CN106831617A - A kind of synthesis technique of Selinexor intermediates - Google Patents
A kind of synthesis technique of Selinexor intermediates Download PDFInfo
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- CN106831617A CN106831617A CN201710041114.4A CN201710041114A CN106831617A CN 106831617 A CN106831617 A CN 106831617A CN 201710041114 A CN201710041114 A CN 201710041114A CN 106831617 A CN106831617 A CN 106831617A
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- reaction system
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- selinexor
- intermediates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention provides a kind of synthesis technique of Selinexor intermediates, comprise the following steps：After intermediate 2 and~N ' N dimethylformamides are put into reactor, NaOH is added, add Magnesium dichloride hexahydrate, after 2~4h of stirring, the pH to 1.8 2.2 of reaction system is adjusted with hydrochloric acid, through extracting, being concentrated to give intermediate 5.After intermediate 5 and methyl alcohol is put into reactor, formylhydrazine and Ethyl formate is added dropwise, is warming up to 90~95 DEG C, and react 6~8h, added water after cooling, by, washing, thickening filtration, dry to obtain Selinexor intermediates.The method is avoided using NaHS, and toxic gas hydrogen sulfide is not regenerated, and environmental pollution is small, is suitable to industrialized production.
Description
Technical field
The present invention relates to biomedicine technical field, especially, it is related to a kind of synthesis technique of Selinexor intermediates.
Background technology
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, into 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 treatments
The Orphan drug title of leukaemia and diffusivity large B cell lymphoid tumor, in June, 2014, EMA is equally granted by Selinexor treatments
The Orphan drug title of both diseases.In January, 2015, obtain FDA treatment Huppert's disease Orphan drugs and assert.
At present, disclosed synthesis technique, its reaction equation is as follows：
Wherein, 1 is Selinexor bulk drug structural formulas.
But in the method, NaHS is used from intermediate 2 to 3, hydrogen sulfide, hydrogen sulfide can be produced to have when synthetically produced
Poison, taste is very big, and environmental pollution is also big, unfavorable to use industrialized production.
The content of the invention
Present invention aim at a kind of a kind of new synthesis technique of Selinexor intermediates 4 is provided, asked with solving technology
Topic.
A kind of synthesis technique of Selinexor intermediates, comprises the following steps：
A, intermediate 2 is dissolved in~N ' dinethylformamides in, regulation solution to alkalescence adds Magnesium dichloride hexahydrate,
2~4h of stirring；
B, regulation pH to highly acid, intermediate 5 is obtained through extraction, washing, concentration, mashing and drying at room temperature；
C, intermediate 5 is dissolved in methyl alcohol after, be added dropwise formylhydrazine and Ethyl formate, react 6 at a temperature of being warming up to 90~95 DEG C
~8h；
D, lower the temperature and add water and methyl tertiary butyl ether(MTBE), by extraction, washing, concentration, mashing, filtering and dry, obtain
Intermediate 4.
Preferably, in described step a, the temperature control of reaction system is below 15 DEG C.
Preferably, in described step c, before intensification, the temperature control of reaction system is below 10 DEG C.
Preferably, the synthesis technique of described Selinexor intermediates, comprises the following steps：
A, to intermediate 2 and~N ' dinethylformamides is put into reactor after, reaction system is cooled to 12~15
℃；
B, be dividedly in some parts NaOH, and control the temperature of reaction system no more than 15 DEG C, add continuation stir 10~
20min；
C, reaction system is cooled to 8~10 DEG C, Magnesium dichloride hexahydrate is added to reaction system, control precursor reactant system temperature
At 10~15 DEG C；
D, reaction system is warmed to room temperature, stirs 2~4h；
E, the pH of reaction system is adjusted with hydrochloric acid to 1.8-2.2, and control precursor reactant system temperature below 20 DEG C；
F, in reaction system add methyl tertiary butyl ether(MTBE) extract, after stratification, then with methyl tertiary butyl ether(MTBE) extract 2
It is secondary；Merge organic layer, and washed with saturated sodium-chloride 2 times；
G, concentration, residue add petroleum ether mashing, and drying at room temperature obtains intermediate 5；
H, to intermediate 5 and methyl alcohol is put into reactor after, reaction system is cooled to 8~10 DEG C；
I, to formylhydrazine is added dropwise in reaction system；
J, reaction system is cooled to 0~5 DEG C；
K, dropwise addition Ethyl formate, and temperature is controlled at 0~5 DEG C；
L, reaction system is warming up to 90~95 DEG C, and reacts 6~8h at this temperature；
M, reaction system is cooled to 35~40 DEG C, then adds water to reaction system；
N, addition methyl tertiary butyl ether(MTBE) extraction, after stratification, water is mutually extracted with methyl tertiary butyl ether(MTBE) again；Merge organic layer
Afterwards, washed with saturated sodium-chloride 2 times；
O, concentration, remove solvent, and crude product dichloromethane is beaten at room temperature, filter, and dry to obtain intermediate 4.
The synthesis technique of Selinexor intermediates of the invention, its chemical equation is as follows：
The invention has the advantages that：The synthesis technique of Selinexor intermediates of the invention, will be published
The synthesis technique of the important intermediate 4 in the synthesis technique of Selinexor is redesigned, it is to avoid is used NaHS, is not regenerated
Into toxic gas hydrogen sulfide；Environmental pollution is small, is suitable to industrialized production.
In addition to objects, features and advantages described above, the present invention also has other objects, features and advantages.
The present invention is further detailed explanation below.
Specific embodiment
Embodiments of the invention are described in detail below, but the present invention can be limited and covered according to claim
Multitude of different ways implement.
Embodiment 1
A kind of synthesis technique of Selinexor intermediates, comprises the following steps：
A, in the reactor of 50L put into 1560g intermediate 2,6.24L~N ' dinethylformamides after, instead
System is answered to be cooled to 15 DEG C；
B, NaOH is dividedly in some parts, and controls the temperature of reaction system no more than 15 DEG C, added continuation and stir 15min；
C, reaction system is cooled to 9 DEG C, Magnesium dichloride hexahydrate is added to reaction system, control precursor reactant system temperature is 10
~15 DEG C；
D, reaction system is warmed to room temperature, stirs 3h；
E, the pH of reaction system is adjusted with hydrochloric acid to 2.0, and control precursor reactant system temperature below 20 DEG C；
F, the methyl tertiary butyl ether(MTBE) extraction to addition 5L in reaction system, after stratification, then are extracted with methyl tertiary butyl ether(MTBE)
Take (2.5L × 2)；Merge organic layer, and washed (2.5L × 2) with saturated sodium-chloride；
G, concentration, residue add petroleum ether mashing, and drying at room temperature obtains 1912g intermediates 5；
H, in the reactor of 50L put into 1.9kg intermediate 5 and 8.9kg methyl alcohol after, reaction system is cooled to 10
℃；
I, to formylhydrazine is added dropwise in reaction system；
J, reaction system is cooled to 3 DEG C；
K, dropwise addition 666g Ethyl formates, and temperature is controlled at 0~5 DEG C；
L, reaction system is warming up to 90~95 DEG C, and reacts 7h at this temperature；
M, reaction system is cooled to 35~40 DEG C, the water of 28L is then added to reaction system；
N, the 12L extractions of addition methyl tertiary butyl ether(MTBE), after stratification, water is mutually extracted with the methyl tertiary butyl ether(MTBE) of 10L again；Close
And after organic layer, washed with saturated sodium-chloride (6L × 2)；
O, concentration, remove solvent, and crude product dichloromethane 3L is beaten at room temperature, filter, and dry to obtain 1.26kg intermediates
4, liquid phase purity 98.8%.
Embodiment 2
A kind of synthesis technique of Selinexor intermediates, comprises the following steps：
A, in the reactor of 50L put into 1560g intermediate 2,6.24L~N ' dinethylformamides after, instead
System is answered to be cooled to 12 DEG C；
B, NaOH is dividedly in some parts, and controls the temperature of reaction system no more than 15 DEG C, added continuation and stir 20min；
C, reaction system is cooled to 10 DEG C, adds Magnesium dichloride hexahydrate, control precursor reactant system temperature to exist to reaction system
10~15 DEG C；
D, reaction system is warmed to room temperature, stirs 4h；
E, the pH of reaction system is adjusted with hydrochloric acid to 2.2, and control precursor reactant system temperature below 20 DEG C；
F, the methyl tertiary butyl ether(MTBE) extraction to addition 5L in reaction system, after stratification, then are extracted with methyl tertiary butyl ether(MTBE)
Take (2.5L × 2)；Merge organic layer, and washed (2.5L × 2) with saturated sodium-chloride；
G, concentration, residue add petroleum ether mashing, and drying at room temperature obtains 1931g intermediates 5；
H, in the reactor of 50L put into 1.9kg intermediate 5 and 8.9kg methyl alcohol after, reaction system is cooled to 10
℃；
I, to formylhydrazine is added dropwise in reaction system；
J, reaction system is cooled to 0 DEG C；
K, dropwise addition 666g Ethyl formates, and temperature is controlled at 0~5 DEG C；
L, reaction system is warming up to 90~95 DEG C, and reacts 6h at this temperature；
M, reaction system is cooled to 35~40 DEG C, the water of 28L is then added to reaction system；
N, the 12L extractions of addition methyl tertiary butyl ether(MTBE), after stratification, water is mutually extracted with the methyl tertiary butyl ether(MTBE) of 10L again；Close
And after organic layer, washed with saturated sodium-chloride (6L × 2)；
O, concentration, remove solvent, and crude product dichloromethane 3L is beaten at room temperature, filter, and dry to obtain 1.28kg intermediates
4, liquid phase purity 98.6%.
Embodiment 3
A kind of synthesis technique of Selinexor intermediates, comprises the following steps：
A, in the reactor of 50L put into 1560g intermediate 2,6.24L~N ' dinethylformamides after, instead
System is answered to be cooled to 15 DEG C；
B, NaOH is dividedly in some parts, and controls the temperature of reaction system no more than 15 DEG C, added continuation and stir 12min；
C, reaction system is cooled to 8 DEG C, Magnesium dichloride hexahydrate is added to reaction system, control precursor reactant system temperature is 10
~15 DEG C；
D, reaction system is warmed to room temperature, stirs 2h；
E, the pH of reaction system is adjusted with hydrochloric acid to 1.8, and control precursor reactant system temperature below 20 DEG C；
F, the methyl tertiary butyl ether(MTBE) extraction to addition 5L in reaction system, after stratification, then are extracted with methyl tertiary butyl ether(MTBE)
Take (2.5L × 2)；Merge organic layer, and washed (2.5L × 2) with saturated sodium-chloride；
G, concentration, residue add petroleum ether mashing, and drying at room temperature obtains 1903g intermediates 5；
H, in the reactor of 50L put into 1.9kg intermediate 5 and 8.9kg methyl alcohol after, reaction system is cooled to 10
℃；
I, to formylhydrazine is added dropwise in reaction system；
J, reaction system is cooled to 5 DEG C；
K, dropwise addition 666g Ethyl formates, and temperature is controlled at 0~5 DEG C；
L, reaction system is warming up to 90~95 DEG C, and reacts 8h at this temperature；
M, reaction system is cooled to 35~40 DEG C, the water of 28L is then added to reaction system；
N, the 12L extractions of addition methyl tertiary butyl ether(MTBE), after stratification, water is mutually extracted with the methyl tertiary butyl ether(MTBE) of 10L again；Close
And after organic layer, washed with saturated sodium-chloride (6L × 2)；
O, concentration, remove solvent, and crude product dichloromethane 3L is beaten at room temperature, filter, and dry to obtain 1.23kg intermediates
4, liquid phase purity 98.6%.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (5)
1. a kind of synthesis technique of Selinexor intermediates, it is characterised in that the reaction equation of the technique is as follows：
Wherein, compound 4 is Selinexor intermediates prepared by the synthesis technique.
2. the synthesis technique of Selinexor intermediates as claimed in claim 1, it is characterised in that comprise the following steps：
A, intermediate 2 is dissolved in~N ' dinethylformamides in, regulation solution to alkalescence adds Magnesium dichloride hexahydrate, stirring 2
~4h；
B, regulation pH to highly acid, intermediate 5 is obtained through extraction, washing, concentration, mashing and drying at room temperature；
C, intermediate 5 is dissolved in methyl alcohol after, be added dropwise formylhydrazine and Ethyl formate, at a temperature of being warming up to 90~95 DEG C react 6~8h；
D, lower the temperature and add water and methyl tertiary butyl ether(MTBE), by extraction, washing, concentration, mashing, filtering and dry, obtain centre
Body 4.
3. the synthesis technique of Selinexor intermediates as claimed in claim 2, it is characterised in that in described step a, instead
The temperature control of system is answered below 15 DEG C.
4. the synthesis technique of Selinexor intermediates as claimed in claim 2, it is characterised in that in described step c, rises
Wen Qian, the temperature control of reaction system is below 10 DEG C.
5. the synthesis technique of Selinexor intermediates as claimed in claim 1, it is characterised in that comprise the following steps：
A, to intermediate 2 and~N ' dinethylformamides is put into reactor after, reaction system is cooled to 12~15 DEG C；
B, NaOH is dividedly in some parts, and controls the temperature of reaction system no more than 15 DEG C, added continuation and stir 10~20min；
C, reaction system is cooled to 8~10 DEG C, Magnesium dichloride hexahydrate is added to reaction system, control precursor reactant system temperature is 10
~15 DEG C；
D, reaction system is warmed to room temperature, stirs 2~4h；
E, the pH of reaction system is adjusted with hydrochloric acid to 1.8-2.2, and control precursor reactant system temperature below 20 DEG C；
F, in reaction system add methyl tertiary butyl ether(MTBE) extract, after stratification, then with methyl tertiary butyl ether(MTBE) extract 2 times；Close
And organic layer, and washed with saturated sodium-chloride 2 times；
G, concentration, residue add petroleum ether mashing, and drying at room temperature obtains intermediate 5；
H, to intermediate 5 and methyl alcohol is put into reactor after, reaction system is cooled to 8~10 DEG C；
I, to formylhydrazine is added dropwise in reaction system；
J, reaction system is cooled to 0~5 DEG C；
K, dropwise addition Ethyl formate, and temperature is controlled at 0~5 DEG C；
L, reaction system is warming up to 90~95 DEG C, and reacts 6~8h at this temperature；
M, reaction system is cooled to 35~40 DEG C, then adds water to reaction system；
N, addition methyl tertiary butyl ether(MTBE) extraction, after stratification, water is mutually extracted with methyl tertiary butyl ether(MTBE) again；After merging organic layer,
Washed with saturated sodium-chloride 2 times；
O, concentration, remove solvent, and crude product dichloromethane is beaten at room temperature, filter, and dry to obtain intermediate 4.
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| JP2003155276A (en) * | 2001-11-19 | 2003-05-27 | Konica Corp | Method for producing amide oxime |
| CN102459203A (en) * | 2009-04-13 | 2012-05-16 | Irm责任有限公司 | Compositions and methods for modulating retinol binding to retinol binding protein 4 (rbp4) |
| CN103002742A (en) * | 2010-03-05 | 2013-03-27 | 卡尔约药物治疗公司 | Nuclear transport modulatiors 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 |
| WO2014152263A1 (en) * | 2013-03-15 | 2014-09-25 | Karyopharm Therapeutics Inc. | Exo olefin-containing nuclear transport modulators and uses thereof |
-
2017
- 2017-01-17 CN CN201710041114.4A patent/CN106831617A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4514416A (en) * | 1981-02-27 | 1985-04-30 | Torii & Co. Ltd. | Amidine compound, process for producing same and anti-complement agent comprising same |
| JP2003155276A (en) * | 2001-11-19 | 2003-05-27 | Konica Corp | Method for producing amide oxime |
| CN102459203A (en) * | 2009-04-13 | 2012-05-16 | Irm责任有限公司 | Compositions and methods for modulating retinol binding to retinol binding protein 4 (rbp4) |
| CN103002742A (en) * | 2010-03-05 | 2013-03-27 | 卡尔约药物治疗公司 | Nuclear transport modulatiors 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 |
| WO2014152263A1 (en) * | 2013-03-15 | 2014-09-25 | Karyopharm Therapeutics Inc. | Exo olefin-containing nuclear transport modulators and uses thereof |
Non-Patent Citations (2)
| Title |
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| SCHMID THIBAULT E等: "Selective NaOH-catalyzed hydration of aromatic nitriles to amides", 《J. NAME.》 * |
| 傅相锴主编: "《高等有机化学》", 30 April 2003, 北京：高等教育出版社 * |
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