CN108264482A - It is a kind of to block the rich preparation method for Buddhist nun - Google Patents
It is a kind of to block the rich preparation method for Buddhist nun Download PDFInfo
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- CN108264482A CN108264482A CN201810110778.6A CN201810110778A CN108264482A CN 108264482 A CN108264482 A CN 108264482A CN 201810110778 A CN201810110778 A CN 201810110778A CN 108264482 A CN108264482 A CN 108264482A
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- buddhist nun
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Block the rich preparation method for Buddhist nun the present invention relates to a kind of; more particularly to 5; 6 dimethoxy, 4 oxyquinoline, TsCl, p-fluoronitrobenzene, 1 (4 fluorophenyl) amino carbonyl cyclopropane first carboxylic acid are raw material, reacted by hydroxyl protection, coupling reaction, reduction reaction, four step of condensation reaction synthesis card it is rich for Buddhist nun；The rich preparation method for Buddhist nun of card provided by the invention be it is a kind of in high yield, low cost, few, easy to operate, safe, the suitable industrialized preparation method of the three wastes.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of to block the rich preparation method for Buddhist nun.
Background technology
It is a novel multiple receptor tyrosine kinases inhibitor that card, which is won for Buddhist nun, by Exelixis biopharmaceutical companys of the U.S.
Research and development.It, can as a kind of tyrosine kinase inhibitor for inhibiting MET, VEGF R2 (VEGFR2) and RET
Tumour cell occurrence and development are blocked, clinically for progressivity, the treatment of metastatic medullary thyroid carcinoma (MTC) patient.
On November 19th, 2012 is ratified to list by U.S. FDA, for the pernicious Locally Advanced for the excision that can not perform the operation or metastatic thyroid gland
The treatment of cephaloma (MTC).It is granted in 2 years in the past be used for that card, which is won for Buddhist nun (cabozantinib, XL184, BMS-907351),
The 2nd kind of drug of medullary carcinoma of thyroid gland is treated, another drug is the Caprelsa of AstraZeneca.Medullary carcinoma of thyroid gland (MTC)
It is a kind of rare property, intractable, slow progressive disease, from the parafollicular cell of secretion calcitonin, (also known as C is thin
Born of the same parents), calcitonin is a kind of hormone, helps to maintain the general level of the health of calcium in blood.Estimate according to National Cancer Institute,
2012, there will be 56460 patients to be diagnosed as thyroid cancer, wherein 1780 will die of the disease.In thyroid cancer, there are about 4%
For medullary carcinoma of thyroid gland.
WO2005030140 discloses a kind of card that synthesizes and wins the method for replacing Buddhist nun, and this method is with cyclopropane -1,1- dicarboxylic acids, 4-
Fluoroaniline is raw material, intermediate 1- (4- fluorophenyls) carbamyl cyclopropane-carboxylic acid is obtained by the reaction, then with O- benzyls to amino
Phenol hydrochloride reacts, and obtains intermediate N (4- benzyloxy-phenyls)-N '-(4- fluorophenyls) cyclopropane -1,1- diformamide；So
It is reacted afterwards with 6,7- dimethoxy-quinoline -4- bases triflate, obtains target compound card and win for Buddhist nun.This route is used
Starting material cyclopropane -1,1- dicarboxylic acids and 6,7- dimethoxy-quinoline -4- base triflates price costly；
In addition, building-up process further relates to benzyl protection and deprotection, complex steps.
WO2012109510A1 discloses the rich method for Buddhist nun of another synthesis card, and this method is with 6,7- dimethoxy 4- hydroxyls
Base quinoline, para-fluoroaniline and 1,3- cyclopropane dicarboxylic acid are raw material, and through chlorination reaction, coupling reaction, condensation reaction, chloride is anti-
It answers, five step of amidation process synthesis card is won for Buddhist nun.The shortcomings that this method is primarily present is largely using toxic articles phosphorus oxychloride, two
Sulfur oxide and oxalyl chloride, environmental pollution is more serious, severe corrosion to equipment.
Invention content
In order to solve the problems in the existing technology, block the rich preparation method for Buddhist nun the present invention provides a kind of.
The present invention uses following technical scheme：
It is a kind of to block the rich preparation method for Buddhist nun, include the following steps：
Step 1：Dichloromethane is added in reaction bulb, 6,7- dimethoxy-4 's-oxyquinoline and alkali are added in, 0~30
DEG C paratoluensulfonyl chloride and dichloromethane solution is added dropwise；After completion of the reaction, liquid separation washs dichloromethane with sodium bicarbonate solution
Layer, concentration, crystallization, filtering, drying obtain intermediate 1；
Step 2：Solvent is added in into reaction bulb, adds in intermediate 1, alkali and p-fluoronitrobenzene, heats up 80~110 DEG C instead
It should；After completion of the reaction, reaction solution is added to the water by concentrate solution；Filtering, washing, drying, obtain intermediate 2；
Step 3：Solvent is added in into autoclave, adds in intermediate 2 and catalyst, 30~50 DEG C of reactions of heating are 10 small
When；Room temperature is down to, press filtration, concentration, crystallization, filtering, drying obtain intermediate 3；
Step 4：Dichloromethane is added in there-necked flask, adds in intermediate 3 and 1- (4- fluorophenyls) amino carbonyl cyclopropane
First carboxylic acid, then adds in condensing agent, and temperature rising reflux reacts 10 hours；Room temperature is down to, is filtered, filtrate is washed with sodium carbonate liquor
It washs, dichloromethane layer concentration, crystallization filters, drying, and with re-crystallizing in ethyl acetate, get Ka Bo replaces Buddhist nun.
Preferably, the alkali described in step 1 is diisopropyl ethyl amine (DIEA), triethylamine or N-methylmorpholine.
Preferably, the solvent described in step 2 is DMF, DMA, DMSO or Isosorbide-5-Nitrae-dioxane.
Preferably, the alkali described in step 2 is K2CO3, sodium ethoxide, sodium methoxide, sodium tert-butoxide or sodium hydride.
Preferably, the solvent described in step 3 is methanol, ethyl alcohol or tetrahydrofuran.
Preferably, the catalyst described in step 3 is Raney's nickel, Pd/C or Pt/C.
Preferably, the condensing agent described in step 4 is DDC, DIC or EDCl.
The beneficial effects of the present invention are：
1) para hydroxybenzene of the invention by being redesigned to reaction route, replacing being commonly used using p-fluoronitrobenzene
Amine greatly improves reaction yield and product quality, reaction route is relatively new.
2) synthesis technology of the invention is easy to operate, and the reaction time is short, without purifying intermediate, can be blocked with high yield
It is rich to replace Buddhist nun.
3) easy to operate, the safe and reliable, convenient post-treatment of the present invention, it is environmentally protective, convenient for industrialization.
Description of the drawings
Fig. 1 is the reactional equation figure for the preparation method that card of the embodiment of the present invention is won for Buddhist nun.
Specific embodiment
With reference to embodiments, the technical solution in the present invention is clearly and completely described.Based in the present invention
Embodiment, those of ordinary skill in the art's all other embodiments obtained without making creative work, all
Belong to the scope of protection of the invention.
Block the rich preparation method for Buddhist nun the present embodiment provides a kind of, as shown in Figure 1, specifically including following steps：
Step 1：In reaction bulb add in 1L dichloromethane, add in 150g 6,7- dimethoxy-4 's-oxyquinoline and
150g paratoluensulfonyl chlorides and 100ml dichloromethane solutions is added dropwise at 0~10 DEG C in 100g triethylamines.After completion of the reaction, liquid separation,
Dichloromethane layer is washed with sodium bicarbonate solution, concentration, crystallization, filtering, drying obtain 260g intermediates 1, yield 99%.
Step 2：1L DMF are added in into reaction bulb, add in 250g intermediates 1,120g potassium carbonate and 100g are to fluorine nitro
Benzene, heat up 100 DEG C of reactions.After completion of the reaction, reaction solution is added to the water by concentrate solution；Filtering, washing, drying, obtain 202g
Intermediate 2, yield 91%.
Step 3：500ml methanol is added in into autoclave, adds in 100g intermediates 2 and 25g Raney's nickels, heats up 30 DEG C instead
Answer 10 hours；Room temperature is down to, press filtration, concentration, crystallization, filtering, drying obtain 86g intermediates 3, yield 95%.
Step 4：250 dichloromethane are added in there-necked flask, add in 50g intermediates 3 and 40g 1- (4- fluorophenyls) amino
Carbonyl cyclopropane first carboxylic acid, then adds in 35g DCC, and temperature rising reflux reacts 10 hours；Room temperature is down to, is filtered, filtrate carbon
Acid sodium solution washs, and dichloromethane layer concentration, crystallization filters, drying, with re-crystallizing in ethyl acetate, obtains 73g cards and wins for Buddhist nun,
Yield is 86%.
The above described is only a preferred embodiment of the present invention, be not intended to limit the scope of the present invention,
Therefore it is all using equivalent substitution or equivalent transformation formed technical solution, all fall within the present invention claims protection domain.
Claims (7)
1. a kind of block the rich preparation method for Buddhist nun, which is characterized in that includes the following steps：
Step 1：Dichloromethane is added in reaction bulb, adds in 6,7- dimethoxy-4 's-oxyquinoline and alkali, in 0~30 DEG C of drop
Add paratoluensulfonyl chloride and dichloromethane solution；After completion of the reaction, liquid separation washs dichloromethane layer with sodium bicarbonate solution, dense
Contracting, crystallization, filtering, drying obtain intermediate 1；
Step 2：Solvent is added in into reaction bulb, adds in intermediate 1, alkali and p-fluoronitrobenzene, heat up 80~110 DEG C of reactions；Instead
After answering, reaction solution is added to the water by concentrate solution；Filtering, washing, drying, obtain intermediate 2；
Step 3：Solvent is added in into autoclave, adds in intermediate 2 and catalyst, is heated up 30~50 DEG C of 10 hours of reaction；Drop
To room temperature, press filtration, concentration, crystallization, filtering, drying obtain intermediate 3；
Step 4：Dichloromethane is added in there-necked flask, adds in intermediate 3 and 1- (4- fluorophenyls) amino carbonyl cyclopropane first carboxylic
Acid, then adds in condensing agent, and temperature rising reflux reacts 10 hours；Room temperature to be down to, is filtered, filtrate is washed with sodium carbonate liquor, and two
Chloromethanes layer concentrates, crystallization, filters, drying, and with re-crystallizing in ethyl acetate, get Ka Bo replaces Buddhist nun.
2. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Alkali described in step 1 is
Diisopropyl ethyl amine (DIEA), triethylamine or N-methylmorpholine.
3. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Solvent described in step 2
For DMF, DMA, DMSO or Isosorbide-5-Nitrae-dioxane.
4. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Alkali described in step 2 is
K2CO3, sodium ethoxide, sodium methoxide, sodium tert-butoxide or sodium hydride.
5. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Solvent described in step 3
For methanol, ethyl alcohol or tetrahydrofuran.
6. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Catalysis described in step 3
Agent is Raney's nickel, Pd/C or Pt/C.
7. a kind of rich preparation method for Buddhist nun of card according to claim 1, it is characterised in that：Condensation described in step 4
Agent is DDC, DIC or EDCl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810110778.6A CN108264482A (en) | 2018-02-05 | 2018-02-05 | It is a kind of to block the rich preparation method for Buddhist nun |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810110778.6A CN108264482A (en) | 2018-02-05 | 2018-02-05 | It is a kind of to block the rich preparation method for Buddhist nun |
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|---|---|
| CN108264482A true CN108264482A (en) | 2018-07-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810110778.6A Withdrawn CN108264482A (en) | 2018-02-05 | 2018-02-05 | It is a kind of to block the rich preparation method for Buddhist nun |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN112979544A (en) * | 2019-12-17 | 2021-06-18 | 江苏先声药业有限公司 | Preparation method of cabozantinib or salt thereof |
| WO2023222946A1 (en) | 2022-05-18 | 2023-11-23 | Fermion Oy | Process for the preparation of cabozantinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| CN106008371A (en) * | 2016-06-24 | 2016-10-12 | 谢阳 | 1-aryl ureido naphthenic base-1-formamide compound and pharmaceutical composition and application thereof |
| CN107556238A (en) * | 2016-06-30 | 2018-01-09 | 深圳万乐药业有限公司 | It is a kind of to block the rich synthetic method for Buddhist nun |
-
2018
- 2018-02-05 CN CN201810110778.6A patent/CN108264482A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| CN106008371A (en) * | 2016-06-24 | 2016-10-12 | 谢阳 | 1-aryl ureido naphthenic base-1-formamide compound and pharmaceutical composition and application thereof |
| CN107556238A (en) * | 2016-06-30 | 2018-01-09 | 深圳万乐药业有限公司 | It is a kind of to block the rich synthetic method for Buddhist nun |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240563A (en) * | 2019-05-09 | 2019-09-17 | 南京法恩化学有限公司 | A kind of rich preparation method for Buddhist nun of card |
| CN112979544A (en) * | 2019-12-17 | 2021-06-18 | 江苏先声药业有限公司 | Preparation method of cabozantinib or salt thereof |
| CN112979544B (en) * | 2019-12-17 | 2024-06-28 | 江苏先声药业有限公司 | Preparation method of cabozitinib or salt thereof |
| WO2023222946A1 (en) | 2022-05-18 | 2023-11-23 | Fermion Oy | Process for the preparation of cabozantinib |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180710 |
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| WW01 | Invention patent application withdrawn after publication |