CN112079764B - Synthesis method of sunitinib intermediate 5-fluoroindol-2-one - Google Patents
Synthesis method of sunitinib intermediate 5-fluoroindol-2-one Download PDFInfo
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Abstract
The invention relates to a synthetic method of sunitinib intermediate 5-fluoroindole-2-ketone, which takes glycollic acid as a raw material, reacts with methanesulfonyl chloride at low temperature, activates carboxyl, changes hydroxyl into methanesulfonate at the same time, and generates intermediate N- (4-fluorophenyl) -2-methanesulfonate acetamide after in-situ addition of p-fluoroaniline; the intermediate directly carries out heating reaction without separation in reaction liquid, and takes intramolecular Friedel-crafts reaction under the catalysis of methanesulfonic acid to generate a cyclization product of 5-fluoroindol-2-one. According to the invention, glycolic acid, methanesulfonyl chloride and p-fluoroaniline are adopted for the first time to perform one-step reaction to obtain 5-fluoroindol-2-one, the starting materials are cheap and easy to obtain, the operation is simple and convenient, the reaction condition is mild, the yield is stable and reliable, and the industrial production is facilitated.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of a sunitinib intermediate 5-fluoroindol-2-one.
Background
Sunitinib (Sutent) is a novel multi-target receptor tyrosine kinase inhibitor developed by the schirtine, can inhibit various signal paths, and has anti-angiogenesis and anti-tumor proliferation activities. Clinically, the traditional Chinese medicine composition is mainly used for treating adult patients with gastrointestinal stromal tumor, renal cell carcinoma and pancreatic neuroendocrine tumor. The drug was initially approved by the FDA in 2006 and marketed in China under the trade name sotan in 2007. The national medical insurance class B catalogs are incorporated by negotiations in 2018; sunitinib from the stone drug group has been approved by the national drug administration at 2019/12/27, and at present, a plurality of domestic drug enterprises submit the drug to the market for application as if the drug passes the consistency evaluation.
5-fluoroindol-2-one is an important intermediate for the synthesis of Sunitinib (Sunitinib), of the formula: c (C) 8 H 6 FNO, CAS is: 56341-41-4, the structure is as follows:
at present, the synthesis routes of 5-fluoroindol-2-one are more, and a plurality of literature [1 ] are listed in the journal of Chinese medical industry [ J ];2007 38 (11), 822-824; 2) Snow on the garden; synthesis process research [ D ] of L-sunitinib malate, university of Zhengzhou, 2013; 3) The synthesis of Wangwei, sunitinib and process optimization [ D ], university of Heilongjiang, 2011; 4) Chen Yunhua, synthesis research of antitumor drug sunitinib [ D ], university of Zhejiang, 2009; the synthesis methods are reviewed in the following mainly:
the method comprises the following steps: literature (Tetrahedron letters, 1987, 28 (35), 4027-4030) reports that 5-fluoroindole is used as a starting material, which is reacted with pyridine, bromine and tribromopyridinium formed by hydrogen bromide to obtain 5-fluoro-3, 3-dibromo-2-indolone, and then the 5-fluoroindol-2-one is obtained by palladium catalytic hydrogenation and debromination, wherein the synthetic route is as follows:
the starting material 5-fluoroindole of the route has high price, and also needs expensive palladium catalyst, thus being not suitable for industrial production.
The second method is as follows: patent US 4721112 (1988) discloses a method for synthesizing 2-indolone, wherein p-fluoroaniline reacts with tert-butyl hypochlorite at-60 ℃, then cyclizes with ethyl 2-methylthioacetate to obtain 2, 3-dihydro-5-fluoro-3-methylthio-2-indolone, and finally, raney nickel is hydrogenated to obtain 5-fluoroindol-2-one, and the synthetic route is as follows:
the synthetic yield of the route is low, the reaction is required at low temperature, the requirement on production equipment is high, and the route is not suitable for industrial production. Another document (j. Comb. Chem.,2007,9, 566-568) which uses the same route reports that the yield is improved by replacing ethyl 2-methylthioacetate with a mercaptomethyl resin, but the mercaptomethyl resin has no commercial supplier, only laboratory reagents, and cannot be mass-produced.
And a third method: patent CN103288709 and literature (journal of chemical engineering, 2012, 26 (4), 29-31) report another method, in which p-fluoroaniline is condensed with chloral dihydrate and hydroxylamine hydrochloride in sequence, then cyclized under concentrated sulfuric acid to obtain 5-fluoroisatin, and finally reduced with water and hydrazine (yellow cron reaction) to obtain the target product. The synthetic route is as follows:
the route has more patent documents reporting optimization and improvement methods, but the waste acid and the generated deep red byproducts in the preparation process are difficult to post-treat, and the environmental pollution is large; in the hydrazine hydrate reduction reaction (wolff-kishner reaction), an excessive or even a large excessive amount of hydrazine hydrate is required to improve the reaction yield, and there is a great danger in the production process.
The method four: the synthetic methods reported in literature (Journal ofFluorine Chemistry, vol.111,1, (2001), p.1-10) are: the p-fluoroaniline is used as an initial raw material, the initial raw material is reacted with chloroacetyl chloride, and then the 5-fluoroindole-2-ketone is prepared through Friedel-Crafts reaction under the catalysis of Lewis acid, wherein the synthetic route is as follows:
the synthesis route is shorter, but the chloroacetyl chloride is extremely toxic, is easy to volatilize, has high production and operation difficulty, has harsh Friedel-crafts reaction conditions, needs anhydrous and 200 ℃ high-temperature operation, has higher requirements on production equipment, and is easy to carbonize reactants, so that the purity of the product is reduced, and the yield is reduced.
And a fifth method: the literature (J.Chem.Soc., chem.Commun.,1992 (12): 921-922) reports that o-nitrophenylacetic acid is used as a starting material, the o-nitrophenylacetic acid is reduced and then cyclized to obtain 4-hydroxy-2, 3-dihydro-2-indolone, and the 4-hydroxy-2, 3-dihydro-2-indolone is fluorinated by diethylaminosulfur trifluoride (DAST) to obtain a target compound. The synthetic route is as follows:
the starting materials for this route are expensive and not readily available. The fluorination reaction requires high production facilities and cannot be used from the viewpoint of safe production.
The method six: patent WO2002006228 and CN104045592A disclose that difluoronitrobenzene reacts with dimethyl malonate under the action of strong alkali to obtain 2- (5-fluoro-2-nitrophenyl) -dimethyl malonate, which is subjected to palladium catalytic hydrogenation or iron powder reduction and then cyclization to obtain 2, 3-dihydro-5-fluoro-3-methoxycarbonyl-2-indolone, and then subjected to 3-position ester hydrolysis and decarboxylation to obtain the target product. The synthetic route is as follows:
the synthetic steps of the route are more, the reaction temperature is higher in the reduction and cyclization processes, and the tube sealing is also needed for reaction, thus being not beneficial to industrial production
And a seventh method: the process reported in literature (synthenis, 1993, 51-53) and patent CN108863900 is a modification of the six-step reaction described above to give the first-step product dimethyl 2- (5-fluoro-2-nitrophenyl) -malonate, which can also be reacted with lithium chloride to give methyl 5-fluoro-2-nitrophenylacetate by Krapch decarboxylation, and finally the target product by reduction cyclization with iron powder or raney nickel. The route is as follows:
similarly, the synthetic steps of the route are more, the reaction temperature is higher, and the method is not beneficial to industrial production.
Method eight: the method reported in literature (synthenis, 1991, 871-877) is that 5-fluoro-2-methylaniline is protected by Boc2O to obtain N- (5-fluoro-2-methylphenyl) carbamic acid tert-butyl ester, CO2 is introduced to obtain 5-fluoro-2- (tert-butoxycarboxamido) phenylacetic acid under the action of isobutyl lithium, and the protective group is deaminated and cyclized under the acidic condition to obtain 5-fluoroindol-2-one, and the synthetic route is as follows:
the synthesis process has long steps, complicated operation, high price and is not suitable for industrial production, and the inflammable reagent isobutyl lithium is needed.
In summary, the existing synthetic preparation methods of 5-fluoroindol-2-one have disadvantages, so that the development of a method for preparing 5-fluoroindol-2-one with low cost and simple operation is particularly necessary.
Disclosure of Invention
The invention aims to provide a synthesis method of a sunitinib intermediate 5-fluoroindole-2-ketone, which has the advantages of easily available starting materials, mild reaction conditions, simple operation, high chemical yield and low cost and is suitable for industrial production.
The technical scheme adopted for solving the technical problems is as follows: a synthetic method of a sunitinib intermediate 5-fluoroindol-2-one comprises the following steps:
(1) Adding glycolic acid, organic base and 4-dimethylaminopyridine into an aprotic solvent, dropwise adding methanesulfonyl chloride at a low temperature, and continuously stirring at the temperature for 0.5-2 hours after the dropwise addition is finished; then adding p-fluoroaniline, stirring and reacting for 1-3 hours at the same temperature, slowly heating to room temperature, stirring and reacting for 8-24 hours to obtain a reaction solution;
(2) Heating the reaction liquid to react for 2-6 hours to generate intramolecular Friedel-crafts cyclization reaction; after the reaction, the reaction solvent is removed by vacuum concentration, the residue is dissolved in an organic solvent, washed by 1N dilute hydrochloric acid, 5 percent sodium bicarbonate and saturated saline water in sequence, dried by anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized by water and ethanol, and dried to obtain the 5-fluoroindol-2-one.
The general chemical reaction formula is as follows:
further, the aprotic solvent in the step (1) is one of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide.
Further, the organic base in the step (1) is one of triethylamine, diisopropylethylamine or pyridine.
Further, the molar ratio of the glycolic acid, the organic base, the 4-dimethylaminopyridine, the methanesulfonyl chloride and the p-fluoroaniline in the step (1) is 1.0:2.0-3.0:0.05-0.15:2.0-2.6:1.0-1.1.
Further, the dropping temperature of the methanesulfonyl chloride in the step (1) is-15 to-5 ℃.
Further, the heating temperature in the step (2) is 35-80 ℃.
Further, the organic solvent in the step (2) is one of ethyl acetate, isopropyl acetate, tert-butyl acetate, isopropyl ether or methyl tert-butyl ether.
The invention takes glycollic acid as raw material, firstly reacts with methanesulfonyl chloride at low temperature, activates carboxyl, and simultaneously changes hydroxyl into methanesulfonate, and generates an intermediate N- (4-fluorophenyl) -2-methanesulfonate acetamide after in-situ addition of p-fluoroaniline; the intermediate directly carries out heating reaction without separation in reaction liquid, and takes intramolecular Friedel-crafts reaction under the catalysis of methanesulfonic acid to generate a cyclization product of 5-fluoroindol-2-one. According to the invention, glycolic acid, methanesulfonyl chloride and p-fluoroaniline are adopted for the first time to perform one-step reaction to obtain 5-fluoroindol-2-one, the starting materials are cheap and easy to obtain, the operation is simple and convenient, the reaction condition is mild, the yield is stable and reliable, and the industrial production is facilitated.
Detailed Description
The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.
Example 1
Synthesizing 5-fluoroindol-2-one by using methylene dichloride as a solvent.
Sequentially adding 263mmol of glycolic acid solid, 650mmol of triethylamine and 30mmol of 4-dimethylaminopyridine into 1000ml of dichloromethane, stirring and dissolving completely, cooling the reaction solution to-10 ℃, slowly dripping 600mmol of methanesulfonyl chloride, and controlling the temperature to be not more than 0 ℃ for about 1 hour; after the completion of the dropwise addition, stirring and reacting for 1 hour at-5 to-10 ℃, then adding 275mmol of p-fluoroaniline in batches, continuously stirring and reacting for 2 hours at-5 to-10 ℃, then slowly rising to room temperature and stirring and reacting for 12 hours, wherein the reaction liquid is reddish brown.
Heating the reaction solution at 65 ℃ for 3 hours, gradually changing the color of the reaction solution into reddish brown, and cooling the reaction solution to separate out solids; the solvent was concentrated under reduced pressure, 1000ml of ethyl acetate was added to the residue, which was washed with 1N diluted hydrochloric acid, 5% sodium bicarbonate and brine in this order, dried over anhydrous sodium sulfate, filtered off with suction, concentrated under reduced pressure, and the obtained residue was recrystallized from water and ethanol to give a white needle-like solid with a yield of 83% and 99% by HPLC.
Example 2
Synthesizing 5-fluoroindol-2-one by using tetrahydrofuran as solvent.
Sequentially adding 263mmol of glycolic acid solid, 526mmol of diisopropylethylamine and 39mmol of 4-dimethylaminopyridine into 1000ml of tetrahydrofuran, stirring and dissolving completely, cooling the reaction liquid to-15 ℃, slowly dripping 684mmol of methanesulfonyl chloride, and controlling the temperature not to exceed-5 ℃ for about 1 hour; after the dripping is finished, stirring and reacting for 0.5 hours at the temperature of-5 to-15 ℃, then adding 276mmol of p-fluoroaniline in batches, continuously stirring the reaction solution for 1 hour at the temperature of-5 to-15 ℃, then slowly heating to room temperature and stirring and reacting for 18 hours, wherein the reaction solution is a tan suspension.
Heating the reaction solution at 50 ℃ for 2 hours, wherein the color of the reaction solution gradually changes to brown; suction filtration, vacuum concentration of the filtrate to remove the solvent, adding 1000ml of tert-butyl acetate to the residue, sequentially using 1N dilute hydrochloric acid, 5% sodium bicarbonate and saline water washing, anhydrous sodium sulfate drying, suction filtration, vacuum concentration, the residue obtained with water and ethanol recrystallization, yield 84%, HPLC99%.
Example 3
Acetonitrile is used as solvent to synthesize 5-fluoroindol-2-one.
Sequentially adding 263mmol of glycolic acid solid, 736mmol of triethylamine and 13mmol of 4-dimethylaminopyridine into 1000ml of acetonitrile, stirring and fully dissolving, cooling the reaction liquid to-10 ℃, slowly dripping 526mmol of methanesulfonyl chloride, and controlling the temperature to be not more than 0 ℃ at the same time, wherein the dripping time is about 1 hour; after the completion of the dropwise addition, the reaction was continued to be carried out at-5 to-10℃for 2 hours with stirring, then 289mmol of p-fluoroaniline was added in portions, the reaction solution was continued to be stirred at-5 to-10℃for 3 hours, and then the reaction solution was stirred at room temperature for 24 hours with stirring, and was a brown suspension.
Heating the reaction solution at 35 ℃ for 4 hours, wherein the color of the reaction solution gradually changes to reddish brown; suction filtration, concentration of the filtrate under reduced pressure to remove the solvent, adding 1000ml isopropyl ether to the residue, washing with 1N dilute hydrochloric acid, 5% sodium bicarbonate and brine in this order, drying over anhydrous sodium sulfate, suction filtration, concentration under reduced pressure, recrystallization of the obtained residue with water and ethanol, to give a white needle-like solid, yield 89%, HPLC99%.
Example 4
N, N-dimethylformamide is used as solvent to synthesize 5-fluoroindol-2-one.
Adding 263mmol of glycolic acid solid, 789mmol of pyridine and 21mmol of 4-dimethylaminopyridine into 1000ml of N, N-dimethylformamide in sequence, stirring and fully dissolving, cooling the reaction liquid to-15 ℃, slowly dripping 631mmol of methanesulfonyl chloride, and controlling the temperature to be not more than 0 ℃ at the same time, wherein the dripping time is about 1 hour; after the completion of the dropwise addition, the reaction was continued to be carried out at-5 to-15℃for 1.5 hours with stirring, then 271mmol of p-fluoroaniline was added in portions, the reaction solution was continued to be stirred at-5 to-15℃for 2 hours, and then the reaction solution was stirred at room temperature for 8 hours with stirring, and was tan.
Heating the reaction solution at 80 ℃ for 6 hours, wherein the color of the reaction solution gradually changes to reddish brown; suction filtration, concentration of the filtrate under reduced pressure to remove the solvent, adding 1000ml methyl tert-butyl ether to the residue, washing with 1N dilute hydrochloric acid, 5% sodium bicarbonate and brine in sequence, drying over anhydrous sodium sulfate, suction filtration, concentration under reduced pressure, recrystallization of the obtained residue with water and ethanol, yield 86.7% of white needle-like solid, HPLC99%.
Claims (6)
1. The synthesis method of the sunitinib intermediate 5-fluoroindol-2-one is characterized by comprising the following steps of:
(1) Adding glycolic acid, organic base and 4-dimethylaminopyridine into an aprotic solvent, dropwise adding methanesulfonyl chloride at the temperature of-15 to-5 ℃, and continuously stirring at the temperature for 0.5 to 2 hours after the dropwise adding is finished; then adding p-fluoroaniline, stirring and reacting for 1-3 hours at the same temperature, slowly heating to room temperature, stirring and reacting for 8-24 hours to obtain a reaction solution;
(2) Heating the reaction liquid to react for 2-6 hours to generate intramolecular Friedel-crafts cyclization reaction; after the reaction, the reaction solvent is removed by vacuum concentration, the residue is dissolved in an organic solvent, washed by 1N dilute hydrochloric acid, 5 percent sodium bicarbonate and saturated saline water in sequence, dried by anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized by water and ethanol, and dried to obtain the 5-fluoroindol-2-one.
2. The method for synthesizing sunitinib intermediate 5-fluoroindol-2-one according to claim 1, wherein the aprotic solvent in step (1) is one of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide.
3. The method for synthesizing sunitinib intermediate 5-fluoroindol-2-one according to claim 1, wherein the organic base in the step (1) is one of triethylamine, diisopropylethylamine or pyridine.
4. The method for synthesizing sunitinib intermediate 5-fluoroindol-2-one according to claim 1, wherein the molar ratio of glycolic acid, organic base, 4-dimethylaminopyridine, methanesulfonyl chloride and p-fluoroaniline in step (1) is 1.0:2.0-3.0:0.05-0.15:2.0-2.6:1.0-1.1.
5. A process for the synthesis of the sunitinib intermediate 5-fluoroindol-2-one according to claim 1, wherein the heating temperature in step (2) is between 35 and 80 ℃.
6. The method for synthesizing sunitinib intermediate 5-fluoroindol-2-one according to claim 1, wherein the organic solvent in the step (2) is one of ethyl acetate, isopropyl acetate, tert-butyl acetate, isopropyl ether or methyl tert-butyl ether.
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