CN105985317B - A kind of Preparation Method And Their Intermediate of Ceritinib - Google Patents
A kind of Preparation Method And Their Intermediate of Ceritinib Download PDFInfo
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- CN105985317B CN105985317B CN201510077075.4A CN201510077075A CN105985317B CN 105985317 B CN105985317 B CN 105985317B CN 201510077075 A CN201510077075 A CN 201510077075A CN 105985317 B CN105985317 B CN 105985317B
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- 0 CC(C)Oc(cc(C1CCN(*)CC1)c(C)c1)c1Nc(nc1)nc(Nc2ccccc2S(C(C)C)(=O)=O)c1N Chemical compound CC(C)Oc(cc(C1CCN(*)CC1)c(C)c1)c1Nc(nc1)nc(Nc2ccccc2S(C(C)C)(=O)=O)c1N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to medicinal chemistry arts; more particularly to a kind of Preparation Method And Their Intermediate of Ceritinib, this method is with 2,4 dichloro, 5 nitro-pyrimidine for raw material; V compound of formula is obtained through two step condensation reactions, and Ceritinib is obtained through reduction, chloro and deprotection base R after V compound of formula.This method significantly improves the step reaction yield, and reaction condition is mild, product is purified without column chromatography, is suitble to industrialized production and avoids heavy-metal residual.
Description
Technical field
The present invention relates to medicinal chemistry arts, specifically, the present invention relates to the preparation sides of Ceritinib (Ceritinib)
Method and its intermediate.
Background technology
Ceritinib is a kind of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor researched and developed by Novartis, should
Medicine is in April, 2014 by FDA approvals for having progression of disease after gram azoles is treated for Buddhist nun (Crizotinib) or not being resistant to
Metastatic NSCLC patient treatment, trade name Zykadia.The entitled chloro- N4- of 5- [2- [(the 1- methyl of chemistry of Ceritinib
Ethyl) sulfonyl] phenyl]-N2- [5- methyl -2- (1- methyl ethoxies) -4- (4- piperidyls) phenyl] -2,4- pyrimidinediamines,
Structure is as follows：
The preparation method of a variety of Ceritinibs is disclosed in the prior art, and wherein CN101616895A is disclosed with 2,4,5-
Trichloropyrimidine (formula 1) is raw material, and 3 compound of formula, formula 3 are condensed to obtain with 2- (isopropelsulfonyl) aniline (formula 2) under NaH effects
Compound is with 4 compound of formula in palladium, xantphos and Cs2CO3Under the action of be condensed to obtain 5 compound of formula, 5 compound of formula exists
The lower de- Boc of trifluoroacetic acid (TFA) effect protects to obtain Ceritinib：
In the synthetic method, 3 compound of formula and the condensation reaction of 4 preparation of compounds of formula of formula, 5 compound have the following problems：
1) palladium, xantphos and the Cs used2CO3It is expensive；2) palladium easily causes heavy-metal residual；3) anti-applied microwave
150 DEG C are exposed to, reaction temperature is high, and microwave heating is difficult to use in industrial expanding production；4) product must be through silica gel color
Spectrum purifying so that purification process is complicated, and industrialization is of high cost.
The dihydrochloride that CN103282359A discloses 6 compound of 3 compound of formula and formula flows back 14 hours in 2- propyl alcohol
React to obtain Ceritinib：
Inventor, which tests, to be found, step reaction is not reacted in 82 DEG C of the reflux temperature of 2- propyl alcohol.
The present invention is directed to the above situation, creatively found through overtesting a kind of new Ceritinib preparation method and and its
Intermediate.The preparation method with 2,4-, bis- chloro- 5- nitro-pyrimidines be raw material, avoid using expensive palladium,
Xantphos and Cs2CO3Equal reagents, avoid the heavy-metal residual in final product Ceritinib, and improve reaction yield, in
Mesosome is purified without column chromatography, reduces production cost, is suitble to industrialized production.
Invention content
One aspect of the present invention is to provide a kind of preparation method of Ceritinib, include the following steps：
Step 1, type I compound and II compound of formula react to obtain III compound of formula,
Step 2, III compound of formula and IV compound of formula react to obtain V compound of formula,
Wherein, R is selected from amino protecting group；
Step 3, V compound of reduction-type obtains VI compound of formula,
Step 4, it converts the primary amino group of VI compound of formula to chloro and deprotection base R obtains Ceritinib,
As one embodiment of the present invention, R is selected from tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), tablet held before the breast by officials methoxy carbonyl
Base (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), methoxycarbonyl group, carbethoxyl group, to toluene sulphur
Acyl group (Tos), trifluoroacetyl group (Tfa), ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, benzoyl, three
Benzyl (Trt), to methoxy-benzyl (PMB), benzyl (Bn) or 2,4- dimethoxy-benzyls (Dmb) preferably are selected from tertiary butyloxycarbonyl
Base (Boc) or benzyloxycarbonyl group (Cbz).
As one embodiment of the present invention, in step 1, reaction carries out in the presence of base, and the alkali is selected from inorganic
Alkali or organic base, the inorganic base are selected from sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, hydrogen
Potassium oxide, calcium hydroxide, magnesium hydroxide or barium hydroxide, the organic base are selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, triethylamine, diisopropyl ethyl amine, pyridine, N, N- dimethylamino naphthyridines, piperidines, N- methyl piperidines, beautiful jade or N- methyl
Beautiful jade, preferably diisopropyl ethyl amine.
As one embodiment of the present invention, in step 1, reaction dissolvent be selected from chloroform, dichloromethane, tetrahydrofuran,
Dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, N- crassitudes
Ketone or hexamethyl phosphoramide etc., preferably chloroform.
As one embodiment of the present invention, in step 1, the molar ratio of type I compound and II compound of formula is (0.5-
4):1, preferably (1.05-1.2):1.
As one embodiment of the present invention, in step 2, reaction dissolvent is selected from methanol, ethyl alcohol, propyl alcohol, isopropanol, just
Butanol, the tert-butyl alcohol, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone
Or hexamethyl phosphoramide, preferred alcohol, propyl alcohol, isopropanol, n-butanol or the tert-butyl alcohol.
As one embodiment of the present invention, in step 3, V compound of formula be reduced VI compound of formula reduction side
The method well known by persons skilled in the art that nitro is reduced to amino can be used in method, including uses containing iron reducer, containing zinc also
Former agent, stanniferous reducing agent, Raney Ni catalytic reduction systems, Pd/C catalytic reduction systems, PtO2Catalytic reduction system, preferably iron
Powder-hydrochloric acid, reduced iron powder-ammonium chloride, reduced iron powder-sulfuric acid, zinc powder-hydrochloric acid, zinc powder-ammonium chloride, zinc powder-sulfuric acid etc. are gone back
Original, further preferred iron powder-ammonium chloride.
As one embodiment of the present invention, in step 3, reaction dissolvent is selected from water, methanol, ethyl alcohol, propyl alcohol, isopropyl
Alcohol, n-butanol, the tert-butyl alcohol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone
Or any one or a few the mixed solvent in hexamethyl phosphoramide, preferably water, methanol, ethyl alcohol, propyl alcohol, isopropanol, positive fourth
The mixed solvent of any one or a few of alcohol or the tert-butyl alcohol, more preferable water and methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol or
The mixed solvent of the tert-butyl alcohol.
As one embodiment of the present invention, in step 4, the method for converting the primary amino group of VI compound of formula to chlorine can
Using the method well known by persons skilled in the art for converting primary amino group to chlorine, diazo reagent and chlorination are including but not limited to used
Reagent is reacted, and the diazo reagent can be selected from HNO2、NaNO2、KNO2、EtNO2Or t-BuNO2Deng preferably being selected from t-
BuNO2；The chlorination reagent can be selected from CuCl.
In step 2, prepared by the method that upper amino protecting group well known by persons skilled in the art can be used in raw material IV, such as but
It is not limited to prepare using following routes one：
Or the preparation of following routes two can be used：
Wherein, R-reagent refers to the corresponding reaction reagents of amino protecting group R, for example, when R is Boc, R-reagent is
(Boc)2O。
In step 4, the deprotection base R can be taken off according to the specific type of R using the well known method of this field
It removes.
Another aspect of the present invention is to provide following formula III and formula V compound：
Wherein, R is identical as aforementioned definitions.
Compared with prior art, the present invention reacts preparation with III compound of formula when preparing Ceritinib with IV compound of formula
V compound of formula can significantly improve the step reaction yield, and reaction condition is mild, product is purified without column chromatography, is suitble to
Industrialized production；It avoids using expensive palladium, xantphos and Cs2CO3Reagent, avoid V compound of product formula and
Heavy-metal residual in final product Ceritinib.
Specific implementation mode
Embodiment 1：The synthesis of III compound of formula
Type I compound (117g, 0.603mol), II compound of formula (100g, 0.502mol) are dissolved in 1500mL chloroforms,
After diisopropyl ethyl amine (78g, 0.60mol) is added at room temperature, it is heated to back flow reaction 2 hours.TLC detection reactions finish
Afterwards, it is concentrated to dryness to obtain brown solid 300g.Then 600mL methanol is added, is stirred at 10 DEG C, 152g is obtained after suction filtration
III compound of faint yellow formula, HPLC purity are more than 98%, yield 85%.1H-NMR(300MHz,CDCl3)δ:11.56(s,1H),
9.26(s,1H),8.26(d,1H),8.03(d,1H),7.76(m,1H),7.48(m,1H),3.21(m,1H),1.33(d,6H)
.MS:379.0[M+Na]+,355.0[M-H]-。
Embodiment 2：The synthesis of V-Boc compounds of formula
By III compound of formula (60g, 0.168mol), IV-Boc compounds (64.5g, 0.185mol) of formula be dissolved in 1800mL without
In water-ethanol, it is heated to 60 DEG C and reacts 8 hours, TLC is detected after completion of the reaction, is concentrated to dryness to obtain brown solid.Use PE：EA=3:
1 is recrystallized to give V-Boc compounds of 91g yellow solids formula, and HPLC purity is more than 98%, yield 81%.1H-NMR(300MHz,
CDCl3)δ:11.58(s,1H),9.21(s,1H),8.15(m,3H),7.87(d,1H),7.64(d,1H),7.46(m,1H),
6.73(m,1H),4.28(m,1H),4.14(m,2H),3.28(m,1H),2.82(m,3H),1.93(m,2H),1.72(m,2H),
1.51(m,3H),1.39(m,10H),1.28(m,11H).MS:669.3[M+H]+,691.3[M+Na]+。
Embodiment 3：The synthesis of VI-Boc compounds of formula
V-Boc compounds (20g, 0.030mol) of formula, reduced iron powder (8.1g, 0.145mol), ammonium chloride (15.5g,
0.290mol) it is dissolved in 600mL second alcohol and waters (V:V=2:1) in mixed solution, it is heated to back flow reaction 1h, TLC detection reaction
After, filtering, filtrate is concentrated to dryness to obtain 16.5g celadon solids, and HPLC purity is more than 98%, yield 86%.1H-NMR
(300MHz,CDCl3)δ:9.49(s,1H),8.70(d,1H),8.13(s,1H),7.91(m,2H),7.64(d,1H),7.41
(m,1H),7.28(m,1H),6.72(m,1H),4.56(m,1H),4.27(m,2H),3.30(m,1H),2.84(m,3H),2.23
(m,3H),1.93(m,2H),1.75(m,2H),1.52(m,2H),1.39(m,10H),1.34(m,11H).MS:639.3[M+H
]+,661.3[M+Na]+。
Embodiment 4：The synthesis of Ceritinib
VI-Boc compounds (50g, 0.078mol) of formula, stannous chloride (11.6g, 0.117mol) are added to 2.5L acetone
In, control temperature is at 5-10 DEG C, after being vigorously stirred 30 minutes, after isobutyl nitrite (12.1g, 0.117mol) is added dropwise, continues
After being reacted 1 hour at 5-10 DEG C, it is concentrated to dryness.2M hydrochloric acid 2.5L are added into concentrate, are heated to back flow reaction 1 hour.TLC
The reaction was complete for detection, is extracted 3 times with dichloromethane, organic layer is washed 2 times with saturated aqueous sodium carbonate, the anhydrous sulphur of organic layer
After sour sodium drying, filtering is concentrated to give brown crude product.Crude product ethyl acetate and petroleum ether recrystallize to obtain 37.5g Ceritinibs,
Yield 86%.1H-NMR(300MHz,CDCl3)δ:9.49 (s, 1H), 8.58 (d, J=8.0Hz, 1H), 8.15 (s, 1H), 7.99
(s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.62 (t, J=8.6Hz, 1H), 7.54 (s, 1H), 7.26 (m, 1H), 6.81 (s,
1H),4.51-4.59(m,1H),3.20-3.31(m,3H),2.74-2.81(m,3H),2.19(s,3H),1.58-1.78(m,
4H), 1.36 (d, J=6.0Hz, 6H), 1.28 (d, J=6.0Hz, 6H) .MS:558.2[M+H]+。
Claims (21)
1. a kind of preparation method of Ceritinib, which is characterized in that include the following steps：
Step 1, type I compound and II compound of formula react to obtain III compound of formula,
Step 2, III compound of formula and IV compound of formula react to obtain V compound of formula,
Wherein, R is selected from amino protecting group；
Step 3, V compound of reduction-type obtains VI compound of formula,
Step 4, it converts the primary amino group of VI compound of formula to chloro and deprotection base R obtains Ceritinib,
2. the preparation method of Ceritinib according to claim 1, which is characterized in that R is selected from tertbutyloxycarbonyl, benzyloxy carbonyl
Base, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group, carbethoxyl group, p-toluenesulfonyl, trifluoro
Acetyl group, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, benzoyl, trityl, to methoxy-benzyl,
Benzyl or 2,4- dimethoxy-benzyls.
3. the preparation method of Ceritinib according to claim 2, which is characterized in that R is selected from tertbutyloxycarbonyl or benzyloxy
Carbonyl.
4. the preparation method of Ceritinib according to claim 1, which is characterized in that in step 1, react the presence in alkali
Lower progress, the alkali be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide,
Calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl second
Base amine, pyridine, N, N- dimethylamino naphthyridines, piperidines, N- methyl piperidines, morpholine or N-methylmorpholine.
5. the preparation method of Ceritinib according to claim 4, which is characterized in that in step 1, it is different that the alkali is selected from two
Ethylamine.
6. the preparation method of Ceritinib according to claim 1, which is characterized in that step 1 carries out in reaction dissolvent,
Reaction dissolvent is selected from chloroform, dichloromethane, tetrahydrofuran, dioxane, ether, dimethyl sulfoxide, N,N-dimethylformamide, third
Ketone, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone or hexamethyl phosphoramide.
7. the preparation method of Ceritinib according to claim 6, which is characterized in that in step 1, reaction dissolvent is selected from chlorine
It is imitative.
8. the preparation method of Ceritinib according to claim 1, which is characterized in that in step 1, type I compound and formula
The molar ratio of II compound is 0.5-4:1.
9. the preparation method of Ceritinib according to claim 8, which is characterized in that in step 1, type I compound and formula
The molar ratio of II compound is 1.05-1.2:1.
10. the preparation method of Ceritinib according to claim 1, which is characterized in that step 2 in reaction dissolvent into
Row, reaction dissolvent be selected from methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, dimethyl sulfoxide, n,N-Dimethylformamide,
Acetone, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone or hexamethyl phosphoramide.
11. the preparation method of Ceritinib according to claim 10, which is characterized in that in step 2, reaction dissolvent is selected from
Ethyl alcohol, propyl alcohol, isopropanol, n-butanol or the tert-butyl alcohol.
12. the preparation method of Ceritinib according to claim 1, which is characterized in that in step 3, using iron powder-salt
Acid, reduced iron powder-ammonium chloride, reduced iron powder-sulfuric acid, zinc powder-hydrochloric acid, zinc powder-ammonium chloride or zinc powder-V chemical combination of sulfate reduction formula
Object.
13. the preparation method of Ceritinib according to claim 12, which is characterized in that in step 3, using reduced iron
Powder-V compound of ammonium chloride reduction-type.
14. the preparation method of Ceritinib according to claim 1, which is characterized in that step 3 in reaction dissolvent into
Row, reaction dissolvent are selected from water, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, dimethyl sulfoxide, N, N- dimethyl formyls
Any one or a few mixing in amine, acetonitrile, toluene, dichloroethanes, N-Methyl pyrrolidone or hexamethyl phosphoramide is molten
Agent.
15. the preparation method of Ceritinib according to claim 14, which is characterized in that in step 3, reaction dissolvent is selected from
Any one or a few mixed solvent of water, methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol or the tert-butyl alcohol.
16. the preparation method of Ceritinib according to claim 15, which is characterized in that in step 3, reaction dissolvent is selected from
Water and methanol, the mixed solvent of ethyl alcohol, propyl alcohol, isopropanol, n-butanol or the tert-butyl alcohol.
17. the preparation method of Ceritinib according to claim 1, which is characterized in that in step 4, by VI compound of formula
Primary amino group be converted into chlorine and reacted using diazo reagent and chlorination reagent, the diazo reagent is selected from HNO2、NaNO2、
KNO2、EtNO2Or t-BuNO2；The chlorination reagent is selected from CuCl.
18. the preparation method of Ceritinib according to claim 17, which is characterized in that in step 4, the diazotising examination
Agent is selected from t-BuNO2。
19. compound described in following formula：
Wherein, R is selected from amino protecting group.
20. compound according to claim 19, which is characterized in that the R of V compound of the formula be selected from tertbutyloxycarbonyl,
Benzyloxycarbonyl group, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group, carbethoxyl group, tolysulfonyl
Base, trifluoroacetyl group, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, benzoyl, trityl, to methoxy
Base benzyl, benzyl or 2,4- dimethoxy-benzyls.
21. compound according to claim 20, which is characterized in that the R of V compound of the formula is selected from tertbutyloxycarbonyl
Or benzyloxycarbonyl group.
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| CN109020898A (en) * | 2018-06-20 | 2018-12-18 | 刘耿熙 | A method of preparing anti-tumor drug Ceritinib intermediate |
| CN108689993A (en) * | 2018-06-22 | 2018-10-23 | 苏州市贝克生物科技有限公司 | The preparation method of Ceritinib |
| CN108707120A (en) * | 2018-06-27 | 2018-10-26 | 苏州市贝克生物科技有限公司 | A kind of synthetic method of Ceritinib intermediate |
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| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN101921236A (en) * | 2003-03-14 | 2010-12-22 | 诺瓦提斯公司 | Can be used for treating 2 of neoplastic disease, inflammatory and disorder of immune system, 4-two (phenylamino) pyrimidine |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
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| CN101921236A (en) * | 2003-03-14 | 2010-12-22 | 诺瓦提斯公司 | Can be used for treating 2 of neoplastic disease, inflammatory and disorder of immune system, 4-two (phenylamino) pyrimidine |
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
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