CN108558828A - The preparation method of tyrosine kinase inhibitor Vande Thani and its key intermediate - Google Patents
The preparation method of tyrosine kinase inhibitor Vande Thani and its key intermediate Download PDFInfo
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- 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
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Abstract
The invention discloses tyrosine kinase inhibitor Vande Thani and its preparation methods of key intermediate, belong to medicine, field of fine chemical.The preparation method of the Gefitinib of the present invention, is a kind of completely new preparation method, no matter from that intermediate, can obtain satisfactory target compound.The method of the present invention has that step is short, operation is simple, safe and reliable, yield is high, at low cost, purity is high, pollutes less and simple operation and other advantages.
Description
Technical field
The present invention relates to tyrosine kinase inhibitor Vande Thani and its preparation method of key intermediate, belong to medicine,
Field of fine chemical.
Background technology
Intracellular signal transduction is one of the research hotspot of current home and abroad, point of proto-oncogene and antioncogene product
Cloth is related to outside cell membrane to whole signal transduction systems in cell membrane, and the signal transmission of film external signal and film is signal transduction
Primary committed step in the process, most typical example be growth factor with its receptor in conjunction with and activated receptor.Tyrosine kinase
Most common growth factor receptors, by block tyrosine kinase can tumoricidal signal transmit, it is anti-to reach
The purpose of tumour.Receptor tyrosine kinase inhibitors include single target spot tyrosine kinase inhibitor and the suppression of multiple target point tyrosine kinase
Preparation.Cell signaling processes are complicated, are related to the biochemical system of polyprotein structure and function variation, and table is crossed by single factors
Up to determine whether there is tumour growth perhaps not comprehensive, it is intended to block some receptor by single target drug to block tumour thin
All signal transductions of born of the same parents, curative effect may be not objective enough, it is also possible to cause drug resistance, then produce the concept of multiple target point drug.
Vande Thani (vandetanib) be researched and developed by AstraZeneca pharmaceutical Co. Ltd of Britain (AstraZeneca) it is small
Molecule multiple receptor tyrosine kinases inhibitor.U.S. FDA approval listing, trade name Zactima are obtained in April, 2011.The medicine
For tablet, it to be used for the treatment of adult patients late period medullary carcinoma of thyroid gland.
Vande Thani is a kind of multiple receptor tyrosine kinases inhibitor, belongs to aniline quinazoline class compound, " two generations are easy by title
Auspicious sand " acts not only on EGFR, VEGFR and RET tyrosine kinase of tumour cell, may also suppress other tyrosine kinase with
And serine/threonine kinase.Vande Thani is the medullary thyroid carcinoma medicine of first approval, and being suitable for treatment cannot
The medullary thyroid carcinoma for having symptom or progress of excision, Locally Advanced or transfer.One random, placebo clinical test
The results show that Vande Thani can significantly delay the time that Locally Advanced or metastatic medullary thyroid carcinoma are in progress.Recommend
Daily dosage is 300mg (oral), should then stop treating when patient generates tolerance to drug or is impatient at its toxicity.The medicine
Most common adverse reaction is diarrhea, fash, acne, nausea, hypertension, headache, tired, anorexia and abdominal pain.Its is bad
Reaction generation is related to dosage,<When 300mg/d, patient's tolerance is good, and maximum tolerated dose (MTD) is 300mg.II phase
There are many disease that clinical research is related to.China is carrying out the clinical test of Vande Thani treatment NSCLC at present.Vande Thani energy
The development for inhibiting medullary carcinoma of thyroid gland is the drug for treating the disease of first acquisition FDA approvals, will be treatment adult patients
Late period medullary carcinoma of thyroid gland provides help.
The chemical name of Vande Thani is 4- (4- bromo-2-fluoroanilinos) -6- methoxyl groups -7- [(1- methyl piperidine -4- bases)
Methoxyl group] quinazoline.Concrete structure is as follows
It is mainly the following at present about the preparation method of Vande Thani：
Method 1：The synthetic method that Astrazeneca AB reports Vande Thani in patent CN100376567C is as follows：
The route is restored using 4- piperidine ethyl formates as starting material through Boc (tertbutyloxycarbonyl) protections amino, ester group
1- tertbutyloxycarbonyl -4- tolysulfonyl is made to 4- t-butoxycarbonylpiperidin methanol, then with paratoluensulfonyl chloride activated hydroxyl groups
Oxygen methyl piperidine, then protected with the condensation of vanillic acid ethyl ester, de- Boc, reduction amination obtains key intermediate
I, after through nitrification, reduction, cyclization, chlorination, then obtain Vande Thani with 4- bromo- 2- fluoroanilines generation substitution reactions.Above-mentioned road
Boc protections reaction, de- Boc protections reaction has occurred in the synthesis of key intermediate I in line, then with reduction amination method in piperidinyl-1
Position introduces methyl, and reaction step is more, and Boc protecting group molecular weight is big, and Atom economy is relatively low.
Method 2：The method that WO2007 36713 and WO2010 028254 are reported is as follows：
Using vanillic acid as raw material, 7- benzyloxy -6- methoxyl group -3,4- dihydros are obtained through alkylation, nitrification, reduction, cyclization
Quinazoline-4-one, then obtain 7- [(1- tertbutyloxycarbonyls) piperidines -4- methoxyl groups]-through chlorination, condensation, deprotection, condensation reaction
Deprotection, reductive amination process finally occur under the conditions of formaldehyde formic acid for 4- (the bromo- 2- fluoroanilines of 4-) -6- methoxyquinazoline hydrochlorides
Vande Thani is obtained, but this 5th step of reaction has used the phosphorus oxychloride of high pollution, high-risk to carry out chlorine as chlorination reagent
Change reaction, it is unfriendly to environment, it is unfavorable for industrialized production.
Method 3：WO2001032651 synthesizes Vande Thani with the following method：
Using 1- t-butoxycarbonyl -4- methanesulfonyloxymethyls piperidines as starting material, directly taken with vanillic acid methyl esters
Generation reaction, then again through deprotection, reduction amination, reduction, cyclization, chlorination, ammonification obtains Vande Thani, in the process, no
Only phenolic hydroxyl group is protected and deprotected, be made troubles for industrial production, and use high-risk, highly toxic when chloro
Chlorination reagent phosphorus oxychloride causes pollution to environment.
Method 4：Zhao Ling, Yang Bo reported a kind of method in 2012 on Wuhan University of Technology's journal：
Method 5：CN 105254614 reports a kind of new method of synthesis Vande Thani, and this method is summarized as follows：
The use of chemical compounds I is starting material, through condensation, nitrification, hydro-reduction, addition, oxidation, hydrolysis, addition reaction, system
Obtain Vande Thani compound.The synthetic method starting material cheap and simple is easy to get, and relative to existing first closed loop, chlorination is last again
The route of ammonification, step are reduced, and yield increases, there are still reaction steps it is more, post-processing is cumbersome the problems such as.
Therefore, this field still need to high income, by-product it is few and pollute few Vande Thani preparation method.
Invention content
To solve the above-mentioned problems, the present invention provides a kind of tyrosine kinase inhibitor Vande Thani and its key are intermediate
The preparation method of body is a kind of completely new preparation method, no matter from that intermediate, can be obtained satisfactory
Target compound.The method of the present invention is short with step, operation is simple, safe and reliable, yield is high, at low cost, purity is high, dirty
Dye is less and simple operation and other advantages.
Providing a kind of tyrosine kinase inhibitor Vande Thani and its preparation method of key intermediate, the method is
With any one in compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7 and compound 8
Either multiple compounds carry out compound shown in formula I to kind for starting material or intermediate；
Wherein, Formulas I is
Wherein compound 1 is
Compound 2 is
Compound 3 is
Compound 4 is
Compound 5 is
Compound 6 is
Compound 7 is
Compound 8 is
In one embodiment of the invention, the method includes so that 5 one step of compound is generated compound 6 and again through two
Step generates the step of target compound Vande Thani (i.e. compound shown in Formulas I).
In one embodiment of the invention, the preparation method includes the following steps appointing in (a) to step (f)
It anticipates one or more step：
Step (a)：Compound 1 in the presence of alkali and/or phase transfer catalyst, reacted with halogenation benzyl generate compound 2；
Step (b)：Compound 2 nitrifies in nitration mixture and obtains compound 3；
Step (c)：Hydrogenated reduction in the presence of metallic catalyst of compound 3 obtains compound 4；
Step (d)：Compound 3 is in a solvent and anti-with trimethyl orthoformate or triethyl orthoformate in the presence of a catalyst
It should obtain compound 4；
Step (e)：Compound 4 reacts cyclization with compound 5 and obtains compound 6；
Step (f)：Compound 6 reacts with compound 7 in the presence of alkali and/or phase transfer catalyst and generates compound 8.
Step (g)：For compound 8 in the presence of formaldehyde and formic acid, it is Vande Thani to take off Boc protections to generate compound 9.
In one embodiment of the invention, the halogenation benzyl in the step (a) is iodate benzyl, cylite or chlorination
Benzyl.
In one embodiment of the invention, the alkali in the step (a) is sodium hydroxide, potassium hydroxide, hydrogen-oxygen
Change lithium, cesium hydroxide, barium hydroxide, can also be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate,
Saleratus, caesium bicarbonate can also be the two kinds or more of alkali mixtures composition in above-mentioned alkali.
In one embodiment of the invention, the alkali in the step (e) is in sodium carbonate, potassium carbonate or lithium carbonate
It is one or more.
In one embodiment of the invention, the phase transfer catalyst in the step (a) is iodide, the iodate
Object be sodium iodide, potassium iodide, cesium iodide, various substituent groups organic amine salt iodide, the substituent group include 1~8 carbon
The various aliphatic of atom, alicyclic, aromatic series.
In one embodiment of the invention, the phase transfer catalyst in the step (a) is tetrabutylammonium iodide, three
Ethylbenzyl ammonium iodide is best.
In one embodiment of the invention, in the reaction of the step (a), the halogen element in halogenation benzyl is iodine, bromine
Or chlorine.
In one embodiment of the invention, the mass ratio of compound 1 and halogenation benzyl is 1 in the step (a)：1~
4。
In one embodiment of the invention, the mass ratio of compound 1 and halogenation benzyl is 1 in the step (a)：1.2
~2.0.
In one embodiment of the invention, in the step (b), the nitration mixture can be the concentrated sulfuric acid and concentrated nitric acid
Mixture can also be the mixture of acetic acid and concentrated nitric acid, can also be the mixture of concentrated nitric acid and the concentrated sulfuric acid and acetic acid.
In one embodiment of the invention, in step (b), concentrated nitric acid and concentrated sulfuric acid volume ratio are in the nitration mixture
1~8：1, concentrated nitric acid and acetic acid volume ratio are 1~8 in the nitration mixture：1.
In one embodiment of the invention, in step (b), concentrated nitric acid and concentrated sulfuric acid volume ratio are in the nitration mixture
3~4：1, concentrated nitric acid and acetic acid volume ratio are 3~4 in nitration mixture：1.
In one embodiment of the invention, the metallic catalyst in the step (c) is PtO2, 5%Pd/C or 0%
Pd/C。
In one embodiment of the invention, the pressure of the hydrogen in reaction of the step (c) is 1~8 atmospheric pressure, instead
It is 15~80 DEG C to answer temperature.
In one embodiment of the invention, the pressure of the hydrogen in reaction of the step (c) is 3~5 atmospheric pressure, instead
It is 25~35 DEG C to answer temperature.
In one embodiment of the invention, the solvent of the step (c) is methanol, ethyl alcohol, propyl alcohol or isopropanol
It is one or more.
In one embodiment of the invention, acid is added in the reaction system of the step (c), the acid is organic acid
Or inorganic acid, the organic acid be formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoro methylene sulfonic acid or p-methyl benzenesulfonic acid,
The inorganic acid is hydrochloric acid, dilute sulfuric acid or phosphoric acid.
In one embodiment of the invention, in the reaction system of the step (c) be added acid, it is described acid be hydrochloric acid or
Sulfuric acid, a concentration of the 25~35% of the hydrochloric acid, a concentration of 10%-25% of the sulfuric acid.
In one embodiment of the invention, acid is added in the reaction system of the step (c), the acid is hydrogen chloride
The saturated solution that gas is formed in one kind of multiple mixed solutions of methanol, ethyl alcohol, propyl alcohol, isopropanol
In one embodiment of the invention, the solvent of the step (d) is toluene, benzene, acetonitrile, THF, alcohols, ether
Class or hydro carbons.
In one embodiment of the invention, compound 3 and trimethyl orthoformate or orthoformic acid three in the step (d)
The mass ratio of ethyl ester is 1：1~4.
In one embodiment of the invention, compound 5 is bis- (the bromo- 2- fluorine of 4- of (E)-N, N'- in the step (e)
Phenyl) carbonamidine.
In one embodiment of the invention, the preparation method of described bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines of (E)-N, N'-
By the bromo- 2- fluoroanilines of 4- in solvent appropriate, under the conditions of existing for catalyst, to be reacted with triethyl orthoformate.
In one embodiment of the invention, the preparation method of described bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines of (E)-N, N'-
It is described in solvent appropriate, under the conditions of existing for catalyst, to react the bromo- 2- fluoroanilines of 4- with triethyl orthoformate
Reaction temperature is 70~90 DEG C, reacts 0.5-1h；Collect the ethyl alcohol generated；Then 100-110 DEG C of reaction 1-2h, reaction are warming up to
After be cooled to room temperature, be placed in ice bath and solid be precipitated, filter, filter cake washs to obtain bis- (the bromo- 2- of 4- of (E)-N, N'- with toluene
Fluorophenyl) carbonamidine.
In one embodiment of the invention, the reaction of the step (e) carries out in a solvent, and the solvent is organic
Solvent, the organic solvent are benzene, toluene or Benzene Chloride.
In one embodiment of the invention, catalyst is added in the reaction of the step (e), the catalyst is
Acid.
In one embodiment of the invention, be added acetic acid in the reaction of the step (e), the acetic acid be solvent and
Catalyst.
In one embodiment of the invention, the step (e) is by compound 5 and compound 4 according to molar ratio 1:2
~2:1 mixing.
In one embodiment of the invention, the reaction of the step (e) is to carry out in organic solvent, the solvent
In contain acid catalyst, reaction condition is 100-120 DEG C of reaction 4-6h, cooling after reaction, concentrate, stirring, and what is obtained consolidates
Body substance is directly used in react in next step.
In one embodiment of the invention, the alkali in the step (e) can be sodium hydroxide, potassium hydroxide, hydrogen
Lithia, cesium hydroxide, barium hydroxide can also be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, bicarbonate
Sodium, saleratus, caesium bicarbonate can also be the two kinds or more of alkali mixtures composition in above-mentioned alkali.
In one embodiment of the invention, the alkali in the step (e) is in sodium carbonate, potassium carbonate or lithium carbonate
It is one or more.
In one embodiment of the invention, the phase transfer catalyst in the step (e) be sodium iodide, potassium iodide,
Cesium iodide, various substituent groups organic amine salt iodide, wherein substituent group includes the various aliphatic of 1~8 carbon atom, fat
Ring race, aromatic substituent group.
In one embodiment of the invention, the phase transfer catalyst in the step (e) be tetrabutylammonium iodide or
Triethylbenzyl ammonium iodide.
In one embodiment of the invention, the technological process of the preparation method is
In one embodiment of the invention, the synthetic method of the compound 5 is：
Second object of the present invention be to provide the method prepare can inhibit kinds of tumors growth, transfer and/or
Application in terms of the drug of angiogenesis.
Third object of the present invention is to provide the methods in terms of preparation can increase the drug of cancer cell-apoptosis
Using.
Fourth object of the present invention is to provide the method and is preparing, for treat cannot cut off, Locally Advanced or turn
The application of the medullary thyroid carcinoma for having symptom or progress moved.
Beneficial effects of the present invention：
Preparation method of the present invention has advantages several in this way：
(1) production method of the invention introduces key intermediate 5, so that cyclization and one step of ammonification is completed, synthetic route is shorter；
The production method yield of the present invention is high, and final step yield reaches 78%, and overall yield reaches 54.3%, effectively reduces life
Cost is produced, and while final product purity is up to 99.5%.
(2) it avoids and avoids having used the high pollutions reagent such as phosphorus oxychloride, thionyl chloride, reduce the generation of " three wastes "..
Specific implementation mode
Here is that the present invention is specifically described.
Embodiment 1：The preparation of -3 methoxy benzonitrile of 4- benzyloxies (compound 2)
8.1g 4- hydroxy 3-methoxybenzenes formonitrile HCNs (compound 1) and 8.3g potassium carbonate are added in 100mL acetonitriles, in room
Temperature is lower to stir 10min, 7mL cylites is added after stirring, heating reflux reaction 5h, TLC monitor reaction process；Reaction terminates
Afterwards, it is cooled to room temperature, filters, solvent is evaporated off and obtains crude product, is rinsed to obtain white solid product 12.5g with a small amount of methanol, produce
Rate 96.8%.
Embodiment 2：The preparation of -3 methoxy benzonitrile of 4- benzyloxies (compound 2)
8.1g 4- hydroxy 3-methoxybenzenes formonitrile HCNs (compound 1) and 8.3g potassium carbonate are added in 100mL acetonitriles, in room
Temperature is lower to stir 10min, 7mL benzyl chlorides is added after stirring, heating reflux reaction 5h, TLC monitor reaction process；Reaction terminates
Afterwards, it is cooled to room temperature, filters, solvent is evaporated off and obtains crude product, a small amount of methanol rinses to obtain target product 12.2g, yield
95.7%.
Embodiment 3：The preparation of 4- benzyloxy -5- methoxyl group -2- nitrobenzonitriles (compound 3)
- 3 methoxy benzonitrile (compound 2) of 8.1g 4- benzyloxies is added in 30mL acetic acid, be placed in ice bath
80mL concentrated nitric acids, time for adding 1h are added dropwise dropwise；After completion of dropwise addition, reaction solution is stirred for reaction 1h, TLC and monitors reaction process；
Reaction mixture is poured into 500mL ice water after reaction, crude product is obtained, filters later, filter cake is rinsed with water to obtain
Target product 9.1g, yield 94.7%.
Embodiment 4:The preparation of 2- amino-4-hydroxy -5- methoxy benzonitriles (compound 4)
2.8g 4- benzyloxy -5- methoxyl group -2- nitrobenzonitriles (compound 3) are added in 20mL methanol, Zhi Houjia
Enter 0.2g10%Pd/C, be placed in catalytic hydrogenation device, pressure 45Psi is set after displaced air, is reacted at room temperature to hydrogen not
Until re-absorption, after reaction, filtering is evaporated off solvent and obtains 2- amino-4-hydroxy -5- methoxy benzonitrile 1.5g, yield
91%.
Embodiment 5：The preparation of 4- ((the bromo- 2- fluorophenyls of 4-) amino) -6- methoxyl group -7- alcohol (compound 6)
Bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines (compound 5) of (6.3g, 16.2mmol) (E)-N, N'- and (2.5g,
15.23mmol) 2- amino-4-hydroxies -5- methoxy benzonitriles (compound 4), 0.2g 4- toluenesulfonic acids are added to 50mL toluene
In, it is placed in oil bath and is heated to 110 DEG C of reaction 5h, TLC is monitored after reaction, and after being cooled to room temperature, ice water stirring is added in concentration
Brown solid 5.2g is obtained after 1h, yield 93.7% can be directly used for reacting in next step.
Embodiment 6：(E) preparation (method 1) of bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines (compound 5) of-N, N'-
The bromo- 2- fluoroanilines (9.5g, 50mmol) of 4- are added in 100ml toluene, are stirring evenly and then adding into 0.4g acetic acid and (make
Catalyst), triethyl orthoformate (3.8g, 25mmol) then is added dropwise with charging hopper at room temperature, is loaded onto after completion of dropwise addition
Reaction mixture is placed in oil bath after Dean-Stark devices and is heated to 80 DEG C of reaction 1h, is collected by Dean-Stark devices
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 solid is precipitated, filter, filter cake is used
A little toluene washs to obtain bis- (the bromo- 2- fluorophenyls of 4-) the carbonamidine 9.6g of (E)-N, N'-, yield 97.9%.
Embodiment 7：(E) preparation (method 2) of bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines (compound 5) of-N, N'-
The bromo- 2- fluoroanilines (9.5g, 50mmol) of 4- are added in 100ml benzene, are stirring evenly and then adding into 0.4g acetic acid and (urge
Agent), trimethyl orthoformate (2.65g, 25mmol) then is added dropwise with charging hopper at room temperature, is loaded onto after completion of dropwise addition
Reaction mixture is placed in oil bath after Dean-Stark devices and is heated to 80 DEG C of reaction 1h, is collected by Dean-Stark devices
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 solid is precipitated, filter, filter cake is used
A little toluene washs to obtain (E)-N'- (3- chloro- 4-((3- chlorobenzyls) oxygroup) phenyl)-N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen
Base) phenyl) carbonamidine 9.5g, yield 96.9%.
Embodiment 8：4- (((4- ((the bromo- 2- fluorophenyls of 4-) amino) -6- methoxyquinazoline hydrochloride -7- bases) oxygroup) methyl) piperazine
The preparation of pyridine -1- t-butyl formates (compound 8)
7.3 (20mmol) 4- ((the bromo- 2- fluorophenyls of 4-) amino) -6- methoxyl group -7- alcohol (compound 6) is added to
In 200mLDMF, when being heated to 75 DEG C, 8.9g (24mmol) 4- ((tosyloxy) methyl) piperidines -1- formic acid is added dropwise
The tert-butyl ester (compound 7), time for adding about 1h；During dropwise addition, 1.4g (10mmol) potassium carbonate is added portionwise and (divides 6 batches, in 1h
Add), the reaction was continued after charging 6h.After reaction, it filters, filter cake is rinsed with a little DMF, filtrate decompression concentration, dense
The stirring of 100g ice water is added in contracting object, and target product is obtained by filtration.
Embodiment 9：N- (the bromo- 2- fluorophenyls of 4-) -6- methoxyl groups -7- ((1- methyl piperidine -4- bases) methoxyl group) quinazoline -
The preparation of 4- amine (compound of formula I)
Compound 8 (224g, 0.4mol) is added in 1L methanol, concentrated hydrochloric acid 200mL is added later, was stirred at room temperature
Methanol is removed in night, reduced pressure, and the dilution of 300mL water is added, and filtering, it is 8~9 that filtrate, which is alkalized with sodium bicarbonate to pH, and solid is precipitated,
80% formic acid 250mL and formalin 250mL is added after filtering, is stirred overnight at room temperature, is concentrated under reduced pressure, the dilution of 800mL water is added,
It is 8~9 to be alkalized to pH with sodium bicarbonate, filtering, dry white solid (91.6g, 78%), mp：240~242 DEG C；HPLC is examined
Survey purity:99.5%.
[HPLC normalization methods:Chromatographic column C18 (4.6mm × 250mm, 5 μm), -5% ammonium acetate (70 of mobile phase methanol:30,
Triethylamine is adjusted to pH 8), Detection wavelength 252nm, flow velocity 0.5mL/min, 25 DEG C of column temperature].1HNMR(DMSO-d6)δ:9.53(s,
1H), 8.34 (s, 1H), 7.79 (s, 1H), 7.63-7.67 (d, 1H), 7.56-7.44 (m, 2H), 7.17 (s, 1H), 3.99-
4.04 (d, 2H), 3.94 (s, 3H), 2.77-2.80 (m, 2H), 2.16 (s, 3H), 1.74-1.90 (m, 5H), 1.29-1.41 (m,
2H), LC-ESI-MS (m/z):475[M+H]+。
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. the preparation method of a kind of tyrosine kinase inhibitor Vande Thani and its key intermediate, which is characterized in that described logical
After first synthesizing compoundIt is reacted using chlorination, and with amine, obtains the change described in Formulas I
Close object；Wherein, it is that I is
2. according to the method described in claim 1, it is characterized in that, the method be with compound 1, compound 2, compound 3,
Any one or multiple compounds in compound 4, compound 5, compound 6, compound 7 and compound 8 are starting material
Or intermediate carrys out compound shown in formula I；
Wherein, Formulas I is
Wherein compound 1 is
Compound 2 is
Compound 3 is
Compound 4 is
Compound 5 is
Compound 6 is
Compound 7 is
Compound 8 is
3. according to the method described in claim 1, it is characterized in that, the preparation method includes the following steps (a) to step (f)
In any one or multiple steps：
Step (a)：Compound 1 in the presence of alkali and/or phase transfer catalyst, reacted with halogenation benzyl generate compound 2；
Step (b)：Compound 2 nitrifies in nitration mixture and obtains compound 3；
Step (c)：Hydrogenated reduction in the presence of metallic catalyst of compound 3 obtains compound 4；
Step (d)：Compound 3 is reacted with trimethyl orthoformate or triethyl orthoformate in a solvent and in the presence of a catalyst
To compound 4；
Step (e)：Compound 4 reacts cyclization with compound 5 and obtains compound 6；
Step (f)：Compound 6 reacts with compound 7 in the presence of alkali and/or phase transfer catalyst and generates compound 8.
Step (g)：For compound 8 in the presence of formaldehyde and formic acid, it is Vande Thani to take off Boc protections to generate compound 9.
4. according to the method described in claim 3, it is characterized in that, the halogenation benzyl in the step (a) is iodate benzyl, cylite
Or benzyl chloride, the halogen element in the halogenation benzyl are iodine, bromine or chlorine；The alkali is sodium hydroxide, potassium hydroxide, hydroxide
Lithium, cesium hydroxide, barium hydroxide can also be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, carbon
Potassium hydrogen phthalate, caesium bicarbonate can also be the two kinds or more of alkali mixtures composition in above-mentioned alkali；The phase transfer catalyst is
Iodide, the iodide be sodium iodide, potassium iodide, cesium iodide, various substituent groups organic amine salt iodide, the substitution
Base includes the various aliphatic of 1~8 carbon atom, alicyclic, aromatic series；The mass ratio of the compound 1 and halogenation benzyl is 1：1
~4.
5. with according to the method described in claim 3, which is characterized in that the nitration mixture in the step (b) can be the concentrated sulfuric acid and dense
The mixture of nitric acid can also be the mixture of acetic acid and concentrated nitric acid, can also be the mixing of concentrated nitric acid and the concentrated sulfuric acid and acetic acid
Object；Concentrated nitric acid and concentrated sulfuric acid volume ratio are 1~8 in the nitration mixture：1, concentrated nitric acid and acetic acid volume ratio are 1 in the nitration mixture
~8：1.
6. with according to the method described in claim 3, which is characterized in that the metallic catalyst in the step (c) is PtO2, 5%
Pd/C or 0%Pd/C；The pressure of the hydrogen in reaction is 1~8 atmospheric pressure, and reaction temperature is 15~80 DEG C；The solvent is
Methanol, ethyl alcohol, propyl alcohol or isopropanol it is one or more；Acid is added in reaction system in the step (c), the acid is to have
Machine acid or inorganic acid, the organic acid are formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoro methylene sulfonic acid or to toluene sulphur
Acid, the inorganic acid are hydrochloric acid, dilute sulfuric acid or phosphoric acid；It is described acid be hydrochloric acid or sulfuric acid, the hydrochloric acid a concentration of 25~
35%, a concentration of 10%-25% of the sulfuric acid；The acid can also be hydrogen chloride gas in methanol, ethyl alcohol, propyl alcohol, isopropyl
The saturated solution that one kind of multiple mixed solutions of alcohol are formed.
7. with according to the method described in claim 3, which is characterized in that solvent in the step (d) be toluene, benzene, acetonitrile,
THF, alcohols, ethers or hydro carbons；The compound 3 is 1 with the mass ratio of trimethyl orthoformate or triethyl orthoformate：1~4.
8. according to the method described in claim 3, which is characterized in that compound 5 is the bis- (4- of (E)-N, N'- in the step (e)
Bromo- 2- fluorophenyls) carbonamidine, the preparation method of bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines of (E)-N, N'- is by the bromo- 2- fluorobenzene of 4-
Amine is in solvent appropriate, under the conditions of existing for catalyst, is reacted with triethyl orthoformate, and the reaction temperature is 70~90
DEG C, react 0.5-1h；Collect the ethyl alcohol generated；Then it is warming up to 100-110 DEG C of reaction 1-2h, is cooled to room temperature after reaction,
It is placed in ice bath and solid is precipitated, filter, filter cake is washed to obtain bis- (the bromo- 2- fluorophenyls of the 4-) carbonamidines of (E)-N, N'- with toluene.
9. according to the method described in claim 3, which is characterized in that the reaction of the step (e) carries out in a solvent, the solvent
For organic solvent, the organic solvent is benzene, toluene or Benzene Chloride；Catalyst is added in the reaction of the step (e), it is described to urge
Agent is acid, and the acid is acetic acid, and the acetic acid is solvent and catalyst；The compound 5 is with compound 4 according to molar ratio 1:
2~2:1 mixes, and acid catalyst is contained in the solvent, and reaction condition is 100-120 DEG C and reacts 4-6h, cooling after reaction,
Concentration, stirring, obtained solid matter is directly used in react in next step；The alkali can be sodium hydroxide, potassium hydroxide, hydrogen-oxygen
Change lithium, cesium hydroxide, barium hydroxide, can also be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate,
Saleratus, caesium bicarbonate can also be the two kinds or more of alkali mixtures composition in above-mentioned alkali；The phase transfer catalyst
Be sodium iodide, potassium iodide, cesium iodide, various substituent groups organic amine salt iodide, wherein substituent group include 1~8 carbon original
The various aliphatic of son, alicyclic, aromatic substituent group.
10. application of any method of claim 1~9 in preparing the prevention and treatment for medullary carcinoma of thyroid gland.
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| WO2010028254A2 (en) * | 2008-09-05 | 2010-03-11 | Auspek Pharmaceuticals, Inc. | Substituted quinazoline inhibitors of growth factor receptor tyrosine kinases |
| 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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| 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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