CN105218463B - The synthetic method of Gefitinib - Google Patents
The synthetic method of Gefitinib Download PDFInfo
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- CN105218463B CN105218463B CN201410238244.3A CN201410238244A CN105218463B CN 105218463 B CN105218463 B CN 105218463B CN 201410238244 A CN201410238244 A CN 201410238244A CN 105218463 B CN105218463 B CN 105218463B
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- acetic acid
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 20
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- -1 p-methyl benzenesulfonic acid ester Chemical class 0.000 claims abstract description 42
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 35
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 84
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- 229960000583 acetic acid Drugs 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000012362 glacial acetic acid Substances 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 20
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
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- 229910017604 nitric acid Inorganic materials 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
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- GLYLMXARZJNUEY-UHFFFAOYSA-N dichloromethane;methanol;hydrate Chemical compound O.OC.ClCCl GLYLMXARZJNUEY-UHFFFAOYSA-N 0.000 claims description 4
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
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- BBDNZMUIQBRBJH-UHFFFAOYSA-N sulfurochloridic acid;toluene Chemical compound OS(Cl)(=O)=O.CC1=CC=CC=C1 BBDNZMUIQBRBJH-UHFFFAOYSA-N 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of preparation method of cancer therapy drug Gefitinib, which is synthesized through novel synthetic intermediate.Before quinazoline female ring is synthesized, the hydroxyl of 3 hydroxypropyls of side chain is first changed into p-methyl benzenesulfonic acid ester, substitute tolysulfonyl epoxide with morpholine again during single step reaction to the end, the operation of pH is debugged repeatedly so as to simplify when whole flow process respectively walks purification of intermediate processing, reduce soda acid dosage and loss of material, purification process is simplified, improves yield.There is big tolysulfonyl group because there is no morpholine group in intermediate structure at the same time, improving the fusing point of each step intermediate is also beneficial to purification process.
Description
Technical field
The present invention relates to a kind of synthetic method of Gefitinib, intermediate used in the method and its preparation are further related to
Method.
Background technology
Gefitinib (Gefitinib, ZD1839, trade name：Iressa it is) that Astrazeneca AB of Britain develops
Antineoplastic target small-molecule drug, lists, is approved in the U.S. and Australia as three in May, 2003 for 2002 in Japan first
Line single therapy medicine is used for the treatment of advanced Non-small cell lung.Entitled 4- (3- the chlorine-4-fluorophenylaminos) -7- methoxies of chemistry
Base -6- (3- morpholines propoxyl group) quinazoline, it can competition cell surface epidermal growth factor recipient tyrosine kinase (EGFR-
TK) on catalysis region Mg-ATP binding site, belong to EGFR-TK inhibitor (EGFR-TKI), by blocking cell surface
EGFR signal transduction pathway hinders growth, transfer and the angiogenesis of tumour, and can induce the apoptosis of tumour cell.Gefitinib
It is not only effective to advanced Non-small cell lung, but also also there is antitumor activity, including prostate cancer, mammary gland to other solid tumors
Cancer, head and neck neoplasm, stomach cancer, intestinal cancer etc..
The preparation method of Gefitinib mainly has following two class：
The more one kind of document report is first to synthesize 7- methoxyl group -3,4- dihydroquinazoline -4- ketone of 6 substitutions, then by 4
React to obtain Gefitinib (EP0566226 with the chloro- 4- fluoroanilines of 3- after chloro；WO1996/33980；WO2005/070909；
WO2004/024703；CN101348471A；CN1733738；China Medicine University's journal, 2005,36 (1)：92-94；Middle traditional Chinese medicines
Thing The Chemicals, 2005,15 (1)：39-41；Bioorganic＆Medicinal Chemistry Letters, 2006,16
(15)：4102-4106).
Wherein R is in different documents by CH3, H, ClCH2CH2, it is eventually converted into
The major defect of this type preparation method is the 4 of the 7- methoxyl group -3,4- dihydroquinazoline -4- ketone of 6 substitutions
The halide reagent of high pollution need to be used during the chloro of position, causes environmental pollution, and step is more, yield is relatively low.
Second class preparation method is the 2- amino-4-methoxyls cyanophenyl and N,N-dimethylformamide dimethyl of 5 substitutions
Acetal generation amidine reacts to obtain Gefitinib with the chloro- 4- fluoroanilines of 3- again；Or the chloro- 4- fluoroanilines of 3- and N, N-- dimethyl methyl
2- amino-4-methoxyl cyanophenyl of the acid amides dimethylacetal generation amidine again with 5 substitutions reacts to obtain Gefitinib.
(WO2004024703, CN101402610A, WO2005/023783) synthetic route is as follows：
Wherein R is in different documents by CH3, H, ClCH2CH2, it is eventually converted into
The difference of each document is mainly H, ClCH in addition to starting material in two types2CH2,Base
The precedence of group's conversion is different.If H is converted into ClCH by the step of below again2CH2, and then introduceThen
Side reaction is more when OH is not protected；OH is deprotected again when protecting, and reactions steps are more.If first OH is changed intoAfter then
Continue each step purification of intermediate to debug pH repeatedly, increase soda acid dosage and loss of material, purification process are cumbersome；And in respectively walking
Between bulk melting point it is relatively low, be unfavorable for purifying, influence yield.
Document (CN102146060A；Chinese journal of Medicinal Chemistry, 2005,15 (1)：39-41 is reported ClCH2CH2Protect
It is left to and is finally then converted intoMethod, pH need to be debugged when avoiding each step purification of intermediate repeatedly, is simplified
Operation.
The content of the invention
The object of the present invention is to provide a kind of environmentally friendly, reactions steps are few, it is each walk intermediate physical behavior it is beneficial
In purification process, and purification process is simple, and yield is higher, is adapted to the Gefitinib preparation method of industrialized production.
The present invention provides a kind of preparation method of compound of formula I Gefitinib,
The present invention is achieved through the following technical solutions：
Compound of formula I Gefitinib has following synthesis step：
Using 3- hydroxyl -4- methoxy benzonitriles and the bromo- 1- propyl alcohol of 3- as raw material, Formula II compound is obtained through alkylated reaction,
Formula II compound reacts to obtain formula III compound with paratoluensulfonyl chloride, then carries out nitration reaction and obtain formula IV compound and then through nitre
Base reduction reaction obtains Formula V compound, reacts to obtain Formula IV compound with N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl carbonamidines again,
Finally Gefitinib is prepared with morpholine reaction；
Wherein in step (a), reaction is alkylated to phenolic hydroxyl group, can be made by many methods well known in the art
It is standby.Such as using 3- hydroxyl -4- methoxy benzonitriles and the bromo- 1- propyl alcohol of 3- as raw material, under the action of suitable catalyst and alkali, in
Reacted in suitable solvent.Suitable solvent is dimethylformamide, benzene,toluene,xylene, acetonitrile；Suitable alkali is carbonic acid
Potassium, sodium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), trimethylamine；Suitable catalyst is tetrabutyl iodate amine, four fourths
Base amine bromide, tetrabutylammonium chloride, potassium iodide；Reaction temperature is 60~100 DEG C；It is preferred that acetonitrile is reaction dissolvent, potassium carbonate is made
For acid binding agent, under potassium iodide catalyst, reaction temperature is 85 DEG C.Acetonitrile solvent post processing is more convenient, potassium alkaline ratio
Sodium carbonate is strong, makes reaction be easier to occur, without purifying, can direct plunge into the next step；3- hydroxyls -4- methoxybenzenes in reaction
Formonitrile HCN:The bromo- 1- propyl alcohol of 3-:The molar ratio of potassium carbonate is 1:1~2:2~4, preferably 1:1.2:2.
In step (b), the reaction of Formula II compound and paratoluensulfonyl chloride in suitable solvent, alkali and catalyst into
OK, suitable solvent such as dichloromethane, ethyl acetate；Inorganic base is sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；Catalysis
Agent is DMAP；It is preferred that dichloromethane is solvent；Sodium carbonate is as acid binding agent；DMAP is as catalyst；Compound II with to toluene
The molar ratio of sulfonic acid chloride is 1:1~3, preferably 1:1.2；15~40 DEG C of reaction temperature, preferably carries out at room temperature.
In step (c), nitration reaction can be carried out easily using a variety of methods.Nitration reaction system chooses mixed acid system
Or single nitric acid system, mixed acid system is acetic acid and nitric acid, sulfuric acid and nitric acid, acetic acid and fuming nitric aicd, acetic acid and sulfuric acid and
Fuming nitric aicd, sulfuric acid and fuming nitric aicd；It is preferred that single nitric acid system.Formula III compound is 1 with nitric acid molar ratio:5~15,
It is preferred that 1:9.6.Range of reaction temperature is preferably reacted at room temperature at 0~70 DEG C.The amount for adding frozen water is the 3 of formula III compound by weight
~6 times, preferably 4 times.
In step (d), nitro reduction can be realized by many methods well known in the art.Such as by catalytic hydrogenation also
Original, reducing agent are hydrogen, and this hydrogenation is such as to be supported on inert carrier such as palladium or platinum on carbon in suitable metallic catalyst
In the presence of, catalyst is the palladium carbon, hydrochloric acid or acetic acid of 2%-20% (percentage by weight) content, in atent solvent or diluent
Carried out in such as water, polar protic solvent or non-protonic solvent ethyl acetate.Reducing agent preferably for example can be living
The metal iron powder of change, zinc powder, sodium hydrosulfite (sodium dithionite) etc..Preferably solvent is：Water, Methanol-water, Methanol-water-
Dichloromethane, Methanol-water-dichloromethane-TBAB (tetrabutylammonium bromide), acetonitrile-water, ethyl acetate-water equal solvent body
System；Reducing agent is iron powder, zinc powder or sodium hydrosulfite.Most preferably sodium hydrosulfite is reducing agent, and ethyl acetate-water is dicyandiamide solution, carbonic acid
Sodium is catalyst.The molar ratio of compound III and sodium hydrosulfite is 1:2~4, preferably 1:3.Reaction temperature is 50~80 DEG C, preferably
For 60~65 DEG C.Sodium hydrosulfite is selected to be to post-process simplicity for reducing agent advantage, and sodium hydrosulfite is cheap.
In step (e), in a suitable solvent, the chloro- 4- fluoroanilines of 3- are first with DMF-DMA under glacial acetic acid effect, in 80
When~120 DEG C of reactions 1.5 are small, solvent, excessive DMF-DMA, glacial acetic acid are removed under reduced pressure, room temperature in vacuo drying, it is solid to obtain white
Body N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl carbonamidines.Wherein suitable solvent includes benzene,toluene,xylene, glacial acetic acid,
Preferably toluene.The chloro- 4- fluoroanilines of 3-:DMF-DMA:Glacial acetic acid molar ratio is 2~6:2~8:1, preferably 4:4.8:1.Reaction temperature
Degree is preferably 100 DEG C.
N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl carbonamidine is under glacial acetic acid effect, with compound V in suitable solvent
In when 120~138 DEG C of reactions 1 are small, solvent and glacial acetic acid is evaporated off, adds the stirring of a little dichloromethane and water, suction filtration obtains white
Color solid chemical compound VI.Wherein suitable solvent includes benzene,toluene,xylene, glacial acetic acid, is preferably dimethylbenzene.Compound V with
The molar ratio of glacial acetic acid is 0.5~1.5:1, it is preferably 1:1.Reaction temperature is preferably 130 DEG C.
In step (f), Formula IV compound 3- [4- (3- chlorine-4-fluorophenylaminos) -7- methoxyl group -6- quinazolyls epoxide]
Propyl group -4- toluenesulfonic acids ester is reacted with morpholine, and optional solvent has n,N-Dimethylformamide, morpholine etc..Reaction temperature is 60
~100 DEG C, preferably 80 DEG C.It is preferred that morpholine makees solvent, reaction speed is most fast and reaction is most complete.
Present invention also offers a series of new intermediates as described below：
And its application of the intermediate in Gefitinib is synthesized.
Present invention also offers the preparation method of the intermediate.
The preparation method of intermediate III compound, including with 3- hydroxyls -4-methoxybenzaldehyde (isovanillin) for starting
Convert aldehyde groups are obtained 3- hydroxyl -4- methoxy benzonitriles by raw material with hydroxyl sulfate reaction for cyano group, then with the bromo- 1- propyl alcohol of 3-
Formula II compound is reacted to obtain, Formula II compound reacts to obtain formula III compound again with paratoluensulfonyl chloride.
The solvent of 3- hydroxyl -4- methoxy benzonitriles 1- propyl alcohol reaction bromo- with 3- is dimethylformamide, benzene, toluene, two
Toluene, acetonitrile；Inorganic base is potassium carbonate, sodium carbonate；Organic base is triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), trimethylamine；
Catalyst is tetrabutyl iodate amine, four butyl bromation amine, tetrabutylammonium chloride, potassium iodide；Reaction temperature is 60~100 DEG C；It is excellent
It is reaction dissolvent to select acetonitrile, and for potassium carbonate as acid binding agent, potassium iodide is catalyst.Acetonitrile solvent post processing is more convenient, carbonic acid
Potash is stronger than sodium carbonate, makes reaction be easier to occur, without purifying, can direct plunge into the next step.Formula II compound with it is right
The reaction of toluene sulfochloride carries out in suitable solvent, alkali and catalyst, such as methylene chloride, ethyl acetate；Inorganic base
For sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus；Catalyst is DMAP；The molar ratio of compound II and paratoluensulfonyl chloride
For 1:1~3,15~40 DEG C of reaction temperature.
The preparation method of intermediate compound IV compound is 3- (5- cyano group -2- methoxyphenoxies) propyl group -4- of nitration III
Toluenesulfonic acid ester, obtains 3- (5- cyano group -2- methoxyl groups -4-nitrophenoxy) propyl group -4- toluenesulfonic acid esters of formula IV.
Nitration reaction can be carried out using concentrated nitric acid, optionally in the presence of the concentrated sulfuric acid, and be optionally present polar protic
Carried out under conditions of solvent such as acetic acid, range of reaction temperature is at 0~70 DEG C.Formula III compound and the molar ratio of nitric acid are 1:5~
15.It is preferred that single concentrated nitric acid system, room temperature reaction, the system convenient post-treatment, a large amount of products can be separated out by adding frozen water, and
Purity is very high.The amount for adding frozen water is 3~6 times of formula III compound by weight.
The preparation method of intermediate V compounds is：3- (5- cyano group -2- methoxyl groups -4-nitrophenoxy) propyl group of formula IV -
4- toluenesulfonic acid esters, then the nitro of formula IV is reduced into amino, obtain the 3- (4- amino-5-cyano -2- methoxybenzenes of Formula V
Epoxide) propyl group -4- toluenesulfonic acid esters.
Nitro reduction can be realized by many methods well known in the art.Such as reduced by catalytic hydrogenation, this hydrogen
Change is the catalyst 2%-20% in the presence of suitable metallic catalyst is such as supported on palladium or platinum on inert carrier such as carbon
The palladium carbon, hydrochloric acid or acetic acid of (percentage by weight) content, in atent solvent or diluent such as water, polar protic solvent or non-
Carried out in protonic solvent ethyl acetate etc..Reducing agent preferably for example can be the metal iron powder, zinc powder, sodium hydrosulfite of activation
(sodium dithionite) etc..Preferably solvent is：Water, Methanol-water, Methanol-water-dichloromethane, Methanol-water-dichloromethane
Alkane-TBAB (tetrabutylammonium bromide), acetonitrile-water, ethyl acetate-water equal solvent system.Most preferably sodium hydrosulfite is reducing agent,
Ethyl acetate-water is dicyandiamide solution, and sodium carbonate is catalyst, and the molar ratio of compound III and sodium hydrosulfite is 1:2~4, reaction
Temperature is 50~80 DEG C.Sodium hydrosulfite is selected to be to post-process simplicity for reducing agent advantage, and sodium hydrosulfite is cheap.
The preparation method of intermediate VI compounds is：Formula V compound and N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl methyls
Amidine reacts to obtain.
Its compound of formula V can be prepared with method disclosed by the invention, can also pass through other methods known to chemical field
Prepare.
Actual conditions is：(1) in toluene, the chloro- 4- fluoroanilines elder generations of 3- and n,N-Dimethylformamide dimethylacetal
(DMF-DMA) under glacial acetic acid effect, in 80~120 DEG C of reactions；The chloro- 4- fluoroanilines of 3-:DMF-DMA:Glacial acetic acid molar ratio is 2
~6:2~8:1, remove solvent, excessive DMF-DMA, glacial acetic acid under reduced pressure, room temperature in vacuo drying, obtains white solid N'- (3-
Chloro- 4- fluorophenyls)-N, N- dimethyl carbonamidines, (2) again with compound V glacial acetic acid effect under, in 120~138 in dimethylbenzene
DEG C reaction, the molar ratio of compound V and acetic acid is 0.5~1.5:1, solvent xylene and glacial acetic acid is evaporated off, adds a little dichloro
Methane and water stirring, suction filtration obtain compound as white solid VI.
The preparation method of the present invention has the advantages that compared with prior art：
(1) use of the halogenating agent of high pollution, such as thionyl chloride, phosphorus oxychloride is completely avoid, is greatly reduced
Environmental pollution so that production environment is more friendly；
(2) before quinazoline female ring is synthesized, the hydroxyl of the 3- hydroxypropyls of side chain is first changed into p-methyl benzenesulfonic acid ester, is arrived
Substitute tolysulfonyl epoxide with morpholine again when final step is reacted, respectively walked so as to simplify whole flow process at purification of intermediate
The operation of pH is debugged during reason repeatedly, soda acid dosage and loss of material is reduced, simplifies purification process, improve yield.While because
There is no morpholine group in intermediate structure and have big tolysulfonyl group, improving the fusing point of each step intermediate is also beneficial to
Purification process.When final step introduces morpholinyl using nucleophilic substitution, substituted is tolysulfonyl epoxide, with other roads
It is more preferable leaving group to substitute chlorine to compare tolysulfonyl epoxide in line, and reaction is more easy to carry out, and yield improves.
(3) preparation method is synthesized through novel synthetic intermediate, shorter, easy to operate, the economic ring of synthesis step
Protect, total recovery significantly improves, suitable industrialized production.
Embodiment
With reference to embodiment, the present invention is further illustrated, but is not limited thereto.
Embodiment 1：The preparation of 3- hydroxyl -4- methoxy cyanophenyls
By the 3- hydroxyls of 10.0g (65.8mmol) -4-methoxybenzaldehyde (isovanillin), the formic acid of 50.0mL, 8.3g
The sodium formate of (0.12mol) is placed in the three-necked bottle of 100mL, and temperature is raised to 85 DEG C under stirring, at this temperature by sulfuric acid hydroxyl
Amine 4.4g (33.9mmol) divides 8 times in two hours to be added in reaction bulb, and it is 5 small that the reaction was continued at this temperature after adding
When, then stop heating, be cooled to room temperature, the distilled water of 25mL is added into reaction bulb, constantly stirring, filtered after half an hour
Go out solid, washed with 10mL frozen water, it is dry, obtain pulverulent solids 8.4g (85.7%) mp of taupe brown:130-132℃.1H-
NMR(CDCl3) 3.96 (3H, s), 5.79 (1H, br s), 6.89 (1H, d, J=8.4Hz), 7.17 (1H, d, J=1.8Hz),
7.21 (1H, dd, J=8.4Hz, 1.8Hz)
Embodiment 2：The preparation of 3- (3- hydroxy propyloxy groups) -4- methoxy cyanophenyls (II)
6.0g (40mmol) 3- hydroxyl -4- methoxy cyanophenyls, the bromo- 1- third of 6.67g (48mmol) 3- are added in reaction bulb
Alcohol and 42mL acetonitriles, stirring, after the dissolving of 3- hydroxyl -4- methoxy cyanophenyls, adds 11g (80mmol) Anhydrous potassium carbonate, heating
To 85 DEG C, reaction 11 it is small when after, be cooled to room temperature, filter desalination, washed with acetonitrile, filtrate concentration, separate out white solid, washing
3 times, weigh 8.07g (yield 96.9%, content 99.6%) mp after dry:91-93℃.1H-NMR(CDCl3)2.05-2.15
(2H, m), 2.20 (1H, t, J=5.7Hz), 3.80-3.96 (5H, m), 4.20 (2H, t, J=5.7Hz), 6.90 (1H, d, J=
8.4Hz), 7.11 (1H, d, J=1.8Hz), 7.29 (1H, dd, J=8.4Hz, 1.8Hz)
Embodiment 3：The preparation of 3- (5- cyano group -2- methoxyphenoxies) propyl group -4- toluenesulfonic acids ester (III)
By 3- (3- hydroxy propyloxy groups) -4- methoxy cyanophenyls of 8.4g (40mmol), the Carbon Dioxide of 4.24g (40mmol)
Sodium, the DMAP of 2.4g (20mmol), the dichloromethane of 40mL are added in the three-necked bottle of 250mL, and holding is stirred under room temperature,
After the paratoluensulfonyl chloride of 9.15g (48mmol) is dissolved with 50mL dichloromethane, it is slowly dropped in three-necked bottle, takes around
3 it is small when, treat drop finish can stop reacting, filter, discard solid, wash filtrate twice with the dilute hydrochloric acid (2%) of 50mL, then use
30mL saturated sodium bicarbonate solutions washed once, and distilled water washes twice, and is dried overnight with anhydrous sodium sulfate, filter, concentration, room
Temperature vacuum drying, obtains white solid 14.22g (97.1%) mp:50-51℃.1H-NMR(CDCl3)2.15-2.20(2H,m),
2.40 (3H, s), 3.87 (3H, s), 3.97 (2H, t, J=6.0Hz), 4.29 (2H, t, J=6.0Hz), 6.88 (1H, d, J=
8.4Hz), 6.95 (1H, d, J=1.6Hz), 6.26-7.31 (3H, m), 7.77 (2H, d, J=8.4Hz)
Embodiment 4：The preparation of 3- (5- cyano group -2- methoxyl groups -4-nitrophenoxy) propyl group -4- toluenesulfonic acids ester (IV)
By 3- (5- cyano group -2- methoxyphenoxies) propyl group -4- toluenesulfonic acid esters of 10.9g (30.17mmol), 20mL
Concentrated nitric acid (65%) (0.441mol) is added in the eggplant-shape bottle of 250mL, is stirred at room temperature, 1 it is small when after separate out a large amount of solids, continue
Stir 1 it is small when, stop reaction, add 40mL frozen water, stir 5min, filter, filter cake with frozen water wash to pH value be 7 or so, do
It is dry, obtain white solid 11.2g (91.37%), mp:167-168℃.1H-NMR(DMSO-d6)2.00-2.15(2H,m),2.26
(3H, s), 3.87 (3H, s), 4.12 (2H, t, J=6.0Hz), 4.18 (2H, t, J=6.0Hz), 7.35 (2H, d, J=
8.1Hz), 7.59 (1H, s), 7.73 (2H, d, J=8.1Hz), 7.85 (1H, s)
Embodiment 5：The preparation of 3- (4- amino-5-cyano -2- methoxyphenoxies) propyl group -4- toluenesulfonic acids ester (V)
10.44g (25.7mmol) 3- (5- cyano group -2- methoxyl groups -4-nitrophenoxy) third is added in 250mL reaction bulbs
Base -4- toluenesulfonic acids ester, 150mL ethyl acetate, are heated to 60 DEG C, stirring is largely dissolved for 1 hour to nitro intermediate, is added
Enter 30mL water, add 4.47g (25.7mmol) sodium hydrosulfites and 0.28g (2.6mmol) sodium carbonate, when reaction 1 is small after add 4.47g
(25.7mmol) sodium hydrosulfite and 0.28g (2.6mmol) sodium carbonate, then react 1 it is small when after add 4.47g (25.7mmol) sodium hydrosulfite
With 0.28g (2.6mmol) sodium carbonate, stop reaction when 1 is small after last time charging, be cooled to room temperature, separate water layer, acetic acid second
Ester layer 150mL5% salt acid elutions, then washed with 150mL saturated aqueous sodium carbonates, it is washed with water and washs twice, with anhydrous sulphur
Sour sodium drying, is evaporated off solvent, obtains 8.7g faint yellow solids (yield 90%) mp：103-105℃.1H-NMR(CDCl3)2.00-
2.15 (2H, m), 2.43 (3H, s), 3.81 (3H, s), 3.87 (2H, t, J=6.0Hz), 4.26 (2H, t, J=6.0Hz), 6.23
(1H, s), 6.69 (1H, s), 7.30 (2H, d, J=8.0Hz), 7.78 (2H, d, J=8.0Hz)
Embodiment 6：N'- (the chloro- 4- fluorophenyls of 3-)-N, the preparation of N- dimethyl carbonamidines
By the chloro- 4- fluoroanilines of 15.3g (0.105mol) 3-, the DMF-DMA (0.126mol) of 15.0g, 50mL toluene,
The glacial acetic acid of 1.5mL (26mmol) is added in the eggplant type bottle of 250mL, temperature is risen to 100 DEG C under stirring, at this temperature instead
Answer 1.5 it is small when, stop reaction, remove solvent, excessive DMF-DMA, glacial acetic acid under reduced pressure, room temperature in vacuo is drying for one day, obtains
2.0g white solids (yield 99.7%).1H-NMR(CDCl3)3.02(6H,s),6.77-6.82(1H,m),6.90-7.03(1H,
m),7.46(1H,s).
Embodiment 7：3- [4- (3- chlorine-4-fluorophenylaminos) -7- methoxyl group -6- quinazolyls epoxide] propyl group -4- methyl
The preparation of benzene sulfonate (VI)
By 3- (4- amino-5-cyano -2- methoxyphenoxies) propyl group -4- toluenesulfonic acids of 4.0g (10.6mmol)
Ester, N'- (the chloro- 4- fluorophenyls of 3-)-N of 2.2g (11mmol), N- dimethyl carbonamidines, the glacial acetic acid of 0.6mL (10mmol), 50mL
Dimethylbenzene be added in 100mL three-necked bottles, stirring is warming up to 130 DEG C, and when reaction 1 is small, solvent and glacial acetic acid is evaporated off, and adds few
Perhaps dichloromethane and water stirring, suction filtration obtain white solid 5.2g (yield 92%), mp：142-144℃.1H-NMR(CDCl3)
2.21 (2H, penta, J=6.0Hz), 2.39 (3H, s), 3.93 (3H, s), 4.13 (2H, t, J=6.0Hz), 4.30 (2H, t, J
=6.0Hz), 7.01 (1H, s), 7.26-7.40 (4H, m), 7.50-7.54 (2H, m), 7.65 (1H, s), 7.77 (2H, d, J=
7.8Hz).
Embodiment 8：(Ji Fei is replaced quinazoline 4- (3- chlorine-4-fluorophenylaminos) -7- methoxyl groups -6- (3- morpholines propoxyl group)
Buddhist nun) preparation
By the 3- [4- (3- chlorine-4-fluorophenylaminos) -7- methoxyl group -6- quinazolyls epoxide] third of 5.0g (9.4mmol)
Base -4- toluenesulfonic acids ester is added in reaction bulb, and 15mL morpholines are added dropwise, and stirring is warming up to 80 DEG C, when reaction 2 is small, stops reaction,
Excessive morpholine is evaporated off, is cooled to room temperature, adds 10mL water, the stirring of 5mL dichloromethane, separates out substantial amounts of khaki solid, take out
Filter, solid stirs in the mixed liquor of 10mL water and 10mL dichloromethane, then filters, washes, and weighs after dry, obtains khaki
Solid powder 4.12g, yield 98.3%.1H-NMR(DMSO-d6)：2.00 (penta, 2H, J=6.6Hz), 2.40-2.60 (m,
6H), 3.07 (s, 6H), 3.70-3.75 (m, 4H), 3.88 (s, 3H), 4.03 (t, 2H, J=6.6Hz), 7.20 (s, 1H, Ar-
H), 7.44 (t, 1H, J=9.0Hz), 7.70-7.85 (m, 2H, Ar-H), 8.18 (dd, 1H, J=6.9Hz, 2.4Hz), 8.50
(s, 1H), 9.56 (s, 1H).
Claims (16)
1. a kind of synthetic method of Gefitinib, it is characterised in that with 3- hydroxyl -4- methoxy benzonitriles and the bromo- 1- propyl alcohol of 3-
For raw material, Formula II compound is obtained through alkylated reaction, Formula II compound reacts to obtain formula III compound with paratoluensulfonyl chloride, then
Carry out nitration reaction obtain formula IV compound then through nitro-reduction reaction obtain Formula V compound, again with N'- (the chloro- 4- fluorobenzene of 3-
Base)-N, N- dimethyl carbonamidines react to obtain Formula IV compound, finally prepare Gefitinib with morpholine reaction；
2. synthetic method as claimed in claim 1, it is characterised in that effect of the alkylated reaction in catalyst and alkali
Under, reacted in suitable solvent, the solvent is dimethylformamide, benzene,toluene,xylene, acetonitrile；The alkali is
Potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), trimethylamine；Catalyst is tetrabutyl iodate amine, the tetrabutyl
Amine bromide, tetrabutylammonium chloride, potassium iodide；Reaction temperature is 60~100 DEG C；3- hydroxyl -4- methoxy benzonitriles and the bromo- 1- of 3-
Propyl alcohol:The molar ratio of alkali is 1:1~2:2~4.
3. synthetic method as claimed in claim 2, it is characterised in that effect of the alkylated reaction in catalyst and alkali
Under, being reacted in suitable solvent, the solvent is acetonitrile, and the alkali is potassium carbonate, and the catalyst is potassium iodide,
Reaction temperature is 85 DEG C；3- hydroxyl -4- methoxy benzonitriles:The molar ratio of the bromo- 1- propyl alcohol of 3- and potassium carbonate is 1:1.2:2.
4. the synthetic method as described in claim 1 or 2 or 3, it is characterised in that Formula II compound that alkylated reaction obtains with
The reaction of paratoluensulfonyl chloride is reacted in suitable solvent, alkali and catalyst, and the solvent is selected from dichloromethane or acetic acid
Ethyl ester；Alkali is sodium carbonate, potassium carbonate, sodium acid carbonate or saleratus；Catalyst is DMAP；Formula II compound and tolysulfonyl
The molar ratio of chlorine is 1:1~3；15~40 DEG C of reaction temperature.
5. synthetic method as claimed in claim 4, it is characterised in that Formula II compound that alkylated reaction obtains with to toluene
In the reaction of sulfonic acid chloride, the solvent is dichloromethane, and the alkali is sodium carbonate, Formula II compound and paratoluensulfonyl chloride
Molar ratio be 1:1.2, reaction temperature is room temperature.
6. the synthetic method as described in claim 1-3 any one, it is characterised in that the nitration reaction system is nitration mixture
System or single nitric acid system, mixed acid system are acetic acid and nitric acid, sulfuric acid and nitric acid, acetic acid and fuming nitric aicd, acetic acid and sulphur
Acid and fuming nitric aicd, sulfuric acid and fuming nitric aicd；When the nitration reaction system is single nitric acid system, formula III compound with
Nitric acid molar ratio is 1:5~15；Range of reaction temperature is at 0~70 DEG C.
7. synthetic method as claimed in claim 6, the nitration reaction system is single nitric acid system, formula III compound
It is 1 with nitric acid molar ratio:9.6, reaction temperature is room temperature.
8. the synthetic method as described in claim 1-3 any one, it is characterised in that the nitro-reduction reaction is by urging
Change hydrogenation reduction, reducing agent is hydrogen, in the presence of the palladium or platinum of load on a inert carrier, and hydrochloric acid or vinegar
Acid, carries out in atent solvent；Or the reducing agent that the nitro-reduction reaction uses is selected from the metal iron powder of activation, zinc
Powder, sodium hydrosulfite (sodium dithionite), solvent are：Water, Methanol-water, Methanol-water-dichloromethane, Methanol-water-dichloro
Methane-TBAB (tetrabutylammonium bromide), acetonitrile-water, ethyl acetate-water.
9. synthetic method as claimed in claim 8, it is characterised in that the palladium loaded on a inert carrier or platinum are
The palladium carbon of 2%-20% weight percent contents.
10. synthetic method according to claim 8, it is characterised in that the nitro-reduction reaction is using sodium hydrosulfite as also
Former agent, using ethyl acetate-water as dicyandiamide solution, using sodium carbonate as catalyst；The molar ratio of compound IV and sodium hydrosulfite is 1:2
~4, reaction temperature is 50~80 DEG C.
11. synthetic method according to claim 10, it is characterised in that in the nitro-reduction reaction, compound IV
Molar ratio with sodium hydrosulfite is 1:3, reaction temperature is 60~65 DEG C.
12. the synthetic method as described in claim 1-3 any one, it is characterised in that N'- (the chloro- 4- fluorophenyls of 3-)-N, N-
Dimethyl carbonamidine glacial acetic acid effect under, with compound V in a suitable solvent in 120~138 DEG C reaction 1 it is small when, be evaporated off molten
Agent and glacial acetic acid, add a little dichloromethane and water stirring, and suction filtration obtains compound as white solid VI, wherein suitable solvent selects
From benzene,toluene,xylene, glacial acetic acid, the molar ratio of compound V and glacial acetic acid is 0.5~1.5:1.
13. synthetic method according to claim 12, it is characterised in that N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl
In the reaction of carbonamidine and compound V, the solvent be dimethylbenzene, and the molar ratio of compound V and glacial acetic acid is 1:1, reaction temperature
Spend for 130 DEG C.
14. series compound as described below：
15. application of the compound described in claim 14 in Gefitinib is prepared.
16. application as claimed in claim 15, it is characterised in that the compound III is prepared via a method which：
3- hydroxyl -4- methoxy benzonitriles and the bromo- 1- propyl alcohol of 3- react to obtain Formula II compound, Formula II compound again with to toluene sulphur
Acyl chloride reaction obtains formula III compound；
The compound IV is prepared via a method which：
3- (5- cyano group -2- methoxyphenoxies) propyl group -4- toluenesulfonic acid esters of nitration III, obtain 3- (the 5- cyanogen of formula IV
Base -2- methoxyl groups -4-nitrophenoxy) propyl group -4- toluenesulfonic acid esters, the nitration reaction uses single concentrated nitric acid body
System, room temperature reaction；
The compound V is prepared via a method which：
The nitro of 3- (5- cyano group -2- methoxyl groups -4-nitrophenoxy) propyl group -4- toluenesulfonic acid esters of formula IV is reduced into ammonification
Base, obtains 3- (4- amino-5-cyano -2- methoxyphenoxies) propyl group -4- toluenesulfonic acid esters of Formula V；
The compound VI is prepared via a method which：
Under glacial acetic acid effect, compound V and N'- (the chloro- 4- fluorophenyls of 3-)-N, N- dimethyl carbonamidines react in dimethylbenzene,
The molar ratio of compound V and acetic acid is 1:1, reaction temperature is 130 DEG C；Dimethylbenzene and glacial acetic acid is evaporated off, adds a little dichloromethane
Alkane and water stirring, suction filtration obtain compound as white solid VI；
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| CN102432553A (en) * | 2011-10-28 | 2012-05-02 | 云南维和控股有限公司 | Process for producing quinazoline derivative and intermediate thereof |
| CN103570633A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Preparation method of gefitinib |
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| CN102432553A (en) * | 2011-10-28 | 2012-05-02 | 云南维和控股有限公司 | Process for producing quinazoline derivative and intermediate thereof |
| CN103570633A (en) * | 2012-07-27 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Preparation method of gefitinib |
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