CN105130887A - Regorafenib preparation method - Google Patents

Regorafenib preparation method Download PDF

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Publication number
CN105130887A
CN105130887A CN201510513082.4A CN201510513082A CN105130887A CN 105130887 A CN105130887 A CN 105130887A CN 201510513082 A CN201510513082 A CN 201510513082A CN 105130887 A CN105130887 A CN 105130887A
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preparation
rui gefeini
compound
reaction
amino
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CN201510513082.4A
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Inventor
徐强
黄双
杨健
王平
夏彬
钱刚
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Jiangsu Zhongbang Pharmaceutical Coltd
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Jiangsu Zhongbang Pharmaceutical Coltd
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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a regorafenib preparation method, and belongs to pharmacy field. According to the method, on the basis of a conventional routine, the routine defects are avoided, a raw material 4-amino-3-fluorophenol, which is low in price and easy to obtain or prepare, is employed for replacing 4-chloro-3-(trifluoromethyl)phenyl isocyanate, a protection group for protection is ingeniously employed during reaction and unnecessary impurities are prevented from generating, the whole routine is simple in operation, and the product is high in yield, stable and easy to purify.

Description

The preparation method of a kind of Rui Gefeini
Technical field
The present invention relates to pharmacy field, be specifically related to the preparation method of a kind of Rui Gefeini.
Background technology
Rui Gefeini (Regorafenib), chemical name is 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] carbamyl } is amino)-3-fluorophenoxy]-N-picoline-2-methane amide, and molecular formula is C 21h 17clF 4n 4o 4, be a kind of oral multi-kinase inhibitor, by suppressing multiple proteins kinases, targeting generates in tumour, tumor vessel occurs and the maintenance of tumor microenvironment intracellular signaling.Developed by Bayer Healthcare, a crucial III phase test in verified Rui Gefeini significance improve previously treatment after disease there is Progression free survival phase of the gastrointestinal stromal tumor patient (GIST) of progress.Ratify Rui Gefeini tablet FDA Food and Drug Administration on February 25 in 2013 (FDA) and be used for the treatment of the Locally Advanced previously accepting imatinib and Sutent treatment, can not excision or transitivity gastrointestinal stromal tumor (GIST) patient.
The Rui Gefeini synthesis technique of current International Publication is less, main synthesis technique has: (1) patent WO2011/128261, (2) patent WO05/009961, (3) patent WO2008/89388, (4) patent US2006/58358, (5) patent WO2008/58644 etc.Wherein rear four sections of synthetic methods are basically identical, by the patent of Bayer AG Health Care Co., Ltd's invention.
(1) 2011 year, the world patent WO2011/128261 that Yuan Yanchanjia Bayer Pharmaceuticals AG announces provided the synthetic method of preparation Rui Gefeini, as follows:
This route with 4-amino-3-fluorophenol for starting raw material first after 4-methyl-2 pentanone replaces again with 1-Methyl-2-Pyrrolidone replace obtain di-substituted after chloro-N-methylpyrrole-2-carboxylic acid amide is obtained by reacting intermediate 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides with 4-again, intermediate 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides carries out amino again and replaces and obtain target product with raw material isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester.Although the method route is short, raw material isocyanic acid (the chloro-3-trifluoromethyl-phenyl of the 4-) ester wherein used is difficult to obtain, and general line cost is high, and overall yield is low, is difficult to realize suitability for industrialized production.
(2) patent WO05/009961, WO2008/89388, US2006/58358, WO2008/58644, be then all invented by Bayer AG Health Care Co., Ltd, synthetic route is as follows.
This route is substantially the same with above-mentioned route; difference to be in this route not to be obtained by reacting intermediate 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides to carrying out the direct and chloro-N-methylpyrrole of the 4--2-carboxylic acid amide of amido protecting with 4-amino-3-fluorophenol, and intermediate 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides carries out amino again and replaces and obtain target product with raw material isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester.Secondary route is not protected due to amino, and side reaction is many, and with above-mentioned route, be difficult to obtain owing to using raw material isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester, overall yield is low, and cost is high, is difficult to purifying.
In sum, the method preparing Rui Gefeini is at present less, and existing route exists following defect: raw and auxiliary material is expensive, and total recovery is low, is only about 23%, and cost is high, is difficult to realize suitability for industrialized production.
Summary of the invention
The object of the invention is to the synthetic method that a kind of new Rui Gefeini is provided by the deficiency overcome in aforesaid method.Its raw material is easy to get, total recovery is high, avoid using be difficult to obtain or be difficult to synthesize raw material, foreign matter content is low, product purity is high, is suitable for suitability for industrialized production.
Object of the present invention can be achieved through the following technical solutions:
A preparation method of Rui Gefeini, the reaction scheme of this preparation method is as follows:
Wherein, R is selected from any one in Trt, Boc, Dmb and Pmb.
The preparation method of described Rui Gefeini comprises the steps:
The first step, 4-amino-3-fluorophenol reacts with amino protecting group generation amido protecting under triethylamine existent condition, obtains compounds Ⅳ;
Second step, compounds Ⅳ first becomes ether to react with compound ii under alkaline reagents existent condition, becomes the rear deaminizating protecting group of ether reaction, obtains compound III;
3rd step, compound III under triethylamine existent condition with chemical compounds I generation substitution reaction, obtain compound V.
The first step is prepared in compounds Ⅳ reaction: in some technical schemes, amino protecting group is tert-Butyl dicarbonate, triphenylmethyl chloride, to any one in methoxy-benzyl and 2,4-dimethoxy-benzyl; Reaction solvent is methylene dichloride.In some preferred technical schemes, 4-amino-3-fluorophenol: triethylamine: the mol ratio of amino protecting group is 1:1:1 ~ 1:4:3.4-amino-3-fluorophenol in some the most preferred technical schemes: triethylamine: the mol ratio of amino protecting group is 1:2:1.5.
Second step is prepared in compound III reaction, first synthetic compound II, and compound ii is prepared by following reaction scheme:
In the reaction process preparing compound ii, reaction solvent is selected from one or more in methylene dichloride, trichloromethane, chloroform, tetrahydrofuran (THF), methyl alcohol and ethanol.In some technical schemes, the amidate action time is 1-12h, 4-chloropyridine-2-methyl-formiate: the mol ratio of methylamine is 1:1.5 ~ 1:10, preferred 1:2 ~ 3.
Secondly, preparation compound III.The detailed process preparing compound III is: take DMA as a solvent, and compounds Ⅳ and alkaline reagents react and generate salt, becomes deprotection after ether to obtain compound III this salt afterwards with compound ii through Williamson synthesis method.In some technical schemes, alkaline reagents is selected from one or more in sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium tert-butoxide.In some preferred technical schemes, the temperature that Williamson synthesis method becomes ether to react is 60 ~ 120 DEG C.
3rd step is prepared in the reaction of compound V: first synthetic compound I, and chemical compounds I is prepared by following reaction scheme:
Wherein, X is H or NO 2.
The detailed process preparing chemical compounds I is: be first dissolved in solvent by compound VI and the chloro-5-5 amido benzotrifluoride of 2-, adds pyrido afterwards and is uniformly mixed, obtain mixed solution under the condition stirred; Add hydrazine hydrate and DIPEA successively in this mixed solution the most backward in batches, stir after adding, be separated and obtain chemical compounds I.In the process preparing chemical compounds I, reaction solvent is THF, methylene dichloride, one or more in chloroform and tetracol phenixin, and preferred reaction solvent is methylene dichloride.In some preferred technical schemes, the chloro-5-5 amido benzotrifluoride of 2-: compound VI: hydrazine hydrate: N, the mol ratio of N-diisopropylethylamine is 1 ~ 2:1 ~ 2:1 ~ 2:1.5 ~ 2, preferred compound VI: hydrazine hydrate: the mol ratio of DIPEA is 1 ~ 2:1 ~ 1.2:1.5:1.5 ~ 2.
Prepare in the reaction process of compound V: substitution reaction solvent used is selected from one or more in methylene dichloride, trichloromethane, chloroform, tetrahydrofuran (THF), methyl alcohol and ethanol.In some technical schemes, chemical compounds I: compound III: the molar equivalent of triethylamine is than being 1:1:1 ~ 1:1:5.
Beneficial effect of the present invention:
The synthetic method of new Rui Gefeini provided by the present invention, the method technique is simple, and raw material is easy to get, pollution-free; Reaction conditions is gentle, is easy to control, and total recovery is high; Byproduct of reaction is few, and product obtains high purity product by a recrystallization; Reaction time consumption is short, and economic benefit is large.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited thereto:
Embodiment 1
The first step, the preparation of compounds Ⅳ: add 127.1g4-amino-3-fluorophenol and 1L methylene dichloride in 2L reaction flask, adds 202.4g triethylamine and drips 327.8g bis-dimethyl dicarbonate butyl ester under stirring, drip and finish, after room temperature reaction 5h, TLC detects, and raw material reaction is complete, stopped reaction, system with 5% sodium bicarbonate 3X500mL wash after wash with 3X500mL again, filter after organic layer drying, steaming desolventizes, and obtains 200.2g white solid, productive rate: 88.1%, HPLC:98.7%.
Second step, first prepares compound ii, and concrete steps are as follows:
4-chloropyridine-2-methyl-formiate 171.6g and 200mL methyl alcohol and 500mL tetrahydrofuran solution is added in 3L reaction flask, system is cooled to 0 DEG C, the tetrahydrofuran solution 1030mL containing 85.8g methylamine is dripped after temperature-stable, system temperature is kept to maintain less than 5 DEG C in dropping process, drip and finish, stirred at ambient temperature about 5h, HPLC follows the tracks of, reaction terminates rear decompression back-out solvent and obtains brown solid crude product, in crude product, add 1700mL ethyl acetate and wash with saturated aqueous common salt 3X1000mL, filter after organic over anhydrous dried over mgso, remove solvent under reduced pressure and obtain 150.1g faint yellow solid, productive rate: 88.0%, HPLC:98.6%.
LCMS:171[M+1] +； 1HNMR(DMSO-d6):δ2.80(d,3H),7.68(dd,J1＝5.4Hz,J2＝2.4Hz,1H),7.97(d,J＝2.4Hz,1H),8.56(d,1H),8.82(s,1H).
Prepared by compound III: add 45.4g compounds Ⅳ (R is Boc) in 3L reaction flask, 300mLDMA, 16.2g sodium methylate is added under stirring, add compound ii after stirred at ambient temperature 1h and be about 34.1g, finish, system is warming up to 110 DEG C of reaction 9h, HPLC detection reaction is completely rear adds 1L ethyl acetate in system, finish, wash with 3X800mL after stirring 10min, water layer uses 1L extraction into ethyl acetate again, merge organic layer, filter after organic over anhydrous dried over mgso, steaming desolventizes and obtains brown oil, 5mol/L hydrochloric acid soln is added add 1L methyl alcohol in system after, filter after stirred at ambient temperature 2h, consider in cake and add 500mL water and 1L ethyl acetate, use in the sodium hydroxide solution of 5mol/L simultaneously and adjust about pH to 7, layering, organic layer 2X500mL saturated sodium bicarbonate solution washes rear anhydrous magnesium sulfate drying, filter, steaming desolventizes and obtains brown solid crude product 46.5g, productive rate: 88.9%, be directly used in lower step.
1HNMR(400MHz,DMSO-d6)δ8.76(m,1H),8.48(d,J＝5.7Hz,1H),7.36(d,J＝2.6Hz,1H),7.10(dd,J＝5.7,2.6Hz,1H),7.02(dd,J＝11.8,2.6Hz,1H),6.86(t,J＝9.8Hz,1H),6.79(dd,J＝8.9,2.5Hz,1H),5.23(s,2H),2.79(d,J＝4.9Hz,3H)；MS(ESI)m/z:262.0(M+H+).
3rd step, first prepares chemical compounds I, and the preparation process of chemical compounds I is as follows:
The chloro-5-5 amido benzotrifluoride of 195.6g2-and 187.9g phenyl chloroformate and 1L methylene dichloride is added in the reaction flask of 5L, 94.9g pyridine is added under stirring, add the hydrazine hydrate 60g of 80% concentration after stirred at ambient temperature 3h in batches, finish and add 193.9gN, N-diisopropylethylamine, in system, 1L methylene dichloride is added after stirring 4h, 2L10% caustic wash(ing) twice is used again after system 2L washing, finally with the washing of 2L saturated common salt, anhydrous magnesium sulfate drying, the crude product methanol/ethyl acetate recrystallization obtained after being spin-dried for solvent obtains 209.8g off-white color crystalline powder, productive rate: 81.3%, HPLC:98.3%.
The preparation process of compound V is as follows: add 52.3g compound III and 51.6g compound 1 and 500mL methylene dichloride in 2L reaction flask, 20.2g triethylamine is added under stirring, in system, 300mL water is added after reacting 2h under room temperature, layering after stirring 10min, organic layer is rear dry with the washing of 3X300mL saturated common salt again after washing with 5% sodium hydrogen carbonate solution 500mL, the hydrochloric acid soln of 10mol/L is added in organic layer, be stirred to and separate out without solid again, filter, water-soluble with in methylene dichloride after considering cake ethyl alcohol recrystallization, in system, drip 10% sodium carbonate solution adjusts pH to neutral, layering, organic layer is with dry after 3X500mL washing, filter, steaming desolventizes and obtains 80.2g sterling, productive rate: 83.0%, HPLC:99.89%.
1HNMR(DMSO-d6)2.78(d,J＝4.9,3H),7.03-7.08(M,1H),7.16(dd,J＝2.6,5.6,1H),7.32(dd,J＝2.7,11.6,1H),7.39(d,J＝2.5,1H),7.60(s,2H),8.07-8.18(M,2H),8.50(d,J＝5.7,1H),8.72(s,1H),8.74-8.80(M,1H),9.50(s,1H)；MS(HPLC/ES)483.06m/z＝(M+1)
Embodiment 2
The first step, the preparation of compounds Ⅳ: add 127.1g4-amino-3-fluorophenol and 1L methylene dichloride in 2L reaction flask, adds 202.4g triethylamine and adds 418.2g triphenylmethyl chloride under stirring, finish, after room temperature reaction 7h, TLC detects, and raw material reaction is complete, stopped reaction, system with 5% sodium bicarbonate 3X500mL wash after wash with 3X500mL again, filter after organic layer drying, steaming desolventizes, and obtains 203.9g white solid, productive rate: 89.7%, HPLC:98.7%.
The reaction conditions of second step and the 3rd step is with embodiment 1.
Embodiment 3
Prepared by compound III: add 45.4g compounds Ⅳ (R is Boc) in compound 3L reaction flask, 300mLDMA, sodium tert-butoxide 28.8g is added under stirring, compound ii 34.1g is added after stirred at ambient temperature 1h, finish, system is warming up to 60 DEG C of reaction 9h, HPLC detection reaction is complete, slowly pour system into 1L ethyl acetate, finish, wash with 3X800mL after stirring 10min, water layer uses 1L extraction into ethyl acetate again, merge organic layer, filter after organic over anhydrous dried over mgso, steaming desolventizes and obtains brown oil, 5mol/L hydrochloric acid soln is added add 1L methyl alcohol in system after, filter after stirred at ambient temperature 2h, consider in cake and add 500mL water and 1L ethyl acetate, use in the sodium hydroxide solution of 5mol/L simultaneously and adjust about pH to 7, layering, organic layer 2X500mL saturated sodium bicarbonate solution washes rear anhydrous magnesium sulfate drying, filter, steaming desolventizes and obtains brown solid crude product 44.2g, productive rate: 84.5%, be directly used in lower step.
Except compound III preparation adopts above-mentioned condition, other conditions are with embodiment 1.
Embodiment 4
The preparation process of compound V is as follows: add 52.3g intermediate 3 and 51.6g intermediate 1 and 500mL tetrahydrofuran (THF) in 2L reaction flask, 30.3g triethylamine is added under stirring, in system, 300mL water is added after reacting 2h under room temperature, layering after stirring 10min, organic layer is rear dry with the washing of 3X300mL saturated common salt again after washing with 5% sodium hydrogen carbonate solution 800mL, the hydrochloric acid soln of 10mol/L is added in organic layer, be stirred to and separate out without solid again, filter, water-soluble with in methylene dichloride after considering cake ethyl alcohol recrystallization, in system, drip 10% sodium carbonate solution adjusts pH to neutral, layering, organic layer is with dry after 3X500mL washing, filter, steaming desolventizes and obtains 85.6g sterling, productive rate: 88.6%, HPLC99.78%.
Prepare except compound V and adopt above-mentioned condition, other conditions are with embodiment 1.

Claims (10)

1. the preparation method of Yi Zhong Rui Gefeini, is characterized in that:
Wherein, R is selected from any one in Trt, Boc, Dmb and Pmb.
2. the preparation method of Rui Gefeini according to claim 1, is characterized in that: the method comprises the steps:
The first step, 4-amino-3-fluorophenol reacts with amino protecting group generation amido protecting under triethylamine existent condition, obtains compounds Ⅳ;
Second step, compounds Ⅳ first becomes ether to react with compound ii under alkaline reagents existent condition, becomes the rear deaminizating protecting group of ether reaction, obtains compound III;
3rd step, compound III under triethylamine existent condition with chemical compounds I generation substitution reaction, obtain compound V.
3. the preparation method of Rui Gefeini according to claim 2, is characterized in that: in the first step, and amino protecting group is tert-Butyl dicarbonate, triphenylmethyl chloride, to any one in methoxy-benzyl and 2,4-dimethoxy-benzyl.
4. the preparation method of Rui Gefeini according to claim 2, is characterized in that: in second step, alkaline reagents is selected from one or more in sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium tert-butoxide.
5. the preparation method of Rui Gefeini according to claim 2, is characterized in that: in the 3rd step, and substitution reaction solvent used is selected from one or more in methylene dichloride, trichloromethane, chloroform, tetrahydrofuran (THF), methyl alcohol and ethanol.
6. the preparation method of Rui Gefeini according to claim 1 and 2, is characterized in that: chemical compounds I adopts following reaction scheme to prepare:
Wherein, X is H or NO 2.
7. the preparation method of Rui Gefeini according to claim 6, it is characterized in that: the synthetic method of chemical compounds I is: first compound VI and the chloro-5-5 amido benzotrifluoride of 2-are dissolved in solvent, under the condition stirred, add pyrido to be afterwards uniformly mixed, obtain mixed solution; Add hydrazine hydrate and DIPEA successively in this mixed solution the most backward in batches, stir after adding, be separated and obtain chemical compounds I.
8. the preparation method of the Rui Gefeini according to claim 6 or 7, is characterized in that: reaction solvent is THF, methylene dichloride, one or more in chloroform and tetracol phenixin.
9. the preparation method of Rui Gefeini according to claim 1 and 2, is characterized in that: compound ii adopts following reaction scheme to prepare:
10. the preparation method of Rui Gefeini according to claim 9, is characterized in that: reaction solvent is selected from one or more in methylene dichloride, trichloromethane, chloroform, tetrahydrofuran (THF), methyl alcohol and ethanol.
CN201510513082.4A 2015-08-19 2015-08-19 Regorafenib preparation method Pending CN105130887A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610284A (en) * 2018-04-08 2018-10-02 梯尔希（南京）药物研发有限公司 A kind of preparation method of Rui Gefeini derivatives
CN109796401A (en) * 2019-04-04 2019-05-24 新乡双鹭药业有限公司 A kind of preparation method of Rui Gefeini bulk pharmaceutical chemicals
CN112851577A (en) * 2019-11-26 2021-05-28 齐鲁制药有限公司 Preparation method of regorafenib
CN114315710A (en) * 2022-01-07 2022-04-12 江苏豪森药业集团有限公司 Method for preparing or purifying regorafenib

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US20100173954A1 (en) * 2007-01-19 2010-07-08 Bayer Healthcare Llc Treatment of cancers having resistance to chemotherapeutic agents
CN103408488A (en) * 2013-08-13 2013-11-27 张家港威胜生物医药有限公司 Optimal synthetic method of sorafenib
CN103724258A (en) * 2012-10-15 2014-04-16 齐鲁制药有限公司 Preparation method of sorafenib
CN104788366A (en) * 2014-01-21 2015-07-22 王若文 Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100173954A1 (en) * 2007-01-19 2010-07-08 Bayer Healthcare Llc Treatment of cancers having resistance to chemotherapeutic agents
CN101674833A (en) * 2007-03-20 2010-03-17 柯瑞斯公司 Raf kinase inhibitors containing a zinc binding moiety
CN103724258A (en) * 2012-10-15 2014-04-16 齐鲁制药有限公司 Preparation method of sorafenib
CN103408488A (en) * 2013-08-13 2013-11-27 张家港威胜生物医药有限公司 Optimal synthetic method of sorafenib
CN104788366A (en) * 2014-01-21 2015-07-22 王若文 Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610284A (en) * 2018-04-08 2018-10-02 梯尔希（南京）药物研发有限公司 A kind of preparation method of Rui Gefeini derivatives
CN109796401A (en) * 2019-04-04 2019-05-24 新乡双鹭药业有限公司 A kind of preparation method of Rui Gefeini bulk pharmaceutical chemicals
CN109796401B (en) * 2019-04-04 2023-10-17 新乡双鹭药业有限公司 Preparation method of regorafenib bulk drug
CN112851577A (en) * 2019-11-26 2021-05-28 齐鲁制药有限公司 Preparation method of regorafenib
CN114315710A (en) * 2022-01-07 2022-04-12 江苏豪森药业集团有限公司 Method for preparing or purifying regorafenib

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