhydride) and DIPEA (n,N-diisopropylethylamine)；Low temperature 25-35min is reacted, to the end of reacting
Methylene chloride is added afterwards and water, liquid separation, organic phase are evaporated to obtain 7 crude product of compound, crude product does not purify directly to be thrown down；
B, the synthesis of compound 8
Compound 7 obtained by upper step, glacial acetic acid and sodium iodide are mixed, are warming up to 110-120 DEG C, reacts 2.5-3.5h；Instead
After answering, system is down to room temperature, and water and methylene chloride is added, after stirring 8-15min, stratification, and organic phase saturated carbon
Sour hydrogen sodium and saturated sodium-chloride washing, distillation obtains 8 crude product of compound after anhydrous sodium sulfate is dry, is dissolved in DMF (fumaric acid diformazan
Ester) in, obtain the DMF solution of compound 8；
C, the synthesis of compound 5
After compound 1, DBACO (triethylene diamine), DMF are mixed, after stirring and dissolving, it is added dropwise to reaction system and walks institute
The DMF solution for obtaining compound 8 after being added dropwise, continues stirring 3-4 hours；After completion of the reaction, water and acetic acid are added into system
Ethyl ester, organic phase is evaporated rear ethyl acetate and petroleum ether is recrystallized to give compound 5.
Preferably, in the step A, the low temperature is 0-2 DEG C.
Preferably, in the DMF solution in the step B, the concentration of 8 crude product of compound is lower than 1%.
The synthetic method of Selinexor bulk pharmaceutical chemicals of the invention, chemical equation are as follows:
The invention has the following advantages: the synthetic method of Selinexor bulk pharmaceutical chemicals of the invention, overcomes traditional
In synthesis technology, it is easy to produce trans- impurity, it is more difficult to remove, it influences yield and needs ultralow temperature, and product needed
Column purification, the low-down problem of yield, reduces synthesis step, improves yield, and the synthesis for Selinexor bulk pharmaceutical chemicals provides
A kind of new technique.
Other than objects, features and advantages described above, there are also other objects, features and advantages by the present invention.
The present invention is further detailed explanation below.
Specific embodiment
The embodiment of the present invention is described in detail below, but the present invention can be limited and be covered according to claim
Multitude of different ways implement.
Embodiment 1
A kind of synthetic method of Selinexor bulk pharmaceutical chemicals, comprising the following steps:
A, the synthesis of compound 7
In the there-necked flask of 50ml, it is added 0.2g compound 6,15ml methylene chloride and 15ml ethyl acetate, after stirring and dissolving,
0.3g compound 4 and 3gT are added at 0 DEG C3P,0.75gDIPEA；System is reacted in 0 DEG C of stirring 30min, wait react knot
50ml methylene chloride and 30ml water, liquid separation are added after beam, organic phase is evaporated to obtain 7 crude product of compound, and crude product does not purify directly past
Lower throwing；
B, the synthesis of compound 8
In the there-necked flask of 50ml, step gained compound 7,40ml glacial acetic acid and 1.38g sodium iodide, are warming up to 115 in addition
DEG C, react 3h；After reaction, system is down to room temperature, and system is transferred in 500ml bottles, and 50ml water and 100ml dichloromethane is added
Alkane, after stirring 10min, stratification, organic phase is washed with saturated sodium bicarbonate and saturated sodium-chloride, after anhydrous sodium sulfate is dry
Distillation obtains 8 crude product of compound, is dissolved in 10mL DMF, obtains the DMF solution of compound 8；
C, the synthesis of compound 5
0.2g compound 1,0.24gDBACO, 20mlDMF are added in 50ml there-necked flask, after stirring and dissolving, to reaction system
The DMF solution of step gained compound 8, after being added dropwise, continues stirring 3.5 hours in dropwise addition；After completion of the reaction, add into system
Enter 20ml water and 50ml ethyl acetate, organic phase is evaporated rear ethyl acetate and petroleum ether is recrystallized to give 0.158g compound 5, receives
Rate 50.9%.
Embodiment 2
A kind of synthetic method of Selinexor bulk pharmaceutical chemicals, comprising the following steps:
A, the synthesis of compound 7
In the there-necked flask of 50ml, it is added 0.2g compound 6,15ml methylene chloride and 15ml ethyl acetate, after stirring and dissolving,
0.3g compound 4 and 3gT are added at 1 DEG C3P,0.75gDIPEA；System is reacted in 1 DEG C of stirring 35min, wait react knot
50ml methylene chloride and 30ml water, liquid separation are added after beam, organic phase is evaporated to obtain 7 crude product of compound, and crude product does not purify directly past
Lower throwing；
B, the synthesis of compound 8
In the there-necked flask of 50ml, step gained compound 7,40ml glacial acetic acid and 1.38g sodium iodide, are warming up to 120 in addition
DEG C, react 2.5h；After reaction, system is down to room temperature, and system is transferred in 500ml bottles, and 60ml water and 120ml dichloro is added
Methane, after stirring 15min, stratification, organic phase is washed with saturated sodium bicarbonate and saturated sodium-chloride, and anhydrous sodium sulfate is dry
Distillation obtains 8 crude product of compound afterwards, is dissolved in 12mLDMF, obtains the DMF solution of compound 8；
C, the synthesis of compound 5
0.2g compound 1,0.24gDBACO, 20mlDMF are added in 50ml there-necked flask, after stirring and dissolving, to reaction system
The DMF solution of step gained compound 8, after being added dropwise, continues stirring 3 hours in dropwise addition；After completion of the reaction, it is added into system
25ml water and 50ml ethyl acetate, organic phase is evaporated rear ethyl acetate and petroleum ether is recrystallized to give 0.152g compound 5, yield
49.0%.
Embodiment 3
A kind of synthetic method of Selinexor bulk pharmaceutical chemicals, comprising the following steps:
A, the synthesis of compound 7
In the there-necked flask of 50ml, it is added 0.2g compound 6,15ml methylene chloride and 15ml ethyl acetate, after stirring and dissolving,
0.3g compound 4 and 3gT are added at 2 DEG C3P,0.75gDIPEA；System is reacted in 0 DEG C of stirring 25min, wait react knot
40ml methylene chloride and 35ml water, liquid separation are added after beam, organic phase is evaporated to obtain 7 crude product of compound, and crude product does not purify directly past
Lower throwing；
B, the synthesis of compound 8
In the there-necked flask of 50ml, step gained compound 7,35ml glacial acetic acid and 1.38g sodium iodide, are warming up to 110 in addition
DEG C, react 3.5h；After reaction, system is down to room temperature, and system is transferred in 500ml bottles, and 50ml water and 100ml dichloro is added
Methane, after stirring 8min, stratification, organic phase is washed with saturated sodium bicarbonate and saturated sodium-chloride, and anhydrous sodium sulfate is dry
Distillation obtains 8 crude product of compound afterwards, is dissolved in 10mL DMF, obtains the DMF solution of compound 8；
C, the synthesis of compound 5
0.2g compound 1,0.24gDBACO, 20mlDMF are added in 50ml there-necked flask, after stirring and dissolving, to reaction system
The DMF solution of step gained compound 8, after being added dropwise, continues stirring 4 hours in dropwise addition；After completion of the reaction, it is added into system
20ml water and 40ml ethyl acetate, organic phase is evaporated rear ethyl acetate and petroleum ether is recrystallized to give 0.155g compound 5, yield
49.9%.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (3)
1. a kind of synthetic method of Selinexor bulk pharmaceutical chemicals, which is characterized in that its chemical equation is as follows:
The following steps are included:
A, the synthesis of compound 7
Compound 6, methylene chloride and ethyl acetate are mixed, after stirring and dissolving, compound 4, T are added at 0-2 DEG C3P and
DIPEA；Stirring 25-35min is reacted, to which methylene chloride and water, liquid separation, being evaporated of organic phase are added after reaction
7 crude product of object is closed, crude product does not purify directly to be thrown down；
B, the synthesis of compound 8
Compound 7 obtained by upper step, glacial acetic acid and sodium iodide are mixed, are warming up to 110-115 DEG C, reacts 2.5-3.5h；Reaction knot
Shu Hou, system are down to room temperature, and water and methylene chloride is added, after stirring 8-15min, stratification, and organic phase unsaturated carbonate hydrogen
Sodium and saturated sodium-chloride washing, distillation obtains 8 crude product of compound after anhydrous sodium sulfate is dry, is dissolved in DMF, obtains compound 8
DMF solution；
C, the synthesis of compound 5
After compound 1, DBACO, DMF are mixed, after stirring and dissolving, the DMF that step gained compound 8 is added dropwise to reaction system is molten
Liquid after being added dropwise, continues stirring 3-4 hours；After completion of the reaction, water is added into system and ethyl acetate, organic phase is evaporated
Ethyl acetate and petroleum ether are recrystallized to give compound 5 afterwards.
2. the synthetic method of Selinexor bulk pharmaceutical chemicals as described in claim 1, which is characterized in that in the step B
In DMF solution, the concentration of 8 crude product of compound is lower than 1%.
3. the synthetic method of Selinexor bulk pharmaceutical chemicals as described in claim 1, which comprises the following steps:
A, the synthesis of compound 7
In the there-necked flask of 50ml, it is added 0.2g compound 6,15ml methylene chloride and 15ml ethyl acetate, after stirring and dissolving, 0
0.3g compound 4 and 3gT are added at DEG C3P,0.75gDIPEA；System is reacted in 0 DEG C of stirring 30min, to after reaction
50ml methylene chloride is added and 30ml water, liquid separation, organic phase are evaporated to obtain 7 crude product of compound, crude product does not purify directly to be thrown down；
B, the synthesis of compound 8
In the there-necked flask of 50ml, step gained compound 7,40ml glacial acetic acid and 1.38g sodium iodide, are warming up to 115 DEG C, instead in addition
Answer 3h；After reaction, system is down to room temperature, and system is transferred in 500ml bottles, and 50ml water and 100ml methylene chloride is added, stirs
After mixing 10min, stratification, organic phase is washed with saturated sodium bicarbonate and saturated sodium-chloride, is distilled after anhydrous sodium sulfate is dry
8 crude product of compound is obtained, is dissolved in 10mL DMF, the DMF solution of compound 8 is obtained；
C, the synthesis of compound 5
0.2g compound 1,0.24gDBACO, 20mlDMF are added in 50ml there-necked flask, after stirring and dissolving, is added dropwise to reaction system
The DMF solution of compound 8 obtained by upper step after being added dropwise, continues stirring 3.5 hours；After completion of the reaction, it is added into system
20ml water and 50ml ethyl acetate, organic phase is evaporated rear ethyl acetate and petroleum ether is recrystallized to give compound 5.
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| WO2019232724A1 (en) * | 2018-06-06 | 2019-12-12 | Xw Laboratories, Inc. | Compounds as nuclear transport modulators and uses thereof |
| WO2020198606A1 (en) * | 2019-03-27 | 2020-10-01 | Karyopharm Therapeutics Inc. | Biomarkers for selinexor |
| CN116514773A (en) * | 2023-04-24 | 2023-08-01 | 重庆汉佩生物科技有限公司 | Verdinexor (KPT-335) and synthesis method of hydrochloride thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842340A (en) * | 2011-07-29 | 2014-06-04 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
| CN103874690A (en) * | 2011-07-29 | 2014-06-18 | 卡尔约药物治疗公司 | Hydrazide containing nuclear transport modulators and uses thereof |
| WO2014205393A1 (en) * | 2013-06-21 | 2014-12-24 | Karyopharm Therapeutics Inc. | Nuclear transport modulators and uses thereof |
| CN107072992A (en) * | 2014-08-15 | 2017-08-18 | 卡尔约药物治疗公司 | Sai Lingkesi polymorph |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842340A (en) * | 2011-07-29 | 2014-06-04 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
| CN103874690A (en) * | 2011-07-29 | 2014-06-18 | 卡尔约药物治疗公司 | Hydrazide containing nuclear transport modulators and uses thereof |
| CN106083827A (en) * | 2011-07-29 | 2016-11-09 | 卡尔约药物治疗公司 | Core transport regulator containing hydrazides and application thereof |
| WO2014205393A1 (en) * | 2013-06-21 | 2014-12-24 | Karyopharm Therapeutics Inc. | Nuclear transport modulators and uses thereof |
| CN107072992A (en) * | 2014-08-15 | 2017-08-18 | 卡尔约药物治疗公司 | Sai Lingkesi polymorph |
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