CN108997209A - A kind of preparation method of Rui Gefeini - Google Patents
A kind of preparation method of Rui Gefeini Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The present invention relates to the preparation methods of Rui Gefeini a kind of, and this method comprises the following steps: 4- amino -3- fluorophenol, 4- chloro-n-methyl pyridine-2-carboxamide under the action of Anhydrous potassium carbonate, PEG-400 to that ether condensation reaction occur and generate intermediate I；Intermediate I, 3- trifluoromethyl -4- chlorobenzoic acid are carried out " one pot " with diphenyl phosphate azide in the presence of alkali afterwards to react, get Rui Gefeini sterling is further purified in get Rui Gefeini crude product.Method high conversion rate of the invention, safety are non-hazardous, pollution-free, reaction condition is mild, high income, product purity are high and is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of preparation method of Rui Gefeini.
Background technique
Rui Gefeini (regorafenib), entitled 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl of chemistry
Base } amino) -3- fluorophenoxy]-N- picoline -2- formamide, it is developed by German Bayer Healthcare company, Yu Mei
State FDA approval listing, trade name Stivarga.This product can inhibit a variety of kinases for promoting cancerous tissue growth, including VEGFR1-
2, PDGFR- β, FGFR1 and KIT etc., and then inhibit the proliferation of tumor vascular generation and tumour cell, clinically it is suitable for turning
The treatment of shifting property colorectal cancer.Its chemical structural formula is as follows:
It is as follows at present about the reported several preparation methods of the synthesis of Rui Gefeini:
Technical solution 1: patent WO2005/009961A, WO2008/89388, WO2008/58644, WO2011128261,
WO2011130728、WO2012012404、US2006/58358、US2005038080、CN 105218440、CN
104910067, side Liu Ya etc. (fine-chemical intermediate, 2012,42 (6) 31-34), Su Peng etc. (pharmacy clinical research), Zheng De
It is strong that (Chinese Journal of Pharmaceuticals, 2016,47 (5) 528-530) etc. is waited to report a kind of method for preparing Rui Gefeini, on the road
During line is reacted at ether, according to the method that above-mentioned document is specifically reported, although reaction only has a step, reaction needs stringent in nitrogen
It protects and is done with DMA and carried out under solvent, there are many side reaction, the by-product that easily generation is docked with amino and phenol is oxidized, rear to locate
Manage many and diverse, product purification is more difficult, and pillar layer separation is needed to purify, and yield is not high, is not suitable for industrialized production.And the reaction
It needs to need using the synthesis of phosgene or isocyanates using phosgene, surpalite or triphosgene.Phosgene is a kind of hypertoxic gas,
By-product causes serious pollution to the environment to production equipment seriously corroded, all brings immense pressure to environmental protection and labour protection, can only be specific
Plant produced and use.Later period research and development surpalite (trichloromethyl chloroformate), [carbonic acid is bis- (trichloromethyl) for triphosgene
Ester] substitution phosgene, but both raw materials are all to be decomposed into monochromatic light gas during the reaction to participate in reaction, are not solved inherently
Phosgene severe toxicity, the intrinsic problem such as pollution environment, there are serious security risks.A kind of severe toxicity of surpalite conduct simultaneously itself has
The liquid of penetrating odor still has biggish risk；Triphosgene property is extremely active and has severe toxicity, it is difficult to control triphosgene
It has an effect with reaction dissolvent and generates various impurity, and be difficult to ensure industrial production safety.
The documents reports such as technical solution 2: Wang Yabo (Chinese antibiotic magazine in August, 2015 the 8th phase of volume 40,590-592)
P-aminobenzene sulfonic acid is starting material by road, obtains target chemical combination through diazotising, coupling, reduction, nucleophilic displacement of fluorine and CDI condensation reaction
Object.
Method synthesis Rui Gefeini yield is general, and time-consuming for entire technique, cumbersome；And N, N'- carbonyl dimidazoles
Price is higher, to moist lability, meets water and is hydrolyzed in a few seconds and releases carbon dioxide, causes charging inaccuracy, be easy
More difficult isolated dimer is generated, while its synthesis is also required to be unfavorable for industrialized production using phosgene.
Technical solution 3: Chinese patent CN 106083711 discloses the synthetic method of Rui Gefeini a kind of, and this method is by 4-
Amidation process occurs for chloro- 3- 5-trifluoromethylaniline and phenyl chloroformate, obtains intermediate, occurs with 4- amino -3- fluorophenol
Amidation process obtains intermediate, and alkylated reaction occurs with starting material 4- chloro-n-methyl -2- pyridine carboxamides, then passes through
Post-process get Rui Gefeini.The method overall yield is lower, uses the n,N-Dimethylformamide for being difficult to recycle in reacting at ether,
Synthesis cost is higher, and pollution is larger, and the synthetic yield of phenyl chloroformate is lower, while the purifying of product also needs column to chromatograph
Separation method, economy are too poor；Although the synthesis process is avoided using triphosgene, but raw material chloro-carbonic acid -2- nitro phenyl ester and chlorine
Phenyl formate is unstable and has corrosivity, has certain damage to equipment, industrial production danger is huge, and not friendly to environment
It is good.
Although the prior art can synthesize Rui Gefeini, generally existing to use complex process, use hypertoxic raw material, behaviour
Make the disadvantages of difficult, yield is low, purity is low, reaction is uncontrollable.It is known that there are the spies such as high risk, high risk for industrialized production
Point, mild condition, reaction be controllable, raw material low toxicity, pollution-free industrial dangerous and production cost can undoubtedly substantially reduced.
Summary of the invention
Technical problem to be solved by the present invention lies in order to overcome, there are techniques to answer in existing preparation Rui Gefeini technology
Miscellaneous, operating difficulties, yield are low, purity is low, expensive catalyst and the defect for not being suitable for industrialized production, and provide one kind
The preparation method of Rui Gefeini.Method high conversion rate of the invention, safety are non-hazardous, pollution-free, reaction condition is mild, yield
Height, product purity are high and are suitable for industrialized production.Technical scheme is as follows:
A kind of preparation method of Rui Gefeini, it is characterised in that including following operating procedure:
1) 4- amino -3- fluorophenol, 4- chloro-n-methyl pyridine-2-carboxamide Anhydrous potassium carbonate and PEG-400 effect
Lower generation ether condensation reaction generates intermediate I；
2) 3- trifluoromethyl -4- chlorobenzoic acid, intermediate I and diphenyl phosphate azide react in the presence of alkali,
Get Rui Gefeini crude product；
3) sterling is further purified to obtain in Rui Gefeini crude product；
In step 1), 4- amino -3- fluorophenol, Anhydrous potassium carbonate, 4- chloro-n-methyl pyridine-2-carboxamide, PEG-400
The mass ratio of the material be 0.9~1.1:1.0:0.8~0.9:0.02~0.03；The reaction dissolvent of ether condensation reaction is two chloroethenes
Alkane.Wherein, 4- amino -3- fluorophenol, Anhydrous potassium carbonate, 4- chloro-n-methyl pyridine-2-carboxamide, PEG-400 substance amount
Than for 1.0:1.0:0.85:0.025.
In step 2), the alkali is pyridine, and reaction dissolvent is Isosorbide-5-Nitrae-dioxane.3- trifluoromethyl -4- chlorobenzoic acid,
Intermediate I, the mass ratio of the material of diphenyl phosphate azide are 1:0.85~0.95:1.1~1.5；3- trifluoromethyl -4- chlorobenzene first
The mass ratio of the material of acid and alkali is 1:1.1~2.0；Preferably, 3- trifluoromethyl -4- chlorobenzoic acid, intermediate I, nitrine phosphoric acid
The mass ratio of the material of diphenyl ester is 1:0.9:1.3；The mass ratio of the material of 3- trifluoromethyl -4- chlorobenzoic acid and alkali is 1:1.5.
In step 3), the purification step are as follows: crude product is added to the water, diluted hydrochloric acid aqueous solution adjusts pH, and crude product is molten
Solution, extracted by ether removal of impurities, water layer are added dropwise sodium bicarbonate aqueous solution and adjust pH, and solid is precipitated；Solid is dissolved in organic solvent, is added
Enter active carbon, stir, filter, washing is evaporated off organic solvent, obtains thick liquid, be added in cold water, precipitates crystal, growing the grain, mistake
Filter, drains, obtains white solid, dry, obtains sterling.Wherein, crude product and the mass volume ratio of aqueous solvent are 1g:12~18mL,
The mass fraction of diluted hydrochloric acid aqueous solution solute is 10%, and the pH of adjusting is 2.0~2.5；The quality of sodium bicarbonate aqueous solution solute
Score is 6%, and the pH of adjusting is 6.5~7.0.
Compared with the prior art, the preparation method of Rui Gefeini provided by the present invention has high conversion rate, safety without danger
Harmful, pollution-free, reaction condition is mild, high income, product purity are high and the features such as being suitable for industrialized production, Core Superiority
It is that 4- amino -3- fluorophenol, 4- chloro-n-methyl pyridine-2-carboxamide occur under the action of Anhydrous potassium carbonate, PEG-400
Ether condensation reaction generates intermediate I, and reaction yield is high, and purity is high, post-processing is simple, and yield is up to 96%, meets greenization
Requirement, while avoiding greatly reducing production cost using expensive catalyst；Afterwards by 3- trifluoromethyl -4- chlorine
Benzoic acid, intermediate I and diphenyl phosphate azide react in the presence of alkali, get Rui Gefeini, and reaction safety is without danger
It is harmful, pollution-free, reaction condition is mild, avoid needing using the synthesis of phosgene or isocyanates using phosgene, surpalite or three
Phosgene；Acid-base accommodation is utilized in present invention purification, removes partial impurities；Crystallization is carried out using solvent afterwards, impurity is removed, finally makes
Impurity is purified substantially, and purified product purity reaches 99.9%.The preparation method is suitble to industrialization amplification to require, and is Rui Gefei
The preparation of Buddhist nun or other compounds provides another important and practical new compound.
Specific embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.
The synthesis of embodiment 1-1 intermediate I
In a 250mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, it is added 100mmol's
4- amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 85mmol, 2.5mmol
PEG-400 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two
Chloroethanes extracts kettle liquid with 240mL ether, dry, concentration, obtains weak yellow liquid i.e. intermediate I 21.39g, yield 96.3%,
Purity 99.90%.
The synthesis of embodiment 1-2 intermediate I
A magnetic stirring apparatus is had one, and in the 250mL there-necked flask of thermometer and reflux condensing tube, the 4- of 90mmol is added
Amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 90mmol, 2mmol PEG-
400 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two chloroethenes
Alkane extracts kettle liquid with 240mL ether, and dry, concentration obtains weak yellow liquid i.e. intermediate I 21.32g, yield 90.6%, purity
99.80%.
The synthesis of embodiment 1-3 intermediate I
A magnetic stirring apparatus is had one, in the 250mL there-necked flask of thermometer and reflux condensing tube, is added 110mmol's
4- amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 80mmol, 3mmol
PEG-400 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two
Chloroethanes extracts kettle liquid with 240mL ether, dry, concentration, obtains weak yellow liquid i.e. intermediate I 19.59g, yield 93.7%,
Purity 99.76%.
The synthesis of embodiment 1-4 intermediate I
A magnetic stirring apparatus is had one, and in the 250mL there-necked flask of thermometer and reflux condensing tube, the 4- of 90mmol is added
Amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 80mmol, 2mmol PEG-
400 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two chloroethenes
Alkane extracts kettle liquid with 240mL ether, and dry, concentration obtains weak yellow liquid i.e. intermediate I 19.11g, yield 91.3%, purity
99.87%.
The synthesis of embodiment 1-5 intermediate I
A magnetic stirring apparatus is had one, in the 250mL there-necked flask of thermometer and reflux condensing tube, is added 110mmol's
4- amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 90mmol, 3mmol
PEG-400 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two
Chloroethanes extracts kettle liquid with 240mL ether, dry, concentration, obtains weak yellow liquid i.e. intermediate I 22.10g, yield 94.0%,
Purity 99.89%.
The synthesis of embodiment 1-6 intermediate I
A magnetic stirring apparatus is had one, in the 250mL there-necked flask of thermometer and reflux condensing tube, is added 100mmol's
4- amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 85mmol, 2.5mmol
PEG-200 and 100mL dichloroethanes, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off two
Chloroethanes extracts kettle liquid with 240mL ether, dry, concentration, obtains weak yellow liquid i.e. intermediate I 19.69g, yield 88.6%,
Purity 99.85%.
The synthesis of embodiment 1-7 intermediate I
A magnetic stirring apparatus is had one, in the 250mL there-necked flask of thermometer and reflux condensing tube, is added 100mmol's
4- amino -3- fluorophenol, 100mmol Anhydrous potassium carbonate, the 4- chloro-n-methyl pyridine-2-carboxamide of 85mmol, 2.5mmol
PEG-400 and 100mL ethyl alcohol, electromagnetic agitation, heating water bath flow back 4 hours.Cooling, filtering, water pump decompression boil off ethyl alcohol, use
240mL ether extracts kettle liquid, dry, and concentration obtains weak yellow liquid i.e. intermediate I 20.32g, yield 91.4%, purity
99.81%.
The synthesis of embodiment 2-1 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 75mmol are dissolved in
In 80mL1,4- dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring
45mmol intermediate compound I is added into bottle for end of reaction, continues heating reflux reaction 1h and is cooled to room temperature after reaction, will
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 20.86g, yield 96.0%.
The synthesis of embodiment 2-2 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 75mmol and pyridine 100mmol are dissolved in
In 80mL Isosorbide-5-Nitrae-dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC prison
End of reaction is surveyed, 42.5mmol intermediate compound I is added into bottle, continues heating reflux reaction 1h and is cooled to room after reaction
Reaction solution is concentrated under reduced pressure temperature, dry, get Rui Gefeini crude product 18.59g, yield 90.6%.
The synthesis of embodiment 2-3 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 55mmol and pyridine 55mmol are dissolved in
In 80mL1,4- dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring
47.5mmol intermediate compound I is added into bottle for end of reaction, continues heating reflux reaction 1h and is cooled to room temperature after reaction,
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 20.94g, yield 91.3%.
The synthesis of embodiment 2-4 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 55mmol and pyridine 75mmol are dissolved in
In 80mL1,4- dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring
42.5mmol intermediate compound I is added into bottle for end of reaction, continues heating reflux reaction 1h and is cooled to room temperature after reaction,
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 19.12g, yield 93.2%.
The synthesis of embodiment 2-5 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 75mmol and pyridine 75mmol are dissolved in
In 80mL1,4- dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring
47.5mmol intermediate compound I is added into bottle for end of reaction, continues heating reflux reaction 1h and is cooled to room temperature after reaction,
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 21.42g, yield 93.4%.
The synthesis of embodiment 2-6 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 55mmol are dissolved in
In 80mL1,4- dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring
45mmol intermediate compound I is added into bottle for end of reaction, continues heating reflux reaction 1h and is cooled to room temperature after reaction, will
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 20.36g, yield 93.7%.
The synthesis of embodiment 2-7 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 100mmol are dissolved in
In 80mL Isosorbide-5-Nitrae-dioxane, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC prison
End of reaction is surveyed, 45mmol intermediate compound I is added into bottle, continues heating reflux reaction 1h and is cooled to room temperature after reaction,
Reaction solution is concentrated under reduced pressure, dry, get Rui Gefeini crude product 20.40g, yield 93.9%.
The synthesis of embodiment 2-8 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 75mmol are dissolved in
In 80mL ethyl acetate, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring reaction
It finishes, 45mmol intermediate compound I is added into bottle, continue heating reflux reaction 1h and be cooled to room temperature after reaction, will react
Liquid is concentrated under reduced pressure, dry, get Rui Gefeini crude product 18.47g, yield 85.0%.
The synthesis of embodiment 2-9 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 75mmol are dissolved in
In 80mL toluene, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring has been reacted
Finish, 45mmol intermediate compound I is added into bottle, continues heating reflux reaction 1h and be cooled to room temperature after reaction, by reaction solution
It is concentrated under reduced pressure, dry, get Rui Gefeini crude product 15.27g, yield 70.3%.
The synthesis of embodiment 2-10 Rui Gefeini crude product
3- trifluoromethyl -4- chlorobenzoic acid 50mmol, diphenyl phosphate azide 65mmol and pyridine 75mmol are dissolved in
In 80mL carbon tetrachloride, 0.5h is stirred under the conditions of 0 DEG C, is then placed into heating reflux reaction 1h in oil bath, TLC monitoring reaction
It finishes, 45mmol intermediate compound I is added into bottle, continue heating reflux reaction 1h and be cooled to room temperature after reaction, will react
Liquid is concentrated under reduced pressure, dry, get Rui Gefeini crude product 14.01g, yield 64.5%.
Embodiment 3-1 Rui Gefeini sterling
Crude product 10g is added in 150mL water, is sufficiently stirred, adjusts pH to 2.0~2.5 with 10% diluted hydrochloric acid aqueous solution,
It is stirred at room temperature, crude product dissolution, filtering obtains crude product solution, goes organic phase with after extracted by ether organic impurities points；It is added dropwise to water layer
6% sodium bicarbonate solution, adjusts pH to 6.5~7.0, and evolution reaction product filters, obtains solid；Obtained solid is dissolved in
In 50mL ether, active carbon is added, is heated to 30 DEG C, is sufficiently stirred, filtrate is obtained after filtering, separates organic layer after stirring, (3*
20mL)H2O washing, filtering are evaporated off ether, obtain thick liquid product, thick liquid product is added in cold water, are precipitated brilliant
Body, growing the grain, filtering drain, obtain white solid, are dried in vacuo, get Rui Gefeini sterling 9.60g, yield 96.0%, purity
99.94%.
Embodiment 3-2 Rui Gefeini sterling
Crude product 10g is added in 120mL water, is sufficiently stirred, adjusts pH to 2.0~2.5 with 10% diluted hydrochloric acid aqueous solution,
It is stirred at room temperature, crude product dissolution, filtering obtains crude product solution, goes organic phase with after extracted by ether organic impurities points；It is added dropwise to water layer
6% sodium bicarbonate solution, adjusts pH to 6.5~7.0, and evolution reaction product filters, obtains solid；Obtained solid is dissolved in
In 50mL ether, active carbon is added, is heated to 30 DEG C, is sufficiently stirred, filtrate is obtained after filtering, separates organic layer after stirring, (3*
20mL)H2O washing, filtering are evaporated off ether, obtain thick liquid product, thick liquid product is added in cold water, are precipitated brilliant
Body, growing the grain, filtering drain, obtain white solid, are dried in vacuo, get Rui Gefeini sterling 9.48g, yield 94.8%, purity
99.92%.
Embodiment 3-3 Rui Gefeini sterling
Crude product 10g is added in 180mL water, is sufficiently stirred, adjusts pH to 2.0~2.5 with 10% diluted hydrochloric acid aqueous solution,
It is stirred at room temperature, crude product dissolution, filtering obtains crude product solution, goes organic phase with after extracted by ether organic impurities points；It is added dropwise to water layer
6% sodium bicarbonate solution, adjusts pH to 6.5~7.0, and evolution reaction product filters, obtains solid；Obtained solid is dissolved in
In 50mL ether, active carbon is added, is heated to 30 DEG C, is sufficiently stirred, filtrate is obtained after filtering, separates organic layer after stirring, (3*
20mL)H2O washing, filtering are evaporated off ether, obtain thick liquid product, thick liquid product is added in cold water, are precipitated brilliant
Body, growing the grain, filtering drain, obtain white solid, are dried in vacuo, get Rui Gefeini sterling 9.41g, yield 94.1%, purity
99.94%.
Embodiment 3-4 Rui Gefeini sterling
Crude product 10g is added in 150mL water, is sufficiently stirred, adjusts pH to 2.5~3.0 with 10% diluted hydrochloric acid aqueous solution,
It is stirred at room temperature, crude product dissolution, filtering obtains crude product solution, goes organic phase with after extracted by ether organic impurities points；It is added dropwise to water layer
6% sodium bicarbonate solution, adjusts pH to 7.0~7.5, and evolution reaction product filters, obtains solid；Obtained solid is dissolved in
In 50mL ether, active carbon is added, is heated to 30 DEG C, is sufficiently stirred, filtrate is obtained after filtering, separates organic layer after stirring, (3*
20mL)H2O washing, filtering are evaporated off ether, obtain thick liquid product, thick liquid product is added in cold water, are precipitated brilliant
Body, growing the grain, filtering drain, obtain white solid, are dried in vacuo, get Rui Gefeini sterling 9.13g, yield 91.3%, purity
99.93%.
Embodiment 3-5 Rui Gefeini sterling
Crude product 10g is added in 150mL water, is sufficiently stirred, adjusts pH to 2.0~2.5 with 10% diluted hydrochloric acid aqueous solution,
It is stirred at room temperature, crude product dissolution, filtering obtains crude product solution, goes organic phase with after extracted by ether organic impurities points；It is added dropwise to water layer
6% sodium bicarbonate solution, adjusts pH to 7.0~7.5, and evolution reaction product filters, obtains solid；Obtained solid is dissolved in
In 50mL ether, active carbon is added, stir thoroughly at room temperature obtains filtrate, separates organic layer after stirring, (3*20mL) H after filtering2O
Washing, filtering, is evaporated off ether, obtains thick liquid product, thick liquid product is added in cold water, is precipitated crystal, growing the grain, mistake
Filter, drains, obtains white solid, is dried in vacuo, get Rui Gefeini sterling 9.35g, yield 93.5%, purity 99.92%.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing technique cans understand the content of the present invention and implement it accordingly, and protection model of the invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of Rui Gefeini, it is characterised in that including following operating procedure:
1) 4- amino -3- fluorophenol, 4- chloro-n-methyl pyridine-2-carboxamide are sent out under the action of Anhydrous potassium carbonate and PEG-400
Raw ether condensation reaction, generates intermediate I；
2) 3- trifluoromethyl -4- chlorobenzoic acid, intermediate I and diphenyl phosphate azide react in the presence of alkali, obtain auspicious
Ge Feini crude product；
3) sterling is further purified to obtain in Rui Gefeini crude product；
2. the preparation method of Rui Gefeini according to claim 1 a kind of, which is characterized in that in step 1), 4- amino -3-
Fluorophenol, Anhydrous potassium carbonate, 4- chloro-n-methyl pyridine-2-carboxamide, PEG-400 the mass ratio of the material be 0.9~1.1:1.0:
0.8~0.9:0.02~0.03；The reaction dissolvent of ether condensation reaction is dichloroethanes.
3. the preparation method of Rui Gefeini according to claim 1 a kind of, which is characterized in that in step 2), the alkali
For pyridine, reaction dissolvent is Isosorbide-5-Nitrae-dioxane.
4. the preparation method of Rui Gefeini according to claim 1 a kind of, which is characterized in that in step 2), 3- fluoroform
Base -4- chlorobenzoic acid, intermediate I, the mass ratio of the material of diphenyl phosphate azide are 1:0.85~0.95:1.1~1.5；3- tri-
The mass ratio of the material of methyl fluoride -4- chlorobenzoic acid and alkali is 1:1.1~2.0.
5. the preparation method of Rui Gefeini according to claim 1 a kind of, which is characterized in that in step 3), described is pure
Change step are as follows: crude product is added to the water, diluted hydrochloric acid aqueous solution adjusts pH, crude product dissolution, extracted by ether removal of impurities, water layer dropwise addition carbon
Sour hydrogen sodium water solution adjusts pH, and solid is precipitated；Solid is dissolved in organic solvent, active carbon is added, is stirred, is filtered, is washed, is steamed
Except organic solvent, thick liquid is obtained, is added in cold water, is precipitated crystal, growing the grain, filtering drains, obtains white solid, and it is dry,
Obtain sterling.
6. the preparation method of Rui Gefeini according to claim 2 a kind of, which is characterized in that in step 1), 4- amino -3-
Fluorophenol, Anhydrous potassium carbonate, 4- chloro-n-methyl pyridine-2-carboxamide, PEG-400 the mass ratio of the material be 1.0:1.0:0.85:
0.025。
7. the preparation method of Rui Gefeini according to claim 4 a kind of, which is characterized in that in step 2), 3- fluoroform
Base -4- chlorobenzoic acid, intermediate I, the mass ratio of the material of diphenyl phosphate azide are 1:0.9:1.3；3- trifluoromethyl -4- chlorobenzene
The mass ratio of the material of formic acid and alkali is 1:1.5.
8. the preparation method of Rui Gefeini according to claim 5 a kind of, which is characterized in that crude product and solvent in step 3)
The mass volume ratio of water is 1g:12~18mL, and the mass fraction of diluted hydrochloric acid aqueous solution solute is 10%, the pH of adjusting is 2.0~
2.5；The mass fraction of sodium bicarbonate aqueous solution solute is 6%, and the pH of adjusting is 6.5~7.0.
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| CN114920689A (en) * | 2022-04-26 | 2022-08-19 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of regorafenib intermediate |
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