CN108440420A - The preparation method of tyrosine kinase inhibitor Lapatinib and its key intermediate - Google Patents
The preparation method of tyrosine kinase inhibitor Lapatinib and its key intermediate Download PDFInfo
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- CN108440420A CN108440420A CN201810238587.8A CN201810238587A CN108440420A CN 108440420 A CN108440420 A CN 108440420A CN 201810238587 A CN201810238587 A CN 201810238587A CN 108440420 A CN108440420 A CN 108440420A
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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
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen atoms
Abstract
The invention discloses the preparation methods of tyrosine kinase inhibitor Lapatinib and its key intermediate, belong to field of medicine and chemical technology.The preparation method of the lapatinib intermediate of the present invention, is a kind of completely new preparation method, avoids conventional method reaction step more, and reaction is complicated.The method of the present invention has many advantages, such as that step is short, operation is simple, safe and reliable, yield is high, at low cost, purity is high, pollution is few.
Description
Technical field
The present invention relates to the preparation methods of tyrosine kinase inhibitor Lapatinib and its key intermediate, belong to medicalization
Work field.
Background technology
With the development of modern economy and science and technology, the mankind to the research of disease there has been sufficient experience and
Enough understanding.Even so, cancer and tumour remain one of the primary arch-criminal for threatening human life and health.According to investigation
Show in U.S.'s breast cancer to be to cause the second largest cancer disease due to of women die.Although China is not the country occurred frequently of breast cancer,
But situation is pessimistic, and the growth rate of China's breast cancer incidence is higher by occurred frequently national 1%~2% in recent years.
In vitro and in vivo in various animal models, Lapatinib can inhibit active ErbB-1 and ErbB-2 driving tumours
The growth of cell, and effect has been shown in clinical breast cancer treatment, as a kind of reversible and dual-proxy inhibitor
Drug will overcome the problems, such as resistance that single inhibitor encounters and.This double target spots for targeted therapy of Lapatinib are small
Molecule tyrosine kinase inhibitor (TKIs) has adequately treatment advantage.A kind of small point reversible as double target spots of Lapatinib
Sub- tyrosine kinase inhibitor, by inhibiting the sites ATP of intracellular EGFR and HER2 to be combined with the site, to generate
A kind of reversible inactive structure has the function that the phosphorylation for hindering tumour cell and tumour cell activation.It uses EGFR
Downward signal is blocked with the homogeneity and heterodimer of HER2.At 25 DEG C of room temperature, solubility in water is Lapatinib
7mg/L, in the hydrochloric acid of 0.1mol/L, solubility 1mg/L.This kind of drug shows that it partly declines through pharmacokinetic
Phase is for 24 hours that after medication when 4~6h, blood concentration can arrive peak value.Lapatinib have it is fat-soluble, therefore, pass through adjust diet example
Such as high-fat foods, its bioavilability can be greatly promoted.
Lapatinib, English name：Lapatinib, trade name Tykerb (lapatinib).It is researched and developed by GSK companies
A kind of dual oral tyrosine kinase inhibitor, may act on EGF-R ELISA I types (EGFR or ErbB1) and epidermis
Growth factor receptors I types (HER2 or ErbB2).In March, 2007, U.S. FDA approval listing with Xeloda for being combined treatment
ErbB2 positives advanced breast cancer either received anthracene class, the late period of taxol and trastuzumab treatment or metastatic
Patient with breast cancer.
Entitled N- (the chloro- 4- of 3- ((3- fluorophenyls) methoxyl group) phenyl) -6- (5- (((2- (methylsulfonyls of chemistry of Lapatinib
Base) ethyl) amino) methyl) a 2- furyls) -4- quinazoline amine.Concrete structure is as follows：
It is mainly the following at present about the preparation method of Lapatinib：
WO9935146A1 it has been reported that a kind of Lapatinib preparation method, this method is summarized in following reaction route 1：
In addition, WO2008024439 reports the synthetic method of another Lapatinib, this method is summarized in following anti-
Answer route 2：
The reaction step of this method includes nitrogen protection operation, that is, needs to carry out the Boc protections on N and slough Boc protections,
This can obviously increase operating time and production cost and there may be the close of some other problem such as issues of purification, reaction vessel
Closing property etc., these are all unfavorable for industrialized production.
N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- iodine quinazoline -4- amine (i.e. compound 1, when R be iodine atom) be
Extremely crucial a kind of intermediate during synthesis Lapatinib.
The big seminars of Wang Wu were reported in 2008 using the chloro- 4- nitrophenols of 2- as starting material, under acetone solvent environment,
Potassium carbonate, potassium iodide and fluorobenzyl chloride is added, obtains the chloro- 4- of 3- (3- fluorobenzyloxies) nitrobenzene.Then in THF, add
Enter hydrazine hydrate, 40 DEG C of temperature control carries out nitro reduction, can obtain the chloro- 4- of 3- (3- fluorine benzyloxy) aniline (2), then with the chloro- 6- of 4-
Iodine quinazoline carries out condensation reaction, obtains title intermediate N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- iodine quinazolines -4-
Amine, yield 82%, as follows：
The strong seminars of Cai Zhi propose a kind of improvement project.They take first progress 3- chloro- 4- [(3- luorobenzyls) oxygen
Base] aniline this substance synthesis, then by docking it with parent nucleus, to produce title intermediate.Pole in this synthetic method
It is Williamson etherification reactions for a crucial step.By a series of experiments listed in document, Cai Zhi is strong etc. has found most
Suitable reaction condition.Optimal reaction temperature should be controlled at 35 DEG C, be higher than this temperature, and reaction speed is accelerated, and by-product generates
It is more, it is less than this temperature, reaction carried out slow, wasted time, and reaction is not thorough, and yield is down to 34%.It is eventually found
Optimal conditions is, with
As alkaline reagent, acetone reacts 12h at 35 DEG C, can realize 90% ideal recovery as solvent potassium carbonate,
It is shown below.
The chloro- 6- iodine quinazolines of 4- are a kind of indispensable intermediate participation reactants in above two synthesis paths, so
And this substance is produced, it needs that quinazolinone chlorination is obtained product, both the above substance using oxalyl chloride or thionyl chloride
There is larger harm to environment, also has damage to health, in addition product postprocessing complex steps.
2- aminobenzonitriles then with the starting material that 2- aminobenzonitriles are reaction, are first carried out iodo by Ji Xing, Sun Xu seminar,
Iodo agent is lodine chloride.Then product 2- amino -5- iodine benzonitrile contracts with DMF-DMA, that is, N,N-dimethylformamide diformazan after iodo
Aldehyde carries out condensation reaction.Condensation can obtain N '-(2- cyano -4- iodophenyls)-N, N- dimethyl carbonamidines.Carry out next step Dimroth
Decompression is needed to boil off DMF-DMA remaining in system before rearrangement reaction, in experiment.Then under glacial acetic acid environment, N '-(2- cyano-
4- iodophenyls)-N, N- dimethyl carbonamidine and the formation imino group pyrimidine intermediate of intermediate 2, it is reset by a step Dimroth
To title intermediate 3, yield 82%.Its ingenious place is to take bromine that ICl is replaced to carry out halogenating reaction, so that it may with
N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- bromine quinazoline -4- amine (3) is obtained, which provides original to Suzuki couplings
Material, and ultimate yield is good, substantially conforms to the requirement of input industrialized production.However, lodine chloride and water in entire reaction process
Close the use of hydrazine, it is possible to lead to environmental pollution.
Therefore, although the synthetic method of N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- iodine quinazoline -4- amine is a variety of more
Sample, document report are using the chloro- 4- nitrophenols of 2- or 2- aminobenzonitriles as raw material mostly, and reaction step is cumbersome, and yield is low, and
Use the reagent of high pollution.
Invention content
To solve the above problems, the present invention provides, a kind of step is short, operation is simple, safe and reliable, yield is high, cost
It is low, purity is high, pollute few lapatinib intermediate preparation method.
The first purpose of the invention is to provide a kind of preparation method of lapatinib intermediate, the method is passing through
It closes object 2 and 4 single step reaction of compound generates compound 1；
Wherein compound 1 is
Compound 2 is
Compound 4 is
In one embodiment of the invention, the R in the compound 1 or compound 2 be nitro, fluorine, chlorine, bromine, iodine,
Boric acid base group,Wherein R1For nitro, fluorine, chlorine, bromine, iodine ,-OH ,-OTS ,-OMS ,-OTfS ,-CN,
NH-Boc, 2- (methyl sulphonyl) second -1- amidos, 2- (methyl mercapto) second -1- amidos or 2- (methylsulfinyl) second -1- amine
Base； R2For nitro, fluorine, chlorine, bromine, iodine,-OH,-OTS,-OMS,-OTfS,-CN, NH-Boc, 2- (methyl sulphonyl) second -1- amine
Base, 2- (methyl mercapto) second -1- amidos or 2- (methylsulfinyl) second -1- amidos.
In one embodiment of the invention, the compound 4 is prepared by compound 3；
Wherein, compound 3 is
In one embodiment of the invention, the preparation method of the compound 4 is：
In one embodiment of the invention, the technological process of the method is：
In one embodiment of the invention, the method specifically comprises the following steps：
(1) compound 3 is reacted with trimethyl orthoformate or triethyl orthoformate in a solvent and in the presence of a catalyst
To compound 4；
(2) compound 4 reacts in a solvent and in the presence of a catalyst cyclization and obtains compound 1 with compound 2.
In one embodiment of the invention, the solvent in the step (1) be toluene, benzene, acetonitrile, THF, alcohols,
Ethers or hydro carbons.
In one embodiment of the invention, compound 3 and trimethyl orthoformate or orthoformic acid three in the step (1)
The ratio of ethyl ester is 1:1~4.
In one embodiment of the invention, the catalyst in the step (1) is acetic acid.
In one embodiment of the invention, the specific reaction condition of the step (1) is to be placed in reaction mixture
70~90 DEG C of 0.8~1.2h of reaction are heated in oil bath；Then 100~120 DEG C of 1.5~2.5h of reaction are warming up to, reaction terminates
After be cooled to room temperature, be placed in ice bath and solid be precipitated, filter, filter cake washs to obtain compound 4 with solvent.
In one embodiment of the invention, the solvent in the step (2) be acetic acid, formic acid, toluene, benzene, acetonitrile,
THF, alcohols, ethers or hydro carbons.
In one embodiment of the invention, the ratio of compound 2 and compound 4 is 1 in the step (2):1~4.
In one embodiment of the invention, catalyst is 4- toluenesulfonic acids, acetic acid in the step (2).
In one embodiment of the invention, the specific reaction condition of the step (2) is that mixture is placed in oil bath
In be heated to 100~120 DEG C of 4~6h of reaction, ice water is poured into reaction solution after being cooled to room temperature, is filtered after stirring, filter cake is with molten
Agent is washed, and compound 1 is obtained after dry.
Advantages of the present invention and effect：
Preparation method of the present invention has advantages several in this way：(1) synthetic route is shorter；(2) making for high pollution raw material is avoided
With；(3) yield is high, and the yield of the compound of the present invention 4 reaches 93.7%, and the yield of compound 1 reaches 92.2%；(4) cost
It is low；(5) product purity is high；(6) " three wastes " are few.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of compound 4；
Fig. 2 is the HPLC collection of illustrative plates of compound 1.
Specific embodiment
The computational methods of yield：After product drying, yield=actual production/theoretical yield * 100%.
The HPLC assay methods of compound 4：Waters high performance liquid chromatographs, chromatographic column (C18250*4.6*4um), column
Warm (25 DEG C), methanol:0.2% triethylamine aqueous solution=80:20, flow velocity 0.5ml/min, Detection wavelength 293nm.
The HPLC assay methods of compound 1：Waters high performance liquid chromatographs, chromatographic column (C18250*4.6*4um), column
Warm (25 DEG C), acetonitrile:Aqueous solution=70 of 0.3 ammonium acetate:30, flow velocity 1.0ml/min, Detection wavelength 254nm.
Here is that the present invention is specifically described.
Embodiment 1：(E)-N'- (3- chloro- 4-((3- luorobenzyls) oxygroup) phenyl)-N- (((3- luorobenzyls) oxygen of 3- chloro- 4-
Base) phenyl) carbonamidine (compound 4) preparation
The chloro- 4- of 3- ((3- luorobenzyls) oxygroup) aniline (12.58g, 50mmol) is added in 100ml toluene, stirs evenly
Afterwards be added 0.4g acetic acid (making catalyst), then at room temperature with charging hopper be added dropwise triethyl orthoformate (3.8g,
25mmol), it loads onto reaction mixture to be placed in oil bath after Dean-Stark devices after completion of dropwise addition and is heated to 80 DEG C of reaction 1h,
Ethyl alcohol is collected by Dean-Stark devices；Then 110 DEG C of reaction 2h are warming up to, is cooled to room temperature after reaction, is placed in ice bath
Middle precipitation solid, filtering, filter cake are washed to obtain (E)-N'- (3- chloro- 4-((3- chlorobenzyls) oxygroup) phenyl)-N- with a little toluene
(the chloro- 4- of 3- ((3- luorobenzyls) oxygroup) phenyl) carbonamidine 12.4g, yield 93.7%.HPLC purity 99.14%.
Embodiment 2：(E)-N'- (3- chloro- 4-((3- luorobenzyls) oxygroup) phenyl)-N- (((3- luorobenzyls) oxygen of 3- chloro- 4-
Base) phenyl) carbonamidine (compound 4) preparation
The chloro- 4- of 3- ((3- luorobenzyls) oxygroup) aniline (12.58g, 50mmol) is added in 100ml benzene, after stirring evenly
0.4g acetic acid (making catalyst) is added, trimethyl orthoformate (2.65g, 25mmol) then is added dropwise with charging hopper at room temperature,
It loads onto reaction mixture to be placed in oil bath after Dean-Stark devices after completion of dropwise addition and is heated to 80 DEG C of reaction 1h, pass through
Dean-Stark devices collect ethyl alcohol；Then 110 DEG C of reaction 2h are warming up to, is cooled to room temperature after reaction, is placed in ice bath and analyses
Go out solid, filter, filter cake is washed to obtain (E)-N'- (3- chloro- 4-((3- chlorobenzyls) oxygroup) phenyl)-N- (3- with a little toluene
Chloro- 4- ((3- luorobenzyls) oxygroup) phenyl) carbonamidine 11.9g, yield 89.9%.
Embodiment 3：(compound 1, R are -6- iodine quinazoline -4- amine N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygroup) phenyl)
Iodine) preparation
(8.69g, 16.2mmol) (E)-N'- (3- chloro- 4-((3- chlorobenzyls) oxygroup) phenyl)-N- (chloro- 4-((3- fluorine of 3-
Benzyl) oxygroup) phenyl) carbonamidine and (3.72g, 15.23mmol) 2- amino -5- iodobenzenes formonitrile HCN, 0.2g 4- toluenesulfonic acids be added to
In 50mL toluene, it is placed in oil bath and is heated to 110 DEG C of reaction 5h, TLC monitoring after reaction, rotated to corpusculum after being cooled to room temperature
Product, ice water is poured into reaction solution, is filtered after stirring, and filter cake is washed with 90% methanol (100ml), and vacuum drying obtains yellowish
Color solid 7.1g, yield 92.2%.HPLC purity 99.6%.
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not limited to the present invention, any to be familiar with this skill
The people of art can do various change and modification, therefore the protection model of the present invention without departing from the spirit and scope of the present invention
Enclosing be subject to what claims were defined.
Claims (10)
1. a kind of preparation method of lapatinib intermediate, which is characterized in that the method is by compound 2 and compound 4
Single step reaction generates compound 1；
Wherein compound 1 is
Compound 2 is
Compound 4 is
Wherein, the R in compound 1 or compound 2 be nitro, fluorine, chlorine, bromine, iodine, boric acid base group,
Wherein R1 is nitro, fluorine, chlorine, bromine, iodine,-OH,-OTS,-OMS,-OTfS,-CN, NH-Boc, 2- (methyl sulphonyl) second -1- amine
Base, 2- (methyl mercapto) second -1- amidos or 2- (methylsulfinyl) second -1- amidos；R2 be nitro, fluorine, chlorine, bromine, iodine ,-OH ,-
OTS,-OMS,-OTfS,-CN, NH-Boc, 2- (methyl sulphonyl) second -1- amidos, 2- (methyl mercapto) second -1- amidos or 2- (first
Base sulfinyl) second -1- amidos.
2. according to the method described in claim 1, it is characterized in that, the compound 4 is prepared by compound 3；
Wherein, compound 3 is
3. according to the method described in claim 1, it is characterized in that, the method specifically comprises the following steps：
(1) compound 3 in a solvent and in the presence of a catalyst with trimethyl orthoformate or being obtained by the reaction of triethyl orthoformate
Close object 4；
(2) compound 4 reacts in a solvent and in the presence of a catalyst cyclization and obtains compound 1 with compound 2.
4. according to the method described in claim 3, it is characterized in that, solvent in the step (1) be toluene, benzene, acetonitrile,
THF, alcohols, ethers or hydro carbons；Catalyst is acetic acid in the step (1).
5. according to the method described in claim 3, it is characterized in that, in the step (1) compound 3 and trimethyl orthoformate or
The ratio of triethyl orthoformate is 1:1~4.
6. according to the method described in claim 3, it is characterized in that, the specific reaction condition of the step (1) is that will react mixed
Conjunction object, which is placed in oil bath, is heated to 70~90 DEG C of 0.8~1.2h of reaction；Then 100~120 DEG C of 1.5~2.5h of reaction are warming up to,
It is cooled to room temperature after reaction, is placed in ice bath and solid is precipitated, filter, filter cake is washed to obtain compound 4 with solvent.
7. according to the method described in claim 3, it is characterized in that, solvent in the step (2) be acetic acid, formic acid, toluene,
Benzene, acetonitrile, THF, alcohols, ethers or hydro carbons.
8. according to the method described in claim 3, it is characterized in that, the ratio of compound 2 and compound 4 is in the step (2)
1:1~4.
9. according to the method described in claim 3, it is characterized in that, catalyst is 4- toluenesulfonic acids, second in the step (2)
Acid.
10. according to the method described in claim 3, it is characterized in that, the specific reaction condition of the step (2) is by mixture
It is placed in oil bath and is heated to 100~120 DEG C of 4~6h of reaction, ice water is poured into reaction solution after being cooled to room temperature, is filtered after stirring,
Filter cake is washed with solvent, and compound 1 is obtained after dry.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010061400A1 (en) * | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
| WO2011039759A1 (en) * | 2009-09-29 | 2011-04-07 | Natco Pharma Limited | A new process for the preparation of lapatinib and its pharmaceutically acceptable salts |
| CN102459174A (en) * | 2009-04-23 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Processes for preparation of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline |
| CN107698523A (en) * | 2017-09-26 | 2018-02-16 | 盐城师范学院 | A kind of preparation method of tyrosine kinase inhibitor Gefitinib |
-
2018
- 2018-03-22 CN CN201810238587.8A patent/CN108440420A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010061400A1 (en) * | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
| CN102459174A (en) * | 2009-04-23 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Processes for preparation of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline |
| WO2011039759A1 (en) * | 2009-09-29 | 2011-04-07 | Natco Pharma Limited | A new process for the preparation of lapatinib and its pharmaceutically acceptable salts |
| CN107698523A (en) * | 2017-09-26 | 2018-02-16 | 盐城师范学院 | A kind of preparation method of tyrosine kinase inhibitor Gefitinib |
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