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
- synthesis
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811622115.9A CN109456267A (en) | 2018-12-28 | 2018-12-28 | A method of synthesis pleasure is cut down for Buddhist nun |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811622115.9A CN109456267A (en) | 2018-12-28 | 2018-12-28 | A method of synthesis pleasure is cut down for Buddhist nun |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2018
- 2018-12-28 CN CN201811622115.9A patent/CN109456267A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| CN112654603B (en) * | 2018-09-07 | 2024-05-03 | 意迪那有限公司 | Preparation method of 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 |
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Application publication date: 20190312 |
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