CN103664778B - A kind of synthetic method of antineoplastic drug cabozant inib - Google Patents
A kind of synthetic method of antineoplastic drug cabozant inib Download PDFInfo
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- CN103664778B CN103664778B CN201310631287.3A CN201310631287A CN103664778B CN 103664778 B CN103664778 B CN 103664778B CN 201310631287 A CN201310631287 A CN 201310631287A CN 103664778 B CN103664778 B CN 103664778B
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- dimethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Abstract
The invention discloses a kind of synthetic method of antineoplastic drug cabozant inib; card is obtained in 5～20 DEG C of 0.5～2h of reaction in organic solvent with 1 ((4 fluorophenyl) carbamoyl) cyclopropane base carboxylic acid halides, acid binding agent using 4 (6,7 dimethoxy-quinoline, 4 epoxide) phenyl amines to win for Buddhist nun；Using technical scheme, its raw material is cheap, and mild condition is easy to operate, and process stabilizing is reproducible, and molar yield is high, low cost, therefore the present invention is that a kind of suitable industrialized production card wins the method for Buddhist nun.
Description
Technical field
The present invention relates to a kind of medical synthesis field, more particularly to increasing and expansion with medullary thyroid carcinoma, prostate cancer
It is target to dissipate relevant proto-oncogene encoded protein products (MET) and vascular endothelial growth factor receptor (VEGFR) EGFR-TK
Point, suppresses the transfer of tumour and the synthetic method of Angiogenesiss antineoplastic drug cabozant inib (Cabozant inib).
Background technology
Card is rich for Buddhist nun, English entitled (Cabozant inib), also known as XL184；Chemical name：N- [4- [(6,7- dimethoxies
Base -4- quinolyls) epoxide] phenyl]-N- (4- fluorophenyls) -1,1- cyclopropane diformamide structural formulas：
Molecular formula：C28H24FN3O5
CAS NO.：849217-68-1
Molecular weight：501.5
By targeted inhibition proto-oncogene encoded protein products (MET), vascular endothelial growth factor receptor (VEGFR) and
Tyrosine-kinase enzyme is received (RET) signal path and plays antitumor action, kills tumour cell, reduces metastases and suppress blood
Pipe is generated.Effectively treatment prostate cancer, malignant tumour and can not surgery excision pernicious Locally Advanced or metastatic thyroid gland
Cephaloma (MTC).76% patient after the rich treatment for Buddhist nun (Cabozant inib) of card is received, tumor section or whole atrophys.
The content of the invention
For the deficiencies in the prior art, present invention offer is a kind of simply efficiently, be suitable to the antitumor of industrialized production application
The rich synthesis path for Buddhist nun (Cabozantinib) of medicine card.
For achieving the above object, the technical solution used in the present invention is as follows：
A kind of synthetic method of antineoplastic drug cabozant inib, using 4- (6,7- dimethoxy-quinoline -4- epoxides) -
Phenyl amine is reacted in -5～20 DEG C in organic solvent with 1- ((4- fluorophenyls) carbamoyl) cyclopropane base carboxylic acid halides, acid binding agent
0.5～2h obtains card and wins for Buddhist nun, and its reaction equation is：
In formula, R is any one in halogen atom；
Wherein, according to molar ratio computing, 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amines and 1- ((4- fluorophenyls) ammonia
Base formoxyl) cyclopropane base carboxylic acid halides, acid binding agent, the ratio of organic solvent be：1: 1: 1: 1: 4.5～1: 1.5: 1.3: 1.5: 8.
Any one in described acid binding agent sodium carbonate, sodium acid carbonate, potassium carbonate, calcium carbonate or ammoniacal liquor.
Described organic solvent be acetonitrile, pyridine, N, N- dimethoxy formamides, N, TMSDEA N diethylamine base formamide, methyl
Any one in tertbutyl ether or tetrahydrofuran.
Described 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amine, its synthetic method is：With 4- hydroxyl -6,7- bis-
Methoxy quinoline is raw material, in organic solvent, with acylating agent in 100～120 DEG C of reaction responses 4～7 hours, generate 4- halogen-
6,7- dimethoxy-quinolines；Again 20～25 DEG C in organic solvent with condensation catalyst and para-aminophenol, 100～120 DEG C
Reaction obtains 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline in 2～6 hours；Its reaction equation is：
Wherein, R is any one in halogen atom
Wherein, according to the molar ratio：Described 4- hydroxyl -6,7- dimethoxy-quinolines and acylating agent, organic solvent are：1∶
1: 3～1: 3: 7；
Wherein, according to the molar ratio, described 4- halogen -6,7- dimethoxy-quinolines with to amine phenol, condensation catalyst, have
The mol ratio of machine solvent is：1: 1: 1: 4.5～1: 1.5: 1.3: 8.
Described 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amine, its synthetic method is：With 4- hydroxyl -6,7- bis-
Methoxy quinoline is raw material, in organic solvent, with acylating agent in 100～120 DEG C of reaction responses 4～7 hours, generate 4- halogen-
6,7- dimethoxy-quinolines；Add organic solvent, condensation catalyst and p-nitrophenols again at 20～25 DEG C, and in 100～
120 DEG C of reactions obtain 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline in 2～6 hours；4- is obtained then at 30～40 DEG C of reduction nitros
(6,7- dimethoxy-quinoline -4- epoxides)-phenyl amine.Its reaction equation is：
Wherein, R is any one in halogen atom
Wherein, according to the molar ratio：Described 4- hydroxyl -6,7- dimethoxy-quinolines and acylating agent, organic solvent are：1∶
1: 3～1: 3: 7；
Wherein, according to the molar ratio, described 4- halogen -6,7 dimethoxy-quinolines and p-nitrophenol, condensation catalyst,
The mol ratio of organic solvent is：1: 1: 1: 4.5～1: 1.5: 1.3: 8；
Wherein reducing agent used by nitro reduction is iron powder-ammonium acetate or Pd/C, in an amount of from 6,7- dimethoxy-4 's-(4- nitre
Phenoxyl) quinoline weight 1%～25%；Organic solvent amount is 2～8 times of its weight.
Described organic solvent be acetonitrile, DMF, N, N- DEFs, N, N- dimethylacetamides
Amine, methyl tertiary butyl ether(MTBE), toluene, benzene or tetrahydrofuran etc.；
Described acylating agent is thionyl chloride, oxalyl chloride, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorosulfuric acid, phosphinylidyne
Any one in chlorine, dihalo triphenylphosphine.
Described condensation catalyst is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, amino
Any one in sodium, sodium hydrogen.
Reducing agent used by described nitro reduction is any one in iron powder-ammonium acetate or Pd/C.
Described 1- ((4- fluorophenyls) carbamoyl) cyclopropane base carboxylic acid halides, its synthetic method is：With 1,1- cyclopropane
Dioctyl phthalate or derivatives thereof be raw material, in organic solvent with acylating agent in 0～10 DEG C react 0.5h, then with to fluorobenzene
Amine reacts 2～3h in 0～10 DEG C and obtains 1- ((4- fluorophenyls) carbamoyl) cyclopropane-carboxylic acid or derivatives thereof；Again organic
Solvent adds acylating agent in 15～30 DEG C, and obtains in 15～35 DEG C of 0.5～2h of reaction.Its reaction equation is：
Wherein, R is any one in halogen atom；R1、R2For at least in alkyl, halogenated alkyl thing, halogen atom, hydrogen atom
Kind；Described alkyl is methyl, ethyl, propyl group, isopropyl, butyl, any one in the tert-butyl group；
Wherein, 1,1- ethylene-malonic acids or derivatives thereof and the mol ratio of para-fluoroaniline, acylating agent and solvent are 1:
0.8: 1: 2～1: 1.2: 1.5: 10；
1- ((4- fluorophenyls) carbamoyl) cyclopropane-carboxylic acid or derivatives thereof is 1 with the mol ratio of acylating agent, solvent:
0.8: 1～1: 1.5: 2；
The acylating agent of the reaction is thionyl chloride, oxalyl chloride, POCl3, phosphorus trichloride, phosphorus pentachloride, sulfonyl
Any one in chlorine, phosgene, dihalo triphenylphosphine；
The organic solvent of the reaction is acetonitrile, DMF, N, N- DEFs, N, N- diformazans
Yl acetamide, methyl tertiary butyl ether(MTBE), toluene, benzene or tetrahydrofuran etc..
Using the beneficial effect of technical scheme it is：Raw material is cheap, mild condition, easy to operate, process stabilizing
Reproducible, molar yield is high, low cost, therefore the present invention is that a kind of suitable industrialized production card wins the method for Buddhist nun.
Specific embodiment
Below according to specific embodiment, the invention will be further described.
Embodiment 1
(1) synthesis of 4- (- 6,7 dimethoxy-quinoline -4- epoxides)-phenyl amine
1. chloro- 6,7 dimethoxy-quinolines of 4- are synthesized
By POCl3 161g (1.05mol) with adding to containing after DMA 200ml (2.15mol) dilutions
4- hydroxyl -6, in 7- dimethoxy-quinoline 205.2g (1.0mol) and 300ml (3.22mol) DMA solution,
It is heated to 100～120 DEG C, reaction 4～7 hours (when HPLC shows that raw material is considered as reaction completely when being less than 3% unreacted).Reaction
After room temperature is down to after complete, 200ml frozen water is added, PH=7～8 is neutralized to 30% sodium hydroxide solution, temperature control during neutralization
Below 25 DEG C.After neutralization is finished, continue stirring 1 hour, fully separate out solid particle, then filter；Filter cake is washed with 200ml
Wash 2 times, with 60～70 DEG C of dryings after filtration, obtain the chloro- 6.7- dimethoxy-quinolines 164.1g of yellow-white powder 4-, molar yield
73.5%, 131.2～132.6 DEG C of fusing point.1H-NMR (400MHz, DMSO-d6/ppm)；δ 3.95 (s, 3H), 3.96 (s, 3H),
7.35 (s, 1H), 7.43 (s, 1H), 7.54 (d, 1H), 8.59 (d, 1H).
2. synthesize 4- (- 6,7 dimethoxy-quinoline -4- epoxides)-phenyl amine
PAP 120g (1.1mol) is dissolved in 150ml (1.61mol) DMA, in 20～
25 DEG C, it is added slowly to the 400ml of chloro- 6, the 7- dimethoxy-quinolines 200g (0.9mol) of 171g containing sodium tert-butoxide (0.9mol) and 4-
(4.30mol) in DMA solution, reactant liquor is heated to into 100 DEG C～120 DEG C after dripping, is reacted 2 hours
Starting material left amount is detected with HPLC afterwards, stopped reaction when 2% unreacteds of ＜, be cooled to room temperature, stir in being poured into 1L frozen water
Filter after mixing 1～2 hour, filter cake 200ml water washings 2 times, and be vacuum dried in 35 DEG C, obtain ivory buff powder 4- (- 6,
7 dimethoxy-quinoline -4- epoxides)-phenyl amine 208.3g, molar yield 78.1%, 214.3～215.0 DEG C of fusing point,1H-NMR
(DMSO-d6,300MHz) δ 3.93 (6H, s), 5.16 (2H, s), 6.37 (1H, d=5.4Hz), 6.67 (2H, d, J=8.7Hz),
6.93 (2H, d, J=8.7Hz), 7.36 (1H, s), 7.50 (1H, s), 8.43 (1H, d, J=5.4Hz).
(2) synthesis of 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride
500g (6.93mol) tetrahydrofuran is added to 320g (2.46mol) 1,1- ethylene-malonic acids, after 0.5 hour, in
0～10 DEG C of dropwise addition 300g (2.52mol) thionyl chloride, reacts 0.5h at this temperature after completion of dropping.It is subsequently adding Jing 200g
(2.77mol) 240g (2.16mol) para-fluoroaniline after tetrahydrofuran dilution, does 0～10 DEG C of 2～3h of reaction.After completion of the reaction
The extraction of 500g ethyl acetate is added, after point liquid, successively with 400ml30% sodium hydrate aqueous solutions, 500ml water, 500ml saturations food
Salt water washing, then to upper organic layer vacuum distillation, obtains buff powder.
500ml petroleum ethers are added, agitator treating was filtered after 1 hour, filter cake 1kg methyl alcohol dissolves, after 30 minutes, slowly
Add 1L water, material slowly to separate out, add stirring and filter for 1～2 hour, then Jing after 500ml water, 500ml petroleum ethers, in 55
DEG C drying, obtain off-white powder 1- ((4- fluorophenyls) carbamoyl) cyclopropane-carboxylic acid 391.2g, molar yield 81.1%.1H
NMR (400MHz, DMSO-d6)：δ 13.06 (s, 1H), 10.55 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s,
4H)。
To add in 179.1g (1.41mol) oxalyl chloride in 15～30 DEG C to ((the 4- fluorobenzene containing 300g (1.34mol) 1-
Base)-carbamyl) cyclopropyl carboxylic acid and 100g (1.39mol) tetrahydrofuran solution in, add and react 0.5 after 15～35 DEG C
～2h, obtains final product 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride, without the need for separating from reactant liquor, directly uses.
(3) N- [4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] phenyl]-N- (4- fluorophenyls) -1,1- cyclopropane two
The synthesis of formamide
By 4- (6,7- dimethoxy-quinoline -4- base epoxides) aniline 417g (1.41mol) 1.5L (18.5mol) tetrahydrochysene furans
Mutter and 500g (1.66mol) potassium carbonate is added after dissolving, then drop to step 1- ((4- fluorophenyls) carbamoyl) ring third
Alkane formyl chloride reactant liquor, reacts in 20 DEG C, reacts 0.5～2h hours.After reaction terminates, 500ml water is added, at 40～45 DEG C
Stir the solution about 2 hours, crystallization, filtration, with 500ml water washings 3 times, then filter cake is vacuum dried at 45 DEG C, obtains titled
Compound 682.4g (1.36mol), 186.6～187.3 DEG C of fusing point, molar yield 96.5%.H NMR (400MHz, d6-DMSO)：δ
10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H),
7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H)
Embodiment 2
(1) synthesis of 4- (- 6,7 dimethoxy-quinoline -4- epoxides)-phenyl amine
Chloro- 6,7 dimethoxy-quinolines of 1 synthesis 4-
Thionyl chloride 1.65kg (13.9mol) is added dropwise to hydroxyl -6 containing 2.2Kg (10.72mol) 4-, 7- dimethoxys
In 5.3L (57mol) the DMA solution of quinoline, 100～120 DEG C after adding, are heated to, are reacted 4～7 hours
(when HPLC shows that raw material is considered as reaction completely when being less than 3% unreacted).Room temperature is down to after having reacted, 2.2L frozen water is added, is used
30% sodium hydroxide solution is neutralized to PH=7～8, and during neutralization, temperature control is below 25 DEG C.After neutralization is finished, continue stirring 1
Hour, solid particle is fully separated out, is filtered；Filter cake 1L water washings 2 times, and in 60～70 DEG C of dryings, obtain yellow-white powder
The chloro- 6.7- dimethoxy-quinolines 1775.9g of 4-, molar yield 74.2%, 131.4～132.7 DEG C of fusing point.1H-NMR (400MHz,
DMSO-d6/ppm)；δ 3.95 (s, 3H), 3.96 (s, 3H), 7.35 (s, 1H), 7.43 (s, 1H), 7.54 (d, 1H), 8.59 (d,
1H)。
2 synthesis 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline
P-nitrophenol 523g (3.76mol) is dissolved in 600ml (6.45mol) DMA, in 20～
25 DEG C, be added slowly to chloro- 6, the 7- dimethoxy-quinolines 800g (3.58mol) of 482g containing potassium tert-butoxide (4.3mol) and 4- and
In 1.5L (16.1mol) DMA solution, reactant liquor is heated to into 100 DEG C～120 DEG C after dripping, reaction 2
Hour.Reactant liquor is cooled to after room temperature, is poured into, filter cake 2L water washings 2 times, so
It is vacuum dried after 35 DEG C, obtains ivory buff powder 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline 918.2g, mole
Yield 78.6%.1H NMR (400MHz, DMSO-d6) δ (ppm)：8.61 (d, J=5.1Hz, 1H), 8.36-8.32 (m, 2H),
7.46-7.42 (m, 3H), 7.37 (s, 1H), 6.87 (d, J=5.1Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H)
3 synthesis 4- (- 6,7 dimethoxy-quinoline -4- epoxides)-phenyl amines
By 100g (0.306mol) 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline 300g N, N- diethyl first
During autoclave is added after acid amides dissolving, 10%Pd/C15g is added, reacted under the conditions of 30～40 DEG C, Hydrogen Vapor Pressure 2.8MPa, when
As do not react during re-absorption hydrogen complete.After removing most of solvent, pour in 150ml water and stir 1 hour, separate out solid
Grain after filtering, with 100ml water washings 2 times, dry in 60 DEG C, obtain 4- (- 6,7 dimethoxy-quinoline -4- epoxides)-benzene again by filter cake
Base amine 86.3g, 213.2～213.7 DEG C of fusing point, molar yield 95.2%.1H-NMR (DMSO-d6,300MHz) δ 3.93 (6H,
S), 5.16 (2H, s), 6.37 (1H, d=5.4Hz), 6.67 (2H, d, J=8.7Hz), 6.93 (2H, d, J=8.7Hz), 7.36
(1H, s), 7.50 (1H, s), 8.43 (1H, d, J=5.4Hz).
(2) synthesis of 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride
1100g (15.25mol) tetrahydrofuran is added to 700g (5.38mol) 1,1- ethylene-malonic acids, after 0.5 hour,
704.4g (5.92mol) thionyl chloride is added dropwise in 0～10 DEG C, 0.5h after completion of dropping, is reacted at this temperature.It is subsequently adding Jing
537.8g (4.84mol) para-fluoroaniline after the dilution of 200g (2.77mol) tetrahydrofuran, reacts 2～3h in 0～10 DEG C.Reaction
The extraction of 1100g ethyl acetate is added after finishing, after point liquid, is satisfied with 880ml30% sodium hydrate aqueous solutions, 1L water, 800ml successively
And brine It, then to upper organic layer vacuum distillation, obtain buff powder.
1L petroleum ethers are added, agitator treating was filtered after 1 hour, filter cake 2kg methyl alcohol dissolves, it is after 30 minutes, slow to add
Enter 2.3L water, material is slowly separated out, add stirring and filter for 1～2 hour, then Jing after 1L water, 1L petroleum ethers, in 55 DEG C of vacuum
Drying, obtains off-white powder 892.3g, molar yield 82.6%.1H NMR (400MHz, DMSO-d6)：δ 13.06 (s, 1H),
10.55 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H).
To add in 488.6g (3.85mol) oxalyl chloride in 15～30 DEG C to ((the 4- fluorobenzene containing 727.6g (3.26mol) 1-
Base)-carbamyl) cyclopropyl carboxylic acid and 245g (3.4mol) tetrahydrofuran solution in.Completion of dropwise addition is reacted after 15～35 DEG C
0.5～2h, obtains final product 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride, without the need for separating from reactant liquor, directly uses.
(3) N- [4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] phenyl]-N- (4- fluorophenyls) -1,1- cyclopropane two
The synthesis of formamide
By 4- (6,7- dimethoxy-quinoline -4- base epoxides) aniline 995.6g (3.36mol) 3.6L (44.39mol) four
1210g (4.03mol) potassium carbonate is added after the dissolving of hydrogen furans, step 1- ((4- fluorophenyls) carbamyl after dissolving, is dropped to
Base) cyclopropanecarbonyl chloride reactant liquor, reacts 0.5～2h in -5～20 DEG C.After reaction terminates, 1L water is added, at 40～45 DEG C
Stir the solution about 2 hours, crystallization, filtration, with 700ml water washings 3 times, then filter cake is vacuum dried at 45 DEG C, obtains titled
Compound 1589.8g (3.17mol), 186.3～187.1 DEG C of fusing point, molar yield 97.2%.1H NMR (400MHz, d6-
DMSO)：δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35
(s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d6H), 1.5 (s, 4H).
Claims (1)
1. a kind of synthetic method of antineoplastic drug cabozant inib, it is characterised in that：
(1) synthesis of 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amine
Chloro- 6, the 7- dimethoxy-quinolines of 1 synthesis 4-
Thionyl chloride 1.65kg, 13.9mol are added dropwise to hydroxyl -6 containing 2.2Kg, 10.72mol4-, 7- dimethoxy-quinolines
In 5.3L, 57mol DMA solution, 100～120 DEG C after adding, are heated to, are reacted 4～7 hours；Work as HPLC
Show that raw material is considered as reaction when being less than 3% unreacted complete；Room temperature is down to after having reacted, 2.2L frozen water is added, is used 30% hydrogen-oxygen
Change sodium solution and be neutralized to pH=7～8, temperature control is below 25 DEG C during neutralization；After neutralization is finished, continue stirring 1 hour, fully
Solid particle is separated out, is filtered；Filter cake 1L water washings 2 times, and in 60～70 DEG C of dryings, obtain yellow-white powder 4- chloro- 6,7-
Dimethoxy-quinoline 1775.9g, molar yield 74.2%, 131.4～132.7 DEG C of fusing point；1H-NMR (400MHz, DMSO-d6/
ppm)；δ 3.95 (s, 3H), 3.96 (s, 3H), 7.35 (s, 1H), 7.43 (s, 1H), 7.54 (d, 1H), 8.59 (d, 1H)；
It is 2-in-1 into 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline
P-nitrophenol 523g, 3.76mol are dissolved in 600ml, 6.45mol DMA, in 20～25 DEG C,
Be added slowly to 482g containing potassium tert-butoxide, 4.3mol and 4- chloro- 6,7- dimethoxy-quinolines 800g, 3.58mol and 1.5L,
In 16.1molN, N- dimethylacetamide solution, reactant liquor is heated to into 100 DEG C～120 DEG C after dripping, is reacted 2 hours；Will
After reactant liquor is cooled to room temperature, pours into, filter cake 2L water washings 2 times, then in 35
DEG C vacuum drying, obtain ivory buff powder 6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline 918.2g, molar yield
78.6%；1H NMR (400MHz, DMSO-d6) δ (ppm)：8.61 (d, J=5.1Hz, 1H), 8.36-8.32 (m, 2H), 7.46-
7.42 (m, 3H), 7.37 (s, 1H), 6.87 (d, J=5.1Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H)；
3 synthesis 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amines
By 100g, 0.306mol6,7- dimethoxy-4 's-(4-nitrophenoxy) quinoline 300g N, N- DEFs are molten
During autoclave is added after solution, 10%Pd/C15g is added, reacted under the conditions of 30～40 DEG C, Hydrogen Vapor Pressure 2.8MPa, when no longer inhaling
As react when receiving hydrogen complete；After removing most of solvent, pour in 150ml water and stir 1 hour, separate out solid particle and pass through
After filter, filter cake with 100ml water washings 2 times, is dried in 60 DEG C, obtains 4- (6,7- dimethoxy-quinoline -4- epoxides)-phenyl amine again
86.3g, 213.2～213.7 DEG C of fusing point, molar yield 95.2%；1H-NMR (DMSO-d6,300MHz) δ 3.93 (6H, s),
5.16 (2H, s), 6.37 (1H, d=5.4Hz), 6.67 (2H, d, J=8.7Hz), 6.93 (2H, d, J=8.7Hz), 7.36 (1H,
S), 7.50 (1H, s), 8.43 (1H, d, J=5.4Hz)；
(2) synthesis of 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride
To 700g, 5.38mol 1,1- ethylene-malonic acids add 1100g, 15.25mol tetrahydrofuran, after 0.5 hour, in 0～
10 DEG C of dropwise addition 704.4g, 5.92mol thionyl chlorides, react 0.5h at this temperature after completion of dropping；Be subsequently adding Jing 200g,
537.8g, 4.84mol para-fluoroaniline after the dilution of 2.77mol tetrahydrofurans, reacts 2～3h in 0～10 DEG C；After completion of the reaction plus
Enter the extraction of 1100g ethyl acetate, after point liquid, successively with 30% sodium hydrate aqueous solutions of 880ml, 1L water, 800ml saturated common salts
Water washing, then to upper organic layer vacuum distillation, obtains buff powder；
1L petroleum ethers are added, agitator treating was filtered after 1 hour, filter cake 2kg methyl alcohol dissolves, and after 30 minutes, is slowly added to
2.3L water, material are slowly separated out, and are added stirring and are filtered for 1～2 hour, then Jing after 1L water, 1L petroleum ethers, dry in 55 DEG C of vacuum
It is dry, obtain off-white powder 892.3g, molar yield 82.6%；1H NMR (400MHz, DMSO-d6)：δ 13.06 (s, 1H),
10.55 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H)；
To add in 488.6g, 3.85mol oxalyl chloride in 15～30 DEG C to ((4- fluorophenyls)-ammonia containing 727.6g, 3.26mol1-
Base formyl) cyclopropyl carboxylic acid and 245g, 3.4mol tetrahydrofuran solution in, completion of dropwise addition reacts 0.5～2h after 15～35 DEG C,
1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride is obtained final product, without the need for separating from reactant liquor, is directly used；
(3) N- [4- [(6,7- dimethoxy-4 's-quinolyl) epoxide] phenyl]-N- (4- fluorophenyls) -1,1- cyclopropane, two formyl
The synthesis of amine
By 4- (6,7- dimethoxy-quinoline -4- base epoxides) aniline 995.6g, 3.36mol 3.6L, 44.39mol tetrahydrofuran
1210g potassium carbonate is added after dissolving, step 1- ((4- fluorophenyls) carbamoyl) cyclopropanecarbonyl chloride after dissolving, is dropped to
Reactant liquor, reacts 0.5～2h in -5 DEG C, after reaction terminates, adds 1L water, stirs the solution about 2 hours at 40～45 DEG C, analyses
It is brilliant, filter, with 700ml water washings 3 times, then filter cake is vacuum dried at 45 DEG C, obtains title compound 1589.8g, 3.17mol,
186.3～187.1 DEG C of fusing point, molar yield 97.2%；1H NMR (400MHz, d6-DMSO)：δ 10.2 (s, 1H), 10.05 (s,
1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m,
2H), 6.4 (s, 1H), 4.0 (d6H), 1.5 (s, 4H).
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