CN108707120A - A kind of synthetic method of Ceritinib intermediate - Google Patents
A kind of synthetic method of Ceritinib intermediate Download PDFInfo
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- CN108707120A CN108707120A CN201810678625.1A CN201810678625A CN108707120A CN 108707120 A CN108707120 A CN 108707120A CN 201810678625 A CN201810678625 A CN 201810678625A CN 108707120 A CN108707120 A CN 108707120A
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- formula
- compound
- ceritinib
- added
- organic solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of Ceritinib intermediate, include the following steps：Under atmosphere of inert gases, the compound of formula (3), the compound of formula (2) and organic base are added in organic solvent, temperature is risen into 50 DEG C to 100 DEG C reactions, obtains the compound of formula (1).Wherein, the molar ratio of the compound of formula (2) compound and formula (3) is 1:1 to 1：4, organic base is diisopropylethylamine or 1,8- Er Danzashuanhuans [5.4.0]The molar ratio of the compound of 11 carbon -7- alkene, organic base and formula (3) is 0.25:1 to 1：1, organic solvent is tetrahydrofuran or acetonitrile, and the quality of organic solvent is 1 to 3 times of the compound quality of formula (3).Reaction equation is as follows.
Description
Technical field
The present invention relates to organic synthesis fields more particularly to organic drug to synthesize field, and in particular among Ceritinib
The synthetic method of body.
Background technology
Ceritinib was approved as the second line treatment drug of ALK positive NSCLC patients in 2015 first, before this these
Patient can receive the ALK inhibitor gram azoles of Pfizer/Merck for the treatment of Buddhist nun first.Therefore once granted, the medicine of Novartis of success
Object can directly treat newest patient NSCLC being diagnosed to be.
The compound of formula (1) is to synthesize the important intermediate of Ceritinib, and it is to use sodium hydrogen as alkali that current original, which grinds route, two
As solvent, 0 DEG C of reaction obtains the compound of formula (1) by column purification again after the completion of reaction for methylformamide and dimethyl sulfoxide,
This method has as following drawbacks, and first is that sodium hydrogen meets water electrode easy firing, brings sizable difficulty to amplification, and effective quantity is difficult to
Confirm；Second is that hydrophilic dimethylformamide and dimethyl sulfoxide is used, as solvent, to be brought very in extraction as solvent
Big repeated work；Third is to react more miscellaneous, it is difficult to react completely, recrystallization behaviour could be carried out after only carrying out column purification
Make.
Invention content
The technical problem to be solved in the present invention is to provide a kind of easy-to-use conjunctions for the intermediate that Ceritinib is important
At method.The compound of formula (1) is medicine intermediates and the important intermediates in relation to drug such as synthesis Ceritinib.
In order to solve the above-mentioned technical problem, present invention employs technical solutions once：
The present invention provides a kind of synthetic methods of Ceritinib intermediate, include the following steps：Under nitrogen atmosphere, will
The compound of formula (3), the compound of formula (2) and organic base are added in organic solvent, and temperature is risen to 50 DEG C to 100 DEG C instead
It answers, obtains the compound of formula (1), reaction equation is as follows：
Wherein, the molar ratio of the compound of formula (2) compound and formula (3) is 1:1 to 1：4, the organic base is two
Wopropyl ethyl amine or 1,8- Er Danzashuanhuans [5.4.0]The molar ratio of the compound of 11 carbon -7- alkene, organic base and formula (3) is
0.25:1 to 1：1, the organic solvent is tetrahydrofuran or acetonitrile, and the quality of organic solvent is the 1 of the compound quality of formula (3)
To 3 times.
Further, the molar ratio of the compound of formula (2) compound and formula (3) is 1:2 to 1：3.
Preferably, the molar ratio of the compound of formula (2) compound and formula (3) is 1:2.5.
Further, organic base is diisopropylethylamine or 1,8- Er Danzashuanhuans [5.4.0]11 carbon -7- alkene.
Preferably, organic base 1,8- Er Danzashuanhuans [5.4.0]11 carbon -7- alkene.
Further, the molar ratio of the compound of organic base and formula (3) is 0.25:1 to 0.75：1.
Preferably, the molar ratio of the compound of organic base and formula (3) is 0.5:1.
Further, organic solvent is tetrahydrofuran or acetonitrile.
Preferably, organic solvent is tetrahydrofuran.
Further, the quality of organic solvent is 1 to 2 times of the compound quality of formula (3).
Further, reaction temperature is 50 DEG C to 100 DEG C.
Further, reaction temperature is 70 DEG C to 90 DEG C.
Preferably, reaction temperature is 80 DEG C.
Further, after the completion of reaction, 35 DEG C to 45 DEG C are naturally cooled to, alcohols solvent is added and stirs 5-24 hours.
Preferably, after the completion of reaction, 40 DEG C are naturally cooled to, alcohols solvent is added and stirs 12 hours.
Further, the alcohols solvent is methanol, ethyl alcohol or isopropanol.
Preferably, the alcohols solvent is isopropanol.
Further, the quality that alcohols solvent is added is 1 to 2 times of organic solvent quality.
Compared with prior art, the present invention has the following advantages：The present invention provides a kind of conjunctions of Ceritinib intermediate
At method, this method is easy to operate, and step is short and environmental-friendly, has a good application prospect.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, so that those skilled in the art can be preferably
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
Embodiment 1
Under nitrogen protection, by the compound (1.9g, 1eq) of formula (3), the compound (1.8g, 1eq) and 1 of formula (2), 8- bis-
Dan Zashuanhuan [5.4.0]11 carbon -7- alkene (0.38g, 0.25eq) are added in acetonitrile (1.9g), and temperature is risen to 50 DEG C instead
It answers, after the completion of reaction, naturally cools to 35 DEG C, methanol (1.9g) is added and stirs 5 hours, be cooled to room temperature, suction filtration obtains formula (1)
Ceritinib midbody compound (0.58g).
Embodiment 2
Under nitrogen protection, by the compound (1.9g, 1eq) of formula (3), the compound (7.2g, 4eq) of formula (2) and diisopropyl
Base ethamine (0.32g, 0.75eq) is added in tetrahydrofuran (5.7g), and temperature is risen to 100 DEG C of reactions, after the completion of reaction, from
45 DEG C are so cooled to, ethyl alcohol (16.1g) is added and stirs 24 hours, is cooled to room temperature, suction filtration obtains the Ceritinib intermediate of formula (1)
Compound (0.48g).
Embodiment 3
Under nitrogen protection, by the compound (1.9g, 1eq) of formula (3), the compound (3.8g, 2eq) and 1 of formula (2), 8- bis-
Dan Zashuanhuan [5.4.0]11 carbon -7- alkene (0.76g, 0.5eq) are added in tetrahydrofuran (3.8g), and temperature is risen to 70 DEG C
Reaction after the completion of reaction, naturally cools to 40 DEG C, and isopropanol (7.6g) is added and stirs 12 hours, is cooled to room temperature, and suction filtration obtains formula
(1) Ceritinib midbody compound (0.73g).
Embodiment 4
Under nitrogen protection, by the compound (1.9g, 1eq) of formula (3), the compound (5.7g, 3eq) and 1 of formula (2), 8- bis-
Dan Zashuanhuan [5.4.0]11 carbon -7- alkene (0.76g, 0.5eq) are added in tetrahydrofuran (3.8g), and temperature is risen to 90 DEG C
Reaction after the completion of reaction, naturally cools to 40 DEG C, and isopropanol (7.6g) is added and stirs 12 hours, is cooled to room temperature, and suction filtration obtains formula
(1) Ceritinib midbody compound (0.82g).
Embodiment 5
Under nitrogen protection, by the compound (1.9g, 1eq) of formula (3), the compound (4.75g, 2.5eq) and 1,8- of formula (2)
Er Danzashuanhuan [5.4.0]11 carbon -7- alkene (0.76g, 0.5eq) are added in tetrahydrofuran (3.8g), and temperature is risen to 80
DEG C reaction, after the completion of reaction, naturally cools to 40 DEG C, isopropanol (7.6g) is added and stirs 12 hours, is cooled to room temperature, suction filtration obtains
The Ceritinib midbody compound (0.88g) of formula (1).
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art on the basis of the present invention made by equivalent substitute or transformation, in the present invention
Protection domain within.Protection scope of the present invention is subject to claims.
Claims (4)
1. a kind of synthetic method of Ceritinib intermediate, which is characterized in that include the following steps：Under nitrogen atmosphere, by formula
(3) compound and organic base of compound, formula (2) are added in organic solvent, and temperature is risen to 50 DEG C to 100 DEG C reactions,
The compound Ceritinib intermediate of formula (1) is obtained, reaction equation is as follows：
Wherein, the molar ratio of the compound of formula (2) compound and formula (3) is 1:1 to 1：4, the organic base is diisopropyl
Base ethamine or 1,8- Er Danzashuanhuans [5.4.0]The molar ratio of the compound of 11 carbon -7- alkene, the organic base and formula (3) is
0.25:1 to 1：1, the organic solvent is tetrahydrofuran or acetonitrile, and the quality of the organic solvent is the chemical combination substance of formula (3)
1 to 3 times of amount.
2. the synthetic method of Ceritinib intermediate as described in claim 1, which is characterized in that after the completion of reaction, natural cooling
To 35 DEG C to 45 DEG C, alcohols solvent is added and stirs 5-24 hours.
3. the synthetic method of Ceritinib intermediate as claimed in claim 2, which is characterized in that the alcohols solvent be methanol,
Ethyl alcohol or isopropanol.
4. the synthetic method of Ceritinib intermediate as claimed in claim 2, which is characterized in that the quality that alcohols solvent is added is
1 to 3 times of organic solvent quality.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810678625.1A CN108707120A (en) | 2018-06-27 | 2018-06-27 | A kind of synthetic method of Ceritinib intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810678625.1A CN108707120A (en) | 2018-06-27 | 2018-06-27 | A kind of synthetic method of Ceritinib intermediate |
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| Publication Number | Publication Date |
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| CN108707120A true CN108707120A (en) | 2018-10-26 |
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| CN201810678625.1A Withdrawn CN108707120A (en) | 2018-06-27 | 2018-06-27 | A kind of synthetic method of Ceritinib intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105985317A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Preparation method for ceritinib and intermediate of ceritinib |
| CN106029646A (en) * | 2014-02-28 | 2016-10-12 | 韩国化学研究院 | Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient |
| CN107531672A (en) * | 2015-03-04 | 2018-01-02 | 诺华股份有限公司 | Prepare the chemical technology of pyrimidine derivatives and its intermediate |
-
2018
- 2018-06-27 CN CN201810678625.1A patent/CN108707120A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029646A (en) * | 2014-02-28 | 2016-10-12 | 韩国化学研究院 | Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient |
| CN105985317A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Preparation method for ceritinib and intermediate of ceritinib |
| CN107531672A (en) * | 2015-03-04 | 2018-01-02 | 诺华股份有限公司 | Prepare the chemical technology of pyrimidine derivatives and its intermediate |
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Application publication date: 20181026 |
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