CN101497607B - Process for synthesizing sunitinib - Google Patents
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- CN101497607B CN101497607B CN2008100331901A CN200810033190A CN101497607B CN 101497607 B CN101497607 B CN 101497607B CN 2008100331901 A CN2008100331901 A CN 2008100331901A CN 200810033190 A CN200810033190 A CN 200810033190A CN 101497607 B CN101497607 B CN 101497607B
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Abstract
The invention discloses a method for synthesizing sunitinib, which comprises the following steps that: tert-butyl acetoacetate and acetylacetic ester are taken as initial raw materials, and tetra-substituted pyrrole is obtained through a nitrosification reduction reaction; then 2,4-dimethyl pyrrole-3-formic acid is obtained through the hydrolysis and is amidated; then an aldehyde group is utilized on position 5 of pyrrole through a Vilsmeier-Hacck reaction; and finally the obtained product and 5-fluorooxindole react to obtain the sunitinib. The method has low cost and simple operation, and is favorable for industrial production.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical compound, relate in particular to a kind of compound method of Sutent.
Background technology
Sutent (Sunitinib, SU011248, structural formula I) is a kind of new small molecules tyrosine kinase inhibitor for oral use, has the angiopoietic potential of inhibition and anti-tumour effect.Sutent is the medicine of new research and development, has good bioavailability, but to a certain extent also antagonism can promote angiopoietic tyrosine kinase receptor (RTKs).Sutent also can suppress other some tyrosine kinase receptor family proteins, and these are all relevant with multiple malignant tumour, like small cell lung cancer, gastrointestinal tumor (GISTs), mammary cancer, acute non-lymphoid leukemia etc.Sutent has good effect to treatment NET, colorectal carcinoma and mammary cancer in the II clinical trial phase.When being used for the gastrointestinal tumor of kidney and anti-imatinib, Sutent has demonstrated good effect equally.The drugs approved by FDA Sutent can be used for treating kidney and gastrointestinal tumor.
The Sutent of bibliographical information synthetic (US6573293 and J.Med.Chem.2003 the earliest; 1116) mainly be to be raw material with the tert-butyl acetoacetate, obtain quaternary pyrroles through nitrosification zinc powder reduction, sour water is taken off the tert-butyl ester and decarboxylation then; Utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles; The ester group of 3 of alkaline hydrolysises is made acid amides with acid then again, and last and 5-fluoro indole reactive ketone obtains Sutent.This method aldehyde radical when doing the acid amides reaction unavoidably will be participated in reaction, and because the existence of aldehyde radical makes this reaction very slow, raw material reaction is not intact when synthetic especially in a large number.The reaction scheme of this method is:
On this basis, Pfizer company has developed an other route (US 20060009510 and J.Org.Chem.2003,6447).This method is set out with the GBL of four annulus; Synthesize acid amides earlier; Nitrosification zinc powder or hydro-reduction obtain quaternary pyrroles then; Sour water is taken off the tert-butyl ester and decarboxylation then, utilize Vilsmeier-Hacck be reflected at 5 of the pyrroles go up aldehyde radicals simultaneously and 5-fluoro indole reactive ketone obtain Sutent.Owing to introduce acid amides in advance, making midbody all is liquid basically, has increased the difficulty of purifying.The reaction scheme of this method is:
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of compound method of Sutent.
The compound method of Sutent provided by the present invention, its concrete grammar step is:
1. be starting raw material with tert-butyl acetoacetate and acetylacetic ester, obtain quaternary pyrroles through the nitrosification reduction reaction; 2. quaternary pyrroles is hydrolyzed to react and obtains 2,4-dimethyl pyrrole-3-formic acid; 3. 2,4-dimethyl pyrrole-3-formic acid carries out amidation; 4. utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles again; 5. last and 5-fluoro indole reactive ketone obtains Sutent;
Wherein acetylacetic ester is the acetylacetic ester of 1-4 carbon.
Step hydrolysis reaction 2. in two steps, the first step is acidic hydrolysis decarboxylation simultaneously, its used acid is hydrochloric acid, sulfuric acid, formic acid or trifluoracetic acid; Second step was alkaline hydrolysis, and its used alkali is Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide.
Step 3. in 2, the amidation of 4-dimethyl pyrrole-3-formic acid is condensation reagent with the carbonyl dimidazoles, solvent uses ethylene dichloride, THF, 1,2-ethylene dichloride, ETHYLE ACETATE or acetonitrile.
Step 4. in 5 of the pyrroles go up with aldehyde radical in the Vilsmeier-Hacck reaction, the preparation of Vilsmeier reagent is pressed classical way and is prepared now-making-now-using.
Step being reflected in the organic solvent 5. carried out, and wherein organic solvent is ethylene dichloride, THF, 1,2-ethylene dichloride, ETHYLE ACETATE or acetonitrile; The alkali that condensation is used is mineral alkali or organic bases; Wherein mineral alkali is Lithium Hydroxide MonoHydrate, Pottasium Hydroxide or sodium hydroxide; Organic bases is triethylamine, diisopropyl ethyl amine, pyridine, piperidines; Tocosamine, piperidines, Pyrrolidine or 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), wherein the reaction density scope of alkali in reaction solution is 0.1M-10M.
Its concrete reaction scheme figure is:
Wherein, R is a 1-4 carbon alkyl.
Other not detailed parts are techniques well known, and those skilled in the art in conjunction with specific embodiment, without creative work, get final product embodiment of the present invention according to foregoing description.
Method of the present invention has following advantage:
1, in the inventive method,, is about to aldehyde radical and in the end with before the condensation of 5-fluoro indole ketone receives on the pyrroles because synthetic route has been carried out suitable adjustment; Make reaction easier; Amidate action is carried out more easily, and the reaction times is short, and yield is high; Practiced thrift half the N simultaneously, N-diethyl ethylenediamine usage quantity.
2, in the inventive method, the reagent of use basically all is common reagent, low price, and cost is low.
3, in the inventive method, the midbody major part is a solid, and very easily crystallization purifying has been simplified purification process greatly.
4. in the inventive method, reaction all is classical reaction, and easy handling is beneficial to suitability for industrialized production.
Embodiment
Following embodiment just is used to explain the present invention, and unrestricted the present invention.
Embodiment 1
Add 7.5 liters of acetic acid and tert-butyl acetoacetate 5.0kg in 25 liters of plastic tanks, 0 degree drips the solution that Sodium Nitrite 2.24kg is dissolved in 3.5 premium on currency down, and controlled temperature is no more than 5 degree, drips to finish to add 3 liters in water; Insulation reaction 30 minutes is removed cryostat, and slowly temperature reaction is after reaction finishes; Add 5 liters in water, carefully be neutralized to nearly neutrality, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction with solid sodium bicarbonate; Drying concentrates, and gets the about 5.6kg of liquid, directly is used for next step reaction.
In 25 liters of plastic tanks, added the product 2.8kg in a last step, 10 liters of methyl aceto acetate 3kg and acetic acid add the mixture of 3.4kg zinc powder and 3.4kg sodium-acetate in batches, control feed rate; Make temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely; Cooling is poured reaction solution in 50 liters of frozen water into, separates out a large amount of solids, suction filtration; With the small amount of ethanol washing, oven dry gets the about 3kg of product, directly is used for next step reaction.
Spectroscopic data is following:
1H?NMR(500M，CDCl
3)δ：9.25(s，1H)，4.28(q，J＝7.1Hz，2H)，2.53(s，3H)，2.50(s，3H)，1.58(s，9H)，1.35(t，J＝7.1Hz，3H).
In 25 liters of plastic tanks, added the product 3kg in a last step, 10 liters of ethanol drip 5 liters of concentrated hydrochloric acids; Finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 32 liters of frozen water, has a large amount of solids to separate out; Suction filtration, oven dry obtains the about 1.2kg of pink solid, directly is used for next step reaction.
Spectroscopic data is following:
1H?NMR(500M，CDCl
3)δ：8.14(s，1H)，6.35(s，1H)，4.28(m，2H)，2.48(s，3H)，2.24(s，3H)，1.34(t，J＝7.0Hz，3H).
A last step product 1.2kg, 1 liter in water, 6 liters of methyl alcohol add Pottasium Hydroxide 2kg; Reflux, reaction concentrates methyl alcohol after finishing, and residuum is used a small amount of dichloromethane extraction, and water is used concentrated hydrochloric acid pH=1; Separate out a large amount of solids, suction filtration, small amount of cold water washing 2-3 time; 50 degree are dry, get the about 800g of pink solid, directly are used for next step reaction.
Spectroscopic data is following:
1H?NMR(400M，DMSO)δ：11.1(s，1H)，7.91(s，1H)，6.37(s，1H)，2.53(s，3H)，2.27(s，3H).
The raw material in a last step of 800g is dissolved in 6 liters of THFs, adds the 1.5kg carbonyl dimidazoles in batches, finishes; Stirred 30 minutes, and dripped N, N-diethyl ethylenediamine 800g is dissolved in the solution of 500 milliliters of THFs; Reaction concentrates THF after finishing, and adds 3 liters in water, uses dichloromethane extraction; Drying, concentrate the about 1.2kg of dark red liquid, directly be used for next step reaction.
400ml DMF is dissolved in 6 liters of the methylene dichloride; Drip the solution that the 600g oxalyl chloride is dissolved in 1 liter of methylene dichloride below 0 degree, controlled temperature is no more than 5 degree, has a large amount of white solids to produce; Finish; Insulation continues to stir 2 hours, drips the solution that a last step product 1.2kg is dissolved in 1 liter of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 3 premium on currency, is neutralized to pH=14 with 10N Pottasium Hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 1kg, directly be used for next step reaction.
Spectroscopic data is following:
1H?NMR(400M，DMSO)δ：11.8(s，1H)，9.54(s，1H)，7.30(t，J＝5.0Hz，1H)，3.25(q，J＝6.5Hz，2H)，2.50(m，6H)，2.37(s，3H)，2.32(s，3H)，0.96(t，J＝7.1Hz，6H).
A last step product 1kg and a 5-fluoro indole ketone 800g, 5 liters of absolute ethyl alcohols, 100 milliliters of Pyrrolidines, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 1.3kg of product that gets, purity is greater than 99%.
Spectroscopic data is following:
1H?NMR(500M，DMSO)δ：13.7(s，1H)，10.9(s，1H)，7.75(dd，J＝2.4，9.4Hz，1H)，7.71(s，1H)，7.41(t，J＝5.3Hz，1H)，6.92(m，1H)，6.85(dd，J＝4.5，8.4Hz，1H)，3.28(m，2H)，2.53(m，6H)，2.45(s，3H)，2.43(s，3H)，0.98(t，J＝7.1Hz，6H).
Embodiment 2
Add 1.5 liters of acetic acid and tert-butyl acetoacetate 1.0kg in 5 liters of four-hole bottles, 0 degree drips the solution that Sodium Nitrite 0.5kg is dissolved in 2 premium on currency down, and controlled temperature is no more than 5 degree, drips to finish to add 1 liter in water; Insulation reaction 30 minutes is removed cryostat, and slowly temperature reaction is after reaction finishes; Add 2 liters in water, carefully be neutralized to nearly neutrality, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction with solid sodium bicarbonate; Drying concentrates, and gets the about 1.2kg of liquid, directly is used for next step reaction.
In 5 liters of four-hole bottles, added the product 1.2kg in a last step, 2 liters of propyl acetoacetate 1kg and acetic acid add the mixture of 0.8kg zinc powder and 0.8kg sodium-acetate in batches, control feed rate; Make temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely; Cooling is poured reaction solution in 10 liters of frozen water into, separates out a large amount of solids, suction filtration; With the small amount of ethanol washing, oven dry gets the about 1kg of product, directly is used for next step reaction.
In 5 liters of four-hole bottles, added the product 1kg in a last step, 2 liters of ethanol drip 500 milliliters of concentrated hydrochloric acids; Finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 2 liters of frozen water, has a large amount of solids to separate out; Suction filtration, oven dry obtains the about 300g of pink solid, directly is used for next step reaction.
A last step product 300g, 200 milliliters in water, 1 liter of methyl alcohol adds Pottasium Hydroxide 200g; Reflux, reaction concentrates methyl alcohol after finishing, and residuum is used a small amount of dichloromethane extraction, and water is used concentrated hydrochloric acid pH=1; Separate out a large amount of solids, suction filtration, small amount of cold water washing 2-3 time; 50 degree are dry, get the about 250g of pink solid, directly are used for next step reaction.
The raw material in a last step of 250g is dissolved in 2 liters of THFs, adds the 300kg carbonyl dimidazoles in batches, finishes; Stirred 30 minutes, and dripped N, N-diethyl ethylenediamine 200g is dissolved in the solution of 100 milliliters of THFs; Reaction concentrates THF after finishing, and adds 3 liters in water, uses dichloromethane extraction; Drying, concentrate the about 350g of dark red liquid, directly be used for next step reaction.
80ml DMF is dissolved in 2 liters of the methylene dichloride; Drip the solution that the 60g thionyl chloride is dissolved in 100 milliliters of methylene dichloride below 0 degree, controlled temperature is no more than 5 degree, has a large amount of white solids to produce; Finish; Insulation continues to stir 2 hours, drips the solution that a last step product 350g is dissolved in 300 milliliters of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 3 premium on currency, is neutralized to pH=14 with 10N Pottasium Hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 300g, directly be used for next step reaction.
A last step product 300g and a 5-fluoro indole ketone 150g, 2 liters of absolute ethyl alcohols, 20 milliliters of DBU, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 350g of product that gets, purity is greater than 99%.
Embodiment 3
Add 100 liters of acetic acid and tert-butyl acetoacetate 50kg in 250 liters of stills, 0 degree drips the solution that Sodium Nitrite 25kg is dissolved in 35 premium on currency down, and controlled temperature is no more than 5 degree, drips to finish to add 30 liters in water; Insulation reaction 30 minutes is removed cryostat, and slowly temperature reaction is after reaction finishes; Add 50 liters in water, carefully be neutralized to nearly neutrality, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction with solid sodium bicarbonate; Drying concentrates, and gets the about 56kg of liquid, directly is used for next step reaction.
In 250 liters of stills, added the product 30kg in a last step, 150 liters of methyl acetoacetate 3kg and acetic acid add the mixture of 50kg zinc powder and 50kg sodium-acetate in batches, control feed rate; Make temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely; Cooling is poured reaction solution in 1000 liters of frozen water into, separates out a large amount of solids, suction filtration; With the small amount of ethanol washing, oven dry gets the about 30kg of product, directly is used for next step reaction.
In 250 liters of stills, added the product 30kg in a last step, 100 liters of ethanol drip 50 liters of concentrated hydrochloric acids; Finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 500 liters of frozen water, has a large amount of solids to separate out; Suction filtration, oven dry obtains the about 15kg of pink solid, directly is used for next step reaction.
A last step product 15kg, 10 liters in water, 100 liters of methyl alcohol add Pottasium Hydroxide 25kg; Reflux, reaction concentrates methyl alcohol after finishing, and residuum is used a small amount of dichloromethane extraction, and water is used concentrated hydrochloric acid pH=1; Separate out a large amount of solids, suction filtration, small amount of cold water washing 2-3 time; 50 degree are dry, get the about 10kg of pink solid, directly are used for next step reaction.
The raw material in a last step of 10kg is dissolved in 100 liters of THFs, adds the 20kg carbonyl dimidazoles in batches, finishes; Stirred 30 minutes, and dripped N, N-diethyl ethylenediamine 10kg is dissolved in the solution of 5 liters of THFs; Reaction concentrates THF after finishing, and adds 30 liters in water, uses dichloromethane extraction; Drying, concentrate the about 12kg of dark red liquid, directly be used for next step reaction.
4 liters of DMF are dissolved in 60 liters of the methylene dichloride; Drip the solution that the 6kg oxalyl chloride is dissolved in 10 liters of methylene dichloride below 0 degree, controlled temperature is no more than 5 degree, has a large amount of white solids to produce; Finish; Insulation continues to stir 2 hours, drips the solution that a last step product 12kg is dissolved in 10 liters of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 50 premium on currency, is neutralized to pH=14 with 10N Pottasium Hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 10kg, directly be used for next step reaction.
A last step product 10kg and a 5-fluoro indole ketone 8kg, 100 liters of absolute ethyl alcohols, the piperidinyl-1 liter, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 12kg of product that gets, purity is greater than 99%.
Claims (4)
1. the compound method of a Sutent is characterized in that this method comprises the steps:
1. be starting raw material with tert-butyl acetoacetate and acetylacetic ester, obtain quaternary pyrroles through the nitrosification reduction reaction; 2. quaternary pyrroles is hydrolyzed to react and obtains 2,4-dimethyl pyrrole-3-formic acid; 3. 2,4-dimethyl pyrrole-3-formic acid carries out amidation; 4. utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles again; 5. last and 5-fluoro indole reactive ketone obtains Sutent; Step 3. in 2, the amidation of 4-dimethyl pyrrole-3-formic acid is condensation reagent with the carbonyl dimidazoles; The alkali that the 5. middle condensation of step is used is organic bases, and wherein organic bases is piperidines, Pyrrolidine or 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene;
Wherein acetylacetic ester is the alkyl ester of etheric acid 1-4 carbon.
2. compound method according to claim 1 is characterized in that step hydrolysis reaction 2. in two steps, and the first step is acidic hydrolysis decarboxylation simultaneously, and its used acid is hydrochloric acid, sulfuric acid, formic acid or trifluoracetic acid; Second step was alkaline hydrolysis, and its used alkali is Lithium Hydroxide MonoHydrate, sodium hydroxide or Pottasium Hydroxide.
3. compound method according to claim 1 is characterized in that the 3. middle solvent of step uses ethylene dichloride, THF, 1,2-ethylene dichloride, ETHYLE ACETATE or acetonitrile.
4. compound method according to claim 1 is characterized in that step being reflected in the organic solvent 5. carry out, and wherein organic solvent is ethylene dichloride, THF, 1,2-ethylene dichloride, ETHYLE ACETATE or acetonitrile; The reaction density scope of the alkali that condensation is used in reaction solution is 0.1M-10M.
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012058780A1 (en) * | 2010-11-01 | 2012-05-10 | Scinopharm (Kunshan) Biochemical Technology Co., Ltd. | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
| EP2828251B1 (en) | 2012-03-23 | 2018-10-31 | Laurus Labs Limited | An improved process for the preparation of sunitinib and its acid addition salts thereof |
| CN103319392B (en) * | 2013-07-10 | 2015-10-28 | 张家港市华昌药业有限公司 | A kind of preparation method of sutent intermediate |
| CN112321569A (en) * | 2020-10-12 | 2021-02-05 | 福建南方制药股份有限公司 | Method for controlling impurity difficult to remove in synthesis of anti-tumor drug sunitinib |
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| WO2006089150A2 (en) * | 2005-02-18 | 2006-08-24 | Novartis Vaccines And Diagnostics Inc. | Antiangiogenic agents with aldesleukin |
| CN101033226A (en) * | 2007-04-06 | 2007-09-12 | 复旦大学 | 1-furylmethyl-3-substituted indolin-2-one derivative |
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| WO2006089150A2 (en) * | 2005-02-18 | 2006-08-24 | Novartis Vaccines And Diagnostics Inc. | Antiangiogenic agents with aldesleukin |
| CN101033226A (en) * | 2007-04-06 | 2007-09-12 | 复旦大学 | 1-furylmethyl-3-substituted indolin-2-one derivative |
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