CN114920689B - Preparation method of regorafenib intermediate - Google Patents
Preparation method of regorafenib intermediate Download PDFInfo
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- CN114920689B CN114920689B CN202210443680.9A CN202210443680A CN114920689B CN 114920689 B CN114920689 B CN 114920689B CN 202210443680 A CN202210443680 A CN 202210443680A CN 114920689 B CN114920689 B CN 114920689B
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- 239000002138 L01XE21 - Regorafenib Substances 0.000 title claims abstract description 42
- 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 42
- 229960004836 regorafenib Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 20
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 45
- 239000003054 catalyst Substances 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- MNPLTKHJEAFOCA-UHFFFAOYSA-N 4-amino-3-fluorophenol Chemical compound NC1=CC=C(O)C=C1F MNPLTKHJEAFOCA-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- -1 4- (4-amino-3-fluorophenoxy) -N-methylpyridine amide Chemical class 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 230000001738 genotoxic effect Effects 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 231100000025 genetic toxicology Toxicity 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-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
- 208000035977 Rare disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 231100000024 genotoxic 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
- 238000002483 medication Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical group [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 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
- 229960001796 sunitinib Drugs 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a regorafenib intermediate. According to the preparation method of the regorafenib intermediate, the catalyst is dissolved independently, then the two raw materials are dissolved together and added into the catalyst-containing solution in a dropwise manner, the two-step dissolution temperature and the molar ratio of the catalyst to the raw materials are controlled, and even if an amino protection step is not adopted, the yield and the purity of the prepared intermediate are effectively improved, and the content of the impurity A is greatly reduced. When regorafenib is further prepared, however, the intermediate raw materials are completely reacted, and the residual quantity of the intermediate raw materials and the content of impurities I in the product are greatly reduced.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a regorafenib intermediate.
Background
Regorafenib is an oral multi-kinase inhibitor developed by bayer healthcare limited for the treatment of patients with locally advanced, inoperable or metastatic gastrointestinal stromal tumor (GIST) who have previously received treatment with imatinib and sunitinib, which drug is simultaneously eligible for orphan medications for the treatment of rare diseases.
The intermediate 4- (4-amino-3-fluorophenoxy) -N-methylpyridine amide (formula 1) widely used in the synthesis of regorafenib is the basis and key for preparing regorafenib. The purity of the compound of formula 1 severely affects the purity of the regorafenib prepared. Therefore, the synthesis research of the compound of the formula 1 is very important, and the specific structural formula is as follows:
the common method is that 4-amino-3-fluorophenol (formula 2) is subjected to amino protection reaction to generate an imine compound, and then the imine compound is reacted with N-methyl-4-chloro-2-pyridine formamide (formula 3) to obtain a compound of formula 1 through deprotection. The method introduces the step of protecting the amino group, and can reduce the occurrence of side reaction to reduce the impurity content in the compound of the formula 1, but introduces the steps of protecting and deprotecting the amino group, thereby increasing the reaction steps and a large amount of post-treatment operations, consuming time and energy, and improving the production cost.
At present, a preparation method without an amino protection step has been reported, for example, a synthetic route of the compound 1 in Chinese patent CN104250226A and CN105218440A is shown in the following synthetic route 1, and the purity of the obtained compound of the formula 1 is as high as 97% -98%, but the content of single impurity (impurity A) is high, and the removal is difficult. In the subsequent process of forming regorafenib, see the following synthetic route 2, the impurity A reacts with the raw material 4-chloro-3- (trifluoromethyl) phenyl isocyanate (formula 4) to generate the impurity I, and the compound of formula 1 is incompletely reacted due to the consumption of the compound of formula 4, so that the residual amount of the compound of formula 1 in the final product regorafenib is higher. The compound of formula 1 is itself a genotoxic impurity, which is a highly bioactive substance with potential oncogenic toxicity.
Synthetic route 1:
synthetic route 2:
because of the drawbacks of the prior art, there is a need for a process for the preparation of compounds of formula 1, which has fewer reaction steps, simple post-treatment and a low content of impurity a.
Disclosure of Invention
Through a great deal of research, the invention discovers that the preparation method of the regorafenib intermediate (the compound of the formula 1) provided by the invention can be used for crystallizing by only using water as a solvent, so that the prepared compound of the formula 1 has high yield and small residue of impurity A. Further, the prepared compound of the formula 1 is used for preparing regorafenib, and the residual quantity of the compound of the formula 1 and the content of impurities I are obviously reduced.
The invention provides a preparation method of a regorafenib intermediate, which is a compound shown in a formula 1 and comprises the following steps:
step 1, adding a solvent and potassium tert-butoxide into a reaction bottle, and heating;
step 2, adding a solvent, a compound of formula 3 and a compound of formula 2 into a reaction bottle, and heating;
step 3, dripping the mixture obtained in the step 2 into the reaction bottle obtained in the step 1, dripping the reaction liquid into the reaction bottle filled with water after the reaction is finished, cooling the reaction liquid, and stirring for crystallization to obtain the compound shown in the formula 1;
wherein the temperature of the step 1 is 50-90 ℃, the temperature of the step 2 is 50-90 ℃, the molar ratio of the potassium tert-butoxide to the compound of the formula 3 is 1.4:1-2.0:1, and the molar ratio of the compound of the formula 2 to the compound of the formula 3 is 1.4:1-2.0:1.
In some embodiments, the temperature of step 1 is from 50 ℃ to 80 ℃, preferably from 50 ℃ to 70 ℃; the temperature in the step 2 is 50-80 ℃, preferably 50-70 DEG C
In some embodiments, the solvent is selected from the group consisting of N-methylpyrrolidone, toluene, 1, 4-dioxane, ethyl acetate.
In some embodiments, the solvent is N-methylpyrrolidone.
In some embodiments, the molar ratio of potassium tert-butoxide to formula 3 is 1.5:1, the molar ratio of formula 2 to formula 3 is 1.5:1, the temperature of step 1 is 60 ℃, and the temperature of step 2 is 50 ℃.
The regorafenib intermediate prepared by the preparation method has the purity of not less than 99%.
The invention has the beneficial effects that:
according to the preparation method of the compound of the formula 1, the catalyst is dissolved independently, then the compound of the formula 2 and the compound of the formula 3 are dissolved together and are added into the solution containing the catalyst in a dropwise manner, the two-step dissolution temperature and the molar ratio of the compound of the formula 2 to the catalyst to the compound of the formula 3 are controlled, and even if an amino protection step is not adopted, the yield and the purity of the prepared compound of the formula 1 are effectively improved, and the content of the impurity A is greatly reduced. When the prepared compound of the formula 1 is further used for preparing regorafenib, the raw materials are completely reacted, and the residual quantity of the compound of the formula 1 and the content of impurities I in the product are greatly reduced.
Wherein the yield of the compound of formula 1 is > 70%, preferably > 88%; purity > 98%, preferably > 99%; the content of the impurity A is less than 0.1 percent. Further, the prepared compound of the formula 1 is used for preparing regorafenib, and the residual quantity of the formula 1 is less than 50ppm; the content of impurity I is less than 0.1%.
Detailed Description
The preparation method of regorafenib intermediate (compound 1) provided by the present invention is described in detail below by way of some examples, but the present invention is not limited to the following examples. Any method and materials similar or equivalent to those described can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or manufacturer recommended conditions. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The impurity detection method comprises the following steps:
(1) Method for detecting impurity I
The measurement is carried out by high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
The sample solution is precisely weighed and dissolved by adding methanol to prepare a solution containing 15mg per 1 ml.
Precisely weighing 15ml of the sample solution in the control solution, placing in a 50ml measuring flask, adding methanol to dilute to scale, and shaking.
The chromatographic conditions use phenyl silane bonded silica gel as a filler; gradient elution was performed using 0.1% trifluoroacetic acid in acetonitrile (97:3) as mobile phase a and acetonitrile as mobile phase B, as follows; the detection wavelength is 232nm; the flow rate is 0.9ml per minute; column temperature was 63 ℃; the injector temperature was 8deg.C and the injection volume was 5 μl.
Gradient elution procedure
| Time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0-2 | 100 | 0 |
| 2-15 | 100→78 | 0→22 |
| 15-25 | 78→60 | 22→40 |
| 25-33 | 60→36 | 40→64 |
| 33-37 | 36 | 64 |
The measuring method precisely measures the solution of the sample and the control solution, respectively injects the solution into a liquid chromatograph, and records the chromatograms.
(2) Method for detecting impurity A
The measurement is carried out by high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part rule 0512).
The sample solution is precisely weighed and dissolved by adding tetrahydrofuran, and diluted to prepare a solution containing 50mg per 1 ml.
Accurately weighing the reference substance solution with a proper amount of impurity A, adding tetrahydrofuran for dissolving and diluting to obtain a solution containing 0.005mg per 1 ml.
Octadecylsilane chemically bonded silica is used as a filler under chromatographic conditions; gradient elution was performed using phosphate buffer (containing dipotassium hydrogen phosphate 0.5g/L, potassium dihydrogen phosphate 1.5 g/L) -acetonitrile (92:8) as mobile phase A and acetonitrile as mobile phase B according to the following table; the detection wavelength is 228nm; the flow rate is 1.0ml per minute; column temperature is 50 ℃; the injector temperature was 8deg.C and the injection volume was 3 μl.
Gradient elution procedure
The measuring method precisely measures the solution of the sample and the solution of the reference substance, respectively injects the solution into a liquid chromatograph, and records the chromatograms.
Comparative example 1: CN104250226A example 1, step C
To a four-necked flask, 3.6mL (1.27 g) of a tetrahydrofuran solution of the compound 4-amino-3-fluorophenol (formula 2) was added, potassium tert-butoxide powder (1.23 g) was added in portions at room temperature, the system temperature was kept at 30℃or lower, and the mixture was stirred for 2 hours, then 40.7mL (1.71 g) of a tetrahydrofuran solution of the compound 4-chloro-N-methylpyridine carboxamide (formula 3) was slowly added dropwise, the system was warmed to reflux, and the reflux reaction was completed. The system was cooled to room temperature, washed with 30mL of saturated brine, and the organic phase was dried and concentrated to give 2.45g of brown solid, intermediate compound 1, yield and purity were measured, and the results are shown in table 1.
Table 1 summary of experimental data for compounds of formula 1
| Sequence number | Yield/% | Purity/% | Impurity A content/% | Other impurity content/% |
| Comparative example 1 | 90.26 | 96.32 | 1.59 | 2.09 |
Comparative example 2: CN105218440A example 1.1
4-chloro-N-methylpyridine formamide (formula 3, 17 g), tetrabutylammonium bromide (3.22 g) were added to 340ml of tetrahydrofuran and stirred well. Sodium tert-butoxide (10 g) was added. The temperature was raised to 50℃and 4-amino-3-fluorophenol (formula 2, 13.9 g) was added thereto, followed by further reaction for 8 hours. After the reaction, water was added to the reaction system to quench the reaction mixture, and the reaction mixture was extracted with methylene chloride. The organic layer was separated, collected and concentrated to a residue. After the residue was dissolved with methylene chloride, methyl tert-butyl ether was added thereto, stirred, and after solid was precipitated, the cake was collected by filtration, and dried to obtain intermediate compound 1, the yield and purity were measured, and the results are shown in table 2.
Table 2 summary of experimental data for compounds of formula 1
| Sequence number | Yield/% | Purity/% | Impurity A content/% | Other impurity content/% |
| Comparative example 2 | 87.03 | 97.66 | 0.80 | 1.54 |
Comparative example 3: preparation of regorafenib
Using intermediate compound 1 prepared in comparative example 1 and comparative example 2, regorafenib was prepared and impurities in regorafenib were measured as follows, respectively.
The preparation method of regorafenib comprises the following steps: to a four-necked flask, the compound of formula 1 (2.0 g) and tetrahydrofuran (10 ml) were added and stirred. To a solution of 4-chloro-3- (trifluoromethyl) phenylisocyanate (1.9 g, formula 4) in tetrahydrofuran (6 ml), a solution of tetrahydrofuran was added dropwise at 15℃and reacted at 15℃for 2 to 4 hours, n-heptane (10 ml) was added, crystallization was carried out for 2 to 4 hours, suction filtration, rinsing, and drying to give a finished product of regorafenib, and the yield and purity were measured, and the results are shown in Table 3.
Table 3 summary of experimental data for regorafenib
From the results shown in table 3, the impurity a content of the intermediate compound of formula 1 prepared in comparative examples 1 and 2 was 1.59% and 0.80%, respectively, so that the raw material formula 1 having genotoxicity was not completely reacted, the residual amount was high, and the impurity I content was also high when regorafenib was prepared.
And (3) preparing a regorafenib finished product, wherein an impurity A in the compound of the formula 1 can also react with the compound of the formula 4 to generate an impurity I, and the impurity I cannot be removed by a conventional refining method. More importantly, impurity a forms impurity I, which requires the consumption of more 4-chloro-3- (trifluoromethyl) phenyl isocyanate (compound of formula 4) such that the intermediate compound of formula 1 does not react sufficiently and a significant amount of compound of formula 1 remains in the finished regorafenib product.
The compound of formula 1 itself has genotoxicity, can damage DNA, and has potential oncogenic toxicity. The compound of formula 1 is also a degrading impurity of regorafenib, and the raw material medicine and the preparation can be continuously increased in the storage process and the production process, so that the lower the content of the compound of formula 1 in the regorafenib raw material medicine is required to be, the better. The quality of the regorafenib preparation can be further ensured, and the quality of the regorafenib tablet still meets the standard within the 36-month effective period.
Experimental example 1: process for the preparation of compound 1
Step 1: n-methylpyrrolidone (150 ml) and potassium tert-butoxide are added into a four-mouth bottle, and the temperature is raised to 60 ℃;
step 2: n-methylpyrrolidone (70 ml), 4-chloro-N-methylpyridine formamide (formula 3, 20g,117.23 mmol) and 4-amino-3-fluorophenol (formula 2) were added to a four-necked flask, and the mixture was stirred and heated to 50 ℃;
step 3: and (3) adding the mixed solution in the step (2) into the four-mouth bottle in the step (1) for reaction for 20-30min. After the reaction, the reaction solution is added into a four-mouth bottle filled with purified water (450 ml), cooled to 15-30 ℃, stirred and crystallized for 2-4h. Suction filtration and drying to obtain intermediate compound 1, the yield and purity were measured, and the results are shown in tables 4 to 5.
The intermediate 1 was prepared by the preparation method of comparative example 3, and the yield and purity were measured and the results are shown in table 6.
TABLE 4 influence of the catalyst and of the amount of formula 2
Table 5 summary of experimental data for compounds of formula 1
| Sequence number | Yield is good | Purity of | Impurity A | Other maximum single impurity |
| 1-1 | 53.65％ | 98.54％ | 0.38％ | 0.43％ |
| 1-2 | 54.37％ | 98.63％ | 0.43％ | 0.33％ |
| 1-3 | 56.27％ | 98.66％ | 0.33％ | 0.36％ |
| 1-4 | 76.34％ | 99.06％ | 0.26％ | 0.23％ |
| 1-5 | 84.09％ | 99.78％ | 0.09％ | 0.10％ |
| 1-6 | 88.28％ | 99.88％ | 0.05％ | 0.07％ |
| 1-7 | 88.58％ | 99.89％ | 0.04％ | 0.08％ |
| 1-8 | 88.36％ | 99.83％ | 0.07％ | 0.05％ |
Table 6 summary of experimental data for regorafenib
The chemical reaction of formula 3 and formula 2 to prepare formula 1 is carried out at 1:1, however the results of examples 1-1 and 1-2 show that when formula 3: formula 2: the yield was 53.65% when the reaction was carried out with a molar ratio of potassium tert-butoxide (catalyst) of 1:1:1, and was increased by 0.72% (yield 54.37%) even when the molar ratio of the catalyst was increased to 1.5. That is, only the excess catalyst moves forward with little effect on the reaction.
The results according to examples 1-1 and 1-3 show that the yield increases by 2.62% (yield 56.27%) when the molar ratio of the compound of formula 2 is increased to 1.5. That is, only an excess of the compound of formula 2 has little effect on the forward shift of the reaction.
From the results of the experiments of examples 1 to 4, it was found that when the amounts of the compound of formula 2 and the catalyst were increased simultaneously, the yield was greatly increased by 34.63% (yield: 76.34%) and the purity was also increased by 1.34%, especially the content of impurity A was increased to 0.26%, but the residual amount of the final product regorafenib formula 1 (genotoxicity) was measured as high as 679ppm.
The inventors found that when the molar ratio of the compound of formula 2 and potassium tert-butoxide to the compound of formula 3 is 1.4-2.0 (see 1-5 to 1-8), the prepared compound of formula 1 has an impurity A content of less than 1.0%, and further regorafenib is prepared, the residual amount of formula 1 is less than 350ppm, and the impurity I content is less than 0.1%.
Example 2: process for the preparation of compound 1
Step 1: n-methylpyrrolidone (150 ml), potassium tert-butoxide (19.7 g,175.56 mmol) and the mixture were added to a four-necked flask, and the temperature was raised;
step 2: n-methylpyrrolidone (70 ml), 4-chloro-N-methylpyridine formamide (20 g,117.23mmol, formula 3) and 4-amino-3-fluorophenol (22.4 g,176.21mmol, formula 2) were added to a four-necked flask, and the mixture was stirred and heated;
step 3: and (3) adding the mixed solution in the step (2) into the four-mouth bottle in the step (1) for reaction for 20-30min. After the reaction, the reaction solution is added into a four-mouth bottle filled with purified water (450 ml), cooled to 15-30 ℃, stirred and crystallized for 2-4h. Suction filtration and drying to obtain intermediate compound 1, the yield and purity were measured, and the results are shown in Table 7.
The intermediate 1 was prepared by the preparation method of comparative example 3, and the yield and purity were measured and the results are shown in table 8.
TABLE 7 influence of temperature in step 1 and step 2
Table 8 summary of experimental data for regorafenib
| Sequence number | Yield/% | Purity/% | Content/ppm of 1 | Impurity I content/% | Other impurity content/% |
| 2-4 | 88.97 | 99.79 | 435 | 0.09 | 0.20 |
| 2-10 | 92.04 | 99.89 | 25.9 | 0.04 | 0.06 |
* : some other impurities can not be crystallized and detected, and most of the impurities are dissolved in the reaction liquid
The inventor researches that if the temperature of the step 3 is too high, the step 3 is heated rapidly, the reaction temperature and the reaction speed cannot be controlled, and the danger coefficient is high because the step 3 is an exothermic reaction. Therefore, in order to ensure mild reaction conditions in the step 3 and reduce the generation of impurities, the temperature ranges of the step 1 and the step 2 need to be strictly controlled.
The above experimental results show that the yield of the intermediate is > 70%, the purity is > 98%, the content of impurity A is < 0.25% and the residual amount of formula 1 is < 450ppm and the content of impurity I is < 0.1% in the further prepared regorafenib at the temperature of step 1 in the range of 50-90 ℃ and the temperature of step 2 in the range of 50-90 ℃ (examples 1-6, examples 2-5 to examples 2-10).
The temperature of the step 1 is 50-70 ℃, the yield of the intermediate is more than 88%, the purity is more than 99%, the content of the impurity A is less than 0.1%, the residual content of the formula 1 in the further prepared regorafenib is less than 30ppm, and the content of the impurity I is less than 0.1% when the temperature of the step 2 is 50-70 ℃ (examples 1-6, 2-5, 2-7 and 2-10).
Claims (4)
1. A preparation method of a regorafenib intermediate, wherein the intermediate is a compound shown in a formula 1, and the preparation method comprises the following steps:
step 1, adding a solvent and potassium tert-butoxide into a reaction bottle, and heating;
step 2, adding a solvent, a compound of formula 3 and a compound of formula 2 into a reaction bottle, and heating;
step 3, dripping the mixture obtained in the step 2 into the reaction bottle obtained in the step 1, dripping the reaction liquid into the reaction bottle filled with water after the reaction is finished, cooling the reaction liquid, and stirring for crystallization to obtain the compound shown in the formula 1;
wherein the temperature of the step 1 is 50-70 ℃, the temperature of the step 2 is 50-70 ℃, the molar ratio of potassium tert-butoxide to the compound of the formula 3 is 1.4:1-2.0:1, and the molar ratio of the compound of the formula 2 to the compound of the formula 3 is 1.4:1-2.0:1.
2. The process for the preparation of regorafenib intermediate according to claim 1, wherein the solvent is selected from the group consisting of N-methylpyrrolidone, toluene, 1, 4-dioxane, ethyl acetate.
3. The process for the preparation of regorafenib intermediate according to claim 1, wherein the solvent is N-methylpyrrolidone.
4. The process for the preparation of regorafenib intermediate according to claim 1, wherein the molar ratio of potassium tert-butoxide to formula 3 is 1.5:1, the molar ratio of formula 2 to formula 3 is 1.5:1, the temperature of step 1 is 60 ℃, and the temperature of step 2 is 50 ℃.
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| 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 |
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| 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 |
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