CN112851577A - Preparation method of regorafenib - Google Patents
Preparation method of regorafenib Download PDFInfo
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- CN112851577A CN112851577A CN201911173019.5A CN201911173019A CN112851577A CN 112851577 A CN112851577 A CN 112851577A CN 201911173019 A CN201911173019 A CN 201911173019A CN 112851577 A CN112851577 A CN 112851577A
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- 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 claims abstract description 39
- 239000002138 L01XE21 - Regorafenib Substances 0.000 title claims abstract description 37
- 229960004836 regorafenib Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 15
- CRNHBOLNRMRNRP-UHFFFAOYSA-N 3-phenoxypyridine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=C1OC1=CC=CC=C1 CRNHBOLNRMRNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- ASPDJZINBYYZRU-UHFFFAOYSA-N 5-amino-2-chlorobenzotrifluoride Chemical compound NC1=CC=C(Cl)C(C(F)(F)F)=C1 ASPDJZINBYYZRU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 230000035484 reaction time Effects 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 229940126214 compound 3 Drugs 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 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
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000004321 preservation Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MPTMLFGAYZBDRW-UHFFFAOYSA-N 4-(3-fluorophenoxy)-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C=CC=2)=C1 MPTMLFGAYZBDRW-UHFFFAOYSA-N 0.000 description 2
- ZQHJPIPGBODVTG-UHFFFAOYSA-N 4-(4-Amino-3-fluorophenoxy)-N-methyl-2-pyridinecarboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(N)=CC=2)=C1 ZQHJPIPGBODVTG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MNPLTKHJEAFOCA-UHFFFAOYSA-N 4-amino-3-fluorophenol Chemical compound NC1=CC=C(O)C=C1F MNPLTKHJEAFOCA-UHFFFAOYSA-N 0.000 description 1
- BGVBBMZMEKXUTR-UHFFFAOYSA-N 4-chloro-n-methylpyridine-2-carboxamide Chemical compound CNC(=O)C1=CC(Cl)=CC=N1 BGVBBMZMEKXUTR-UHFFFAOYSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229940090374 stivarga Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 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)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a method for preparing regorafenib, which comprises the steps of adding 4-chloro-3-trifluoromethylaniline and an alkaline reagent into an organic solvent of triphosgene, and stirring for reaction to obtain a compound 2; then, N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide and an alkaline reagent are put into the organic solvent of the compound 2 to react to obtain the regorafenib. The method provided by the invention has the advantages of short reaction time, easiness in large-scale preparation, simplicity in operation, good stability, high purity and yield, no need of separating intermediates and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of regorafenib.
Background
Regorafenib, having a chemical name of 4- [4- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] formyl ] amino ] -3-fluorophenoxy ] -N-methylpyridine-2-formamide, has a chemical structure shown in formula 4, is an oral multi-kinase inhibitor, and is targeted to tumor generation, tumor angiogenesis and maintenance of tumor microenvironment signal transduction by inhibiting various protein kinases. Regorafenib has been shown in a key phase III trial developed by bayer healthcare, germany to significantly improve the progression-free survival of gastrointestinal stromal tumor patients (GIST) who have progressed on treatment. Regorafenib tablets were approved by the Food and Drug Administration (FDA) in 25 japanese america in 2013 for the treatment of patients with advanced local, non-surgically resectable or metastatic gastrointestinal stromal tumors (GIST) who had previously received imatinib and sunitinib therapy. The product is marketed in China at 12 months and 05 days in 2017 under the trade name of Bydago/Stivarga.
The patent: WO2011/128261, WO05/009961, WO2016005874, WO2016051422, WO2016101714, CN104557689, CN104910067, CN104592105 and CN 105218440; and documents: jingxi hugong Zhongjianti,42(6), 31-34; 2012. research on Chemical Intermediates,42(4), 3209-; 2016, a method for preparing regorafenib from 4-chloro-3-trifluoromethyl phenyl isocyanate is adopted. The defects of the route are that 4-chloro-3-trifluoromethyl phenyl isocyanate which has certain toxicity and is extremely unstable is used as a starting material, and the 4-chloro-3-trifluoromethyl phenyl isocyanate is easy to degrade in the storage process and is not beneficial to industrial production.
Patent CN105130887 describes the preparation of regorafenib from N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound III) and carbamylated compound under triethylamine condition. The disadvantage of this route is that phenyl chloroformate with high toxicity and corrosiveness is used as raw material to prepare compound I, and the yield is low, the cost is high, and it is not suitable for industrial production.
Wherein X is H or NO2。
The preparation of regorafenib using 4- (3-fluorophenoxy) -N-methylpyridine-2-carboxamide (5) and 4- (3-fluoro-4-aminophenoxy) -N-methylpyridine-2-carboxamide (6) as intermediates is described in patent CN 105566215. The defects of the route are that the nitration selectivity is poor, and impurities are difficult to control.
Patent CN105330600 and CN106083711 describe that Regorafenib is obtained by reacting 4-chloro-3-trifluoromethylaniline with allyl chloroformate, and then reacting with 4-amino-3-fluorophenol and N-methyl-4-chloro-2-pyridinecarboxamide. The disadvantages of this route are poor selectivity and difficulty in impurity control.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a green synthesis process for preparing regorafenib, which has the advantages of simple synthesis route, mild conditions, simple and convenient operation, high yield, high product purity and suitability for industrial production, and the route has stable starting materials and is easy to store.
The invention provides a method for preparing regorafenib, which comprises the following steps:
the first stage is as follows: adding 4-chloro-3-trifluoromethylaniline (compound 1) and an alkaline reagent into an organic solvent of triphosgene, and stirring to react to obtain a compound 2;
and a second stage: n-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (compound 3) and an alkaline reagent are put into the organic solvent of the compound 2, and after the stirring reaction is finished, regorafenib is obtained.
Wherein the alkaline agent is selected from: triethylamine, N-diisopropylethylamine and sodium hydroxide. One or more of potassium hydroxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide. The organic solvent is selected from: one or more of acetonitrile, dichloromethane, trichloromethane, tetrahydrofuran, ethyl acetate, methanol or ethanol.
The amount of triphosgene used is 0.34 to 0.54 times (mol/mol), preferably 0.44 times (mol/mol) of the molar amount of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound 3). The amount of 4-chloro-3-trifluoromethylaniline (compound 1) used is 1.1 to 1.5 times (mol/mol), preferably 1.3 times (mol/mol) the molar amount of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound 3). The amount of the alkaline agent to be used is 1.0 to 1.4 times (mol/mol), preferably 1.17 times (mol/mol) the molar amount of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound 3).
The reaction temperature in the first stage is-10-20 ℃, and preferably 0-10 ℃; the reaction time is 0.5-2.5 h, preferably 1-2 h;
the reaction temperature of the second stage is 5-40 ℃, and preferably 15-30 ℃; the reaction time is 0.5-1.5 h, preferably 1 h.
It should be noted that, in the present invention, unless otherwise specified, the amounts of the reaction solvent and the related reagents are the conventional amounts for the reaction, and can be determined by those skilled in the art according to the prior art; the reagents used in the present invention are conventional reagents and commercially available, and the starting materials and reactants used can be prepared by the prior art or the published literature.
The preparation method of regorafenib has the following beneficial effects: (1) the reaction time is short, and the energy consumption is saved; (2) the reaction substrate does not need to be used excessively, so that waste is avoided; (3) the product has high yield and high purity, and is easy for industrial production; (4) and a green process is adopted, and an organic solvent is not used, so that the method conforms to the trend of green environmental protection.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods.
Example 1 preparation of regorafenib
Adding 14.34kg of 4-chloro-3-trifluoromethylaniline (compound 1) and 82.4kg of acetonitrile into a reaction kettle for dissolving, and adding 6.7kg of triethylamine to obtain a solution a; adding 14.89kg of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (compound 3) and 188.2kg of acetonitrile into a reaction kettle, heating to 75-85 ℃ for dissolution, cooling to 20-30 ℃, and adding 6.7kg of triethylamine to obtain a solution b; adding 7.47kg of triphosgene into acetonitrile, stirring and dissolving, and cooling to 0-10 ℃; slowly adding the solution a into an acetonitrile solution of triphosgene, controlling the internal temperature to be 0-10 ℃, carrying out heat preservation reaction for 1-2 h, then adding N, N-dimethylformamide, carrying out heat preservation reaction for 30-40 min, and vacuumizing for 5-10 min; heating to 15-30 ℃, slowly adding the solution b, and controlling the temperature to 15-30 ℃; after the slow addition is finished, stirring at 15-30 ℃ for reaction, and detecting by TLC after 1h until the reaction is finished; and (3) heating to 45-50 ℃, slowly adding 149kg of purified water into the reaction system, stirring and crystallizing for 20-30 min, slowly adding 268kg of purified water, cooling, crystallizing and centrifuging to obtain 24.17kg of regorafenib with the yield of 87.82%.
MS(ESI，m/z)：483.06(M+1)；
1H NMR(400MHz,DMSO)：9.51(s,1H)；8.75-8.80(m,1H)；8.73(s,1H)；8.50(d,1H)；8.07～8.18(m,2H)；7.60(s,2H)；7.39(d,1H)；7.32(d,1H)；7.16(d,1H)；7.03～7.08(m,1H)；2.79(d,3H)。
Example 2 Regorafenib refining
24.00kg of regorafenib obtained in example 1 is added into 1210L of acetonitrile to be heated, refluxed and dissolved; adding 484g of activated carbon, stirring for 15-20 min, carrying out hot filtration, and washing a filter cake with 20L of acetonitrile; heating and dissolving the filtrate, cooling to 50-60 ℃, adding 200g of seed crystal, slowly cooling to-10-0 ℃, and carrying out heat preservation and crystallization for 1.5-2 h; performing suction filtration, and washing with 30L of acetonitrile (-10-0 ℃); and (3) vacuum drying at 75-85 ℃ for 5-7 h, and sieving with a 20-mesh sieve to obtain 22.70kg of regorafenib product, wherein the yield is 94.58%, and the purity is 99.95%.
MS(ESI，m/z)：483.06(M+1)；
1H NMR(400MHz,DMSO)：9.53(s,1H)；8.75-8.81(m,1H)；8.74(s,1H)；8.52(d,1H)；8.09～8.20(m,2H)；7.63(s,2H)；7.40(d,1H)；7.32(d,1H)；7.18(d,1H)；7.04～7.08(m,1H)；2.80(d,3H)。
Example 3 preparation of regorafenib
Adding 12.13kg of 4-chloro-3-trifluoromethylaniline (compound 1) and 82.4kg of acetonitrile into a reaction kettle for dissolving, and adding 5.73kg of triethylamine to obtain a solution a; adding 14.89kg of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (compound 3) and 188.2kg of acetonitrile into a reaction kettle, heating to 75-85 ℃ for dissolution, cooling to 20-30 ℃, and adding 5.73kg of triethylamine to obtain a solution b; adding 5.75kg of triphosgene into acetonitrile, stirring and dissolving, and cooling to 0-10 ℃; slowly adding the solution a into an acetonitrile solution of triphosgene, controlling the internal temperature to be 0-10 ℃, carrying out heat preservation reaction for 1-2 h, then adding N, N-dimethylformamide, carrying out heat preservation reaction for 30-40 min, and vacuumizing for 5-10 min; heating to 15-30 ℃, slowly adding the solution b, and controlling the temperature to 15-30 ℃; after the slow addition is finished, stirring at 15-30 ℃ for reaction, and detecting by TLC after 1h until the reaction is finished; and (3) heating to 45-50 ℃, slowly adding 149kg of purified water into the reaction system, stirring and crystallizing for 20-30 min, slowly adding 268kg of purified water, cooling, crystallizing and centrifuging to obtain 23.79kg of regorafenib with the yield of 86.42%.
MS(ESI，m/z)：483.06(M+1)；
1H NMR(400MHz,DMSO)：9.51(s,1H)；8.76-8.81(m,1H)；8.74(s,1H)；8.51(d,1H)；8.09～8.20(m,2H)；7.61(s,2H)；7.40(d,1H)；7.32(d,1H)；7.16(d,1H)；7.05～7.08(m,1H)；2.79(d,3H)。
Example 4 preparation of regorafenib
Adding 16.55kg of 4-chloro-3-trifluoromethylaniline (compound 1) and 82.4kg of acetonitrile into a reaction kettle for dissolving, and adding 8.23kg of triethylamine to obtain a solution a; adding 14.89kg of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (compound 3) and 188.2kg of acetonitrile into a reaction kettle, heating to 75-85 ℃ for dissolution, cooling to 20-30 ℃, and adding 8.23kg of triethylamine to obtain a solution b; adding 9.13kg of triphosgene into acetonitrile, stirring and dissolving, and cooling to 0-10 ℃; slowly adding the solution a into an acetonitrile solution of triphosgene, controlling the internal temperature to be 0-10 ℃, carrying out heat preservation reaction for 1-2 h, then adding N, N-dimethylformamide, carrying out heat preservation reaction for 30-40 min, and vacuumizing for 5-10 min; heating to 15-30 ℃, slowly adding the solution b, and controlling the temperature to 15-30 ℃; after the slow addition is finished, stirring at 15-30 ℃ for reaction, and detecting by TLC after 1h until the reaction is finished; and (3) heating to 45-50 ℃, slowly adding 149kg of purified water into the reaction system, stirring and crystallizing for 20-30 min, slowly adding 268kg of purified water, cooling, crystallizing and centrifuging to obtain 23.98kg of regorafenib with the yield of 87.11%.
MS(ESI，m/z)：483.06(M+1)；
1H NMR(400MHz,DMSO)：9.54(s,1H)；8.76-8.81(m,1H)；8.75(s,1H)；8.53(d,1H)；8.10～8.21(m,2H)；7.62(s,2H)；7.43(d,1H)；7.33(d,1H)；7.18(d,1H)；7.06～7.08(m,1H)；2.81(d,3H)。
Claims (9)
1. A preparation method of regorafenib, which has the following reaction formula:
among these, triphosgene was used as a reagent for preparing compound 2.
2. A method of preparing regorafenib according to claim 1, wherein:
the first stage is as follows: adding 4-chloro-3-trifluoromethylaniline (compound 1) and an alkaline reagent into an organic solvent of triphosgene, and stirring to react to obtain a compound 2;
and a second stage: adding N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (a compound 3) and an alkaline reagent into an organic solvent of the compound 2, and stirring to react to obtain regorafenib;
the alkaline agent is selected from: triethylamine, N-diisopropylethylamine and sodium hydroxide. One or more of potassium hydroxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide;
the organic solvent is selected from: one or more of acetonitrile, dichloromethane, trichloromethane, tetrahydrofuran, ethyl acetate, methanol or ethanol.
3. A method of preparing regorafenib according to claim 2, wherein: the dosage of the reagent triphosgene is 0.34-0.54 times (mol/mol), preferably 0.44 times (mol/mol) of the molar quantity of the N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-formamide (compound 3).
4. A method of preparing regorafenib according to claim 2, wherein: the amount of the 4-chloro-3-trifluoromethylaniline (compound 1) is 1.1 to 1.5 times (mol/mol), preferably 1.3 times (mol/mol) of the molar amount of the N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound 3).
5. A process for the preparation of regorafenib according to claim 2, wherein the alkaline agent is used in an amount of 1.0 to 1.4 times (mol/mol), preferably 1.17 times (mol/mol) the molar amount of N-methyl-4- (4-amino-3-fluoro) phenoxypyridine-2-carboxamide (compound 3).
6. A method of preparing regorafenib according to claim 2, wherein:
the reaction temperature in the first stage is-10-20 ℃, and preferably 0-10 ℃;
the reaction temperature in the second stage is 5-40 ℃, and preferably 15-30 ℃.
7. A method of preparing regorafenib according to claim 2, wherein:
the reaction time of the first stage is 0.5-2.5 h, preferably 1-2 h;
the reaction time of the second stage is 0.5-1.5 h, preferably 1 h.
8. A process for the preparation of regorafenib as claimed in any one of claims 1-7, wherein: the yield of the prepared regorafenib is over 86%.
9. A process for the preparation of high purity regorafenib characterized in that it comprises the steps of any one of claims 2-7; the purity of the prepared regorafenib is 99.95%.
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