CN114920689A - Preparation method of regorafenib intermediate - Google Patents
Preparation method of regorafenib intermediate Download PDFInfo
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- CN114920689A CN114920689A CN202210443680.9A CN202210443680A CN114920689A CN 114920689 A CN114920689 A CN 114920689A CN 202210443680 A CN202210443680 A CN 202210443680A CN 114920689 A CN114920689 A CN 114920689A
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- 239000002138 L01XE21 - Regorafenib Substances 0.000 title claims abstract description 46
- 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 46
- 229960004836 regorafenib Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 17
- 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
- 238000010438 heat treatment Methods 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
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 46
- 239000003054 catalyst Substances 0.000 abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 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
- 230000001738 genotoxic effect Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 231100000024 genotoxic Toxicity 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
- -1 4- (4-amino-3-fluorophenoxy) -N-methylpyridine amide Chemical class 0.000 description 3
- BGVBBMZMEKXUTR-UHFFFAOYSA-N 4-chloro-n-methylpyridine-2-carboxamide Chemical compound CNC(=O)C1=CC(Cl)=CC=N1 BGVBBMZMEKXUTR-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
- 238000007865 diluting Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005303 weighing 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
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 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
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012488 sample solution 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006731 degradation reaction 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
- 239000012065 filter cake Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 231100000025 genetic toxicology 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
- 238000002386 leaching Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000000203 mixture Substances 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
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical group [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 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
- 238000010992 reflux 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
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010626 work up procedure Methods 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, the two raw materials are dissolved together and dripped into the solution containing the catalyst, the two-step dissolution temperature and the molar ratio of the catalyst to the raw materials are controlled, the yield and the purity of the prepared intermediate can be effectively improved even if an amino protection step is not adopted, and the content of the impurity A is greatly reduced. When regorafenib is further prepared, the intermediate raw materials can completely react, and the residual quantity of the intermediate raw materials and the content of the impurity 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 multikinase inhibitor developed by bayer healthcare limited for the treatment of locally advanced, non-surgically resectable or metastatic gastrointestinal stromal tumor (GIST) patients who have previously received imatinib and sunitinib therapy, which is used for the treatment of rare diseases while gaining orphan drug eligibility.
4- (4-amino-3-fluorophenoxy) -N-methylpyridine amide (formula 1), an intermediate widely used in the synthesis of regorafenib, is a basis and key for preparing regorafenib. The purity of the compound of formula 1 seriously affects the purity of the regorafenib prepared. Therefore, it is important to study the synthesis of the compound of formula 1, which has the following specific structural formula:
the commonly used method is that the amino protection reaction of 4-amino-3-fluorophenol (formula 2) is firstly carried out to generate imine compound, and then the imine compound reacts with N-methyl-4-chloro-2-pyridine carboxamide (formula 3), and the obtained compound is deprotected to obtain the compound shown in formula 1. The method introduces a step of protecting amino, can reduce side reactions to reduce the content of impurities in the compound shown in the formula 1, but introduces a step of protecting and deprotecting amino, increases reaction steps and a large amount of post-treatment operations, consumes time and energy, and increases production cost.
At present, there are reports of preparation methods without amino protection step, such as the synthetic route of compound 1 in chinese patents CN104250226A and CN105218440A, see the following synthetic route 1, and the purity of the obtained compound of 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 producing regorafenib, as shown in the following synthetic scheme 2, the impurity a reacts with the raw material 4-chloro-3- (trifluoromethyl) phenyl isocyanate (formula 4) to produce the impurity I, and the compound of formula 4 is consumed, so that the compound of formula 1 does not react completely, and the residue of the compound of formula 1 in the final product regorafenib is high. The compound of the formula 1 is a genotoxic impurity per se, and the genotoxic impurity is a high-biological active substance and has potential carcinogenic toxicity.
Scheme 1:
scheme 2:
due to the drawbacks of the prior art, there is a need for a process for the preparation of the compound of formula 1, which has few reaction steps, simple workup and low content of impurity a.
Disclosure of Invention
Through a large number of researches, the inventor finds that the regorafenib intermediate (the compound shown in the formula 1) is prepared by a preparation method, and only water is used as a solvent for crystallization, so that the prepared compound shown in the formula 1 has high yield and small residual quantity of impurity A. Further, when the prepared compound of formula 1 is used for preparing regorafenib, the residual amount of the compound of formula 1 and the content of impurity I are obviously reduced.
The invention provides a preparation method of a regorafenib intermediate, wherein the intermediate is a compound shown in 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 shown in a formula 3 and a compound shown in a formula 2 into a reaction bottle, and heating;
step 3, dripping the mixed liquid 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 after the dripping is finished, and stirring for crystallization to obtain a compound shown in the formula 1;
wherein the temperature in the step 1 is 50-90 ℃, the temperature in the step 2 is 50-90 ℃, 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.
In some embodiments, the temperature of step 1 is from 50 ℃ to 80 ℃, preferably from 50 ℃ to 70 ℃; the temperature of the step 2 is 50-80 ℃, preferably 50-70 DEG C
In some embodiments, the solvent is selected from 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 purity of the regorafenib intermediate prepared by the preparation method is not lower than 99%.
The invention has the beneficial effects that:
according to the preparation method of the compound shown in the formula 1, the catalyst is dissolved independently, the compounds shown in the formulas 2 and 3 are dissolved together and dripped into the solution containing the catalyst, the two-step dissolution temperature and the molar ratio of the compounds shown in the formulas 2 and 3 are controlled, the yield and the purity of the prepared compound shown in the formula 1 can be effectively improved even if an amino protection step is not adopted, and the content of the impurity A is greatly reduced. When the prepared compound in the formula 1 is further used for preparing regorafenib, the raw materials are reacted completely, and the residue of the compound in the formula 1 in the product and the content of the impurity I 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 formula 1 is used for preparing regorafenib, and the residual quantity of formula 1 is less than 50 ppm; the content of impurity I is less than 0.1%.
Detailed Description
The following examples are intended to illustrate the preparation of the regorafenib intermediate (compound 1) provided by the present invention, but the present invention is not limited to the following examples. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples do not indicate any specific conditions, and are carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. 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
Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
The test solution is prepared by precisely weighing a proper amount of the product, adding methanol to dissolve and diluting to prepare a solution containing 15mg per 1 ml.
The control solution is precisely weighed 15ml of the test solution, placed in a 50ml measuring flask, diluted to the scale by adding methanol and shaken up.
The chromatographic condition uses phenyl silane bonded silica gel as a filling agent; gradient elution was performed using 0.1% trifluoroacetic acid solution-acetonitrile (97:3) as mobile phase a and acetonitrile as mobile phase B according to the following table; the detection wavelength is 232 nm; the flow rate was 0.9ml per minute; the column temperature was 63 ℃; the injector temperature was 8 ℃ and the injection volume was 5. mu.l.
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 comprises precisely measuring test solution and control solution, respectively injecting into liquid chromatograph, and recording chromatogram.
(2) Method for detecting impurity A
Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general rules 0512).
The sample solution is prepared by precisely weighing appropriate amount of the product, dissolving with tetrahydrofuran, and diluting to obtain solution containing 50mg per 1 ml.
The reference solution is prepared by precisely weighing an appropriate amount of impurity A reference, dissolving with tetrahydrofuran, and diluting to obtain 0.005mg solution per 1 ml.
Octadecylsilane chemically bonded silica is used as a filling agent under the chromatographic condition; gradient elution is carried out by taking phosphate buffer solution (containing 0.5g/L of dipotassium hydrogen phosphate and 1.5g/L of monopotassium phosphate) -acetonitrile (92:8) as a mobile phase A and acetonitrile as a mobile phase B according to the following table; the detection wavelength is 228 nm; the flow rate was 1.0ml per minute; the column temperature is 50 ℃; the injector temperature was 8 ℃ and the injection volume was 3. mu.l.
Gradient elution procedure
The measurement method comprises precisely measuring the sample solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
Comparative example 1: CN104250226A example 1, step C
3.6mL (1.27g) of a tetrahydrofuran solution of the compound 4-amino-3-fluorophenol (formula 2) was added to a four-necked flask, potassium tert-butoxide powder (1.23g) was added in portions at room temperature, the system temperature was controlled to 30 ℃ or lower and stirred for 2 hours, then 40.7mL (1.71g) of a tetrahydrofuran solution of the compound 4-chloro-N-methylpyridine carboxamide (formula 3) was slowly added dropwise, the system was heated to reflux, and the reaction was refluxed until the reaction was completed. The system was cooled to room temperature, washed with 30mL of saturated brine, the organic phase was dried and concentrated to give 2.45g of a brown solid, intermediate compound 1, and the yield and purity were measured and the results are shown in table 1.
TABLE 1 summary of experimental data for compounds of formula 1
| Serial number | Yield/% | Purity/%) | Content of impurity A/%) | Content of other impurities/%) |
| Comparative example 1 | 90.26 | 96.32 | 1.59 | 2.09 |
Comparative example 2: CN105218440A example 1.1
4-chloro-N-methylpyridine carboxamide (formula 3, 17g) and tetrabutylammonium bromide (3.22g) were added to 340ml of tetrahydrofuran, and stirred well. Sodium tert-butoxide (10g) was added. The temperature was raised to 50 ℃ and 4-amino-3-fluorophenol (formula 2, 13.9g) was added to continue the reaction for 8 hours. After the reaction, water was added to the reaction system to quench, and the reaction solution was extracted with dichloromethane. Separating, collecting organic layer, and concentrating to obtain residue. After the residue was dissolved in dichloromethane, methyl tert-butyl ether was added, stirred, and after precipitating a solid, filtered, the filter cake was collected and dried to obtain intermediate compound 1, and 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
| Serial number | Yield/% | Purity/%) | Content of impurity A/%) | Other impuritiesContent/% |
| Comparative example 2 | 87.03 | 97.66 | 0.80 | 1.54 |
Comparative example 3: preparation of regorafenib
Regorafenib was prepared and impurities in regorafenib were measured using the intermediate compound 1 prepared in comparative example 1 and comparative example 2, respectively, as follows.
The preparation method of regorafenib comprises the following steps: a four-necked flask was charged with the compound of formula 1 (2.0g) and tetrahydrofuran (10ml), and stirred. Adding a tetrahydrofuran (6ml) solution dissolved in 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.9g, formula 4), dropwise adding the tetrahydrofuran solution at 15 ℃, reacting at 15 ℃ for 2-4h, adding n-heptane (10ml), crystallizing for 2-4h, performing suction filtration, leaching, and drying to obtain a regorafenib finished product, and measuring the yield and purity, wherein the results are shown in Table 3.
Table 3 summary of experimental data for regorafenib
As can be seen from the results of table 3, the contents of impurity a in the intermediate compound of formula 1 prepared in comparative example 1 and comparative example 2 were 1.59% and 0.80%, respectively, so that the reaction of the starting material of formula 1 having genotoxicity was incomplete, the residue was high, and the content of impurity I was high when regorafenib was prepared.
When the finished product of regorafenib is prepared, the impurity A in the intermediate compound shown in formula 1 can react with the compound shown in formula 4 to generate the impurity I, and the impurity I cannot be removed by a conventional refining method. More importantly, the impurity A generates the impurity I, and more 4-chloro-3- (trifluoromethyl) phenyl isocyanate (the compound shown in the formula 4) needs to be consumed, so that the intermediate compound shown in the formula 1 cannot be fully reacted, and a large amount of the compound shown in the formula 1 remains in the finished regorafenib product.
The compound of formula 1 is genotoxic in itself, can damage DNA, and has potential carcinogenic toxicity. And the compound in the formula 1 is also a degradation impurity of regorafenib, and the storage process and the production process of bulk drugs and preparations can be continuously increased, so that the lower the content of the compound in the formula 1 in the regorafenib bulk drug is, the better the content is. The quality of the regorafenib formulation can be further guaranteed and the quality of the regorafenib tablets can still meet the standard within the 36-month validity period.
Experimental example 1: process for producing Compound 1
Step 1: adding N-methylpyrrolidone (150ml) and potassium tert-butoxide into a four-mouth bottle, and heating to 60 ℃;
step 2: adding N-methylpyrrolidone (70ml), 4-chloro-N-methylpyridine formamide (formula 3, 20g, 117.23mmol) and 4-amino-3-fluorophenol (formula 2) into a four-neck flask, and stirring and heating to 50 ℃;
and step 3: and (3) adding the mixed solution in the step (2) into the four-mouth bottle in the step (1), and reacting for 20-30 min. After the reaction is finished, adding the reaction solution into a four-mouth bottle filled with purified water (450ml), cooling to 15-30 ℃, and stirring for crystallization for 2-4 h. Suction filtration and drying were carried out to obtain intermediate compound 1, and the yield and purity were measured, and the results are shown in tables 4-5.
The prepared intermediate 1 was used to prepare regorafenib using 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 amount of catalyst and formula 2
TABLE 5 summary of experimental data for compounds of formula 1
| Serial number | Yield of | 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
Formula 3 and formula 2 the chemical reaction for preparing 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: when the reaction was carried out with a molar ratio of potassium tert-butoxide (catalyst) of 1:1:1, the yield was 53.65%, and even when the molar ratio of the catalyst was increased to 1.5, the yield was improved by 0.72% (yield 54.37%). That is, only the catalyst excess moves forward in the reaction, with little effect.
The results of examples 1-1 and 1-3 show that the yield was increased by 2.62% (56.27%) by increasing the molar ratio of the compound of formula 2 to 1.5. That is, only an excess of the compound of formula 2 has little effect on the forward movement of the reaction.
From the experimental results of examples 1-4, it can be seen that when the amounts of the compound of formula 2 and the catalyst are increased simultaneously, the yield is greatly increased by 34.63% (yield is 76.34%), and the purity is also increased by 1.34%, especially the content of impurity a is increased to 0.26%, but the residual amount of the final product, regorafenib formula 1 (genotoxic), is still as high as 679 ppm.
The inventor finds that when the molar ratio of the compound shown in the formula 2 to the potassium tert-butoxide to the compound shown in the formula 3 is 1.4-2.0 (see 1-5 to 1-8), the prepared compound shown in the formula 1 has the impurity A content of less than 1.0 percent, and further prepares regorafenib, wherein the residual quantity of the compound shown in the formula 1 is less than 350ppm, and the impurity I content is less than 0.1 percent.
Example 2: process for producing Compound 1
Step 1: adding N-methylpyrrolidone (150ml) and potassium tert-butoxide (19.7g, 175.56mmol) into a four-necked bottle, and heating;
step 2: adding N-methylpyrrolidone (70ml), 4-chloro-N-methylpyridine formamide (20g, 117.23mmol, formula 3), and 4-amino-3-fluorophenol (22.4g, 176.21mmol, formula 2) into a four-neck flask, and stirring and heating;
and step 3: and (3) adding the mixed solution in the step (2) into the four-mouth bottle in the step (1), and reacting for 20-30 min. After the reaction is finished, adding the reaction solution into a four-mouth bottle filled with purified water (450ml), cooling to 15-30 ℃, and stirring for crystallization for 2-4 h. Suction filtration and drying gave intermediate compound 1, the yield and purity were measured and the results are shown in table 7.
The prepared intermediate 1 was used to prepare regorafenib 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
| Serial number | Yield/% | Purity/%) | Formula 1 content/ppm | Content of impurity I/%) | Content of other impurities/%) |
| 2-4 | 88.97 | 99.79 | 435 | 0.09 | 0.20 |
| 2-10 | 92.04 | 99.89 | 25.9 | 0.04 | 0.06 |
*: part of other impurities cannot be crystallized and detected, and most of the impurities are dissolved in the reaction solution
The inventor researches and discovers that if the temperature of the step 1 and the step 2 is too high, the step 3 is heated rapidly because the step 3 is also an exothermic reaction, so that the reaction temperature and the reaction speed cannot be controlled, and the danger coefficient is high. Therefore, in order to ensure mild reaction conditions in step 3 and reduce the generation of impurities, the temperature ranges of step 1 and step 2 need to be strictly controlled.
The above experimental results show that when the temperature of step 1 is in the range of 50 ℃ to 90 ℃, and the temperature of step 2 is in the range of 50 ℃ to 90 ℃, the yield of the intermediate is more than 70%, the purity is more than 98%, the content of impurity a is less than 0.25%, and in the further prepared regorafenib, the residual amount of formula 1 is less than 450ppm, and the content of impurity I is less than 0.1% (examples 1-6, examples 2-5 to examples 2-10).
When the temperature of the step 1 is in the range of 50-70 ℃, and the temperature of the step 2 is in the range of 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%, in the further prepared regorafenib, the residual quantity of the formula 1 is less than 30ppm, and the content of the impurity I is less than 0.1% (examples 1-6, 2-5, 2-7 and 2-10).
Claims (6)
1. A preparation method of a regorafenib intermediate, wherein the intermediate is a compound shown in 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 shown in a formula 3 and a compound shown in a formula 2 into a reaction bottle, and heating;
step 3, dripping the mixed liquid obtained in the step 2 into the reaction bottle obtained in the step 1, after the reaction is finished, dripping the reaction liquid into the reaction bottle filled with water, cooling after dripping, stirring and crystallizing to obtain a compound shown in the formula 1;
wherein the temperature in the step 1 is 50-90 ℃, the temperature in the step 2 is 50-90 ℃, 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 as claimed in claim 1 wherein the temperature of step 1 is from 50 ℃ to 80 ℃, preferably from 50 ℃ to 70 ℃; the temperature in step 2 is 50 ℃ to 80 ℃, preferably 50 ℃ to 70 ℃.
3. The process for preparing regorafenib intermediate according to claim 1 wherein the solvent is selected from the group consisting of N-methylpyrrolidone, toluene, 1, 4-dioxane, ethyl acetate.
4. The process for the preparation of regorafenib intermediate as claimed in claim 1, wherein the solvent is N-methylpyrrolidone.
5. The preparation method of regorafenib intermediate as claimed in 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 ℃.
6. The purity of the regorafenib intermediate prepared by the preparation method is not lower than 99%.
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| CN104250226A (en) * | 2013-06-27 | 2014-12-31 | 爱康药业有限公司 | Method for preparing regorafenib intermediate |
| US20170204062A1 (en) * | 2014-07-09 | 2017-07-20 | Shilpa Medicare Limited | Process for the preparation of regorafenib and its crystalline forms |
| 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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| CN104250226A (en) * | 2013-06-27 | 2014-12-31 | 爱康药业有限公司 | Method for preparing regorafenib intermediate |
| US20170204062A1 (en) * | 2014-07-09 | 2017-07-20 | Shilpa Medicare Limited | Process for the preparation of regorafenib and its crystalline forms |
| 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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| Title |
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| 李晓鹏等: "瑞戈非尼有关物质的合成", 《化学试剂》, vol. 41, no. 8, pages 862 * |
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