CN104250226A - Method for preparing regorafenib intermediate - Google Patents
Method for preparing regorafenib intermediate Download PDFInfo
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- CN104250226A CN104250226A CN201310262792.5A CN201310262792A CN104250226A CN 104250226 A CN104250226 A CN 104250226A CN 201310262792 A CN201310262792 A CN 201310262792A CN 104250226 A CN104250226 A CN 104250226A
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 239000002138 L01XE21 - Regorafenib Substances 0.000 title abstract description 4
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 title abstract description 4
- 229960004836 regorafenib Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- -1 methoxyl group Chemical group 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 2
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 3
- 238000001311 chemical methods and process Methods 0.000 abstract 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract 1
- 238000011084 recovery Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a method for preparing a regorafenib intermediate; a compound represented by the formula II and a compound represented by the formula III are subjected to three stages of a step A, a step B and a step C, intermediates of all the stages are not separated, and thus the regorafenib intermediate I is prepared. According to the method, the intermediates of all the steps are not separated, post-treatment procedures are reduced, the process operational flow is saved, the solvent recovery and utilization efficiency is improved, pollution emissions and energy consumption are reduced, the requirements on green chemical process are met, and the method is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of method preparing Rui Gefeini intermediate compound I.
Background technology
Rui Gefeini (Regorafenib) is the tyrosine kinase inhibitor of a kind of Mutiple Targets developed by Bayer Med Care S. R. L., is used for the treatment of metastatic colorectal cancer.The intermediate structure formula of preparation Rui Gefeini is as shown in the formula shown in I:
Beyer Co., Ltd discloses the preparation method of this intermediate compound I at patent CN1721397A, with fluoro-4 nitrophenolss of 3-and 4-chloropyrimide-2-methyl-formiate for starting raw material, through hydrogenation, ammonification and coupling three step, and obtained intermediate compound I.This operational path shortcoming is that often walking intermediate needs to be separated, each step solvent disunity; Consider from the angle of Green Chemistry, this synthetic schemes aftertreatment is complicated, lock out operation time consumption and energy consumption, and multi-solvents uses and is unfavorable for reclaiming.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method preparing Rui Gefeini intermediate compound I, the method respectively walks intermediate and is not separated, decrease postprocessing working procedures, save technical operation flow, improve recycled solvent efficiency, reduce exhaust emission and energy consumption, meet green chemistry process requirement, be applicable to suitability for industrialized production.
The described method preparing Rui Gefeini intermediate compound I, by making formula II and formula III through steps A, step B and step C three phases, each intermediary is not separated obtained Rui Gefeini intermediate compound I.Reaction formula is as follows:
Wherein R is chlorine, methoxyl group, or oxyethyl group.
In steps A, the organic solution of formula II compound and methylamine is reacted, and methylamine mole number is 1.0-10.0 times of formula II, and preferred 2.0-6.0 doubly; Temperature of reaction is 0 ~ 25 ° of C, preferably 5 ~ 10 ° of C.After completion of the reaction, system, through filtered through silica gel, obtains intermediate II X solution, after quantitative analysis, is directly used in step C.
In step B, formula III compound and Pd/C react in presence of hydrogen, wherein the 5wt%-20wt% of Pd content to be the consumption of 1wt% ~ 20wt%, Pd/C be formula III compound in Pd/C.Reaction pressure is 0.1 ~ 1MPa, preferably 0.1 ~ 0.6MPa.Temperature of reaction is 0 ~ 100 ° of C, preferably 20 ~ 50 ° of C.After completion of the reaction, after filtration, filtering Pd/C, obtains intermediate III X solution to system, after quantitative analysis, is directly used in step C.
In step C, the formula III X solution that the formula IIX solution obtained by steps A and step B obtain, under the effect of alkali, is obtained by reacting Rui Gefeini intermediate compound I.Wherein said alkali is selected from: mineral alkali, as sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, or sodium hydrogen etc.; Or organic bases, as potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium isopropylate, potassium isopropoxide, hexamethyldisilane base Lithamide, hexamethyldisilane base sodium amide, hexamethyldisilane base potassium amide, or their organic solution; Or more the combination of described arbitrarily two or more alkali.Temperature of reaction is between-20 ~ 120 ° of C, preferably-5 ~ 90 ° of C.
It should be noted that, above by steps A to step C, in each stage of step B to step C, use identical non-polar organic solvent, be selected from: the ethers of C2-C8, as methyl tertiary butyl ether, ether, Isosorbide-5-Nitrae-dioxane, methyl-phenoxide, or phenyl ethyl ether etc.; Or tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or the aromatic hydrocarbon solvent of C6-C9, as benzene,toluene,xylene, or a trimethylbenzene etc.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described in further detail, but described embodiment does not limit the scope of the invention.Should be noted that, following examples are only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Example 1 uses tetrahydrofuran (THF) to do each step of solvent to become Rui Gelieting intermediate compound I regardless of clutch.
Method 1
Steps A: add 4-chloropyridine-2-methyl-formiate hydrochloride (10.4g in four mouthfuls of round-bottomed flasks, 50mmol) with 40mL THF, be cooled to 0 ° of C, drip the tetrahydrofuran solution (150mL of the methylamine of 2M to system, 300mmol), keep system temperature to be no more than 10 ° of C, dropwise, system is at 5 ~ 10 ° of C insulation reaction 6h, through filtered through silica gel, silica gel 50mL tetrahydrofuran (THF) drip washing, after merging organic phase, is directly used in step C operation.Organic phase, through HPLC content analysis, obtains product compound IIX8.4g, external standard yield 98%.
HPLC?ES/MS?m/z:171((M+H)
+)
Step B: add 3-fluoro-4-nitrophenol (7.9g, 50mmol) in autoclave, 10%Pd/C(0.4g, 5wt%) and 20mL THF, system is under 0.3Mpa hydrogen pressure, and 20 ° of C react 8h.After completion of the reaction, system is filtered, and filtrate is directly used in step C operation.Organic phase HPLC content analysis, obtains product compound IIIX6.0g, external standard yield 95%.
HPLC?ES/MS?m/z:128((M+H)
+)
Step C: THF solution (being obtained by the step C) 3.6mL(1.27g adding compound III X in four-hole bottle, 10mmol), at room temperature add potassium tert.-butoxide powder (1.23g in batches, 11mmol), system temperature controls to stir 2h at 30 ° of below C, slowly drips THF solution (being obtained by step B) 40.7mL(1.71g, the 10mmol of Compound II per X afterwards), system is warming up to backflow, and back flow reaction is until reaction terminates.System is cooled to room temperature, adds the water washing of 30mL saturated common salt, organic phase is dry, concentrated, obtains brown solid 2.45g, i.e. Rui Gelieting intermediate compound I, and it is 97% that yield 94%, HPLC surveys purity.
HPLC?ES/MS?m/z:262((M+H)
+)
Method 2
Steps A: add 4-chloropyridine-2-carbonyl chloride hydrochloride (10.6g in four mouthfuls of round-bottomed flasks, 50mmol) and 40mLTHF, be cooled to 0 ° of C, drip the tetrahydrofuran solution (100mL of the methylamine of 2M to system, 200mmol), keep system temperature to be no more than 5 ° of C, dropwise, system is at 0 ~ 5 ° of C insulation reaction 4h, through filtered through silica gel, silica gel 50mL tetrahydrofuran (THF) drip washing, after merging organic phase, is directly used in step C operation.Organic phase, through HPLC content analysis, obtains product compound IIX8.0g, external standard yield 93%.
Step B: add 3-fluoro-4-nitrophenol (7.9g, 50mmol) in autoclave, 5%Pd/C(0.8g, 10wt%) and 20mL THF, system is under the hydrogen pressure of 0.6MPa, and 50 ° of C react 3h.After completion of the reaction, system is filtered, and filtrate is directly used in step C operation.Organic phase HPLC content analysis, obtains product compound IIIX6.2g, external standard yield 98%.
Step C: THF solution (being obtained by the step C) 3.8mL(1.27g adding compound III X in four-hole bottle, 10mmol), at room temperature add potassium carbonate powder (1.52g in batches, 11mmol), system temperature controls to stir 2h at 30 ° of below C, slowly drips THF solution (being obtained by step B) 38mL(1.71g, the 10mmol of Compound II per X afterwards), system is warming up to backflow, and back flow reaction is until reaction terminates.System is cooled to room temperature, adds the water washing of 30mL saturated common salt, organic phase is dry, concentrated, obtains brown solid 1.90g, i.e. Rui Gelieting intermediate compound I, and it is 97% that yield 73%, HPLC surveys purity.
HPLC?ES/MS?m/z:262((M+H)
+)
Example 2 uses toluene to do each step of solvent to become Rui Gelieting intermediate compound I regardless of clutch.
Steps A: add 4-chloropyridine-2-methyl-formiate hydrochloride (10.4g in four mouthfuls of round-bottomed flasks, 50mmol) with 40mL THF, be cooled to 0 ° of C, drip the tetrahydrofuran solution (50mL of the methylamine of 2M to system, 100mmol), keep system temperature to be no more than 10 ° of C, dropwise, system is at 5 ~ 10 ° of C insulation reaction 6h, through filtered through silica gel, silica gel 50mL tetrahydrofuran (THF) drip washing, after merging organic phase, is directly used in step C operation.Organic phase, through HPLC content analysis, obtains product compound IIX 7.5g, external standard yield 87%.
Step B: add 3-fluoro-4-nitrophenol (7.9g, 50mmol) in autoclave, 20% Pd/C(0.4g, 5wt%) and 20mL toluene, drip two formic acid, system is under the hydrogen pressure of 0.2MPa, and 30 ° of C react 6h.After completion of the reaction, filter, filtrate is directly used in step C operation.Organic phase HPLC content analysis, obtains product compound IIIX 6.2g, external standard yield 98%.
Step C: toluene solution (being obtained by the step C) 4.1mL(1.27g adding compound III X in four-hole bottle, 10mmol), at room temperature add sodium methylate powder (0.6g, 11mmol), system temperature controls to stir 3h at 30 ° of below C in batches, slowly drip toluene solution (being obtained by the step B) 39mL(1.71g of Compound II per X afterwards, 10mmol), potassium carbonate powder (0.7g, 5mmol) is being added, system is warming up to 90 ° of C, and insulation reaction is until reaction terminates.System is cooled to room temperature, adds the water washing of 30mL saturated common salt, organic phase is dry, concentrated, obtains brown solid 2.1g, i.e. Rui Gelieting intermediate compound I, and it is 98% that yield 80%, HPLC surveys purity.
HPLC?ES/MS?m/z:262((M+H)
+)
Example 3 uses Isosorbide-5-Nitrae-dioxane to do each step of solvent to become Rui Gelieting intermediate compound I regardless of clutch.
Steps A: add 4-chloropyridine-2-methyl-formiate hydrochloride (10.4g, 50mmol) and 40mL1,4-dioxane in four mouthfuls of round-bottomed flasks, be cooled to 5 ° of C, drip the tetrahydrofuran solution (150mL, 300mmol) of the methylamine of 2M to system, keep system temperature to be no more than 10 ° of C, dropwise, system at 5 ~ 10 ° of C insulation reaction 12h, through filtered through silica gel, silica gel 50mL tetrahydrofuran (THF) drip washing, after merging organic phase, be directly used in step C operation.Organic phase, through HPLC content analysis, obtains product compound IIX 8.2g, external standard yield 96%.
Step B: add 3-fluoro-4-nitrophenol (7.9g, 50mmol) in autoclave, 1% Pd/C(1.6g, 20wt%) and 20mL1,4-dioxane, system is under the hydrogen pressure of 0.1Mpa, and 30 ° of C react 12h.After completion of the reaction, filter, filtrate is directly used in step C operation.Organic phase, through HPLC content analysis, obtains product compound IIIX 5.8g, external standard yield 92%.
Step C: add 1 of compound III X in four-hole bottle, 4-dioxane solution (being obtained by step C) 3.7mL(1.27g, 10mmol), at room temperature add cesium carbonate powder (3.9g, 11mmol) in batches, system temperature controls to stir 4h at 40 ° of below C, slowly drip Isosorbide-5-Nitrae-dioxane solution (being obtained by the step B) 39mL (1.71g, 10mmol) of Compound II per X afterwards, system is warming up to backflow, and back flow reaction is until reaction terminates.System is cooled to room temperature, adds the water washing of 30mL saturated common salt, organic phase is dry, concentrated, obtains brown solid 2.3g, i.e. Rui Gelieting intermediate compound I, and it is 98% that yield 88%, HPLC surveys purity.
HPLC?ES/MS?m/z:262((M+H)
+)。
Claims (9)
1. prepare a method for Rui Gefeini intermediate compound I, it is characterized in that, by making formula II and formula III through steps A, step B and step C three phases, each intermediary is not separated obtained Rui Gefeini intermediate compound I; Reaction formula is as follows:
Wherein R is chlorine, methoxyl group, or oxyethyl group.
2. method according to claim 1, is characterized in that, in steps A, the organic solution of formula II compound and methylamine is reacted, and the mole number of methylamine is 1.0-10.0 times of formula II.
3. method according to claim 2, is characterized in that, temperature of reaction is 0 ~ 25 ° of C, and after completion of the reaction, system, through filtered through silica gel, obtains intermediate II X solution.
4. method according to claim 1, is characterized in that, in step B, formula III compound and Pd/C react in presence of hydrogen, wherein the 5wt%-20wt% of Pd content to be the consumption of 1wt%-20wt%, Pd/C be formula III compound in Pd/C.
5. method according to claim 4, is characterized in that, reaction pressure is 0.1-1MPa, and temperature of reaction is 0-100 ° of C.
6. method according to claim 1, is characterized in that, in step C, the formula III X solution that the formula IIX solution obtained by steps A and step B obtain, under the effect of alkali, is obtained by reacting Rui Gefeini intermediate compound I.
7. method according to claim 6, is characterized in that, described alkali is selected from: sodium carbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen; Or potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium isopropylate, potassium isopropoxide, hexamethyldisilane base Lithamide, hexamethyldisilane base sodium amide, hexamethyldisilane base potassium amide, or their organic solution; Or more the combination of described arbitrarily two or more alkali.
8. method according to claim 6, is characterized in that, temperature of reaction is-20 ~ 120 ° of C.
9. the method according to any one of claim 1 ~ 8, it is characterized in that, by steps A to step C, each stage of step B to step C, use identical organic solvent, as: methyl tertiary butyl ether, ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl-phenoxide, phenyl ethyl ether, benzene,toluene,xylene, or a trimethylbenzene.
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| CN201310262792.5A CN104250226B (en) | 2013-06-27 | 2013-06-27 | A method of preparing Rui Gefeini intermediate |
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| CN201310262792.5A CN104250226B (en) | 2013-06-27 | 2013-06-27 | A method of preparing Rui Gefeini intermediate |
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| WO2016101714A1 (en) * | 2014-12-24 | 2016-06-30 | 浙江海正药业股份有限公司 | Preparation method of 4-(4-amino-3-fluorophenoxy)-n-methylpyridine-2- formamide |
| CN108911997A (en) * | 2018-08-01 | 2018-11-30 | 苏州盖德精细材料有限公司 | A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol |
| CN108929235A (en) * | 2018-07-19 | 2018-12-04 | 苏州盖德精细材料有限公司 | A kind of high-efficiency synthesis method of 4- amino -3- fluorophenol |
| CN108997209A (en) * | 2018-06-11 | 2018-12-14 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Rui Gefeini |
| 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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| WO2016101714A1 (en) * | 2014-12-24 | 2016-06-30 | 浙江海正药业股份有限公司 | Preparation method of 4-(4-amino-3-fluorophenoxy)-n-methylpyridine-2- formamide |
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| CN108997209B (en) * | 2018-06-11 | 2020-08-04 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of regorafenib |
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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 |
| CN114920689B (en) * | 2022-04-26 | 2024-04-02 | 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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