CN110143917A - A kind of rich preparation method for Buddhist nun's metabolin of card - Google Patents
A kind of rich preparation method for Buddhist nun's metabolin of card Download PDFInfo
- Publication number
- CN110143917A CN110143917A CN201910614859.4A CN201910614859A CN110143917A CN 110143917 A CN110143917 A CN 110143917A CN 201910614859 A CN201910614859 A CN 201910614859A CN 110143917 A CN110143917 A CN 110143917A
- Authority
- CN
- China
- Prior art keywords
- base
- preparation
- oxygroup
- quinoline
- cyclopropane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Abstract
The present invention provides a kind of rich preparation methods for Buddhist nun's metabolin of card; including; 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and 4- ((6; 7- dimethoxy-quinoline -4- base) oxygroup) aniline progress reacted at amide; obtain 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenylcarbamoyl) cyclopropanecarboxylate.This method can carry out in one pot, and the present invention overcomes the prejudice of the prior art, and a kind of method for preparing amide is screened from carboxylic acid halides method, and the molar yield of this method may be up to 95% instead, and purity may be up to 98%, and post-processing is also very simple.
Description
Technical field
The present invention relates to a kind of rich preparation methods for Buddhist nun's metabolin of card.
Background technique
The research of metabolin has important meaning in many fields of medicinal pharmacology, such as: (1) research, exploitation of new drug
And design;(2) clinical medicine detects;(3) bioavilability of pharmaceutical preparation and bioequivalence Journal of Sex Research;(4) toxicologic study.
Lu Anthony Y.H point out research topic most challenging in drug metabolism first is that illustrating individual reaction in drug therapy
The individual difference of the reason of difference and drug metabolism influences therapeutic effect and causes the mechanism of toxic side effect, really to realize
Clinical application it is safe, reasonable and personalized.Especially since ethnic group is different, external clinical medicine more needs to study it in compatriots
Intracorporal metabolic condition.But in metabolin research, the scarcity relatively of research metabolin synthesis, many documents or yield are not
High or not record yield (often meaning that very low).
Card is rich to have ratified listing in foreign countries several years ago for Buddhist nun, currently used for treating medullary carcinoma of thyroid gland, clear-cell carcinoma, liver cancer
Deng, but granted listing at home not yet so far.Instantly, medullary carcinoma of thyroid gland advanced stage and patients with recurrent there is no standard regimens,
There is clinical blank in this therapy field in China.Data shows that the rich ariyoshi metabolin for replacing Buddhist nun of card includes 1- ((4- ((6,7-
Dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropanecarboxylate is a kind of amide.Currently, synthesis acyl
The method of amine is very more, and most traditional carboxylic acid halides method is since reaction step is more, yield is low, reaction controlling is complicated etc., out of vogne, mesh
It is preceding it is popular be condensing agent method, this method high income, reaction condition are simple.
Summary of the invention
The present invention overcomes the prejudice of the prior art, and a kind of method for preparing amide, this method are screened from carboxylic acid halides method
Molar yield may be up to 95% instead, purity may be up to 98%, and post-processing is also very simple.
In order to achieve the above objectives, the technical solution adopted by the present invention are as follows:
A kind of rich preparation method for Buddhist nun's metabolin of card, including, 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and 4- ((6,7- dimethoxies
Base quinolyl-4) oxygroup) aniline progress reacted at amide, i.e., the reaction for the purpose of preparing amide product obtains 1- ((4-
((6,7- dimethoxy-quinoline -4- base) oxygroup) phenylcarbamoyl) cyclopropanecarboxylate.This method can in one pot into
Row, optionally, it is described at amide reaction include, with before 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline reaction, 1-
(methoxycarbonyl group) cyclopropane-carboxylic acid first carries out acyl chloride reaction with carbonic acid trichloromethyl ester.It is straight after may filter that after acyl chloride reaction
It connects for later reaction.
Optionally, described, the molar ratio of 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and carbonic acid trichloromethyl ester is 1:0.4-
0.5, for example 1:0.45.
Optionally, the acyl chloride reaction carries out in the presence of imidazoles.
Optionally, the molar ratio of the imidazoles and 1- (methoxycarbonyl group) cyclopropane-carboxylic acid is 1:0.03-0.05, for example 1:
0.04。
Optionally, the acyl chloride reaction carries out under melting temperature, and for example 100-120 DEG C, be for another example 110 DEG C.Reaction
Time can be 2h.
Optionally, 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) benzene
The molar ratio of amine is 1.05-1.15:1, for example 1.1:1.
Optionally, 4- ((6, the 7- dimethoxy-quinoline -4- base) oxygroup) aniline carries out in the presence of water and inorganic base
Described to react at amide, the reaction time can be 2h；Optionally, the inorganic base can be sodium carbonate.
Optionally, the molar ratio of 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline and the inorganic base is
1:1-2, for example 1:1.5.
Optionally, the post-processing at amide reaction includes: that reactant mixed liquor is extracted with ethyl acetate, and is then being contained
Crystallization (volume ratio of the mixed liquor as used acetone and water, acetone and water can be 1:1), obtains 1- in the system of acetone and water
((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenylcarbamoyl) cyclopropanecarboxylate.Crystallization can be low by being down to
Temperature realizes that the crystallization such as at 0 DEG C, the time can be 1h.Stirring can be aided with when crystallization.
The invention has the benefit that
The present invention overcomes the prejudice of the prior art, and a kind of method for preparing amide is screened from carboxylic acid halides method, and this method is rubbed
Your yield may be up to 95% instead, and purity may be up to 98%, and post-processing is also very simple, and the far super prior art of these effects, is pre-
Unexpectedly.
Specific embodiment
Embodiment 1:
By 11mmol 1- (methoxycarbonyl group) cyclopropane-carboxylic acid, 0.44mmol imidazoles and 4.4mmol carbonic acid trichloromethyl ester in flask
Middle mixing, heating make reactant be melt into liquid, open stirring, carry out in 110 DEG C of heat preservations into acyl chloride reaction 2h, then will reaction
Liquid cooling but and filters spare.
Into flask be added 10mmol 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline, 15mmol sodium carbonate and
Then plus 100ml water and with 3 20ml water, then chloride product obtained by upper step is all added, is stirred to react 2h at room temperature,
The extraction of x 50mL ethyl acetate merges extraction gained organic layer and is simultaneously concentrated into 20ml, is then added to the acetone and water of 200ml
In mixed liquor (volume ratio of acetone and water is 1:1), it is cooled to 0 DEG C, crystal is precipitated sufficiently in stirring 1h, and sodium sulphate is whitely dry
Color solid 3.9g is identified as 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane first
Sour methyl esters, purity are up to 90%.
1H NMR(CDCl3): δ 10.96 (s, 1H)；8.46(d,1H)；7.67(d,2H)；7.55(s,1H)；7.41(s,
1H)； 7.16(d,2H)；6.45(d,1H)；4.04(s,6H)；3.76(s,3H)；1.86-1.82(m, 2H),1.73-1.70
(m,2H)；
MS:423.2 (M+H)
Embodiment 2:
By 11mmol 1- (methoxycarbonyl group) cyclopropane-carboxylic acid, 0.44mmol imidazoles and 4.95mmol carbonic acid trichloromethyl ester in burning
It is mixed in bottle, heating makes reactant be melt into liquid, opens stirring, carries out in 110 DEG C of heat preservations into acyl chloride reaction 2h, then will be anti-
It answers liquid cooling but and filters spare.
Into flask be added 10mmol 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline, 15mmol sodium carbonate and
Then plus 100ml water and with 3 20ml water, then chloride product obtained by upper step is all added, is stirred to react 2h at room temperature,
The extraction of x 50mL ethyl acetate merges extraction gained organic layer and is simultaneously concentrated into 20ml, is then added to the acetone and water of 200ml
In mixed liquor (volume ratio of acetone and water is 1:1), it is cooled to 0 DEG C, crystal is precipitated sufficiently in stirring 1h, and sodium sulphate is whitely dry
Color solid 4.1g is identified as 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane first
Sour methyl esters, purity are up to 98%.
Embodiment 3:
By 11mmol 1- (methoxycarbonyl group) cyclopropane-carboxylic acid, 0.44mmol imidazoles and 5.5mmol carbonic acid trichloromethyl ester in flask
Middle mixing, heating make reactant be melt into liquid, open stirring, carry out in 110 DEG C of heat preservations into acyl chloride reaction 2h, then will reaction
Liquid cooling but and filters spare.
Into flask be added 10mmol 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline, 15mmol sodium carbonate and
Then plus 100ml water and with 3 20ml water, then chloride product obtained by upper step is all added, is stirred to react 2h at room temperature,
The extraction of x 50mL ethyl acetate merges extraction gained organic layer and is simultaneously concentrated into 20ml, is then added to the acetone and water of 200ml
In mixed liquor (volume ratio of acetone and water is 1:1), it is cooled to 0 DEG C, crystal is precipitated sufficiently in stirring 1h, and sodium sulphate is whitely dry
Color solid 4.2g is identified as 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane first
Sour methyl esters, purity are up to 91%.
Embodiment 4:
By 10.5mmol 1- (methoxycarbonyl group) cyclopropane-carboxylic acid, 0.42mmol imidazoles and 4.73mmol carbonic acid trichloromethyl ester in
It is mixed in flask, heating makes reactant be melt into liquid, opens stirring, carries out in 110 DEG C of heat preservations into acyl chloride reaction 2h, then will
Reaction solution is cooling and filters spare.
Into flask be added 10mmol 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline, 15mmol sodium carbonate and
Then plus 100ml water and with 3 20ml water, then chloride product obtained by upper step is all added, is stirred to react 2h at room temperature,
The extraction of x 50mL ethyl acetate merges extraction gained organic layer and is simultaneously concentrated into 20ml, is then added to the acetone and water of 200ml
In mixed liquor (volume ratio of acetone and water is 1:1), it is cooled to 0 DEG C, crystal is precipitated sufficiently in stirring 1h, and sodium sulphate is whitely dry
Color solid 4.4g is identified as 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane first
Sour methyl esters, purity are up to 90%.
Embodiment 5:
By 11.5mmol 1- (methoxycarbonyl group) cyclopropane-carboxylic acid, 0.46mmol imidazoles and 5.17mmol carbonic acid trichloromethyl ester in
It is mixed in flask, heating makes reactant be melt into liquid, opens stirring, carries out in 110 DEG C of heat preservations into acyl chloride reaction 2h, then will
Reaction solution is cooling and filters spare.
Into flask be added 10mmol 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline, 15mmol sodium carbonate and
Then plus 100ml water and with 3 20ml water, then chloride product obtained by upper step is all added, is stirred to react 2h at room temperature,
The extraction of x 50mL ethyl acetate merges extraction gained organic layer and is simultaneously concentrated into 20ml, is then added to the acetone and water of 200ml
In mixed liquor (volume ratio of acetone and water is 1:1), it is cooled to 0 DEG C, crystal is precipitated sufficiently in stirring 1h, and sodium sulphate is whitely dry
Color solid 4.2g is identified as 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane first
Sour methyl esters, purity are up to 92%.
Comparative example:
Tetrahydrofuran 60ml, the drop of n,N-Dimethylformamide 3 and 1- (methoxycarbonyl group) cyclopropane first are added into 250ml three-necked bottle
Oxalyl chloride 55.3mmol is added dropwise in sour 31.6mmol at 0-20 DEG C of temperature of control, drop finishes, and 10-20 DEG C of temperature control is reacted 2 hours, reaction
Liquid is stand-by.
4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline 31.6mmol, water are added into 250ml three-necked bottle
30ml, potassium carbonate 94.9mmol are added dropwise at 10-20 DEG C and walk reaction solution, and drop finishes, and reacts at room temperature 2 hours, is added into reaction solution
Water 300ml is stirred at room temperature 5 hours, filters, and filter cake is washed with tetrahydrofuran/water (50ml/100ml) mixed liquor prepared in advance, takes out
Filter, obtained solid column chromatography for separation (mobile phase V/V: ethyl acetate/dichloromethane=1/1), component needed for collecting remove under reduced pressure
Solvent obtains solid 6.38g, wherein 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) cyclopropane
Methyl formate purity is 94.5%.
Claims (10)
1. the rich preparation method for Buddhist nun's metabolin of card, including, 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and 4- ((6,7- dimethoxys
Quinolyl-4) oxygroup) aniline progress reacted at amide, obtain 1- ((4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl
Carbamyl) cyclopropanecarboxylate.
2. preparation method as described in claim 1, characterized in that it is described at amide reaction include, with 4- ((6,7- diformazans
Phenoxyl quinoline -4- base) oxygroup) before aniline reaction, 1- (methoxycarbonyl group) cyclopropane-carboxylic acid first carries out acyl with carbonic acid trichloromethyl ester
Chlorination reaction.
3. preparation method as claimed in claim 2, characterized in that 1- (methoxycarbonyl group) cyclopropane-carboxylic acid and carbonic acid trichloromethyl
The molar ratio of ester is 1:0.4-0.5, for example 1:0.45.
4. preparation method as claimed in claim 2 or claim 3, characterized in that the acyl chloride reaction carries out in the presence of imidazoles.
5. preparation method as claimed in claim 4, characterized in that the imidazoles rubs with 1- (methoxycarbonyl group) cyclopropane-carboxylic acid
You are than being 1:0.03-0.05, for example 1:0.04.
6. preparation method as claimed in claim 2, characterized in that the acyl chloride reaction carries out under melting temperature, for example
100-120 DEG C, be for another example 110 DEG C.
7. the preparation method as described in any first claim, characterized in that 1- (methoxycarbonyl group) cyclopropane-carboxylic acid with
The molar ratio of 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline is 1.05-1.15:1, for example 1.1:1.
8. the preparation method as described in any first claim, characterized in that 4- ((6,7- dimethoxy-quinoline -4- base) oxygen
Base) aniline carried out in the presence of water and inorganic base it is described reacted at amide, the inorganic base can be sodium carbonate.
9. preparation method as claimed in claim 9, characterized in that 4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline
Molar ratio with the inorganic base is 1:1-2, for example 1:1.5.
10. the preparation method as described in any first claim, characterized in that it is described at amide reaction post-processing include:
Reactant mixed liquor is extracted with ethyl acetate, then the crystallization in the system containing acetone and water, obtains 1- ((4- ((6,7- diformazans
Phenoxyl quinoline -4- base) oxygroup) phenylcarbamoyl) cyclopropanecarboxylate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910614859.4A CN110143917B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib metabolite |
| CN202010431104.3A CN111440119B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910614859.4A CN110143917B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib metabolite |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010431104.3A Division CN111440119B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110143917A true CN110143917A (en) | 2019-08-20 |
| CN110143917B CN110143917B (en) | 2020-03-31 |
Family
ID=67596815
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910614859.4A Active CN110143917B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib metabolite |
| CN202010431104.3A Active CN111440119B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib intermediate |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010431104.3A Active CN111440119B (en) | 2019-07-09 | 2019-07-09 | Preparation method of cabozantinib intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN110143917B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN104592013A (en) * | 2014-12-31 | 2015-05-06 | 东莞市长安东阳光铝业研发有限公司 | Method for synthesizing p-fluorobenzoyl chloride |
| CN106715397A (en) * | 2014-07-31 | 2017-05-24 | 埃克塞里艾克西斯公司 | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
| CN109988107A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The rich preparation method for Buddhist nun of card |
-
2019
- 2019-07-09 CN CN201910614859.4A patent/CN110143917B/en active Active
- 2019-07-09 CN CN202010431104.3A patent/CN111440119B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664776A (en) * | 2012-09-26 | 2014-03-26 | 正大天晴药业集团股份有限公司 | Preparation method for tyrosine kinase inhibitor and midbody thereof |
| CN106715397A (en) * | 2014-07-31 | 2017-05-24 | 埃克塞里艾克西斯公司 | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
| CN104592013A (en) * | 2014-12-31 | 2015-05-06 | 东莞市长安东阳光铝业研发有限公司 | Method for synthesizing p-fluorobenzoyl chloride |
| CN109988107A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The rich preparation method for Buddhist nun of card |
Non-Patent Citations (2)
| Title |
|---|
| 彭安顺: "《有机化学》", 31 December 2012 * |
| 段行信: "《实用精细有机合成手册》", 31 December 2000 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111440119B (en) | 2021-08-24 |
| CN110143917B (en) | 2020-03-31 |
| CN111440119A (en) | 2020-07-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| CN105837493B (en) | The synthetic method and its intermediate of Nintedanib | |
| CN101891715A (en) | Novel compound and preparation method and use thereof | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN110143917A (en) | A kind of rich preparation method for Buddhist nun's metabolin of card | |
| CN103965093A (en) | 2-perfluoroalkyl indole compound as well as preparation and application thereof | |
| CN105367470A (en) | Method for preparing vildagliptin | |
| CN104193638A (en) | Method for preparing (S)-2',6'-dimethyl tyrosine and derivative of (S)-2',6'-dimethyl tyrosine, and derivative | |
| CN108349872A (en) | The synthesis of terphenyl compounds | |
| CN105523985A (en) | Preparation method of vildagliptin | |
| CN113480480B (en) | Synthesis method of (R) -5' -methoxy laudan | |
| CN106831474B (en) | One kind-the α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method and application | |
| CN107698648A (en) | Containing cholesteric naphthalimide analog derivative and its synthesis and application | |
| CN104603104B (en) | Crystal formation of azetidine ketonic compound and preparation method thereof | |
| CN108409657B (en) | High-purity lappaconitine and preparation method thereof | |
| CN102786489A (en) | Preparation method of 5-methyl isoxazole-4-ethyl formate | |
| CN101066924B (en) | 2-hexyl-3-hydroxy-5-R1Oxyhexadecanoic acid R2ester, preparation method and application thereof for preparing weight-reducing medicine orlistat | |
| CN104262201A (en) | Synthesis method of chiral optically-pure (S)-3-aminovaleric acid | |
| Ikai et al. | Synthesis of polysaccharide derivatives bearing bromobenzoate pendants for use as chiral auxiliaries | |
| CN104557943A (en) | Preparation method of vildagliptin impurities | |
| CN104829591B (en) | Preparation method of deuterated pimozide | |
| CN105566422B (en) | The preparation method of Suo Feibuwei intermediate or derivatives thereof | |
| CN105017269B (en) | A kind of different tetronic acid derivatives of chiral spiro and its preparation | |
| CN106632028A (en) | Cabozantinib preparation method | |
| CN107936034B (en) | Benzyloxy dibenzo [b, f] dislikes English in heptan cyclopropylene acid compounds and intermediate and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |