WO2013162390A1 - Process for preparation of high purity n- [2- (diethylamine) ethyl] - 5 - formyl - 2, 4 - dimethyl - 1h - pyrrole - 3 - carboxyamide - Google Patents
Process for preparation of high purity n- [2- (diethylamine) ethyl] - 5 - formyl - 2, 4 - dimethyl - 1h - pyrrole - 3 - carboxyamide Download PDFInfo
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- WO2013162390A1 WO2013162390A1 PCT/PL2013/000059 PL2013000059W WO2013162390A1 WO 2013162390 A1 WO2013162390 A1 WO 2013162390A1 PL 2013000059 W PL2013000059 W PL 2013000059W WO 2013162390 A1 WO2013162390 A1 WO 2013162390A1
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- pyrrole
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- HSLPADZQDAUNBW-UHFFFAOYSA-N CCN(CC)CCNC(c1c(C)[nH]c(C=C)c1C=C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(C=C)c1C=C)=O HSLPADZQDAUNBW-UHFFFAOYSA-N 0.000 description 1
- DDIIYGHHUMKDGI-UHFFFAOYSA-N O=C(Cc1c2)Nc1ccc2F Chemical compound O=C(Cc1c2)Nc1ccc2F DDIIYGHHUMKDGI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
Definitions
- the present invention relates to the process for preparation of high purity N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide and its use in preparation of active pharmaceutical ingredient sunitinib.
- Sunitinib N-[2-(diethylamine)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H- indol-3-ylidyne)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxyamide, represented by formula (1) is the receptor tyrosine kinase inhibitor approved for the treatment of renal cell cancer and gastrointestinal stromal tumor.
- Sunitinib belongs to a new group of targeted anticancer drugs, which exert biological activity only in specific types of cancer cells, leaving healthy cells of organ tissues intact.
- the anticancer activity of sunitinib is based on selective inhibition of receptor tyrosine kinases, the enzymes involved in cell signaling pathways and thus influencing cell proliferation and differentiation.
- the said enzymes are present in some membrane receptors located on the surface of some types of cancer cells, for example in the stem cells factor graspKIT", on the surface of the GIST and RCC cancer cells, where they participate in metastasis and neoplastic cells growth.
- VEGFR- 1 , CSF 1 R, KIT, VEGRF-3, PDGFR-3beta, VEGRF-2, Fit-2 receptors are among those, which are inhibited by sunitinib. It has been proved, tyrosine kinases participate in signal transduction during angiogenesis in tumors as well. Sunitinib as the inhibitor of tyrosine kinases blocks cancer cell growth directly and indirectly, decreasing blood perfusion and the supply of cancer cells with nutrients.
- Sunitinib is marketed under the brand name Sutent® capsules for oral administration containing sunitinib L-malate as the active substance.
- sunitinib L-malate proves infeasible to obtain pharmaceutically pure sunitinib, therefore another approach towards eliminating the byproducts formation in the synthetic step of the key intermediate, N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide (2), is necessary.
- the term pharmaceutically pure sunitinib refers to the product of purity higher than 99.5 % (according to HPLC), containing the main impurity: desethyl sunitynib L-malate (6) at the level ⁇ 0.15%, while contents of other single impurities is not higher than 0.10%.
- the said purity of active substance meets the requirements regarding the purity of medicinal products approved for treatment in humans and recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
- the aim of the present invention was to develop the purification method of the crude N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide to diminish desethyl (4) impurity content, to make possible obtaining the final product sunitinib L-malate which meets the purity requirements for active pharmaceutical ingredient.
- the active pharmaceutical ingredient is 'a substance used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings'.
- FPP finished pharmaceutical product
- One aspect of the present invention is the process for preparation of high purity N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2), accomplished by the purification of the crude N-[2-(diethylamine)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxyamide to reduce desethyl impurity (4) content to less than 0.07%.
- purification of N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to reduce desethyl impurity (4) content to less than 0.07% is achieved by subjecting the crude N- [2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to purification by means of crystallization in an organic solvent, optionally in the mixture thereof with water.
- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to reduce desethyl impurity (4) content to less than 0.07% is achieved by subjecting the crude N- [2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide to an extraction-adsorption method using silica gel in an organic solvent.
- Another aspect of the invention is the use of N-[2-(diethylamine)ethyl]-5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide containing less than 0.07% of desethyl impurity, N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3- carboxyamide (4), for preparation of sunitynib L-malate of purity higher than 99.5%, and having the content of less than 0.15% of desethyl sunitynib L-malate and less than 0.10% of other single impurities.
- the other aspect of the invention is the process for preparation of sunitynib L- malate of purity higher than 99.5%, and having the content of less than 0.15% of desethyl sunitynib L-malate and less than 0.10% of other single impurities, characterized by that N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide (2), containing less than 0.07% of desethyl derivative (4) is condensed with 5-fluoro-l,3-dihydroindol-2-one (3).
- the extraction-adsorption method is applied for purification of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxy- amide.
- adsorption of the impurity (4) on silica gel is preceded by removal of other polar impurities during extraction with water.
- extraction-adsorption purification method of N-[2- (dietyhlamine)ethyl] -5 -formyl-2,4-dimethyl- 1 H-pyrrole-3 -carboxyamide (2), using silica gel in an organic solvent comprises the following steps: a. dissolving crude N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide in a mixture of an organic solvent immiscible with water and water, while vigorous stirring the two-phase mixture, b. separating organic phase, c. adding silica gel to organic layer, stirring and filtering silica gel, d. evaporating organic solvent, e. separating N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide.
- the intermediate (2) is suspended in the mixture of an organic solvent and water, two-phase mixture is vigorously stirred, and organic layer is separated.
- a number of colored impurities (dark-brown) are removed from an organic to water phase.
- silica gel which adsorbs the impurity (4) is added. After filtration of silica gel and evaporation of the solvent, compound (2) containing the impurity (4) at the level which allows to prepare sunitinib of pharmaceutical purity, is obtained.
- the solvent immiscible with water is halogen derivative of hydrocarbons, most preferably, methylene dichloride. Selected resulted are presented in Table 4.
- the product (2) containing only 0.06% of the impurity (4) is obtained.
- the purification process can be influenced by portion-wise addition of different amounts of silica gel and increase of reaction time.
- the yields of extraction-adsorption process account for 80 - 90% and are significantly higher in comparison with multiple crystallization.
- the purified intermediate (2) is condensed with 5-fluoro-l,3-dihydroindol-2-one (3) in the presence of catalytic amount of inorganic or organic base, preferably pyrrolidine, in ethanol under reflux, according to the procedure revealed in EP 1255752 Bl, and the resulted sunitinib free base (lb) is transformed into sunitinib L-malate (1), according to the procedure disclosed in EP 1419151 Al .
- inorganic or organic base preferably pyrrolidine
- N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (100 g, contents of impurity (4) - 0.3%) was suspended in the hot (60 - 70 °C) mixture of ethanol (138 mL) and water (805 mL) (85%, vol./vol.), the resulting mixture was stirred and refluxed until the solid was completely dissolved. The solution was filtered to remove solid impurities, while stirring the filtrate was cooled down to room temperature (crystalline product was formed very soon). Next day the solid was filtered off and washed twice with the mixture of ethanol and water (60 mL portions, 85% (vol./vol.). After air and vacuum (45°C) drying, the first crop of the product was collected (yield 71.0 g). Purity according to HPLC 99,79% (contents of (4) - 0.10%).
- the second crystallization was performed in the similar manner.
- the crude material (71 ,0 g) was used in crystallization in the mixture of ethanol (98 mL) and water (570 mL) (85%, vol./vol.) to yield 52.84 g of product of 99.86% purity according to HPLC (contents of (4) - 0.06%).
- Example 3 Crystallization of N-[2-(diethylamine)ethyI]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide in different solvents.
- Intermediate (2) including 0.3% of impurity (4) was crystallized in different organic solvents and water in the similar manner as it was disclosed in example 2.
- the obtained results, compared to Example 1 are collected in Table 2.
- Solvent Content Solvent Contents of Ethanol/water Contents s of 4 4 (%) mixture of 4 (%)
- Example 4 Purification of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole- 3-carboxyamide 2 using extraction-adsorption method N-[2-(diethylarnine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (100 g) containing 0.17 % of (4), was dissolved in methylene dichloride (800 mL). To this solution water (800 mL) was added and the resulting mixture was stirred vigorously for 20 min. To the separated organic layer silica gel (24 g) was added and the mixture was stirred for 4 h.
- the wet paste was transferred into the flask, suspended in ethanol (500 mL) and refluxed for 15 min. After cooling down the solution to room temperature, the solid was filtered off, washed with ethanol (2 x 100 mL) and air dried.
Abstract
The present invention relates to preparation of high purity N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide, comprising purification to obtain the product including less than 0.07% of desethyl derivative, N- [2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide. N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide containing less than 0.07% of desethyl derivative is the valuable intermediate in the process for preparation of active pharmaceutical ingredient sunitinib.
Description
PROCESS FOR PREPARATION OF HIGH PURITY
N- [2- (DIETHYLAMINE) ETHYL] - 5 - FORMYL - 2 , 4 - DIMETHYL - 1 H - PYRROLE - 3 - CARBOXYAMIDE
Field of the invention
The present invention relates to the process for preparation of high purity N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide and its use in preparation of active pharmaceutical ingredient sunitinib.
Sunitinib, N-[2-(diethylamine)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H- indol-3-ylidyne)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxyamide, represented by formula (1) is the receptor tyrosine kinase inhibitor approved for the treatment of renal cell cancer and gastrointestinal stromal tumor.
Background of the invetion
Sunitinib belongs to a new group of targeted anticancer drugs, which exert biological activity only in specific types of cancer cells, leaving healthy cells of organ tissues intact. The anticancer activity of sunitinib is based on selective inhibition of receptor tyrosine kinases, the enzymes involved in cell signaling pathways and thus influencing cell proliferation and differentiation. The said enzymes are present in some membrane receptors located on the surface of some types of cancer cells, for example in the stem cells factor„KIT", on the surface of the GIST and RCC cancer cells, where they participate in metastasis and neoplastic cells growth. The VEGFR- 1 , CSF 1 R, KIT, VEGRF-3, PDGFR-3beta, VEGRF-2, Fit-2 receptors are among those, which are inhibited by sunitinib. It has been proved, tyrosine kinases participate in signal transduction during angiogenesis in tumors as well. Sunitinib as the inhibitor of tyrosine kinases blocks cancer cell growth directly and indirectly, decreasing blood perfusion and the supply of cancer cells with nutrients.
Sunitinib is marketed under the brand name Sutent® capsules for oral administration containing sunitinib L-malate as the active substance.
Process for preparation of sunitinib base has been disclosed in the patent application EP 1255752 Bl and in the publication by L. Sun et al., J. Med. Chem. 2003, 46, 1116-1119.
According to EP 1255752 Bl the key step in the synthesis of sunitinib is the condensation of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3- carboxyamide (2) with 5-fluoro-l,3-dihydroindol-2-one (3) in the presence of inorganic or organic base, for example pyrrolidine, as it is illustrated on the scheme below:
Sunitinib (free base)
The free base (lb) is transformed into its salt - sunitinib L-malate (1) in additional step, which has been disclosed, among other, in the patent application EP 1419151 Al . In none of the mentioned publications, detailed data regarding purity of the obtained products were revealed.
During experimental works to prepare sunitinib L-malate following the procedure disclosed in EP 1255752 Bl, it has been proved that obtaining the active pharmaceutical ingredient of pharmaceutical purity is impossible. This failure is caused due to formation, as a byproduct, of desethyl sunitinib free base (5), the known sunitinib main metabolite, which forms salt with L-malic acid (6) in the process of sunitinib L-malate formation. On account of very similar physico-chemical properties of these two compounds, desethyl impurities (5) and (6) are very difficult to get rid of by routinely used purification methods, such as crystallization.
The results of experimental works to remove desethyl byproducts (5) or (6) from sunitinib free base or sunitinib L-malate by crystallization, are set forth in Table 1.
Table 1. Crystallization of sunitinib L-malate 1 and sunitinib free base lb
Crystallization of sunitinib L-malate, 1
Substrate purity Product purity after
(%, HPLC) Conditions crystallization (%, HPLC)
1 6 1 6
99.3 0.37 water/isopropanol, 85°C 99.44 0.31
99.2 0.35 n-butanol, reflux 99.52 0.34
Crystallization of sunitinib L-malate, 1
99.2 0.35 isopropanol, reflux 99.46 0.3
97.8 1.3 ethanol, reflux 98,21 1.25
97.8 1.3 ethyl acetate, reflux 97.9 1.10
97.8 1.3 dichloromethane, reflux 97.94 1.09
97.8 1.3 acetone, reflux 98.06 1.07
99.08 0.29 water/isopropanol, 90 UC 99.34 0.31
98.99 0.34 water/isopropanol, 90 °C 99.03 0.35
99.34 0.31 isopropanol, reflux 99.52 0.31
99.34 0.31 dichloromethane, reflux 99.38 0.29
96.89 0.28 isopropanol, reflux 98.45 0.29
99.52 0,3 water/ethanol (different 99.45 0.26-0.28 proportions), reflux
99.52 0.3 THF, reflux 99.60 0,25
99.52 0,3 toluene, reflux 99,56 0.26
99.52 0.3 n-butanol, reflux 99.6 0.23
Crystallization of sunitinib free base, lb
Substrate purity Product purity after
(%, HPLC) Conditions crystallization (%, HPLC) lb 5 lb 5
99.24 % 0,33 % ethanol, reflux, lh 99.29 0.4
99.24 % 0.33 % ethanol, reflux, 2h 99.21 0.4
In spite of attempts of crystallization of sunitinib or sunitinib L-malate samples contaminated with different impurities enables separation of the main products from most impurities, (5) or (6) compounds are still detected at least at the level > 0.2% (according to the high-performance liquid chromatography, HPLC). The contents of these impurities could not be diminished even following multiple crystallizations.
According to the guidelines on the limits of chemical impurities, pharmaceutically active substance containing impurity at the level higher than 0.2% will not be approved for medical treatment in humans.
It has been proved during the research, that difficult to remove desethyl impurities are process-related and are formed in the early steps of sunitinib synthesis. An unidentified impurity has also been found in the key intermediate, N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide (2). The amount of that impurity varies, depending on the source of purchase, and may even reach 0.4%.
Using liquid chromatography - mass spectrometry (LC-MS) analytical technique it was possible to determine the chemical structure of the impurity, which turned out to be desethyl derivative of the intermediate (2). The LC-MS data showed the main peak at 265.3 molecular mass (TR=15,6 min; [M+H]+ m/z 266), which corresponds to the compound (2), and another peak at 238.3 (TR=9,7 min; [M+H]+ m/z 237). The fragment ion mass analysis and independent synthesis of the unidentified compound confirmed its chemical structure as N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide (4):
In the literature any data concerning contamination of the intermediate (2) with desethyl derivative (4) have not been found yet.
Consequently, condensation of the intermediate (2) with 5-fluoro-l,3-dihydro- indol-2-one (3) provides sunitinib free base (lb), which is accompanied by desethyl sunitinib base (5) formed in this process from desethyl derivative (4), the impurity of the compound (2). In the end, reaction of desethyl sunitinib base (5) with L-malic acid results in formation of desethyl sunitinib L-malate (6):
Since purification by crystallization of sunitinib free base and the end product, sunitinib L-malate proves infeasible to obtain pharmaceutically pure sunitinib, therefore another approach towards eliminating the byproducts formation in the synthetic step of the key intermediate, N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide (2), is necessary.
The term pharmaceutically pure sunitinib", as used throughout the description, refers to the product of purity higher than 99.5 % (according to HPLC), containing the main impurity: desethyl sunitynib L-malate (6) at the level < 0.15%, while contents of other single impurities is not higher than 0.10%. The said purity of active substance meets the requirements regarding the purity of medicinal products approved for treatment in humans and recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
Thus, the aim of the present invention was to develop the purification method of the crude N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide to diminish desethyl (4) impurity content, to make possible obtaining the final product sunitinib L-malate which meets the purity requirements for active pharmaceutical ingredient.
The active pharmaceutical ingredient (API), according to the definition proposed by WHO in Working document QAS/1 1.426/Rev. l of July 201 1 , is 'a substance used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention
of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings'.
Summary of the invention
This aim was achieved due to the use of N-[2-(diethylamine)ethyl]-5-formyl-
2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) intermediate, containing less than 0.07% of desethyl impurity, ie. N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide (4).
One aspect of the present invention is the process for preparation of high purity N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2), accomplished by the purification of the crude N-[2-(diethylamine)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxyamide to reduce desethyl impurity (4) content to less than 0.07%.
In one embodiment of that aspect of the invention, purification of N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to reduce desethyl impurity (4) content to less than 0.07%, is achieved by subjecting the crude N- [2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to purification by means of crystallization in an organic solvent, optionally in the mixture thereof with water.
In another embodiment of that aspect of the invention, the purification of N-[2-
(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) to reduce desethyl impurity (4) content to less than 0.07% is achieved by subjecting the crude N- [2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide to an extraction-adsorption method using silica gel in an organic solvent.
Another aspect of the invention is the use of N-[2-(diethylamine)ethyl]-5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide containing less than 0.07% of desethyl impurity, N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3- carboxyamide (4), for preparation of sunitynib L-malate of purity higher than 99.5%, and having the content of less than 0.15% of desethyl sunitynib L-malate and less than 0.10% of other single impurities.
The other aspect of the invention is the process for preparation of sunitynib L- malate of purity higher than 99.5%, and having the content of less than 0.15% of desethyl sunitynib L-malate and less than 0.10% of other single impurities,
characterized by that N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide (2), containing less than 0.07% of desethyl derivative (4) is condensed with 5-fluoro-l,3-dihydroindol-2-one (3). Detailed description of the invention
Upon crystallization of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3 -carboxyamide in a selected mixture of solvents, the content of desethyl derivative, N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3 -carboxyamide (4) can be diminished to less than 0.07%.
The results of experimental works performed to purify N-[2-
(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2), comprising the crystallization of the crude compound containing about 0.3% of desethyl derivative (4) in different organic solvents such as tetrahydrofuran, diisopropyl ether, toluene, ethyl acetate, dichloromethane, isopropyl alcohol, ethyl alcohol, water and the mixture of ethyl alcohol and water at different ratios, are presented in Table 2.
The best results, in terms of the compound purity and crystallization yields, are achieved using the mixture of C1-3 -aliphatic alcohol and water, preferably the mixture of water - ethanol (85 : 15 or 80 : 20, vol./vol.).
Starting from N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3- carboxyamide (2), comprising 0.3% of the impurity (4), and following two crystallizations in the mixture of water - ethanol from 15 to 20% ( vol./vol.), the product is obtained in approximately 50% yield, containing about 0.06 - 0.07% of the impurity (4). The intermediate (2) characterized by said purity enables preparation of high purity sunitinib in further synthetic steps. In the second embodiment, the extraction-adsorption method is applied for purification of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxy- amide. Addition of silica gel to the stirred solution of the compound (2), containing impurity (4), in an organic solvent, results in almost entire removal of the impurity (4), which is the secondary amine. Preferably, adsorption of the impurity (4) on silica gel is preceded by removal of other polar impurities during extraction with water.
Preferably, extraction-adsorption purification method of N-[2- (dietyhlamine)ethyl] -5 -formyl-2,4-dimethyl- 1 H-pyrrole-3 -carboxyamide (2), using silica gel in an organic solvent, comprises the following steps:
a. dissolving crude N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide in a mixture of an organic solvent immiscible with water and water, while vigorous stirring the two-phase mixture, b. separating organic phase, c. adding silica gel to organic layer, stirring and filtering silica gel, d. evaporating organic solvent, e. separating N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide.
Preferably, in the preferred embodiment of the invention, the intermediate (2) is suspended in the mixture of an organic solvent and water, two-phase mixture is vigorously stirred, and organic layer is separated. In this purification step a number of colored impurities (dark-brown) are removed from an organic to water phase. In the next step, to the organic extract silica gel, which adsorbs the impurity (4) is added. After filtration of silica gel and evaporation of the solvent, compound (2) containing the impurity (4) at the level which allows to prepare sunitinib of pharmaceutical purity, is obtained.
Preferably, the solvent immiscible with water is halogen derivative of hydrocarbons, most preferably, methylene dichloride. Selected resulted are presented in Table 4.
For example, using substrate containing 0.15% of the compound (4), the product (2) containing only 0.06% of the impurity (4) is obtained. When the substrate includes the impurity (4) at higher level, the purification process can be influenced by portion-wise addition of different amounts of silica gel and increase of reaction time.
The yields of extraction-adsorption process account for 80 - 90% and are significantly higher in comparison with multiple crystallization.
To obtain sunitynib L-malate 1, the purified intermediate (2) is condensed with 5-fluoro-l,3-dihydroindol-2-one (3) in the presence of catalytic amount of inorganic or organic base, preferably pyrrolidine, in ethanol under reflux, according to the procedure revealed in EP 1255752 Bl, and the resulted sunitinib free base (lb) is transformed into sunitinib L-malate (1), according to the procedure disclosed in EP 1419151 Al .
Sunitinib L-malate (1) obtained from the intermediate (2), purified according to the present invention and including less than 0.07% of the impurity (4), contains less than 0.15% of desethyl sunitinib L-malate and other single impurities at the level < 0.02%, meets the requirements regarding purity of the pharmaceutical products approved for treatment in humans.
The present invention is illustrated by the following examples
Examples
Example 1. Preparation of N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole- 3-carboxyamide (4)
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2.0 g, 11.96 mmol) was added to the solution of 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU, 4.23 g, 13.16 mmol) and N-hydroxybenzotriazole (HOBt, 2.01 g, 13.16 mmol) in N,N-dimethylformamide (10 mL). Next, N,N- diisopropylethylamine (DIPEA, 4.5 mL, 26 mmol) was added and the mixture was stirred at room temperature for 30 min. After addition of N-ethyl-ethylenediamine (2.78 mL, 26 mmol) the solution became brown-red, it was stirred overnight. 1M HC1 (10 mL) was added to this mixture, which was stirred for 1 h, after completion of the reaction water (10 mL) and methylene dichloride (150 mL) were added. The organic phase was separated and water layer was diluted with saturated NaHC03 solution (30 mL), brine (30 ml) and 10 % NaOH to reach pH ~13. The obtained mixture was extracted with 10% methanolic solution in methylene dichloride (3 x 30 mL), the combined organic extracts were dried over anhydrous MgS04 and condensed to yield dark oily crude product. The crude material (4 g) was purified by column chromatography filled with silica gel (150 g), using methanol as the eluent. After combining appropriate fractions and removing the solvent, product 4 was obtained. HPLC 96,34%, ES-MS for (M+H)+ calc. 238.30, found 238.3. Ή NMR (600 MHz, DMSOd6): δ 1.00 (t,3H,CH3, Ν-6 ι), 2.31(s,3H,C2-CH3), 2.36(s,3H,C4-CH3), 2.55(q,2H,CH2,N-e,hyi), 2.65 (t,2H,CH2-Nethyiene), 3.27(dt,2H,CH2-NHamide), 7.48 (t,lH,NHamide), 9.54 (s,lH,CHO), 11.8 (bs,lH,NHpyrr0,e) ;
13C NMR: δ 177.22(CH0f0rmyi), 164.55(C=Oamide), 137.72(C2), 130.57(C4), 127.68
(C5), 119.64(C3), 48.49(CH2-Nethy.ene), 43.11 (CH2,N-etKy.), 38.72CH2-NHamide), 12.40(C5-CH3), 15.08(CH3, N-ethyi), 9.55(C3-CH3). Example 2. Purification of intermediate (2) by crystallization in ethanol and water A/ First crystallization
N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (100 g, contents of impurity (4) - 0.3%) was suspended in the hot (60 - 70 °C) mixture of ethanol (138 mL) and water (805 mL) (85%, vol./vol.), the resulting mixture was stirred and refluxed until the solid was completely dissolved. The solution was filtered to remove solid impurities, while stirring the filtrate was cooled down to room temperature (crystalline product was formed very soon). Next day the solid was filtered off and washed twice with the mixture of ethanol and water (60 mL portions, 85% (vol./vol.). After air and vacuum (45°C) drying, the first crop of the product was collected (yield 71.0 g). Purity according to HPLC 99,79% (contents of (4) - 0.10%).
B/ Second crystallization
The second crystallization was performed in the similar manner. The crude material (71 ,0 g) was used in crystallization in the mixture of ethanol (98 mL) and water (570 mL) (85%, vol./vol.) to yield 52.84 g of product of 99.86% purity according to HPLC (contents of (4) - 0.06%).
Example 3. Crystallization of N-[2-(diethylamine)ethyI]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide in different solvents. Intermediate (2) including 0.3% of impurity (4) was crystallized in different organic solvents and water in the similar manner as it was disclosed in example 2. The obtained results, compared to Example 1 are collected in Table 2.
Table 2
Solvent Content Solvent Contents of Ethanol/water Contents s of 4 4 (%) mixture of 4 (%)
(%) (HPLC) (HPLC)
(HPLC)
THF 0,25 ethyl acetate 0.19 5% H20 0.12
Dichloromethane 0.33 water 0.14 10% H20 0.10
2-Propanol 0.22 ethanol 0.17 15% H20 0.10
Toluene 0.28 diisopropyl 0.28 20% H20 0.07 ether
- - 50% H20 0.11
In Table 3 the results of crystallization of N-[2-(diethylamine)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxyamide (2) (85-100 g) containing 0.3% of impurity (4), in the mixture of water - ethanol (85 : 15 vol./vol.) are presented.
Table 3
Example 4. Purification of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole- 3-carboxyamide 2 using extraction-adsorption method
N-[2-(diethylarnine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (100 g) containing 0.17 % of (4), was dissolved in methylene dichloride (800 mL). To this solution water (800 mL) was added and the resulting mixture was stirred vigorously for 20 min. To the separated organic layer silica gel (24 g) was added and the mixture was stirred for 4 h. Silica gel was filtered off, second portion of silica gel was added to the solution and stirring was continued for 24 h. After filtration, the filtrate was condensed under reduced pressure. The compound (2) was obtained as a solid ( 85.7 g yield, 87.5%, purity according to HPLC: 99.86%, contents of (4) - 0.05 %). Example 5. Preparation of sunitynib L-malate (1)
N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide (2) (50 g, 0.188 mol) of 99.86 % purity, containing 0.06 % (HPLC) of (4), and 5-fluoro-l ,3- dihydroindol-2-one (3) (28.46 g, 0,188 mol) were dissolved in ethanol (650 mL). After addition of pyrrolidine (807 μί), the mixture was stirred and refluxed, in 1.40 h precipitation of the product was observed. After 3 h the mixture was cooled down to room temperature, than the solid was filtered off and washed with ethanol (2 x 150 mL). The wet paste was transferred into the flask, suspended in ethanol (500 mL) and refluxed for 15 min. After cooling down the solution to room temperature, the solid was filtered off, washed with ethanol (2 x 100 mL) and air dried.
After transfer of the wet solid into the flask, methanol (625 mL) and L-malic acid (27.12 g, 0.202 mol) were added, the resulting mixture was stirred for 10 min. The solvents were removed under reduced pressure, to the residue acetonitrile (625 mL) was added. The solution was stirred for 10 min., than the product was filtered off, washed with methylene dichloride (3 x 200 mL) and air dried to furnish 87.7 g of sunitynib L- malate (1) with 87% yield. Purity according to HPLC: 99.61%, contents of desethyl sunitynib L-malate (6) - 013% and other single impurities < 0.02%.
Ή NMR (600 MHz, DMSOd6): δ 1.14 (6H,2 x CH3, Ν-6 ιΛ J= 7.1 Hz), 2.45(s,3H,C4- CH3,pyrro,e), 2.47 (s,3H,C2-CH3,pyrroie), 2.96(4H, 2 x CH2, N-ethyi, q, J = 7.2 Hz), 2.98(2H,CH2-NEt2, t, J = 6.4 Hz), 3.48(2H, CH2-NHamide, dt, J = 6.1, 6.0 Hz), 6.85(lH,C7-Hindoi,dd, J = 8.4, 4.5 Hz), 6.93(1H, C6-Hindoi, ddd, J = 9.3, 8.5, 2.3 Hz), 7.69 (1H, NHamide,t, J =5.4 Hz), 7.73(s,lH,CHvinyl), 7.77(1H, C4-Hindol, dd, J = 9.9, 2.2 Hz), 10.92 (s,lH,NHindoi), 13.73(s,lH,pyrroie), and L-malic acid: 2.36(lH,dd, J = 15.6,
5.3Hz i 2.55(lH,dd, J = 15.6, 8.2 Hz), 4.01(1H,CH-OH, dd, J = 8.1, 5.4 Hz), ~10.2(lH,OH,bs), ~10.2(lH,COOH,bs), -10.2 (lH,COOH,bs);
,3C NMR: δ 169.56(Cl=Oindoi), 165.18(C=Oamide), 158.22(C5-Findoi,d, J - 232.8 Hz), 136.82(C2pyrroie), 134.56(C8i„doi), 130.58(C4), 130.19(C4pyrro,e), 127.09(C3indol,d, J = 9.9 Hz), 125.83(C5 indol), 124.81(Cvinyl), 119.95(C3pyrrole), 114.92(C2indol,d, J = 2.8 Hz), 112.46(C6indoi,d, J = 24.2 Hz), 110.04(C7indoi, d, J = 8.1 Hz), 105.97(C4indol,d, J = 2.9 Hz), 50.59(CH2-NEt2), 46.71(CH2,Nethyi), 35.19(CH2-NHamide), 13.41(C2-CH3), 10.63(C4-CH3), 9.78(CH3,Nethyi) and L-malic acid: 176.04, 172.10 (2 x COOH), 66.41(C-OH), 40.89(CH2).
Claims
1. Process for preparation of high purity N-[2-(diethylamine)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxyamide, characterized in that the crude N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is subjected to purification to contain less than 0.07% of desethyl derivative, N-[2-(ethylamine)ethyl]- 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide.
2. Process according to claim 1, characterized in that the crude N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is subjected to purification by means of crystallization in an organic solvent, optionally in the mixture thereof with water.
3. Process according to claim 2, characterized in that the crude N-[2- (diethylamine)ethyI]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is subjected to crystallization in the mixture of an aliphatic alcohol C1-3 and water.
4. Process according to claim 3, characterized in that the crude N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is subjected to crystallization in the mixture of ethanol and water.
5. Process according to claim 4, characterized in that the crude N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is subjected to crystallization in the mixture of ethanol and water, containing from 15 to 20% (vol./vol.) of ethyl alcohol.
6. Process according to claim 1, characterized in that the crude N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide is purified by extraction-adsorption method using silica gel in an organic solvent.
7. Process according to claim 6, comprising the following steps: a. dissolving the crude N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide in a mixture of an organic solvent immiscible with water and water, while vigorous stirring the two-phase mixture, b. separating the organic phase, c. adding silica gel to the organic phase, stirring and filtering off silica gel, d. evaporating an organic solvent, e. separating N-[2-(diethylarnine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide.
8. Process according to claim 6 or 7, characterized in that the organic solvent is a halogen derivative of aliphatic hydrocarbons.
9. Process according to claim 8, characterized in that the organic solvent is methylene dichloride.
10. Use of N-[2-(diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxyamide containing less than 0.07 % of desethyl derivative, N-[2- (ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide, obtained by the process according to any of claims 1-9, for preparation of sunitinib L-malate of purity higher than 99.5% and having the content of less than 0.15% of desethyl sunitinib L- malate and less than 0.10% of other single impurities.
11. Process for preparation of sunitinib L-malate of pharmaceutical purity higher than 99.5% and having the content of of desethyl sunitinib L-malate less than 0.15% and of other single impurities less than 0.10%, characterized in that the N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide containing less than 0.07% of desethyl derivative, N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH- pyrrole-3-carboxyamide, obtained by the process according to any of claims 1-9, is condensed with 5-fluoro-l,3-dihydroindol-2-one.
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