CN112159351A - Preparation method of multi-target antitumor drug - Google Patents
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- CN112159351A CN112159351A CN202010991464.9A CN202010991464A CN112159351A CN 112159351 A CN112159351 A CN 112159351A CN 202010991464 A CN202010991464 A CN 202010991464A CN 112159351 A CN112159351 A CN 112159351A
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Abstract
The invention relates to a preparation method of a multi-target antitumor drug, which comprises the following steps: the method comprises the following steps of firstly, under the protection of nitrogen, reacting 4-amino-3-fluorophenol and 4-chloro-2-pyridinecarboxamide serving as raw materials and dimethyl sulfoxide and tetrahydrofuran serving as a mixed solvent by using a williamson ether synthesis method under the action of potassium tert-butoxide to generate 2-carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine; and secondly, reacting 2-carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine and 4-chloro-3- (trifluoromethyl) phenylisocyanate in a dioxane solvent to obtain a crude product, and refining to obtain a final product, namely 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-formamide.
Description
Technical Field
The invention relates to the field of drug synthesis, and in particular relates to a preparation method of a multi-target antitumor drug 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-formamide.
Background
Vascular Endothelial Growth Factor (VEGF) is one of the most important cell growth factors in the process of tumor angiogenesis, tumor vessels are highly sensitive to VEGF, and VEGF mRNA concentrations are significantly higher in many tumor cells, including lung cancer, than in normal cells. In addition, Raf is present in all eukaryotic cellsthe/MEK/ERK transduction pathway is transmitted extracellularly into the nucleus via specific cascade phosphorylation signals of Ras, Raf, MEK and ERK. Many tumor cells have upregulation of this pathway, and once the pathway is over-activated, acceleration of cell proliferation and prolongation of cell survival lead to tumor formation and progression. 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea]-3-fluorophenoxy } pyridine-2-carboxamide having the formula:
english name: 4- (4- (3- (4-chloro-3- (trifluoromethylphenyl) phenyl) ureido) -3-fluorophenoxy) -picolinamide, CAS number: 1343498-72-5, is a potent VEGF and RAF kinase inhibitor, and belongs to a multi-target antitumor drug.
There is a method for preparing 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-carboxamide, which is reported in patent CN102643229A, by dissolving 4-chloropyridine-2-carboxamide and 3-fluoro-4-aminophenol in DMF, adding t-BuOK, and stirring at 165 ℃ for 75 minutes to prepare 2-carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine. Then 2-carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine is dissolved in ethyl acetate, then 3-trifluoromethyl-4-chlorophenyl isocyanate is added, the mixture is stirred for 4 hours at the temperature of 60 ℃, the solvent is evaporated under reduced pressure, and the mixture is purified by a silica gel column to obtain 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-formamide as a white solid. The reaction conditions are harsh, and relate to high-temperature and strong-base reactions, and particularly, a reaction solvent DMF is partially degraded under the conditions and is difficult to recycle, so that environmental protection pressure is caused. Meanwhile, the yield is low, silica gel column purification is needed, and the method is not suitable for large-scale production.
Patent CN102885814A discloses a synthesis method of an anticancer active compound 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-formamide, which takes 4-chloropyridine-2-formamide as a raw material, and prepares 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-formamide through 2 synthesis steps of metal catalytic coupling reaction and isocyanate addition reaction. The reaction needs a metal composite catalyst, the cost is higher, the generated product has more impurities, the yield is not high, and the requirements of medicine quality are not met.
Therefore, in order to meet the demands in production, the present application provides a new process which is greatly improved in terms of industrial applicability, purity and yield.
Disclosure of Invention
The invention aims to provide an industrial preparation method for preparing a compound 1, which adopts the following scheme:
。
the present invention comprises a process for preparing compound 1:
，
the method comprises two steps of: first, under nitrogen, intermediate 4 was synthesized using williamson ether synthesis: taking a compound 3 and a compound 2 as raw materials, taking dimethyl sulfoxide and tetrahydrofuran as a mixed solvent, and reacting under the action of potassium tert-butoxide to generate an intermediate 4; in the second step, compound 1 is synthesized using the isocyanate-urea reaction: the intermediate 4 and the compound 5 react in dioxane solvent to obtain a crude product, and the compound 1 is obtained after refining.
Wherein the molar ratio of dimethyl sulfoxide to tetrahydrofuran in the mixed solvent in the first step is 2-4:1, and preferably 2.5: 1.
Wherein, the molar ratio of the mixed solvent of dimethyl sulfoxide and tetrahydrofuran to potassium tert-butoxide in the first step is 5-15:1, preferably 10: 1.
Wherein the molar ratio of dioxane to intermediate 4 in the second step is 20-100:1, preferably 50: 1.
Wherein the reaction temperature of the first step is 70-100 ℃, and the preferable reaction temperature is 80-90 ℃.
Wherein the reaction temperature of the second step is 45-65 ℃, and the preferable reaction temperature is 50-60 ℃.
Wherein the reaction time of the first step is 1.5-2 hours.
Wherein the reaction time of the second step is 2-4 hours.
The preparation method comprises the following steps:
the method comprises the following steps: adding dimethyl sulfoxide and tetrahydrofuran into a reaction kettle, introducing nitrogen for protection, adding potassium tert-butoxide, and controlling the temperature to be 10-20 ℃ after complete dissolution. Adding 4-amino-3-fluorophenol, stirring at normal temperature for 10 minutes, adding 4-chloro-2-pyridinecarboxamide, stirring for 10 minutes, and heating the reaction solution to over 80 ℃ within 30 minutes. The reaction was carried out at 85. + -. 2 ℃ for 2.0 hours while keeping the temperature constant from the internal temperature to 80 ℃. After the reaction is finished, cooling to below 20 ℃, dropwise adding 1M sodium hydroxide aqueous solution, and slowly cooling the inner temperature of the reaction kettle to 0-2 ℃ after dropwise adding. The slurry was filtered while cold and the filter cake was washed with deionized water. The filter cake was suspended in deionized water, slurried for 30 minutes, and filtered. The filter cake is washed by deionized water and dried under reduced pressure to obtain an intermediate 4.
Step two: adding dioxane into a reaction kettle, adding the intermediate 4 under the protection of nitrogen, stirring, and heating to 55 ℃. After the intermediate 4 is completely dissolved, 4-chloro-3- (trifluoromethyl) phenylisocyanate is dissolved in dioxane and precooled to 10 ℃, dropwise added into the reaction kettle for 1 hour, and continuously reacted with the intermediate 4 for 1 hour after the dropwise addition is finished. Cooling, and crystallizing the reaction solution at 24 ℃ for 15 hours to obtain the compound 1.
Crystallizing and purifying the compound 1: centrifuging and filtering, leaching the filter cake twice with ethyl acetate, and drying under reduced pressure to obtain a filter cake; adding methanol into a reaction kettle, adding the compound 1, heating to reflux, keeping the temperature for 3.0 hours, cooling, and cooling to ensure that the internal temperature is reduced to 34 ℃ for recrystallization; the crystals were rinsed twice with methanol and dried under vacuum for 72 hours to give off-white crystals.
For the first step of the ether forming reaction according to the technical scheme of the present invention, patent US2005245530 reports a method for preparing a compound by microwave reaction in N-methylpyrrolidone using diisopropylethylamine as a base, which has a low yield and cannot be scaled up, and is not suitable for process development:
。
for the second step urea reaction according to the technical scheme of the present invention, patent WO2009111061 reports another route to synthesize sorafenib by first preparing active compound 9 from compound 7 and then reacting with compound 6. However, the experiment shows that the yield of the route is low, and the reaction becomes more complex:
。
through groping and repeated tests, the invention finally grops out an industrial method for preparing the compound 1.
Compared with the prior art, the beneficial technical effects of the invention are as follows:
1) compared with the prior art, the technical scheme of the invention improves the reaction yield by improving the solvent, and greatly reduces the reaction temperature, improves the yield and reduces the production cost by taking the specific mixed solvent of tetrahydrofuran and dimethyl sulfoxide as the solvent.
2) Compared with the prior art, the technical scheme of the invention improves the reaction conditions, not only improves the yield and purity of the product, but also reduces the quantity and content of impurities, meets the requirements of the medical industry, and avoids using chromatographic column for purification, thereby directly changing the technical scheme of the invention from laboratory-level standard in the prior art to industrial-level standard.
3) Compared with the prior art, the application uses dioxane as a solution, avoids using organic alkali reagents and dichloromethane with high toxicity as a solvent, and reduces the risk of environmental pollution.
4) Compared with the prior art, the method does not need to use a metal catalyst, reduces the risk of heavy metal pollution, reduces the cost, and avoids using toluene with relatively high toxicity as a reaction solvent.
Detailed Description
EXAMPLE 12 preparation of carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine (Compound 4)
Adding 19.36 kg of dimethyl sulfoxide and 7.2 kg of tetrahydrofuran into a 100L reaction kettle, introducing nitrogen for protection, adding 4.88 kg of potassium tert-butoxide, and controlling the temperature to be 10-20 ℃ after complete dissolution. 4.54 kg of 4-amino-3-fluorophenol (Compound 3) was further added thereto, and the mixture was stirred at room temperature for 10 minutes, 5.57 kg of 4-chloro-2-pyridinecarboxamide (Compound 2) was added thereto, and the mixture was further stirred for 10 minutes, whereupon the temperature of the reaction mixture was raised to 80 ℃ or higher within 30 minutes. The reaction was carried out at 85. + -. 2 ℃ for 2.0 hours while keeping the temperature constant from the internal temperature to 80 ℃. After the reaction is finished, cooling to below 20 ℃, dropwise adding 70 kg of 1M sodium hydroxide aqueous solution, and slowly cooling the inner temperature of the reaction kettle to 0-2 ℃ after dropwise adding. The slurry was filtered while cold and the filter cake was washed with 120 kg of deionized water. The filter cake was suspended in 80 kg of deionized water, slurried for 30 minutes, and filtered. The filter cake was washed with 20 kg of deionized water and dried under reduced pressure to give intermediate 4, which was weighed 6.5 kg (yield about 82.3%).
EXAMPLE 24 preparation of- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-carboxamide (Compound 1)
37.3kg of dioxane is added into a 100L reaction kettle, nitrogen is used for protection, 2.5 kg of intermediate 4 is added, stirring is carried out, and the temperature is raised to 55 ℃. After the intermediate 4 is completely dissolved, 2.2 kg of 4-chloro-3- (trifluoromethyl) phenylisocyanate (compound 5) is dissolved in 6.7 kg of dioxane, precooled to 10 ℃, added dropwise into a 100L reaction kettle for 1 hour, and continuously reacted with the intermediate 4 for 1 hour after the dropwise addition is finished. Cooling, and crystallizing the reaction solution at 24 ℃ for 15 hours to obtain the compound 1. The mixture was centrifuged, the cake was rinsed twice with 6.0 kg of ethyl acetate and the weight of the cake was 3.8 kg after drying under reduced pressure. 40.0 kg of methanol was charged into a 100L reactor, the above-mentioned compound 1 was added, the temperature was raised to reflux, the temperature was maintained for 3.0 hours, and cooling was carried out to lower the internal temperature to 34 ℃ for recrystallization. The crystals were rinsed twice with 4.0 kg of methanol and dried under vacuum for 72 hours to give 3.5 kg of off-white crystals with a yield of about 75% and a HPLC purity: not less than 99.5 percent.1H NMR (500 MHz, DMSO-d 6 )： 7.17 (d，1H), 7.21(m, 1H), 7.32(m, 1H), 7.41(d, 1H),7.62(d, 2H), 7.73(s, 1H), 8.17(m, 3H), 8.54(d, 1H), 8.72(s, 1H),9.51(s, 1H); MS(ESI) m/z: 469.1(M+H)+。
EXAMPLE 32 preparation of carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine (Compound 4)
Adding 23.23 kg of dimethyl sulfoxide and 6.0 kg of tetrahydrofuran into a 100L reaction kettle, introducing nitrogen for protection, adding 5.37 kg of potassium tert-butoxide, and controlling the temperature to be 10-20 ℃ after complete dissolution. 4.99 kg of 4-amino-3-fluorophenol (Compound 3) was further added thereto, and the mixture was stirred at normal temperature for 10 minutes, 6.13 kg of 4-chloro-2-pyridinecarboxamide (Compound 2) was added thereto, and the mixture was further stirred for 10 minutes, whereupon the temperature of the reaction mixture was raised to 80 ℃ or higher within 30 minutes. The reaction was carried out at 85. + -. 2 ℃ for 2.0 hours while keeping the temperature constant from the internal temperature to 80 ℃. After the reaction is finished, cooling to below 20 ℃, dropwise adding 80 kg of 1M sodium hydroxide aqueous solution, and slowly cooling the inner temperature of the reaction kettle to 0-2 ℃ after dropwise adding. The slurry was filtered while cold and the filter cake was washed with 140 kg of deionized water. The filter cake was suspended in 90kg of deionized water, slurried for 30 minutes, and filtered. The filter cake was washed with 25 kg of deionized water and dried under reduced pressure to give intermediate 4, which was weighed 6.9 kg (yield about 81.4%).
EXAMPLE 44 preparation of- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-carboxamide (Compound 1)
41.0kg of dioxane is added into a 100L reaction kettle, nitrogen is used for protection, 3.0 kg of intermediate 4 is added, stirring is carried out, and the temperature is raised to 60 ℃. After the intermediate 4 is completely dissolved, 2.6 kg of 4-chloro-3- (trifluoromethyl) phenylisocyanate (compound 5) is dissolved in 7.4 kg of dioxane, precooled to 10 ℃, added dropwise into a 100L reaction kettle for 1 hour, and continuously reacted with the intermediate 4 for 1 hour after the dropwise addition is finished. Cooling, and crystallizing the reaction solution at 25 ℃ for 12 hours to obtain the compound 1. The mixture was centrifuged, the cake was rinsed twice with 7.0 kg of ethyl acetate and dried under reduced pressure to give a cake weight of 4.4 kg. Adding 45.0 kg of methanol into a 100L reaction kettle, adding the compound 1, heating to reflux, keeping the temperature for 3.0 hours, cooling, and cooling to reduce the internal temperature to 32 ℃ for recrystallization. The crystals were rinsed twice with 4.5 kg of methanol and dried under vacuum for 72 hours to give 3.9 kg of off-white crystals with a yield of about 70% and a HPLC purity: not less than 99.4 percent.
EXAMPLE 52 preparation of carbamoyl-4- ((3-fluoro-4-amino) phenoxy) pyridine (Compound 4)
Adding 12.90kg of dimethyl sulfoxide and 4.3 kg of tetrahydrofuran into a 100L reaction kettle, introducing nitrogen for protection, adding 4.0 kg of potassium tert-butoxide, and controlling the temperature to be 10-20 ℃ after complete dissolution. 3.78 kg of 4-amino-3-fluorophenol (Compound 3) was further added thereto, and the mixture was stirred at room temperature for 15 minutes, 4.64 kg of 4-chloro-2-pyridinecarboxamide (Compound 2) was added thereto, and the mixture was further stirred for 15 minutes, whereupon the temperature of the reaction mixture was raised to 80 ℃ or higher within 40 minutes. The reaction was carried out at 80. + -. 2 ℃ for 2.5 hours while keeping the temperature constant from the internal temperature to 80 ℃. After the reaction is finished, cooling to below 20 ℃, dropwise adding 50 kg of 1M sodium hydroxide aqueous solution, and slowly cooling the inner temperature of the reaction kettle to 0-2 ℃ after dropwise adding. The slurry was filtered while cold and the filter cake was washed with 100 kg of deionized water. The filter cake was suspended in 60 kg of deionized water, slurried for 30 minutes, and filtered. The filter cake was washed with 15kg of deionized water and dried under reduced pressure to give intermediate 4, which was weighed 5.2kg (yield about 78.4%).
EXAMPLE 64 preparation of- {4- [3- (4-chloro-3-trifluoromethylphenyl) urea ] -3-fluorophenoxy } pyridine-2-carboxamide (Compound 1)
Adding 25.0kg of dioxane into a 100L reaction kettle, adding 1.7kg of intermediate 4 under the protection of nitrogen, stirring, and heating to 50 ℃. After the intermediate 4 is completely dissolved, 1.5 kg of 4-chloro-3- (trifluoromethyl) phenylisocyanate (compound 5) is dissolved in 4.5 kg of dioxane, precooled to 10 ℃, added dropwise into a 100L reaction kettle for 1 hour, and continuously reacted with the intermediate 4 for 1 hour after the dropwise addition is finished. Cooling, and crystallizing the reaction solution at 24 ℃ for 15 hours to obtain the compound 1. The mixture was centrifuged, the cake was rinsed twice with 5.0kg of ethyl acetate and dried under reduced pressure to give a cake weight of 2.4 kg. Adding 30.0 kg of methanol into a 100L reaction kettle, adding the compound 1, heating to reflux, keeping the temperature for 3.0 hours, cooling, and cooling to reduce the internal temperature to 32 ℃ for recrystallization. The crystals were rinsed twice with 3.0 kg of methanol and dried under vacuum for 72 hours to give 2.2 kg of off-white crystals with a yield of about 71%, HPLC purity: not less than 99.3 percent.
EXAMPLE 7 quality control of Compound 1 and method of detection
The purity determination method comprises the following steps: (HPLC, area normalization method.)
A chromatographic column: waters Symmetry C184.6X 50mm, 3.5um detector: an ultraviolet detector;
flow rate: 1.0 mL/min;
the detection wavelength is 262 nm;
the concentration is 0.3 mg/mL;
sampling amount is 10 mu l;
diluent agent: acetonitrile/methanol =1/1 (v/v);
mobile phase A: 10mmol/L ammonium formate;
mobile phase B: acetonitrile/methanol =1/1 (v/v);
and (3) measuring results:
the compound 1 obtained in example 2 was measured, and the results were as follows:
wherein the impurities are as follows:
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A preparation method of a multi-target antitumor drug compound 1 is characterized by comprising the following steps:
first, intermediate 4 was synthesized using williamson ether synthesis: taking a compound 3 and a compound 2 as raw materials, taking tetrahydrofuran and dimethyl sulfoxide as a mixed solvent, and reacting under the action of potassium tert-butoxide to generate an intermediate 4;
in the second step, compound 1 is synthesized using the isocyanate-urea reaction: reacting the intermediate 4 and the compound 5 in a dioxane solvent to obtain a crude product, and refining to obtain a compound 1;
the specific chemical reaction formula is as follows:
。
2. the production process according to claim 1, wherein the molar ratio of dimethyl sulfoxide to tetrahydrofuran in the mixed solvent of the first step is 2-4:1, preferably 2.5: 1.
3. The process according to claim 1, wherein the molar ratio of the mixed solvent of dimethyl sulfoxide and tetrahydrofuran to potassium t-butoxide in the first step is 5-15:1, preferably 10: 1.
4. The process according to claim 1, wherein the molar ratio of dioxane to intermediate 4 in the second step is 20-100:1, preferably 50: 1.
5. The process according to claim 1, wherein the reaction temperature in the first step is 70 to 100 ℃, preferably 80 to 90 ℃.
6. The process according to claim 1, wherein the second reaction temperature is 45 to 65 ℃, preferably 50 to 60 ℃.
7. The process according to claim 1, wherein the first reaction time is 1.5 to 2 hours.
8. The process according to claim 1, wherein the second-step reaction time is 2 to 4 hours.
9. A preparation method of a multi-target antitumor drug compound 1 is characterized by comprising the following steps:
the method comprises the following steps: adding dimethyl sulfoxide and tetrahydrofuran into a reaction kettle, introducing nitrogen for protection, adding potassium tert-butoxide, controlling the temperature to be 10-20 ℃ after complete dissolution, continuously adding 4-amino-3-fluorophenol, stirring for 10 minutes at normal temperature, adding 4-chloro-2-pyridinecarboxamide, continuously stirring for 10 minutes, and heating the temperature of the reaction solution to be above 80 ℃ within 30 minutes; starting timing when the internal temperature is increased to 80 ℃, carrying out heat preservation reaction at 85 +/-2 ℃ for 2.0 hours, after the reaction is finished, cooling to be below 20 ℃, dropwise adding 1M sodium hydroxide aqueous solution, slowly reducing the internal temperature of the reaction kettle to 0-2 ℃ after the dropwise adding is finished, filtering slurry while the slurry is cold, washing a filter cake with deionized water, suspending the filter cake in the deionized water, pulping for 30 minutes, filtering, washing the filter cake with the deionized water, and drying under reduced pressure to obtain an intermediate 4;
step two: adding dioxane into a reaction kettle, protecting with nitrogen, adding an intermediate 4, stirring, heating to 55 ℃, dissolving 4-chloro-3- (trifluoromethyl) phenylisocyanate into the dioxane after the intermediate 4 is completely dissolved, precooling to 10 ℃, dropwise adding into the reaction kettle for 1 hour, continuously reacting with the intermediate 4 for 1 hour after the dropwise adding is finished, cooling, and crystallizing the reaction liquid for 15 hours at 24 ℃ to obtain a compound 1;
crystallizing and purifying the compound 1: centrifuging and filtering, leaching the filter cake twice with ethyl acetate, and drying under reduced pressure to obtain a filter cake; adding methanol into a reaction kettle, adding the compound 1, heating to reflux, keeping the temperature for 3.0 hours, cooling, and cooling to ensure that the internal temperature is reduced to 34 ℃ for recrystallization; leaching the crystals twice by using methanol, and drying for 72 hours in vacuum to obtain white-like crystals;
the specific chemical reaction formula is as follows:
。
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| CN104592105A (en) * | 2015-02-10 | 2015-05-06 | 杭州朱养心药业有限公司 | Regorafenib and manufacture method thereof |
| CN105924390A (en) * | 2016-05-19 | 2016-09-07 | 广州南新制药有限公司 | Synthesis method of metafenib |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022057164A1 (en) * | 2020-09-21 | 2022-03-24 | 广州南鑫药业有限公司 | Preparation method for multi-target anti-tumor drug |
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| CN112159351B (en) | 2021-12-07 |
| WO2022057164A1 (en) | 2022-03-24 |
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