CN109456267A - A method of synthesis pleasure is cut down for Buddhist nun - Google Patents
A method of synthesis pleasure is cut down for Buddhist nun Download PDFInfo
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- CN109456267A CN109456267A CN201811622115.9A CN201811622115A CN109456267A CN 109456267 A CN109456267 A CN 109456267A CN 201811622115 A CN201811622115 A CN 201811622115A CN 109456267 A CN109456267 A CN 109456267A
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- chloro
- cut down
- buddhist nun
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- phenyl
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 22
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 17
- FOARXBSDMBUBEG-UHFFFAOYSA-N 2-chloro-7-methoxyquinoline Chemical compound C1=CC(Cl)=NC2=CC(OC)=CC=C21 FOARXBSDMBUBEG-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZYZQSCWSPFLAFM-UHFFFAOYSA-N 4-amino-2-chlorophenol Chemical compound NC1=CC=C(O)C(Cl)=C1 ZYZQSCWSPFLAFM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims abstract description 4
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000004176 ammonification Methods 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 230000001035 methylating effect Effects 0.000 claims abstract description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- CJYCKYKUEPEYAS-UHFFFAOYSA-N COC(C1=CCC(C=C1)(OC)ON)=O Chemical class COC(C1=CCC(C=C1)(OC)ON)=O CJYCKYKUEPEYAS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 125000003431 oxalo group Chemical group 0.000 claims 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 claims 1
- QVPZNUIZEVRITP-UHFFFAOYSA-N 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea Chemical compound ClC1=CC(O)=CC=C1NC(=O)NC1CC1 QVPZNUIZEVRITP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- -1 cyclopropylaminocarbonyl Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 4
- 229960003784 lenvatinib Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- OLJXRTRRJSMURJ-UHFFFAOYSA-N 4-amino-2-methoxybenzoic acid Chemical compound COC1=CC(N)=CC=C1C(O)=O OLJXRTRRJSMURJ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- CPMPTBGDMLIZCY-UHFFFAOYSA-N [O].ClC=1C=C(C=CC1C(=O)NC1CC1)N Chemical compound [O].ClC=1C=C(C=CC1C(=O)NC1CC1)N CPMPTBGDMLIZCY-UHFFFAOYSA-N 0.000 description 1
- YVNRUPSDZZZUQJ-UHFFFAOYSA-N [O].NC1=CC=CC=C1 Chemical compound [O].NC1=CC=CC=C1 YVNRUPSDZZZUQJ-UHFFFAOYSA-N 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- OZKIMYLEHNQVTI-UHFFFAOYSA-N benzene;carbonochloridic acid Chemical compound OC(Cl)=O.C1=CC=CC=C1 OZKIMYLEHNQVTI-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical class [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to chemical pharmacy fields, and in particular to a method of synthesis pleasure is cut down for Buddhist nun, comprising the following steps: step 1, using 4-ASA as raw material, through methylating, with the condensation of Maxwell acid, high temperature cyclization, chloro, ammonification, the chloro- 7- methoxy quinoline -6- formamide of 4- is obtained；Step 2, using the chloro- 4-aminophenol of 3- as raw material, reacted to obtain 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea with phenyl chloroformate and cyclopropylamine；Step 3,1- made from the chloro- 7- methoxy quinoline -6- formamide of 4- made from step 1 and step 2 (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is reacted under the action of potassium tert-butoxide and obtains happy cut down for Buddhist nun；The present invention provides a kind of happy completely new routes cut down for Buddhist nun of synthesis.Agents useful for same is cheap and easily-available, easy to operate, and productivity ratio other methods are high, and easy to industrialized production.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular to a method of synthesis pleasure is cut down for Buddhist nun.
Background technique
Lenvatinib (E7080,1), entitled 4- (3- chloro- 4- (cyclopropylaminocarbonyl) the amino-benzene oxygen) -7- of chemistry
Methoxyl group -6- quinoline formyl amine is inhibited by the oral polyceptor tyrosine kinase of Japanese Eisai Co., Ltd (Eisai) research and development
Agent is the potential treatment medicine of thyroid cancer, liver cancer, non-small cell lung cancer and other solid tumors.2 months 2013,
Lenvatinib obtains the Orphan drug identification that FDA is authorized, for treating follicularis, marrow sample, undifferentiated and transfer or part evening
Phase thyroid papillary carcinoma.On 2 13rd, 2015, lenvatinib obtained FDA approval for the intractable differentiated of radioiodine again
The treatment of thyroid cancer.In the prior art, there is the happy complex synthetic route cut down for Buddhist nun, the not high technical problem of yield.
Summary of the invention
The present invention solves the above-mentioned technical problems in the prior art, provides a kind of happy method cut down for Buddhist nun of synthesis.
To solve the above problems, technical scheme is as follows:
A method of synthesis pleasure is cut down for Buddhist nun, synthetic route are as follows:
A method of synthesis pleasure is cut down for Buddhist nun, comprising the following steps:
Step 1, using 4-ASA as raw material, through methylating, and the condensation of Maxwell acid, high temperature cyclization, chloro, ammonification,
Obtain the chloro- 7- methoxy quinoline -6- formamide of 4-；
Step 2, using the chloro- 4-aminophenol of 3- as raw material, reacted to obtain 1- that (2- is chloro- with phenyl chloroformate and cyclopropylamine
4- hydroxy phenyl) -3- cyclopropyl urea；
Step 3, by 1- (the chloro- 4- of 2- made from the chloro- 7- methoxy quinoline -6- formamide of 4- made from step 1 and step 2
Hydroxy phenyl) -3- cyclopropyl urea reacted under the action of potassium tert-butoxide obtain pleasure cut down for Buddhist nun.
Preferably, the organic solvent of the step 3 is dimethyl sulfoxide, the tert-butyl alcohol.
Preferably, the reaction temperature of the step 3 is 60-70 DEG C, and the reaction time is 8-9 hours.
Preferably, the step 3 existing for the potassium carbonate under the conditions of reacted.
Preferably, the step 1 specifically includes:
Step 1.1, PAS is anti-with dimethyl suflfate in the presence of acetone, tetrabutylammonium bromide, potassium hydroxide
4- amino-O-Anisic Acid methyl esters should be generated；
Step 1.2, Maxwell acid is in the presence of triethyl orthoformate, isopropanol, with 4- amino-O-Anisic Acid methyl esters
Reaction generates 5- [(3- methoxyl group -4- methoxycarbonyl anilino-) methylene] -2,2- dimethyl-1,3-dioxane -4,6-
Diketone (4)；
Step 1.3, in the presence of biphenyl, diphenyl ether, under nitrogen protection, 5- [(3- methoxyl group -4- methoxycarbonyl aniline
Base) methylene] -2,2- dimethyl-1,3-dioxane -4,6- diketone (4) high temperature cyclization generation oxo -1 7- methoxyl group -4-,
4- dihydroquinoline -6- carboxylate methyl ester；
Step 1.4,7- methoxyl group -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -6- carboxylate methyl ester in the presence of methylene chloride, DMF with
After oxalyl chloride reaction, then reacts with ammonia water generate the chloro- 7- methoxy quinoline -6- formamide of 4- in methyl alcohol.
Preferably, the step 2 specifically includes: the chloro- 4-aminophenol of 3- is the DMF, pyridine in the presence of and chloro-carbonic acid benzene
After ester reaction, cyclopropylamine is added dropwise, 1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea is made.
Compared with the existing technology, advantages of the present invention is as follows,
The present invention provides a kind of happy completely new routes cut down for Buddhist nun of synthesis.Agents useful for same is cheap and easily-available, easy to operate, and
Productivity ratio other methods are high, and easy to industrialized production.
Specific embodiment
The synthesis of embodiment 1:4- amino-O-Anisic Acid methyl esters (3)
It weighs PAS (2) 10g (65mmol) to be added in 250mL three-necked bottle, acetone 100mL, the tetrabutyl is added
Ammonium bromide 10.45g (32.5mmol) is stirred to being completely dissolved, is added potassium hydroxide 9.80g (0.176mmol), control reaction
Temperature is at 20~30 DEG C, and stirring to a large amount of precipitatings generates, and is added dropwise dimethyl suflfate 15.40mL (16.3mmol), and control temperature exists
30~45 DEG C, in being added dropwise in 20min, temperature is controlled, stirs 2h.End of reaction removes acetone under reduced pressure, adds 80mL ice water,
There is white solid precipitation, filter, washes, it is dry, obtain white solid (3) 10.51g, yield 84%, 157~159 DEG C of mp.
Embodiment 2:5- [(3- methoxyl group -4- methoxycarbonyl anilino-) methylene] -2,2- dimethyl -1,3- dioxy six
The synthesis of ring -4,6- diketone (4)
Maxwell acid 15g (104mmol) is weighed, is added in triethyl orthoformate 50mL (300mmol), is stirred at 90 DEG C
3h.Add isopropanol 50mL, 4- amino-O-Anisic Acid methyl esters (3) 21.92g (0.121mmol), back flow reaction 1h.
End of reaction has a large amount of yellow mercury oxides to generate, is cooled to room temperature, and filters, and filter cake is sufficiently washed with ether, places drying, obtains light
Yellow solid (4) 29.76g, yield 85%.
The synthesis of embodiment 3:7- methoxyl group -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -6- carboxylate methyl ester (5)
It weighs biphenyl 45g (292mmol) to be placed in three-necked bottle, 150mL diphenyl ether is added, heats solvent under nitrogen protection
To 180 DEG C, it is rapidly added 18g (53.7mmol) compound 4 in a nitrogen atmosphere, there is bulk gas releasing, maintains temperature 170
~185 DEG C, 45min is reacted, stops heating.It is cooled to room temperature, there are a large amount of yellow solids to be precipitated, petroleum ether, filtering, filter cake is added
Crude product is sufficiently washed to obtain with ether.Crude product is beaten with petroleum ether-ethyl acetate (volume ratio 5: 2) and is purified, and is filtered, and is done
It is dry, obtain yellow solid (5) 10.11g, yield 80.7%.
The synthesis of the chloro- 7- methoxy quinoline -6- formamide (6) of embodiment 4:4-
It weighs 5g (0.022mmol) compound 5 to be placed in single neck bottle, methylene chloride 30mL, DMF3 drop is added, drips at room temperature
Add oxalyl chloride, reacts 9h.It is cooled to room temperature, depressurizes steaming vibrating dichloromethane, ethyl acetate is added, then rotated, repeatedly twice
It is evaporated off substantially to oxalyl chloride, methanol 20mL, ammonium hydroxide 50mL is added, fluid-tight is heated to back flow reaction 3h.It is cooled to room temperature, filters,
Filter cake is sufficiently washed with water, dry, obtains yellow-brown solid (6) 3.89g, yield 87%.
The synthesis of embodiment 5:1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (8)
The chloro- 4-aminophenol of 10g (69.6mmol) 3- (7) is dissolved in 40mLDMF, adds 10mL pyridine, is dripped under ice bath
Chlorination phenyl formate 9.80mL (78mmol), reacts 1h at room temperature.Reaction system is placed in ice bath, cyclopropylamine 9.64mL is added dropwise
(139mmol), is added dropwise and 3h is stirred at room temperature.Add water 200mL, 2molL-1Hydrochloric acid 50mL stirs 30min, and acetic acid second is added
Ester 120mL, separates organic layer, and aqueous layer with ethyl acetate 120mL extracts primary, merging organic layer, with saturated common salt water washing 2
Secondary, anhydrous sodium sulfate dries, filters, and is concentrated to give grease, and petroleum ether-ethyl acetate (volume ratio 3: 1) 70mL is added, stirs
It mixes, solid is precipitated, filter, it is dry, off-white color compound (8) 13.57g is obtained, 86% (document yield 77%) is received.
Embodiment 6:4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline formyl amine
The synthesis of (lenvatinib, 1)
1- (2- chloro-4-hydroxyl phenyl) -3- cyclopropyl urea (8) 3g (13mmol) is weighed, dimethyl sulfoxide 15mL, uncle is added
Butanol 1.6g (14.3mmol), is stirred at room temperature 1h, is warming up to 70 DEG C, puts into chloro- 7- methoxy quinoline -6- amide (6) 1.54g of 4-
(6.5mmol) and potassium carbonate 0.898g (8.5mmol) maintains 70 DEG C of temperature, reacts 8h.It is cooled to room temperature, 15mL water, mistake is added
Filter, filter cake are washed with water repeatedly, dry.Gained crude product is suspended in the aqueous acetone solution of volume fraction 33%, is stirred at 60 DEG C
It mixes overnight, it is cooling, it filters, obtains white solid (1) 2.304g, yield 82.8%, 226~228 DEG C of mp.The purity of HPLC
99.50%.
It should be noted that above-described embodiment is only presently preferred embodiments of the present invention, there is no for the purpose of limiting the invention
Protection scope, the equivalent substitution or substitution made on the basis of the above all belong to the scope of protection of the present invention.
Claims (7)
1. a kind of happy method cut down for Buddhist nun of synthesis, which is characterized in that synthetic route are as follows:
2. the happy method cut down for Buddhist nun of synthesis as described in claim 1, which comprises the following steps:
Step 1, it using 4-ASA as raw material, through methylating, with the condensation of Maxwell acid, high temperature cyclization, chloro, ammonification, obtains
The chloro- 7- methoxy quinoline -6- formamide of 4-；
Step 2, using the chloro- 4-aminophenol of 3- as raw material, through reacting to obtain 1- (the chloro- 4- hydroxyl of 2- with phenyl chloroformate and cyclopropylamine
Base phenyl) -3- cyclopropyl urea；
Step 3, by 1- (2- chloro-4-hydroxyl made from the chloro- 7- methoxy quinoline -6- formamide of 4- made from step 1 and step 2
Phenyl) -3- cyclopropyl urea reacted under the action of potassium tert-butoxide obtain pleasure cut down for Buddhist nun.
3. the happy method cut down for Buddhist nun of synthesis as claimed in claim 2, which is characterized in that the organic solvent of the step 3 is two
Methyl sulfoxide, the tert-butyl alcohol.
4. the happy method cut down for Buddhist nun of synthesis as claimed in claim 2, which is characterized in that the reaction temperature of the step 3 is 60-
70 DEG C, the reaction time is 8-9 hours.
5. the happy method cut down for Buddhist nun of synthesis as claimed in claim 2, which is characterized in that the step 3 is existing for the potassium carbonate
Under the conditions of reacted.
6. the happy method cut down for Buddhist nun of synthesis as claimed in claim 2, which is characterized in that the step 1 specifically includes:
Step 1.1, PAS reacts life with dimethyl suflfate in the presence of acetone, tetrabutylammonium bromide, potassium hydroxide
At 4- amino-O-Anisic Acid methyl esters；
Step 1.2, Maxwell acid reacts in the presence of triethyl orthoformate, isopropanol with 4- amino-O-Anisic Acid methyl esters
Generate 5- [(3- methoxyl group -4- methoxycarbonyl anilino-) methylene] -2,2- dimethyl-1,3-dioxane -4,6- diketone
(4)；
Step 1.3, in the presence of biphenyl, diphenyl ether, under nitrogen protection, [(3- methoxyl group -4- methoxycarbonyl anilino-) is sub- by 5-
Methyl] -2,2- dimethyl-1,3-dioxane -4,6- diketone (4) high temperature cyclization generation 7- methoxyl group -4- oxo-Isosorbide-5-Nitrae-dihydro
QUINOLINE-6-CARBOXYLIC ACID's methyl esters；
Step 1.4,7- methoxyl group -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -6- carboxylate methyl ester is in the presence of methylene chloride, DMF and oxalyl
After chlorine reaction, then reacts with ammonia water generate the chloro- 7- methoxy quinoline -6- formamide of 4- in methyl alcohol.
7. the happy method cut down for Buddhist nun of synthesis as claimed in claim 2, which is characterized in that the step 2 specifically includes: 3-
After chloro- 4-aminophenol is reacted in the presence of DMF, pyridine with phenyl chloroformate, cyclopropylamine is added dropwise, 1- (2- chloro-4-hydroxyl is made
Phenyl) -3- cyclopropyl urea.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110845406A (en) * | 2019-12-04 | 2020-02-28 | 广州安岩仁医药科技有限公司 | Preparation method of quinoline compound |
| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| CN115368301A (en) * | 2022-07-18 | 2022-11-22 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
| CN117447338A (en) * | 2023-10-17 | 2024-01-26 | 南昌大学第二附属医院 | Synthesis method of lenvatinib intermediate |
| CN118993910A (en) * | 2024-10-16 | 2024-11-22 | 山东佰隆医药有限公司 | Preparation method of 2-methoxy-4-aminobenzoic acid methyl ester |
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2018
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| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| KR20210056390A (en) * | 2018-09-07 | 2021-05-18 | 인데나 에스.피.에이 | How to Prepare Renbatinib |
| CN112654603B (en) * | 2018-09-07 | 2024-05-03 | 意迪那有限公司 | Preparation method of lenvatinib |
| KR102770830B1 (en) | 2018-09-07 | 2025-02-24 | 인데나 에스.피.에이 | Method for manufacturing lenvatinib |
| CN110845406A (en) * | 2019-12-04 | 2020-02-28 | 广州安岩仁医药科技有限公司 | Preparation method of quinoline compound |
| CN115368301A (en) * | 2022-07-18 | 2022-11-22 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
| CN115368301B (en) * | 2022-07-18 | 2023-10-20 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
| CN117447338A (en) * | 2023-10-17 | 2024-01-26 | 南昌大学第二附属医院 | Synthesis method of lenvatinib intermediate |
| CN118993910A (en) * | 2024-10-16 | 2024-11-22 | 山东佰隆医药有限公司 | Preparation method of 2-methoxy-4-aminobenzoic acid methyl ester |
| CN118993910B (en) * | 2024-10-16 | 2025-03-14 | 山东佰隆医药有限公司 | A preparation method of methyl 2-methoxy-4-aminobenzoate |
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